Microtubule Destabilizing Sulfonamides as an Alternative to Taxane-Based Chemotherapy

Pan-Gyn cancers entail 1 in 5 cancer cases worldwide, breast cancer being the most commonly diagnosed and responsible for most cancer deaths in women. The high incidence and mortality of these malignancies, together with the handicaps of taxanes—first-line treatments—turn the development of alternative therapeutics into an urgency. Taxanes exhibit low water solubility that require formulations that involve side effects. These drugs are often associated with dose-limiting toxicities and with the appearance of multi-drug resistance (MDR). Here, we propose targeting tubulin with compounds directed to the colchicine site, as their smaller size offer pharmacokinetic advantages and make them less prone to MDR efflux. We have prepared 52 new Microtubule Destabilizing Sulfonamides (MDS) that mostly avoid MDR-mediated resistance and with improved aqueous solubility. The most potent compounds, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methylaminobenzenesulfonamide 38, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 42, and N-benzyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 45 show nanomolar antiproliferative potencies against ovarian, breast, and cervix carcinoma cells, similar or even better than paclitaxel. Compounds behave as tubulin-binding agents, causing an evident disruption of the microtubule network, in vitro Tubulin Polymerization Inhibition (TPI), and mitotic catastrophe followed by apoptosis. Our results suggest that these novel MDS may be promising alternatives to taxane-based chemotherapy in chemoresistant Pan-Gyn cancers.     

Dynamical modelling of an activated sludge system of a petrochemical plant operating at high temperatures.

The Mexican petrochemical industry, Morelos S.A. de C.V., is one of the biggest and more important petroleum industries in Mexico and Latin America. It has an activated sludge system to treat its wastewater flow, which is approximately 7,000 m3/d. The wastewater contains volatile organic carbon substances classified as toxics. The old surface aeration system was changed for fine bubble diffusers; however, one major drawback of the new aeration system is that the temperature in the bioreactor has increased due to the compression of the air, which at the compressor exit reaches 85 degrees C. This effect results in the temperature in the bioreactor attaining 32 degrees C during the fall, whereas in the spring and summer, the bioreactor temperature reaches higher values than 40 degrees C. The high temperatures reduce the microorganism activity and cause a higher volatilisation rate of volatile compounds, among other effects, which affect the performance of the biological treatment. This work was performed to obtain a better modelling of the wastewater treatment from the petrochemical industry. The model describes the effect of the temperature on the performance of the biological treatment. The model was obtained from tests that were carried out in laboratory reactors with 14 L capacity, which were operated at different temperatures (from 30 to 45 degrees C), with the same wastewater and conditions as the actual system.     

Improvement of the optical properties of electrodeposited CuInSe2 thin films by thermal and chemical treatments

Cu, In and Se have been codeposited in thin films by potentiostatic one-step electrodeposition. The as-deposited material has shown direct optical transitions attributable to the CuInSe₂ semiconductor, but also additional absorption corresponding to another semimetallic phase. The secondary phases are selenium and copper selenide compounds which have been determined by composition measurements. In order to eliminate the semimetallic phases and to improve the semiconductor behaviour of the electrodeposited material, thermal and chemical treatments have been performed. After heat-treatment of the samples at 400°C in flowing argon, elemental selenium loss has been detected together with an enhancement of the allowed direct optical transition. The subsequent chemical etching of the layers in a KCN solution has showed to be successful in eliminating the copper selenide phases which were responsible of the remaining sub-bandgap absorption.     

Structural Changes in EPDM Subjected to Ageing in High Voltage Transmission Lines

This work presents a study of the structural changes in aged EPDM (ethylene-propylene-diene monomer) from outdoor high voltage transmission lines. Samples were taken from failed and non-failed insulators after up to ten years in service on a 33 kV line. Infrared absorption, hydrophobicity index, dynamical mechanical analysis (DMA) and dielectric relaxation (DR) were employed as experimental techniques. The same experimental techniques were also applied to new samples of EPDM that were subjected to high electric fields (up to 14 kV/mm) for several hours. Results from DMA and DR techniques are in good agreement and, together with previous results from neutron irradiation techniques, suggest that the experimental data obtained from outdoor-aged and laboratory tested samples may be explained by a decrease in the degree of crystallinity due to the interaction between electrical and mechanical effects in the dielectric. The proposed model is based on the disentanglement of the crystallites by forces originated in the interaction of the electric field with the polar groups located in the amorphous phase of the polymer matrix. An alternative explanation, based on a relaxation process appearing at the interfaces between the filler (ATH) and the polymer matrix conflicts with several experimental results presented in this work.     

Dispersion characterization in layered double hydroxide/Nylon 66 nanocomposites using FIB imaging

Layered double hydroxides (LDHs), a newly emerging 2D host material, consist of cationic brucite-like layers and exchangeable interlayer anions. In this work, the morphology and dispersion of LDH particles in LDH/Nylon 66 (salt) nanocomposites has been investigated using focused ion beam (FIB) techniques, transmission electron microscopy (TEM) and X-ray diffraction (XRD). The FIB images show that LDHs are present in the polymer phase dispersed to different degrees, with partial intercalation, exfoliation, and aggregation all being observed. The most even dispersion was achieved in nanocomposites with the lowest loading (0.5 wt % LDH). Residual tactoids and agglomerates were most common in the samples made with the highest concentration of LDHs studied here (5 wt %). The dispersion observed using FIB was consistent with TEM and XRD analysis, yet this technique had significant benefits in terms of time and simplicity over these “conventional” technologies. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Thermodynamic compatibility of sepiolite-filled poly(vinylidene fluoride)-polystyrene blends

Summary Inverse gas chromatography (IGC) and differential scanning calorimetry (DSC) were used to investigate the effect produced by sepiolite on the thermodynamical compatibility of poly(vinylidene fluoride)-polystyrene blends. Polymer-polymer interaction parameters were calculated from the retention data, for various polar and non-polar probes in pure and mixed stationary phases of these polymers, using sepiolite as solid support, as well as from melting point depression analysis of the sepiolite filled blends. Both techniques give us positive values of the interaction parameters, in accordance with the non-compatibility of these blends; However negative values of the interaction parameters were obtained for polystyrene-rich blends (_PS 85 wt%) and high sepiolite loadings, indicating that sepiolite acts as a compatibilizing agent for the system PVF₂/PS.     

Changes in carbohydrates during germination of lentils

Summary The effect of germination on soluble carbohydrates, total and digestible starch, and components of dietary fiber (neutral detergent fiber, cellulose and hemicellulose) in two varieties of lentils (Lens culinaris medicus var. vulgaris and variabilis) were investigated. In germinated lentils the amount of total soluble sugars decreased (from 4.3% to 2.0% and from 5.3% to 2.2%, respectively); glucose, not present in raw seeds, was relatively high (0.6% and 0.7%), fructose increased slightly, and sucrose decreased slightly. The oligosaccharides of the raffinose family disappeared from germinated seeds. Total starch decreased considerably in germinated lentils (from 60.3% to 41.4% and from 57.4% to 36.4%), but the digestibility of the starch was greatly improved. In germinated lentils, the content of neutral detergent fiber and hemicellulose were lower but that of cellulose and lignin were higher than in raw lentils. Thus, the nutritive value of both varieties of lentils may increase with germination processes.

---

Veränderungen im Kohlenhydratgehalt in keimenden Linsen

Zusammenfassung In der vorliegenden Arbeit wurde der Einfluß der Keimung auf die Gehalte an löslichen Kohlenhydraten, Gesamt- und verdaulicher Stärke und Komponenten der Rohfaser (neutral detergent fiber, Cellulose und Hemicellulose), in zwei Linsensorten (Lens culinaris medicus var. vulgaris und variabilis) untersucht. Der Gesamtzuckergehalt nimmt durch die Keimung bei beiden Sorten ab (von 4,3% bis 2,0% und von 5,3% bis 2,2%). Glucose, die sich in rohen Samen nicht findet, lag bei 0,6% und 0,7% in den gekeimten Linsen. Fructose und Sucrose änderten sich nur wenig. Die Raffinose-Oligosaccharide sind bei den gekeimten Linsen nicht vorhanden. Die Gesamt-Stärke nimmt deutlich während der Keimung ab (von 60,27% bis 41,39% und von 57,41% bis 36,39%), aber die Verdaulichkeit der Stärke wurde signifikant verbessert. Die Gehalte an neutral detergent fiber und Hemicellulose bei gekeimten Linsen waren niedriger als bei rohen Linsen, aber die Cellulose- und Ligningehalte waren nach der Keimung größer. Der Proteinnährwert bei beiden Linsensorten kann durch die Keimung verbessert werden.

     

A New Tool to Study Parkinsonism in the Context of Aging: MPTP Intoxication in a Natural Model of Multimorbidity

The diurnal rodent Octodon degus (O. degus) is considered an attractive natural model for Alzheimer’s disease and other human age-related features. However, it has not been explored so far if the O. degus could be used as a model to study Parkinson’s disease. To test this idea, 10 adult male O. degus were divided into control group and MPTP-intoxicated animals. Motor condition and cognition were examined. Dopaminergic degeneration was studied in the ventral mesencephalon and in the striatum. Neuroinflammation was also evaluated in the ventral mesencephalon, in the striatum and in the dorsal hippocampus. MPTP animals showed significant alterations in motor activity and in visuospatial memory. Postmortem analysis revealed a significant decrease in the number of dopaminergic neurons in the ventral mesencephalon of MPTP animals, although no differences were found in their striatal terminals. We observed a significant increase in neuroinflammatory responses in the mesencephalon, in the striatum and in the hippocampus of MPTP-intoxicated animals. Additionally, changes in the subcellular expression of the calcium-binding protein S100β were found in the astrocytes in the nigrostriatal pathway. These findings prove for the first time that O. degus are sensitive to MPTP intoxication and, therefore, is a suitable model for experimental Parkinsonism in the context of aging.