Retrograde Amnesia Induced by Drugs Acting on Different Molecular Systems.

The gamma aminobutyric acid-A (GABAA) agonist, muscimol, the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, D-2-amino-5-phosphonopentanoic acid (AP5), and the inhibitor of the extracellularly regulated kinases (ERKs), UO 126, cause retrograde amnesia when administered to the hippocampus. In the present study, the authors found that they all cause retrograde amnesia for 1-trial inhibitory avoidance, not only when infused into the dorsal CA1 region of the hippocampus, but also when infused into the basolateral amygdala or the entorhinal, parietal, and posterior cingulate cortices. The posttraining time course of the effect of each drug was, however, quite different across brain structures. Thus, in all of them, NMDA receptors and the ERK pathway are indispensable for memory consolidation, and GABAA receptor activation inhibits memory consolidation: but in each case, their influence is interwoven differently. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Synthetic and Biological Studies of Sesquiterpene Polygodial: Activity of 9‐Epipolygodial against Drug‐Resistant Cancer Cells

Polygodial, a terpenoid dialdehyde isolated from Polygonum hydropiper L., is a known agonist of the transient receptor potential vanilloid 1 (TRPV1). In this investigation a series of polygodial analogues were prepared and investigated for TRPV1‐agonist and anticancer activities. These experiments led to the identification of 9‐epipolygodial, which has antiproliferative potency significantly exceeding that of polygodial. 9‐Epipolygodial was found to maintain potency against apoptosis‐resistant cancer cells as well as those displaying the multidrug‐resistant (MDR) phenotype. In addition, the chemical feasibility for the previously proposed mechanism of action of polygodial, involving the formation of a Paal–Knorr pyrrole with a lysine residue on the target protein, was demonstrated by the synthesis of a stable polygodial pyrrole derivative. These studies reveal rich chemical and biological properties associated with polygodial and its direct derivatives. These compounds should inspire further work in this area aimed at the development of new pharmacological agents, or the exploration of novel mechanisms of covalent modification of biological molecules with natural products.     

From the ganglioside GQ1balpha to glycomimetic antagonists of the myelin-associated glycoprotein (MAG)

The tetrasaccharide 4, a substructure of ganglioside GQ1balpha, shows a remarkable affinity for the myelin-associated glycoprotein (MAG) and was therefore selected as starting point for a lead optimization program. In our search for structurally simplified and pharmacokinetically improved mimics of 4, antagonists with modifications of the core disaccharide Galbeta(1-3)GalNAc, as well as the terminal alpha(2-3)- and the internal alpha(2-6)-linked neuraminic acid were synthesized and tested in target-based binding assays. Compared to the reference tetrasaccharide 4, the most potent antagonist 17 exhibits a 360-fold improved affinity. Furthermore, pharmacokinetic parameters such as stability in the cerebrospinal fluid, logD and permeation through the BBB indicate the drug-like properties of antagonist 17.     

Ab Initio Study of Hydrogen Interaction with Defective BC2N Nanotubes

The spin polarized density functional theory is used to investigate the incorporation of hydrogen adatoms and the interaction between molecular H₂ with antisites and vacancies in both zigzag (4,0) and armchair (3,3) BC₂N nanotubes. We find that the presence of antisites and vacancies increases the binding energy of hydrogen adatoms on the tube surface. In the most stable antisites (C_B, C_N, N_CI and B_CII), the hydrogen adatoms bind preferentially on carbon atoms of the defective site (C_B, and C_N) or closer to it (N_CI and B_CII). For a single adsorbed H, the calculated binding energies show that the H adsorption on a carbon vacancy (V_CII) is the most stable site with a binding energy of ?4.23?eV. The adsorption of a second H atom near the previous one is an exothermic process compared to of a single H₂ molecule physisorbed on the nanotube surface.     

In Vitro Inactivation of Herpes Virus by Ozone

Viruses represent a major threat to human health and might be transmitted by direct and indirect contact. Reducing the viral load, either in the host or in the environment greatly reduces virus spreading. In this work we aimed to evaluate the virucidal activity of ozone against herpes virus of human (Herpes Simplex Virus 1 – HSV-1) and bovine (Bovine Herpes Virus 1 – BoHV-1) origin. The virucidal activity was measured by tittering aliquots of HSV-1 and BoHV-1 exposed for 1, 2, and 3 h to ozone generated by a domestic device. In addition, the possible cytotoxic effect of ozone to cultured MDBK cells was also assessed using the MTT method. MDBK cells exposed to ozone for 3 h and tested immediately after exposure, or after culturing for 24 h, had viability similar to non-exposed cells, indicating that ozone per se was not cytotoxic to the cells. Furthermore, a significant reduction in BoHV-1 (99.62%) and HSV-1 (90.0%) titer was observed after 3 h exposure to ozone. Our results indicate that ozone might be safely used to reduce environmental load of herpes virus.     

Metal-binding particles alleviate lead and zinc toxicity during seed germination of metallophyte grass Astrebla lappacea

Combining metal-binding particles and metal-tolerant plants (metallophytes) offers a promising new approach for rehabilitation of heavy metal contaminated sites. Three types of hydrogel metal-binding polymer particles were synthesized and their effects on metal concentrations tested in vitro using metal ion solutions. The most effective of the tested polymers was a micron-sized thiol functional cross-linked acrylamide polymer which reduced the available solution concentrations of Pb(2+) (9.65 mM), Cu(2+) (4mM) and Zn(2+) (10mM) by 86.5%, 75.5% and 63.8%, respectively, and was able to store water up to 608% of its dry mass. This polymer was not toxic to seed germination. In deionised water, it enhanced seed germination, and at otherwise phytotoxic Pb(2+) (9.65 mM) and Zn(2+) (10mM) concentrations, it allowed normal germination and root elongation of the metallophyte grass Astrebla lappacea. We conclude that the polymer has the potential to facilitate restoration of heavy metal contaminated lands by reducing the concentration of metal cations in the soil solution and improving germination rates through reduced toxicity and enhanced plant water relations.     

Probing small-molecule binding to cytochrome P450 2D6 and 2C9: An in silico protocol for generating toxicity alerts

Drug metabolism, toxicity, and their interaction profiles are major issues in the drug-discovery and lead-optimization processes. The cytochromes P450 (CYPs) 2D6 and 2C9 are enzymes involved in the oxidative metabolism of a majority of marketed drugs. Therefore, the prediction of the binding affinity towards CYP2D6 and CYP2C9 would be beneficial for identifying cytochrome-mediated adverse effects triggered by drugs or chemicals (e.g., toxic reactions, drug-drug, and food-drug interactions). By identifying the binding mode by using pharmacophore prealignment, automated flexible docking, and by quantifying the binding affinity by multidimensional QSAR (mQSAR), we validated a model family of 56 compounds (46 training, 10 test) and 85 compounds (68 training, 17 test) for CYP2D6 and CYP2C9, respectively. The correlation with the experimental data (cross-validated r2=0.811 for CYP2D6 and 0.687 for CYP2C9) suggests that our approach is suited for predicting the binding affinity of compounds towards CYP2D6 and CYP2C9. The models were challenged by Y-scrambling and by testing an external dataset of binding compounds (15 compounds for CYP2D6 and 40 for CYP2C9). To assess the probability of false-positive predictions, datasets of nonbinders (64 compounds for CYP2D6 and 56 for CYP2C9) were tested by using the same protocol. The two validated mQSAR models were subsequently added to the VirtualToxLab (VTL, http://www.virtualtoxlab.org).     

Adsorption technology for the storage of natural gas and biomethane from biogas

As natural gas, biogas has been used for nobler purposes in recent years, such as the use of purified biogas (biomethane) in the transport sector. Currently, natural gas storage for use in transportation is accomplished primarily through compressed natural gas (CNG) technologies and liquefied natural gas (LNG), which require large amounts of energy. In recent years, the storage technology of absorbed natural gas (ANG) on porous materials has been studied, fundamentally highlighted by reduced energy use and increased safety in the transport of gaseous fuel. In this sense, the present study aimed to gather information about the main adsorbent materials which are being studied and the conditions normally employed in surveys that use ANG technology, as well as pointing out the main challenges for the storage of biogas in the adsorbed form at low pressures and room temperature in an attempt to meet the target of 180 V/V established by Department of Energy. Researchers reported high storage capacities in moderate conditions of temperature and pressure; however, the biggest challenge of the research involving methane adsorbed is also achieving high rates of desorption with the lowest possible energy expenditure. Copyright © 2016 John Wiley & Sons, Ltd.     

Evidence for a stimulatory role of follicle-stimulating hormone on the spermatogonial population in adult males

Inactivation of the integrin beta6 subunit gene in mice resulted in an unexpected phenotype-functionally significant inflammation of the skin and lungs. These findings suggested a role for ligation of the alphav beta6 integrin on epithelial cells in downregulating epithelial inflammation. However, the results of gene inactivation could have been due to inactivation of adjacent genes and provided no information about the role of this integrin in specific populations of epithelial cells. In the current study, we used transgenic mice constitutively expressing the human beta6 subunit in alveolar type II cells and bronchiolar epithelial cells to examine directly the significance of alphav beta6 in these cells. Expression of this transgene largely inhibited the increases in airspace lymphocytes and macrophages and the lymphocyte and macrophage activation caused by inactivation of the beta6 subunit gene, and reduced the peribronchial and perivascular accumulations of lymphocytes. In the genetically mixed mice used for this study, we identified airway eosinophilia as an additional effect of beta6 inactivation. This effect was also partially inhibited by limited expression of the human transgene. These results definitively identify a role for distal lung epithelial alphav beta6 in downregulating pulmonary inflammation and suggest that interventions augmenting beta6 expression or function in these cells could influence the course of inflammatory lung diseases.