Structural Determinants of the Selectivity of 3‐Benzyluracil‐1‐acetic Acids toward Human Enzymes Aldose Reductase and AKR1B10

The human enzymes aldose reductase (AR) and AKR1B10 have been thoroughly explored in terms of their roles in diabetes, inflammatory disorders, and cancer. In this study we identified two new lead compounds, 2‐(3‐(4‐chloro‐3‐nitrobenzyl)‐2,4‐dioxo‐3,4‐dihydropyrimidin‐1(2H)‐yl)acetic acid (JF0048, 3 ) and 2‐(2,4‐dioxo‐3‐(2,3,4,5‐tetrabromo‐6‐methoxybenzyl)‐3,4‐dihydropyrimidin‐1(2H)‐yl)acetic acid (JF0049, 4 ), which selectively target these enzymes. Although 3 and 4 share the 3‐benzyluracil‐1‐acetic acid scaffold, they have different substituents in their aryl moieties. Inhibition studies along with thermodynamic and structural characterizations of both enzymes revealed that the chloronitrobenzyl moiety of compound 3 can open the AR specificity pocket but not that of the AKR1B10 cognate. In contrast, the larger atoms at the ortho and/or meta positions of compound 4 prevent the AR specificity pocket from opening due to steric hindrance and provide a tighter fit to the AKR1B10 inhibitor binding pocket, probably enhanced by the displacement of a disordered water molecule trapped in a hydrophobic subpocket, creating an enthalpic signature. Furthermore, this selectivity also occurs in the cell, which enables the development of a more efficient drug design strategy: compound 3 prevents sorbitol accumulation in human retinal ARPE‐19 cells, whereas 4 stops proliferation in human lung cancer NCI‐H460 cells.     

Thermodynamics of copper‐manganese and copper‐iron spinel solid solutions

High‐temperature oxide melt solution calorimetry has been performed to investigate the energetics of spinel solid solutions in the Mn₃O₄‐CuMn₂O₄ and Fe₃O₄‐CuFe₂O₄ systems. The spinel solid solutions were synthesized by a ceramic route and calcined at appropriate temperatures to obtain single phase samples. The drop solution enthalpies of the solid solutions in the Mn₃O₄‐CuMn₂O₄ system are the same within experimental error as the enthalpies of drop solution of mechanical mixtures of the end‐members, indicating a zero heat of mixing, i.e., ideal mixing in terms of enthalpy. In Fe₃O₄‐CuFe₂O₄, the drop solution enthalpy of the solid solutions shows a positive deviation from those of the mechanical mixture of the end‐members, suggesting negative mixing enthalpy. The formation enthalpies of the spinel solid solutions from their constituent oxides plus oxygen and from the elements were also determined.     

Combined experimental and computational investigation of thermodynamics and phase equilibria in the CaO–TiO2 system

Phase relations in the CaO–TiO₂ system are of considerable interest in geology, metallurgy, and ceramics. Despite a number of studies of phase equilibria in the CaO–TiO₂ system, there are still some open questions regarding the stability of intermediate compounds. In this work, a series of specimens with different CaO:TiO₂ ratios were prepared by solid‐state reaction. The heat capacities of Ca₃Ti₂O₇ and Ca₄Ti₃O₁₀ from 300 to 1073 K were measured by differential scanning calorimetry and their formation enthalpies from the component oxides at 298 K were measured by high temperature oxide melt solution calorimetry. Using phase diagram information and thermodynamic data from the literature and the present measurements, thermodynamic optimization of the CaO–TiO₂ system was carried out by the CALPHAD technique. The phase diagram and the thermodynamic properties of the CaO–TiO₂ system were calculated using the obtained thermodynamic database, which clarify the stable and metastable phase equilibria of the system. The thermodynamic stability of the various compounds was discussed.     

Liquid-phase theoretical antioxidant activity trend of some cinnamic acid antioxidants

The trend in antioxidant activity of four cinnamic acid antioxidants, derived on the basis of their liquid-phase phenolic O H bond dissociation enthalpies, is determined theoretically, with the aid of the polarizable continuum model at the density functional theory level. Three solvents, differing in their hydrogen-bonding ability and polarity—n-heptane, acetonitrile, and ethanol—were used to model different environmental situations. The trends in solution-phase antioxidant activity appeared different in each solvent; still, the theoretical antioxidant activity trend derived in n-heptane was in excellent agreement with the experimental one in the lipid systems and the gas-phase system. Different ortho substituents show notably different solvent effects. These results could lead to the determination of reliable antioxidant activity trends in real-solution environments of interest in food or biological science frameworks.     

Chemical Mediation of Ternary Interactions Between Marine Holobionts and Their Environment as Exemplified by the Red Alga Delisea pulchra

The need for animals and plants to control microbial colonization is important in the marine environment with its high densities of microscopic propagules and seawater that provides an ideal medium for their dispersal. In contrast to the traditional emphasis on antagonistic interactions of marine organisms with microbes, emerging studies lend support to the notion that health and performance of many marine organisms are functionally regulated and assisted by associated microbes, an ecological concept defined as a holobiont. While antimicrobial activities of marine secondary metabolites have been studied in great depth ex-situ, we are beginning to understand how some of these compounds function in an ecological context to maintain the performance of marine holobionts. The present article reviews two decades of our research on the red seaweed Delisea pulchra by addressing: the defense chemistry of this seaweed; chemically-mediated interactions between the seaweed and its natural enemies; and the negative influence of elevated seawater temperature on these interactions. Our understanding of these defense compounds and the functional roles they play for D. pulchra extends from molecular interactions with bacterial cell signaling molecules, to ecosystem-scale consequences of chemically-controlled disease and herbivory. Delisea pulchra produces halogenated furanones that antagonize the same receptor as acylated homoserine lactones (AHL)-a group of widespread intercellular communication signals among bacteria. Halogenated furanones compete with and inhibit bacterial cell-to-cell communication, and thus interfere with important bacterial communication-regulated processes, such as biofilm formation. In a predictable pattern that occurs at the ecological level of entire populations, environmental stress interferes with the production of halogenated furanones, causing downstream processes that ultimately result in disease of the algal holobiont.     

Temperature of post‐flashover compartment fires—Calculations and validation

This paper describes and validates by comparisons with tests a one‐zone model for computing temperature of fully developed compartment fires. Like other similar models, the model is based on an analysis of the energy and mass balance assuming combustion being limited by the availability of oxygen, ie, a ventilation‐controlled compartment fire. However, the mathematical solution techniques in this model have been altered. To this end, a maximum fire temperature has been defined depending on combustion efficiency and opening heights only. This temperature together with well‐defined fire compartment parameters was then used as a fictitious thermal boundary condition of the surrounding structure. The temperature of that structure could then be calculated with various numerical and analytical methods as a matter of choice, and the fire temperature could be identified as a weighted average between the maximum fire temperature and the calculated surface temperature of the surrounding structure as a function of time. It is demonstrated that the model can be used to predict fire temperatures in compartments with boundaries of semi‐infinitely thick structures as well as with boundaries of insulated and noninsulated steel sheets where the entire heat capacity of the surrounding structure is assumed to be concentrated to the steel core. With these assumptions, fire temperatures could be calculated with spreadsheet calculation methods. For more advanced problems, a general finite element solid temperature calculation code was used to calculate the temperature in the boundary structure. With this code, it is possible to analyze surrounding structures of various kinds, for example, structures comprising several materials with properties varying with temperature as well as voids. The validation experiments were accurately defined and surveyed. In all the tests, a propane diffusion burner was used as the only fire source. Temperatures were measured with thermocouples and plate thermometers at several positions.     

Vegetable fillers for electric stimuli responsive elastomers

Dielectric elastomer actuators (DEAs) have been studied widely in recent years for artificial muscle applications, but their implementation into production is limited due to high operating voltages required. The actuation behavior of dielectric elastomer under an applied electric field is predicted by Maxwell's pressure and thickness strain equations. According to these equations, the best electromechanical response is achieved when the relative permittivity is high and elastic modulus is low. The potential source for additives increasing the relative permittivity of rubbers can be vegetable powders that have much higher dielectric constant than common elastomers. In the present research, the dielectric and actuation properties of polyacrylate rubber (ACM) were studied after the addition of different vegetable‐based fillers such as potato starch, corn starch, garlic, and paprika. The results were compared to ACM filled with barium titanate. The compounds containing vegetable fillers showed higher relative dielectric permittivity at 1 Hz frequency than the compounds containing barium titanate due to higher interfacial polarization. The actuation studies showed that lower electric fields are required to generate certain actuation forces when the starches and garlic are used in the rubber instead of barium titanate. Therefore, the vegetable‐based fillers can be used to improve actuation performance of DEAs. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45081.     

Application of β-Sitosterol + γ-Oryzanol-Structured Organogel as Migration Barrier in Filled Chocolate Products

Oil migration in filled pralines is a phenomenon that is highly correlated with the occurrence of chocolate bloom. In this study the potential to suppress or prevent oil migration by incorporation of sterol/sterolster-structured organogels was evaluated. Different quantities, 2.5 or 14% (w/w), of gel with structurant levels of either 10 or 25% (w/w) were studied in a layered model system. The gel was either a part of the nougat or of the chocolate phase, or as a separate layer. Samples were monitored regularly for a period of 24 weeks at storage temperatures of 10, 18 and 28 °C. The amount of migrated oil was determined via DSC analysis of a surface sample. The results indicate that, despite the additional oil brought into the system via the oleogel, the level of oil found in the chocolate layer is reduced through the presence of the gel. In particular, the three-layer system and gelled chocolate appear to be promising routes to either suppress oil migration or improve nutritional profiles by incorporation of liquid oils.     

Erythropoietin Modulates Autophagy Signaling in the Developing Rat Brain in an In Vivo Model of Oxygen-Toxicity

Autophagy is a self-degradative process that involves turnover and recycling of cytoplasmic components in healthy and diseased tissue. Autophagy has been shown to be protective at the early stages of programmed cell death but it can also promote apoptosis under certain conditions. Earlier we demonstrated that oxygen contributes to the pathogenesis of neonatal brain damage, which can be ameliorated by intervention with recombinant human erythropoietin (rhEpo). Extrinsic- and intrinsic apoptotic pathways are involved in oxygen induced neurotoxicity but the role of autophagy in this model is unclear. We analyzed the expression of autophagy activity markers in the immature rodent brain after exposure to elevated oxygen concentrations. We observed a hyperoxia-exposure dependent regulation of autophagy-related gene (Atg) proteins Atg3, 5, 12, Beclin-1, microtubule-associated protein 1 light chain 3 (LC3), LC3A-II, and LC3B-II which are all key autophagy activity proteins. Interestingly, a single injection with rhEpo at the onset of hyperoxia counteracted these oxygen-mediated effects. Our results indicate that rhEpo generates its protective effect by modifying the key autophagy activity proteins.     

Combining 1,3-Ditriazolylbenzene and Quinoline to Discover a New G-Quadruplex-Interactive Small Molecule Active against Cancer Stem-Like Cells

Quadruplex nucleic acids are promising targets for cancer therapy. In this study we used a fragment-based approach to create new flexible G-quadruplex (G4) DNA-interactive small molecules with good calculated oral drug-like properties, based on quinoline and triazole heterocycles. G4 melting temperature and polymerase chain reaction (PCR)-stop assays showed that two of these compounds are selective G4 ligands, as they were able to induce and stabilize G4s in a dose- and DNA sequence-dependent manner. Molecular docking studies have suggested plausible quadruplex binding to both the G-quartet and groove, with the quinoline module playing the major role. Compounds were screened for cytotoxicity against four cancer cell lines, where 4,4′-(4,4′-(1,3-phenylene)bis(1H-1,2,3-triazole-4,1-diyl))bis(1-methylquinolin-1-ium) ( 1 d ) showed the greater activity. Importantly, dose–response curves show that 1 d is cytotoxic in the human colon cancer HT-29 cell line enriched in cancer stem-like cells, a subpopulation of cells implicated in chemoresistance. Overall, this study identified a new small molecule as a promising lead for the development of drugs targeting G4 in cancer stem cells.