A Novel Anti-Inflammatory d-Peptide Inhibits Disease Phenotype Progression in an ALS Mouse Model

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by selective neuronal death in the brain stem and spinal cord. The cause is unknown, but an increasing amount of evidence has firmly certified that neuroinflammation plays a key role in ALS pathogenesis. Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and has been implicated as driver of disease progression. Here, we describe a treatment study demonstrating the therapeutic potential of a tandem version of the well-known all-d-peptide RD2 (RD2RD2) in a transgenic mouse model of ALS (SOD1*G93A). Mice were treated intraperitoneally for four weeks with RD2RD2 vs. placebo. SOD1*G93A mice were tested longitudinally during treatment in various behavioural and motor coordination tests. Brain and spinal cord samples were investigated immunohistochemically for gliosis and neurodegeneration. RD2RD2 treatment in SOD1*G93A mice resulted not only in a reduction of activated astrocytes and microglia in both the brain stem and lumbar spinal cord, but also in a rescue of neurons in the motor cortex. RD2RD2 treatment was able to slow progression of the disease phenotype, especially the motor deficits, to an extent that during the four weeks treatment duration, no significant progression was observed in any of the motor experiments. Based on the presented results, we conclude that RD2RD2 is a potential therapeutic candidate against ALS.     

Determination of <Superscript>241</Superscript>Am/<Superscript>243</Superscript>Am ratios

Determination of ²⁴¹Am/²⁴³Am ratios is required for vanous purposes including assay of Am by isotope dilution techniques. Alpha-spectrometry on electrodeposited sources is a preferred technique for this determination. However, there is an inherent problem of tail contribution which necessitates the use of suitable algorithms to account for the same. Recently, in the frame of a Coordinated Research Program (CRP) of the International Atomic Energy Agency (IAEA), WinALPHA software has been developed which is a combination of an asymmetrical Gaussian for the main part of the peak and a low energy function. Therefore, it was of interest to compare the use of this algorithm with the routinely used method, in our laboratory, based on geometric progression (G. P.) decrease. Since, there are no reference materials available commercially for ²⁴¹Am/²⁴³Am ratios, synthetic mixtures covening a wide range (0.3 to 2.0) of ²⁴¹Am/²⁴³Am α-activity ratios were used and un-ignited electrodeposited sources were prepared for α-spectrometry. The α-spectra obtained using PIPS detector, were evaluated using the two algonthms The ²⁴¹Am/²⁴³Am α-activity ratios obtained were also compared with those determined by thermal ionization mass spectrometry (TIMS). An agreement of about 1% was obtained in the ²⁴¹Am/²⁴³Am ratios determined by the two methods and also by using the two algorithms for α-spectrum evaluation.     

C—H⋯N and C—H⋯π interactions in 2‐ethoxy‐4,6‐diphenylpyridine‐3‐carbonitrile

The title compound, C₂₀H₁₆N₂O, has two mol­ecules in the asymmetric unit and the crystal structure shows that the central pyridine ring of each mol­ecule has a flat boat conformation. The terminal C atom in one of the mol­ecules is disordered over two positions, with relative occupancies of 0.594 (14) and 0.398 (14). Intermolecular C—H?N and C—H?π interactions and π–π stacking, along with intramolecular C—H?N and C—H?π interactions, help to stabilize the structure.     

Mixed-ligand complexes of copper with some amino-acids and malonate

The mixed-ligand complexes formed by copper(II) with an amino-acid (valine, threonine, isoleucine, aspartic acid, glutamic acid, lysine) and malonic acid have been investigated polarographically and their stability constants determined. The complexes are less stable than the corresponding complexes with oxalic acid instead of malonic, but also exhibit less disproportionation into the simple complexes, because the simple oxalate complexes are more stable than the malonate complexes.     

Speciation of cationic selenium compounds in Brassica juncea leaves by strong cation-exchange chromatography with inductively coupled plasma mass spectrometry

Strong cation-exchange chromatography (SCX-HPLC) was used in conjunction with inductively coupled plasma mass spectrometry (ICP-MS) to investigate cationic selenium species present in leaf extract of wild-type Brassica juncea supplemented with selenite. Total amount of Se accumulated by the leaves was found to be 352 microg g(-1). Cation-exchange solid-phase extraction (SCX-SPE) was used to pre-concentrate the cationic species present in the leaf extract. Methylselenomethionine (MeSeMet) and dimethylselenoniumproprionate (DMSeP) were synthesized and characterized by electrospray quadrupole time-of-flight MS (ESI-QTOF-MS). Laboratory synthesized and commercially available standards were used in chromatographic studies to identify the Se species in the leaf extract through retention time comparisons and standard addition method. Major cationic selenium species identified in the present study were MeSeMet and methylselenocysteine (MeSeCys) while selenomethionine (SeMet) was found in minor quantities.     

Synthesis and S-methylation of 2-thioxopyrido[3′,2′:4,5]thieno[3,2-d]-pyrimidin-4(3H)-ones with and without a phase transfer catalyst

A number of 2-thioxopyrido[3′,2′:4,5]thieno[3,2-H]pyrimdin-4(3H-ones (5) have been synthesized by cyclocondensation of 2-carbethoxy-3-amino-4-phenyl-6-substituted-thieno[2,3-b]pyridines (3) with various isothiocyanates. Compounds 5 were S-methylated routinely and the reactions compared under solid-liquid phase transfer conditions to obtain 2-methylthiopyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-^ones (6). The new triheterocyclic pyridothienopyrimidines were prepared with the objective to study their pharmacological properties.     

High performance liquid chromatographic-mass spectrometric assay for the quantitation of BMS-204352 in dog K(3)EDTA plasma

A high performance liquid chromatographic-mass spectrometric (LC/MS) assay was developed and validated for the determination of BMS-204352 in dog K(3)EDTA plasma. A 0.5 mL aliquot of control plasma was spiked with BMS-204352 and internal standard (IS) and buffered with 1 mL of 5 mM ammonium acetate. The mixture was then extracted with 3 mL of toluene. After separation and evaporation of the organic phase to dryness using nitrogen at 40 degrees C, the residue was reconstituted in the mobile phase and 25 microL of the sample were injected onto a Hypersil C(18) column (2 x 50 mm; 3 microm) at a flow rate of 0.5 mL/min. The mobile phase was consisted of two solvent mixtures (A and B). Solvent A was composed of 5 mM ammonium acetate and 0.1% triethylamine in 75:25 v/v water:methanol, pH adjusted to 5.5 with glacial acetic acid, and solvent B was 5 mM ammonium acetate in methanol. A linear gradient system was used to elute the analytes. The mass spectrometer was programmed to admit the de-protonated molecules at m/z 352.7 (IS) and m/z 357.9 (BMS-204352). Standard curves of BMS-204352 were linear (r(2) > or = 0.998) over the concentration range of 0.5-1000 ng/mL. The mean predicted quality control (QC) concentrations deviated less than 5.1% from the corresponding nominal values (ie 4, 80, 400 and 2000 ng/mL); the within- and between-assay precision of the assay were within 5.5% relative standard deviation. Stability of BMS-204352 was confirmed after at least three freeze/thaw cycles and BMS-204532 was stable in dog plasma when stored frozen at or below -20 degrees C for at least 16 weeks in spiked QC samples and for at least 4 1/2 weeks for in vivo study samples. BMS-204352 and IS were stable in the injection solvent at room temperature for at least 24 h. The assay was applied to delineate the pharmacokinetic disposition of BMS-204352 in dogs following a single intravenous dose administration. In conclusion, the assay is accurate, precise, specific, sensitive and reproducible for the pharmacokinetic analysis of BMS-204532 in dog plasma.     

Flow-injection spectrophotometric determination of chloramben

Abstract

A method for the dechlorination of PCB mixtures (Aroclor formulations) to biphenyl was extended to soils. The contaminated sample was mixed with magnesium flakes, potassium hexachloropalladiate (K₂PdCl₆), propan-2-ol and water then permitted to react for up to six hours. Biphenyl, recovered by extraction into hexane, was quantified by gas chromatography with flame ionization detection. The reaction was very efficient in propan-2-ol / water (～95%), surfactant emulsion or sand mixture and virtually complete in soil provided that excess magnesium (2 g) and the K₂PdCl₆ were added to the sample prior to the addition of water. Higher PCB loadings were readily determined in field contaminated soils either by direct determination within the matrix or by standard additions. However, analyte concentrations were appreciably over-estimated in Soxhlet or sonication extracts of a certified reference material that contained sub-ppm levels of analyte. The over-estimation is considered to result from the conversion in part of natural organic matter to biphenyl.     

Synthesis and Characterization of New Polyetheramides

Polyetheramides (PEAs) are prepared by polycondensation of N,N′-diacetyl-o-tolidide with Bisphenol A, C, or F, phenolphthalein, resorcinol, catechol, hydroquinone, or 1,5- or 2,7-dihydroxynaphthalene or ethylene, butylene, propylene, diethylene, or triethylene glycol. The fusible and soluble oligomers are characterized. An attempt is made to bring out the relationship between various properties of PEAs and their structures.