Substituted thiazolamide coupled to a redox delivery system: a new gamma-secretase inhibitor with enhanced pharmacokinetic profile

Inhibition of gamma-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce pathogenic A beta peptides, is an attractive approach for the treatment of Alzheimer's disease. We have designed a new gamma-secretase thiazolamide inhibitor bearing a dihydronicotinoyl moiety as Redox Delivery System which allows specific delivery of the drug to the brain. Through, on the one hand, A beta peptide production measurements by specific in vitro assays (gamma-secretase Cell Free assay and Cell Based assay on HEK 293 APP transfected cells) and, on the other hand, pharmacokinetic studies on animal models, the new inhibitor shows a good pharmacokinetic profile as well as a potent gamma-secretase inhibitory activity in vitro. From the obtained results, it is expected that drug will be mainly delivered to the CNS with low diffusion in the peripheral tissues. Consequently the side effects of this gamma-secretase inhibitor on the immune cells could be reduced.     

Identification of archaeal proteins that affect the exosome function in vitro

Background  

The archaeal exosome is formed by a hexameric RNase PH ring and three RNA binding subunits and has been shown to bind and degrade RNA in vitro. Despite extensive studies on the eukaryotic exosome and on the proteins interacting with this complex, little information is yet available on the identification and function of archaeal exosome regulatory factors.     

Ionic conductivity and dielectric properties of plasticized PVA0.7(LiBr)0.3(H2SO4)2.7M solid acid membrane and its performance in a magnesium battery

This paper describes the synthesis and characterization of a new solid acid polymer electrolyte (SAPE) based on polyvinyl alcohol, lithium bromide and sulfuric acid. Ethylene carbonate was used as plasticizer in the matrix for membranes prepared by a solution cast technique. AC impedance spectroscopy was used to determine the ionic conductivity of SAPE at different temperature and frequency values giving some insight into its potential utility as a solid acid membrane in solid state batteries. The ionic transference number of mobile ions has been estimated by a dc polarization method and the results reveal that the conducting species are predominately ions. A solid state magnesium battery is fabricated and characterized. A cell with the configuration Mg/SAPE/MnO₂ gives a capacity of 270 mAh/g and has an internal resistance ≈ 175 Ω. The electrode degradation after discharge was characterized by XRD analysis.     

Modulation of humoral immune response to oral BCG vaccination by Mycobacterium bovis BCG Moreau Rio de Janeiro (RDJ) in healthy adults

We hypothesize that the energy strategy of a cell is a key factor for determining how, or if, the immune system interacts with that cell. Cells have a limited number of metabolic states, in part, depending on the type of fuels the cell consumes. Cellular fuels include glucose (carbohydrates), lipids (fats), and proteins. We propose that the cell's ability to switch to, and efficiently use, fat for fuel confers immune privilege. Additionally, because uncoupling proteins are involved in the fat burning process and reportedly in protection from free radicals, we hypothesize that uncoupling proteins play an important role in immune privilege. Thus, changes in metabolism (caused by oxidative stresses, fuel availability, age, hormones, radiation, or drugs) will dictate and initiate changes in immune recognition and in the nature of the immune response. This has profound implications for controlling the symptoms of autoimmune diseases, for preventing graft rejection, and for targeting tumor cells for destruction.     

Quantitative thin-layer chromatographic method of analysis of azithromycin in pure and capsule forms

A validated stability-indicating thin-layer chromatographic (TLC) method of the analysis of azithromycin (AZT) in bulk and capsule forms is developed. Both AZT potential impurity and degradation products can be selectively and accurately estimated in both raw material and product onto one precoated silica-gel TLC plate 60F254. The development system used is n-hexane-ethyl acetate-diethylamine (75:25:10, v/v/v). The separated bands are detected as brown to brownish red spots after spraying with modified Dragendorff's solution. The Rf values of AZT, azaerythromycin A, and the three degradation products are 0.54, 0.35, 0.40, 0.20, and 0.12, respectively. The optical densities of the separated spots are found to be linear in proportion to the amount used. The stress testing of AZT shows that azaerythromycin A is the major impurity and degradation product, accompanied by three other unknown degradation products. The stability of AZT is studied under accelerated conditions in order to provide a rapid indication of differences that might result from a change in the manufacturing process or source of the sample. The forced degradation conditions include the effect of heat, moisture, light, acid-base hydrolysis, sonication, and oxidation. The compatibility of AZT with the excipients used is also studied in the presence and absence of moisture. The amounts of AZT and azaerythromycin A are calculated from the corresponding linear calibration curve; however, the amounts of any other generated or detected unknown impurities are calculated as if it were AZT. This method shows enough selectivity, sensitivity, accuracy, precision, linearity-range, and robustness to satisfy Federal Drug Administration/International Conference of Harmonization regulatory requirements. The method developed can also be used for the purity testing of AZT raw material and capsules, content uniformity testing, dissolution testing, and stability testing of AZT capsules. The potential impurity profiles of both active AZT material and capsule forms are found comparable. The linear range of AZT is between 5 and 30 mcg/spot with a limit of quantitation of 2 mcg/spot. The intraassay relative standard deviation percentage is not more than 0.54%, and the day-to-day variation is not more than 0.86%, calculated on the amounts of AZT RS recovered using different TLC plates.     

Anti-Inflammatory and Anti-Rheumatic Potential of Selective Plant Compounds by Targeting TLR-4/AP-1 Signaling: A Comprehensive Molecular Docking and Simulation Approaches

Plants are an important source of drug development and numerous plant derived molecules have been used in clinical practice for the ailment of various diseases. The Toll-like receptor-4 (TLR-4) signaling pathway plays a crucial role in inflammation including rheumatoid arthritis. The TLR-4 binds with pro-inflammatory ligands such as lipopolysaccharide (LPS) to induce the downstream signaling mechanism such as nuclear factor κappa B (NF-κB) and mitogen activated protein kinases (MAPKs). This signaling activation leads to the onset of various diseases including inflammation. In the present study, 22 natural compounds were studied against TLR-4/AP-1 signaling, which is implicated in the inflammatory process using a computational approach. These compounds belong to various classes such as methylxanthine, sesquiterpene lactone, alkaloid, flavone glycosides, lignan, phenolic acid, etc. The compounds exhibited different binding affinities with the TLR-4, JNK, NF-κB, and AP-1 protein due to the formation of multiple hydrophilic and hydrophobic interactions. With TLR-4, rutin had the highest binding energy (−10.4 kcal/mol), poncirin had the highest binding energy (−9.4 kcal/mol) with NF-κB and JNK (−9.5 kcal/mol), respectively, and icariin had the highest binding affinity (−9.1 kcal/mol) with the AP-1 protein. The root means square deviation (RMSD), root mean square fraction (RMSF), and radius of gyration (RoG) for 150 ns were calculated using molecular dynamic simulation (MD simulation) based on rutin’s greatest binding energy with TLR-4. The RMSD, RMSF, and RoG were all within acceptable limits in the MD simulation, and the complex remained stable for 150 ns. Furthermore, these compounds were assessed for the potential toxic effect on various organs such as the liver, heart, genotoxicity, and oral maximum toxic dose. Moreover, the blood–brain barrier permeability and intestinal absorption were also predicted using SwissADME software (Lausanne, Switzerland). These compounds exhibited promising physico-chemical as well as drug-likeness properties. Consequently, these selected compounds portray promising anti-inflammatory and drug-likeness properties.     

Synthesis and Sorption Performance of Novel Sorbents for Selective Solid-Phase Extraction of Eu(III) Ions from Aqueous Solutions

Russian Journal of Applied Chemistry - Magnesium-cadmium hydroxyapatite [(Mg-Cd)HAP] and novel multi-wall carbon nanotubes Mg-Cd hydroxyapatite (CNTs/(Mg-Cd)HAP) composites were synthesized by a...     

Application of a carbonized apricot stone for the treatment of some radioactive nuclei

Apricot stone shells were carbonized under certain chemical and thermal conditions to produce sorbents having a quantitative affinity to retain some radioactive nuclei. The sorbent shows a thermal stability upto 500 °C. The diffraction patterns clarify that the sorbent is mainly amorphous in structure. Carbon in these shells was elementally analyzed and the data reveal a predominant content of acidic surface centers with hydrophilic properties. The isoelectric point (pH_PZC) was determined and found to be 4.2 implying the acidic nature of the sorbent surface. The sorption of Cs⁺, Co²⁺ and Eu³⁺ on the prepared sorbent was studied from aqueous solution under different variables and the sorption capacity had values from 0.23-1.15 meq/g.