Revisiting the Proposition of Binding Pockets and Bioactive Poses for GSK-3β Allosteric Modulators Addressed to Neurodegenerative Diseases

Glycogen synthase kinase-3 beta (GSK-3β) is an enzyme pertinently linked to neurodegenerative diseases since it is associated with the regulation of key neuropathological features in the central nervous system. Among the different kinds of inhibitors of this kinase, the allosteric ones stand out due to their selective and subtle modulation, lowering the chance of producing side effects. The mechanism of GSK-3β allosteric modulators may be considered still vague in terms of elucidating a well-defined binding pocket and a bioactive pose for them. In this context, we propose to reinvestigate and reinforce such knowledge by the application of an extensive set of in silico methodologies, such as cavity detection, ligand 3D shape analysis and docking (with robust validation of corresponding protocols), and molecular dynamics. The results here obtained were consensually consistent in furnishing new structural data, in particular by providing a solid bioactive pose of one of the most representative GSK-3β allosteric modulators. We further applied this to the prospect for new compounds by ligand-based virtual screening and analyzed the potential of the two obtained virtual hits by quantum chemical calculations. All potential hits achieved will be subsequently tested by in vitro assays in order to validate our approaches as well as to unveil novel chemical entities as GSK-3β allosteric modulators.     

Performance of a diesel generator fuelled with palm oil

Pure palm oil may be employed in diesel engines as an alternative fuel. Engine performance and emissions were influenced by basic differences between diesel fuel and palm oils such as mass based heating values, viscosity, density and molecular oxygen content. The high viscosity of palm oil resulted in poor atomisation, carbon deposits, clogging of fuel lines and starting difficulties in low temperatures. When heated at 100 °C palm oil presented lower viscosity, better combustion and less deposits. Tests were conducted in a naturally aspirated MWM 229 direct injection four-stroke 70 kW diesel-generator fueslled with 100% palm oil.     

Phase Equilibria in the Al-Co-Ni Alloy System

The phase equilibria in the Ni-Co rich region (<50 at.%Al) of the Al-Co-Ni system were studied experimentally for two isothermal sections at 1100 and 800 °C. Metallography, energy dispersive spectroscopy, hardness and x-ray diffraction were used for characterization and determination of γ, γ′ and β phases within the ternary system. Phase boundaries in the isothermal sections and a partial liquidus projection are modified compared to previously published work. Comparison is made to the isothermal sections computed using Thermo-Calc and the TCNI8 database. No definitive experimental evidence corroborating the predicted existence of a Nishizawa horn was obtained.     

Novel thermo-responsive membranes composed of interpenetrated polymer networks of alginate-Ca and poly(N-isopropylacrylamide)

In this work, interpenetrated polymer networks (IPN) composed of alginate-Ca²⁺ and poly(N-isopropylacrylamide), PNIPAAm, were synthesized and their water uptake capability was measured at temperatures from 25 to 40 °C and compared to that of pure alginate-Ca²⁺ hydrogels without PNIPAAm. A sharp decrease of WU was observed when IPN hydrogels are heated above 32-33 °C. The phenomenon is associated to a drastic shrinking of hydrogels. At temperatures above 32 °C the PNIPAAm chains collapse, contracting their network and pulling back the alginate-Ca²⁺ network. The rate of shrinking depends of the heating rate. The phenomenon is more effective and faster in IPN containing lower amount of alginate-Ca²⁺. The shrunken IPN hydrogels can be re-swollen but the expansion is slower than the shrinking. The diffusion of Orange II dye through the membrane of IPN hydrogels decreases if the temperature is raised up to 35 °C. The shrinking results in a decrease of the average pores size that makes more difficult the diffusion of Orange II. The average pore size was evaluated in several stages by analysis of SEM micrographs of freeze dried samples: 102.0±14.3 μm at 25 °C, 15.7±5.4 μm at 33 °C and 0.4±0.3 μm at 40 °C. Below the LCST of PNIPAAm, the IPN hydrogels exhibit a morphology characterized by open pores but above the LCST their surface becomes more regular and compact. As a consequence, an increase of the apparent activation energy for permeability, , of Orange II is measured.     

ATRvD1 Attenuates Renal Tubulointerstitial Injury Induced by Albumin Overload in Sepsis-Surviving Mice

Novel strategies for the prevention and treatment of sepsis-associated acute kidney injury and its long-term outcomes have been required and remain a challenge in critical care medicine. Therapeutic strategies using lipid mediators, such as aspirin-triggered resolvin D1 (ATRvD1), can contribute to the resolution of acute and chronic inflammation. In this study, we examined the potential effect of ATRvD1 on long-term kidney dysfunction after severe sepsis. Fifteen days after cecal ligation and puncture (CLP), sepsis-surviving BALB/c mice were subjected to a tubulointerstitial injury through intraperitoneal injections of bovine serum albumin (BSA) for 7 days, called the subclinical acute kidney injury (subAKI) animal model. ATRvD1 treatment was performed right before BSA injections. On day 22 after CLP, the urinary protein/creatinine ratio (UPC), histologic parameters, fibrosis, cellular infiltration, apoptosis, inflammatory markers levels, and mRNA expression were determined. ATRvD1 treatment mitigated tubulointerstitial injury by reducing proteinuria excretion, the UPC ratio, the glomerular cell number, and extracellular matrix deposition. Pro-fibrotic markers, such as transforming growth factor β (TGFβ), type 3 collagen, and metalloproteinase (MMP)-3 and -9 were reduced after ATRvD1 administration. Post-septic mice treated with ATRvD1 were protected from the recruitment of IBA1⁺ cells. The interleukin-1β (IL-1β) levels were increased in the subAKI animal model, being attenuated by ATRvD1. Tumor necrosis factor-α (TNF-α), IL-10, and IL-4 mRNA expression were increased in the kidney of BSA-challenged post-septic mice, and it was also reduced after ATRvD1. These results suggest that ATRvD1 protects the kidney against a second insult such as BSA-induced tubulointerstitial injury and fibrosis by suppressing inflammatory and pro-fibrotic mediators in renal dysfunction after sepsis.     

Tumor Resection Induces Alterations on Serum Phospholipidome of Liver Cancer Patients

Hepatocellular carcinoma and cholangiocarcinoma are the most common primary malignant liver tumors. Since the liver plays a key role in lipid metabolism, the study of serum phospholipid (PL) profiles may provide a better understanding of alterations in hepatic lipid metabolism. In this study, we used a high-resolution HILIC-LC–MS lipidomic approach to establish the serum phospholipidome profile of patients with liver cancer before (T0) and after tumor resection (T1) and a control group (CT) of healthy individuals. After the analysis of PL profiles, we observed that the phospholipidome of patients with liver cancer was significantly modified after the tumor resection procedure. We observed an upregulation of some phosphatidylcholine (PtdCho) species, namely, PtdCho(36:6), PtdCho(42:6), PtdCho(38:5), PtdCho(36:5), PtdCho(38:6) and choline plasmalogens (PlsCho), and/or 1-O-alkyl-2-acyl-glycerophosphocholine (PakCho) in patients with liver cancer at T0 compared to the CT group, and a downregulation after tumor resection (T1) when compared to T0. These results show that LC–MS can detect different serum PL profiles in patients with liver cancer, before and after tumor resection, by defining a specific PL fingerprint that was used to determine the effect of tumor and tumor resection on lipid metabolism.     

Role of Silicon and Salicylic Acid in the Mitigation of Nitrogen Deficiency Stress in Rice Plants

Application of silicon (Si) and salicylic acid (SA) mitigates plant stress; however, this effect is not known under nitrogen (N) deficiency conditions in rice plants. The objective of the present study was to determine whether foliar application with a soluble form of Si and SA, individually or in combination, could mitigate N deficiency stress in rice plants. The treatments consisted of application of 3.45 g L⁻¹ Si only (sprayed on the leaves), 4.5 mM SA only, a combination of both, and no application as control. Net CO₂ assimilation rate, transpiration, lignin and carbon contents, C:N:P:Si stoichiometric ratio and grain yield were evaluated. Foliar application of Si combined with SA or isolated application of SA did not mitigate N deficiency stress in rice plants. However, silicon application increased rice yield by 18.6% in N-deficient conditions. Our results show that the beneficial effects of Si under nitrogen deficient conditions are related to the stoichiometry change in C with Si and increases of lignin synthesis.

     

Analyzing the influence of different synthetic talcs in waterborne polyurethane nanocomposites obtainment

Waterborne polyurethane (WPU) nanocomposites were produced utilizing synthetic talc in gel form in order to improve its physical–chemical properties. Synthetic talc manufactured in nano‐gel form are interesting because their interaction with water occurs through hydrogen bonding favoring fillers dispersion within the WPU matrix. WPUs are environmental friendly materials because no organic solvents are used in its production. The nanocomposites obtained with the three synthetic talc nano‐gel fillers presented a good dispersion even when higher amounts of fillers were added, as seen by X‐ray diffraction, transmission electron microscopy, field emission scanning electron microscopy, and atomic force microscopy analyses. The addition of synthetic talcs improved WPU nanocomposites mechanical properties. Storage and loss modulus results proved fillers incorporation into the WPU matrix corroborating with Fourier transform infrared spectroscopy results. Results demonstrated that synthetic talcs in nano‐gel form are interesting to obtain WPU nanocomposites with superior mechanical properties. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46107.