Fused 3-Hydroxy-3-trifluoromethylpyrazoles Inhibit Mutant Huntingtin Toxicity

[Image: see text] Here, we describe the selection and optimization of a chemical series active in both a full-length and a fragment-based Huntington’s disease (HD) assay. Twenty-four thousand small molecules were screened in a phenotypic HD assay, identifying a series of compounds bearing a 3-hydroxy-3-trifluoromethylpyrazole moiety as able to revert the toxicity induced by full-length mutant Htt by up to 50%. A chemical exploration around the series led to the identification of compound 4f, which demonstrated to be active in a Htt171–82Q rat primary striatal neuron assay and a PC12-Exon-1 based assay. This compound was selected for testing in R6/2 mice, in which it was well-tolerated and showed a positive effect on body weight and a positive trend in preventing ventricular volume enlargment. These studies provide strong rationale for further testing the potential benefits of 3-hydroxy-3-trifluoromethylpyrazoles in treating HD

ТЕРМІЧНІ ТА ТЕПЛОФІЗИЧНІ ВЛАСТИВОСТІ ЕПОКСИДНО‑ПОЛІСИЛОКСАНОВИХ НАНОКОМПОЗИТІВ КАТІОННОЇ ПОЛІМЕРИЗАЦІЇ

The polymer and composites were received using epoxy resin EPONEX 1510 – diglycidyl ether of dicyclohexylolpropane and 15 % solution of boron trifluoride in diethylene glycol. The silica particles were formed in situ via the sol-gel method using hydrolytic polycondensation of tetraethoxysilane. The silica sol was obtained in acetone as the organic solvent. Silica filler content in the composites varied from 0.5 to 3 wt%. The effect of the nanofiller on the thermophysical and thermal properties of the obtained polymers was studied. Thermophysical characteristics were determined by differential scanning calorimetry on a TA Instruments DSC Q2000 apparatus at a rate of heating of 20 °С/min in the temperature range from 5 to 190 °C. With the objective of decreasing the influence of the technological (kinetic) and thermal prehistory of the sample on its thermophysical characteristics, the scanning was done twice. The glass transition temperature and heat capacity jump of the composite coatings based on epoxy-silica prepared by cationic polymerization were studied. It was established that with an increase of filler content the glass transition temperature of composites increases, and the value of the heat capacity jump remains almost unchanged. Parameters of thermostability of polymer and composites were determined by thermogravimetric analysis on a TA Instruments Q50 apparatus at a rate of heating of 20 °С/min in the temperature range from 20 to 1000 °C in an atmosphere of oxygen. The destruction process of epoxy-silica composites proceeds in several stages. In the deep stages of the thermo-oxidative destruction of obtained composites the effect of the silica filler is insignificant. The obtained polymer coatings were subjected to a long-term (100 hours) isothermal aging at 160 °C in an atmosphere of oxygen. It was determined that the maximum rate of mass loss rate of epoxy-silica composites is 1.5 times lower than that of unmodified polymer.Золь-гель методом одержано епоксидно-полісилоксанові нанокомпозити катіонної полімеризації на основі епоксидної смоли EPONEX 1510 і тетраетоксисилану. Вивчено вплив нанонаповнювача на термічні та теплофізичні властивості отриманих полімерів. Встановлено, що зі збільшенням вмісту полісилоксанової складової від 0,5 до 3 мас% підвищуються температура склування, а значення стрибка теплоємностімайже не змінюється. Визначено, що максимальна швидкість втрати маси епоксидно-полісилоксанових композитів в 1,5 рази менша, ніж у немодифікованого полімеру

Investigation of age-related decline of microfibril-associated glycoprotein-1 in human skin through immunohistochemistry study

Qian Zheng, Siming Chen, Ying Chen, John Lyga, Russell Wyborski, Uma SanthanamGlobal Research and Development, Avon Products Inc., Suffern, New York, USAAbstract: During aging, the reduction of elastic and collagen fibers in dermis can lead to skin atrophy, fragility, and aged appearance, such as increased facial wrinkling and sagging. Microfibril-associated glycoprotein-1 (MAGP-1) is an extracellular matrix protein critical for elastic fiber assembly. It integrates and stabilizes the microfibril and elastin matrix network that helps the skin to endure mechanical stretch and recoil. However, the observation of MAGP-1 during skin aging and its function in the dermis has not been established. To better understand age-related changes in the dermis, we investigated MAGP-1 during skin aging and photoaging, using a combination of in vitro and in vivo studies. Gene expression by microarray was performed using human skin biopsies from young and aged female donors. In addition, immunofluorescence analysis on the MAGP-1 protein was performed in dermal fibroblast cultures and in human skin biopsies. Specific antibodies against MAGP-1 and fibrillin-1 were used to examine protein expression and extracellular matrix structure in the dermis via biopsies from donors of multiple age groups. A reduction of the MAGP-1 gene and protein levels were observed in human skin with increasing age and photoexposure, indicating a loss of the functional MAGP-1 fiber network and a lack of structural support in the dermis. Loss of MAGP-1 around the hair follicle/pore areas was also observed, suggesting a possible correlation between MAGP-1 loss and enlarged pores in aged skin. Our findings demonstrate that a critical “pre-elasticity” component, MAGP-1, declines with aging and photoaging. Such changes may contribute to age-related loss of dermal integrity and perifollicular structural support, which may lead to skin fragility, sagging, and enlarged pores.Keywords: microfibril-associated glycoprotein-1, aging, elastic fibers, extracellular matrix, immumohistochemistr

THERMAL AND THERMOPHYSICAL PROPERTIES OF EPOXY-SILICA NANOCOMPOSITES OF CATIONIC POLYMERIZATION

The polymer and composites were received using epoxy resin EPONEX 1510 – diglycidyl ether of dicyclohexylolpropane and 15 % solution of boron trifluoride in diethylene glycol. The silica particles were formed in situ via the sol-gel method using hydrolytic polycondensation of tetraethoxysilane. The silica sol was obtained in acetone as the organic solvent. Silica filler content in the composites varied from 0.5 to 3 wt%. The effect of the nanofiller on the thermophysical and thermal properties of the obtained polymers was studied. Thermophysical characteristics were determined by differential scanning calorimetry on a TA Instruments DSC Q2000 apparatus at a rate of heating of 20 °С/min in the temperature range from 5 to 190 °C. With the objective of decreasing the influence of the technological (kinetic) and thermal prehistory of the sample on its thermophysical characteristics, the scanning was done twice. The glass transition temperature and heat capacity jump of the composite coatings based on epoxy-silica prepared by cationic polymerization were studied. It was established that with an increase of filler content the glass transition temperature of composites increases, and the value of the heat capacity jump remains almost unchanged. Parameters of thermostability of polymer and composites were determined by thermogravimetric analysis on a TA Instruments Q50 apparatus at a rate of heating of 20 °С/min in the temperature range from 20 to 1000 °C in an atmosphere of oxygen. The destruction process of epoxy-silica composites proceeds in several stages. In the deep stages of the thermo-oxidative destruction of obtained composites the effect of the silica filler is insignificant. The obtained polymer coatings were subjected to a long-term (100 hours) isothermal aging at 160 °C in an atmosphere of oxygen. It was determined that the maximum rate of mass loss rate of epoxy-silica composites is 1.5 times lower than that of unmodified polymer