Changes in malondialdehyde content and in superoxide dismutase, catalase and glutathione reductase activities in sunflower seeds as related to deterioration during accelerated aging

Sunflower ( Helianthus annuus L.) seeds progressively lost their ability to germinate at 25°C, the optimal temperature for germination, after accelerated aging was carried out at 45°C (a temperature too high to permit germination) in water or at 76 or 100% relative humidity (RH). The deleterious effects of the high-temperature treatment increased with increasing seed moisture content. Incubation of seeds at 45°C in water resulted in electrolyte leakage, which indicated a loss of membrane integrity. A relationship between leakage and loss of seed viability could not be assumed, since no increase in electrolyte efflux occurred after aging al 100% RH. Accelerated aging induced accumulation of malondialdehyde, suggesting that seed deterioration was associated with lipid peroxidation. However, there was no direct relationship between lipid peroxidation and deterioration in membrane integrity. Loss of seed viability was also associated with a decrease in superoxide dismutase, catalase and glutathione reductase activities. Finally, the results obtained suggest that sunflower seed deterioration during accelerated aging is closely related to a decrease in the activities of detoxifying enzymes and to lipid peroxidation.     

Nanoscale Elastic Changes in 2D Ti3C2Tx (MXene) Pseudocapacitive Electrodes

Designing sustainable electrodes for next generation energy storage devices relies on the understanding of their fundamental properties at the nanoscale, including the comprehension of ions insertion into the electrode and their interactions with the active material. One consequence of ion storage is the change in the electrode volume resulting in mechanical strain and stress that can strongly affect the cycle life. Therefore, it is important to understand the changes of dimensions and mechanical properties occurring during electrochemical reactions. While the characterization of mechanical properties via macroscopic measurements is well documented, in situ characterization of their evolution has never been achieved at the nanoscale. It is reported here with in situ imaging, combined with density functional theory of the elastic changes of a 2D titanium carbide (Ti₃C₂T_x) based electrode in direction normal to the basal plane (electrode surface) during alkaline cation intercalation/extraction. 2D carbides, known as MXenes, are promising new materials for supercapacitors and various kinds of batteries, and understanding the coupling between their mechanical and electrochemical properties is therefore necessary. The results show a strong correlation between the cations content and the out‐of‐plane elastic modulus. This strategy enables identifying the preferential intercalation pathways within a single particle, which is important for understanding ionic transport in these materials.     

ROCK inhibitors 3: Design,synthesis and structure-activity relationships of 7-azaindole-based Rho kinase (ROCK) inhibitors

Rho kinase (ROCK) inhibitors are potential therapeutic agents for the treatment of a variety of disorders including hypertension, glaucoma and erectile dysfunction. Here we disclose a series of potent and selective ROCK inhibitors based on a substituted 7-azaindole scaffold. Substitution of the 3-position of 7-azaindole led to compounds such as 37, which possess excellent ROCK inhibitory potency and high selectivity against the closely related kinase PKA.     

4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: Potent and selective p70S6 kinase inhibitors

We report herein the design and synthesis of 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-amine derivatives as inhibitors of p70S6 kinase. Screening hits containing the 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine scaffold were optimized for p70S6K potency and selectivity against related kinases. Structure-based design employing an active site homology model derived from PKA led to the preparation of benzimidazole 5-substituted compounds 26 and 27 as highly potent inhibitors (K_i <1 nM) of p70S6K, with >100-fold selectivity against PKA, ROCK and GSK3.     

Novel thiol-based TACE inhibitors: rational design, synthesis, and SAR of thiol-containing aryl sulfonamides

A series of potent thiol-containing aryl sulfonamide TACE inhibitors was designed and synthesized. The SAR and MMP selectivity of the series were investigated. In particular, compound 4b has shown excellent in vitro potency against the isolated TACE enzyme and good selectivity over MMP-2, -7, -8, -9, and -13. The X-ray structure of 4b bound to TACE was obtained.     

2-Aminopyrazolo[1,5-a]pyrimidines as potent and selective inhibitors of JAK2

Constitutive activation of the EPO/JAK2 signaling cascade has recently been implicated in a variety of myeloproliferative disorders including polycythemia vera, essential thrombocythemia and myelofibrosis. In an effort to uncover therapeutic potential of blocking the EPO/JAK2 signaling cascade, we sought to discover selective inhibitors that block the kinase activity of JAK2. Herein, we describe the discovery and structure based optimization of a novel series of 2-amino-pyrazolo[1,5-a]pyrimidines that exhibit potent inhibition of JAK2.     

IL-12, STAT4-dependent up-regulation of CD4(+) T cell core 2 beta-1,6-n-acetylglucosaminyltransferase, an enzyme essential for biosynthesis of P-selectin ligands

TCR activation of naive T cells in the presence of IL-12 drives polarization toward a Th1 phenotype and synthesis of P- and E-selectin ligands. Fucosyltransferase VII (Fuc-T VII) and core 2 beta-1,6-N-acetylglucosaminyltransferase (C2GnT) are critical for biosynthesis of selectin ligands. P-selectin glycoprotein ligand-1 is the best characterized ligand for P-selectin and also binds E-selectin. The contributions of TCR and cytokine signaling pathways to up-regulate Fuc-T VII and C2GnT during biosynthesis of E- and P-selectin ligands, such as P-selectin glycoprotein ligand 1, are unknown. IL-12 signals via the STAT4 pathway. Here, naive DO11.10 TCR transgenic and STAT4(-/-) TCR transgenic CD4(+) T cells were stimulated with Ag and IL-12 (Th1 condition), IL-4 (Th2), or neutralizing anti-IL-4 mAb only (Th0). The levels of Fuc-T VII and C2GnT mRNA in these cells were compared with their adhesive interactions with P- and E-selectin in vitro under flow. The data show IL-12/STAT4 signaling is necessary for induction of C2GnT, but not Fuc-TVII mRNA, and that STAT4(-/-) Th1 cells do not traffic normally to sites of inflammation in vivo, do not interact with P-selectin, and exhibit a partial reduction of E-selectin interactions under shear stress in vitro. Ag-specific TCR activation in CD4(+) T cells was sufficient to trigger induction of Fuc-TVII, but not C2GnT, mRNA and expression of E-selectin, but not P-selectin, ligands. Thus, Fuc-T VII and C2GnT are regulated by different signals during Th cell differentiation, and both cytokine and TCR signals are necessary for the expression of E- and P-selectin ligands.