Bioavailability Studies and in vitro Profiling of the Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor UCPH‐102

Although the selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor UCPH‐101 has become a standard pharmacological tool compound for in vitro and ex vivo studies in the EAAT research field, its inability to penetrate the blood–brain barrier makes it unsuitable for in vivo studies. In the present study, per os (p.o.) administration (40 mg kg^?1) of the closely related analogue UCPH‐102 in rats yielded respective plasma and brain concentrations of 10.5 and 6.67 μm after 1 h. Three analogue series were designed and synthesized to improve the bioavailability profile of UCPH‐102, but none displayed substantially improved properties in this respect. In vitro profiling of UCPH‐102 (10 μm ) at 51 central nervous system targets in radioligand binding assays strongly suggests that the compound is completely selective for EAAT1. Finally, in a rodent locomotor model, p.o. administration of UCPH‐102 (20 mg kg^?1) did not induce acute effects or any visible changes in behavior.     

The production of a lead glaze with galena: Thermal transformations in the PbS–SiO2 system

Galena, also known as PbS, was widely used in the production of lead glazes from the beginning of the 18th century to the second half of the 20th century. Although the PbO‐SiO₂ system has been studied for years, the PbS–SiO₂ phase diagram, involved in the formation of a glaze with galena, has not yet been investigated. Temperature transformations for the system 75 wt% PbS‐25 wt% SiO₂ are investigated in a high‐temperature resolved X‐ray diffraction experiment with synchrotron radiation and compared to those of the equivalent system 70 wt% PbO‐30 wt% SiO₂. Lanarkite, PbO·PbSO₄, is the phase predominantly formed as soon as galena decomposes during the heating. The results show that the system melts at a temperature higher than the PbO–SiO₂ system, but far lower than those expected for the PbO–PbSO₄–PbS system. A historical misfired lead glaze produced with galena is also studied. The presence of galena, lanarkite, and mattheddleite, Pb₁₀(SiO₄)_3.5(SO₄)₂Cl_2, is determined and discussed in terms of the composition of the galena mineral used and the firing conditions in light of the high‐temperature transformations previously obtained.     

Effect of pre‐treatments based on UV photocatalysis and photo‐oxidation on toluene biofiltration performance

BACKGROUND: The integration of UV photocatalysis and biofiltration seems to be a promising combination of technologies for the removal of hydrophobic and poorly biodegradable air pollutants. The influence of pre‐treatments based on UV_{254 nm} photocatalysis and photo‐oxidation on the biofiltration of toluene as a target compound was evaluated in a controlled long‐term experimental study using different system configurations: a standalone biofilter, a combined UV photocatalytic reactor‐biofilter, and a combined UV photo‐oxidation reactor (without catalyst)‐biofilter. RESULTS: Under the operational conditions used (residence time of 2.7 s and toluene concentrations 600–1200 mg C m^?3), relatively low removal efficiencies (6–3%) were reached in the photocatalytic reactor and no degradation of toluene was found when the photo‐oxidation reactor was operated without catalyst. A noticeable improvement in the performance of the biofilter combined with a photocatalytic reactor was observed, and the elimination capacity of the biological process increased by more than 12 g C h^?1 m^?3 at the inlet loads studied of 50–100 g C h^?1 m^?3. No positive effect on toluene removal was observed for the combination of UV photoreactor and biofilter. CONCLUSIONS: Biofilter pre‐treatment based on UV_{254 nm} photocatalysis showed promising results for the removal of hydrophobic and recalcitrant air pollutants, providing synergistic improvement in the removal of toluene. Copyright © 2011 Society of Chemical Industry     

冷喷涂单颗粒铜在铝基体上的显微结构研究

采用冷喷涂法在铝(Al)基体上沉积单颗粒铜(Cu),利用聚焦离子束/电子束(FIB/SEM)系统精确定位并原位制备了完整单个颗粒Cu沉积在Al基体上的透射样品,分析其显微结构及形成原因。实验结果表明,撞击过程中温度与应力分布不均匀,导致沉积Cu颗粒不均匀形变。Cu/Al界面受影响较大:颗粒动能转化为形变能和热能,打破了界面处氧化膜,使界面附近温度迅速升高,发生动态再结晶,生成金属间化合物Cu_9Al_4;Cu颗粒内距界面越远的区域,受温度和应力的影响越小,其变形主要是通过晶体内位错增殖和移动;沉积颗粒顶部,远离Cu/Al界面,几乎不受应力和温度影响,保持原始显微结构。     

Effluent content from albedo degradation and kinetics at different temperatures in the enzymatic peeling of grapefruits

This work studies the variation in the effluent content from the reactor in enzymatic peeling of grapefruits, to determine the loss of soluble solids, reducing sugars and galacturonic acid, the main component from the albedo of the skin to model the solid–liquid transfer in this process. Experiments to study the efficiency of the enzymatic reaction include the effect of the temperature on the kinetics of albedo degradation to find an equation relating both variables and also the activation energy of this process, its value being 36.9 kJ/mol.     

Quantitative Proteomic Approach Reveals Altered Metabolic Pathways in Response to the Inhibition of Lysine Deacetylases in A549 Cells under Normoxia and Hypoxia

Growing evidence is showing that acetylation plays an essential role in cancer, but studies on the impact of KDAC inhibition (KDACi) on the metabolic profile are still in their infancy. Here, we analyzed, by using an iTRAQ-based quantitative proteomics approach, the changes in the proteome of KRAS-mutated non-small cell lung cancer (NSCLC) A549 cells in response to trichostatin-A (TSA) and nicotinamide (NAM) under normoxia and hypoxia. Part of this response was further validated by molecular and biochemical analyses and correlated with the proliferation rates, apoptotic cell death, and activation of ROS scavenging mechanisms in opposition to the ROS production. Despite the differences among the KDAC inhibitors, up-regulation of glycolysis, TCA cycle, oxidative phosphorylation and fatty acid synthesis emerged as a common metabolic response underlying KDACi. We also observed that some of the KDACi effects at metabolic levels are enhanced under hypoxia. Furthermore, we used a drug repositioning machine learning approach to list candidate metabolic therapeutic agents for KRAS mutated NSCLC. Together, these results allow us to better understand the metabolic regulations underlying KDACi in NSCLC, taking into account the microenvironment of tumors related to hypoxia, and bring new insights for the future rational design of new therapies.     

Update on the Diagnostic Pitfalls of Autopsy and Post-Mortem Genetic Testing in Cardiomyopathies

Inherited cardiomyopathies are frequent causes of sudden cardiac death (SCD), especially in young patients. Despite at the autopsy they usually have distinctive microscopic and/or macroscopic diagnostic features, their phenotypes may be mild or ambiguous, possibly leading to misdiagnoses or missed diagnoses. In this review, the main differential diagnoses of hypertrophic cardiomyopathy (e.g., athlete’s heart, idiopathic left ventricular hypertrophy), arrhythmogenic cardiomyopathy (e.g., adipositas cordis, myocarditis) and dilated cardiomyopathy (e.g., acquired forms of dilated cardiomyopathy, left ventricular noncompaction) are discussed. Moreover, the diagnostic issues in SCD victims affected by phenotype-negative hypertrophic cardiomyopathy and the relationship between myocardial bridging and hypertrophic cardiomyopathy are analyzed. Finally, the applications/limits of virtopsy and post-mortem genetic testing in this field are discussed, with particular attention to the issues related to the assessment of the significance of the genetic variants.     

Dietary procyanidins lower triglyceride levels signaling through the nuclear receptor small heterodimer partner

Hypertriglyceridemia is an independent risk factor in the development of cardiovascular diseases, and we have previously reported that oral administration of a grape seed procyanidin extract (GSPE) drastically decreases plasma levels of triglycerides (TG) and apolipoprotein B (ApoB) in normolipidemic rats, with a concomitant induction in the hepatic expression of the nuclear receptor small heterodimer partner (NR0B2/SHP). Our objective in this study was to elucidate whether SHP is the mediator of the reduction of TG-rich ApoB-containing lipoproteins triggered by GSPE. We show that GSPE inhibited TG and ApoB secretion in human hepatocarcinoma HepG2 cells and had and hypotriglyceridemic effect in wild-type mouse. The TG-lowering action of GSPE was abolished in HepG2 cells transfected with a SHP-specific siRNA and in a SHP-null mouse. Moreover, in mouse liver, GSPE downregulated several lipogenic genes, including steroid response element binding protein 1c (SREBP-1c), and upregulated carnitine palmitoyltransferase-1A (CPT-1A) and apolipoprotein A5 (ApoA5), in a SHP-dependent manner. In HepG2 cells GSPE also inhibited ApoB secretion, but in a SHP-independent manner. In conclusion, SHP is a key mediator of the hypotriglyceridemic response triggered by GSPE. This novel signaling pathway of procyanidins through SHP may be relevant to explain the health effects ascribed to the regular consumption of dietary flavonoids.     

Proanthocyanidin metabolites associated with dietary fibre from in vitro colonic fermentation and proanthocyanidin metabolites in human plasma

Proanthocyanidins (PAs) or condensed tannins, a major group of dietary polyphenols, are oligomers and polymers of flavan‐3‐ol and flavan‐3, 4‐diols widely distributed in plant foods. Most literature data on PAs' metabolic fate deal with PAs that can be extracted from the food matrix by aqueous‐organic solvents ( extractable proanthocyanidins). However, there are no data on colonic fermentation of non‐extractable proanthocyanidins (NEPAs), which arrive almost intact to the colon, mostly associated to dietary fibre (DF). The aim of the present work was to examine colonic fermentation of NEPAs associated with DF, using a model of in vitro small intestine digestion and colonic fermentation. Two NEPA‐rich materials obtained from carob pod (Ceratonia siliqua L. proanthocyanidin) and red grapes (grape antioxidant dietary fibre) were used as test samples. The colonic fermentation of these two products released hydroxyphenylacetic acid, hydroxyphenylvaleric acid and two isomers of hydroxyphenylpropionic acid, detected by HPLC‐ESI‐MS/MS. Differences between the two products indicate that DF may enhance the yield of metabolites. In addition, the main NEPA metabolite in human plasma was 3,4‐dihydroxyphenyl acetic acid. The presence in human plasma of the same metabolites as were detected after in vitro colonic fermentation of NEPAs suggests that dietary NEPAs would undergo colonic fermentation releasing absorbable metabolites with potential healthy effects.     

Flavour index and aroma profiles of fresh and processed honeys

This paper discusses the importance of flavour profiling in detecting indicative parameters for quality control of fresh and heated honey. Flavour compounds of six unifloral honeys (Lavandula stoechas, Castanea sativa, Dorycnium pentaphyllum, Rosmarinus officinalis, Eucalyptus sp and Robinia pseudoacacia) were investigated. The aroma extracts were obtained by a two‐step procedure involving (i) preliminary steam distillation under reduced pressure to evaluate the methylpyrazines generated in heated honeys by spectrophotometry (flavour index) and (ii) Likens–Nickerson's simultaneous steam distillation and solvent extraction (SDE) method with added NaCl. A combined total of 64 compounds were detected by gas chromatography/mass spectrometry (GC/MS), 58 of which were identified. Some compounds appeared to be characteristic of the floral source, particularly in Spanish lavender (methylated aliphatic acids and aromatic esters), eucalyptus (2,3‐pentanedione, acetoin, 1‐hexyl alcohol, 2‐acetyl‐5‐methylfuran, furfuryl propionate, 2‐phenylacetaldehyde and nerolidol), chestnut (acetophenone and 2‐aminoacetophenone), rosemary and D pentaphyllum (aromatic acids and esters, 2‐phenylacetaldehyde, farnesol and thymol) honeys. Robinia honey samples were characterised by very low levels of aromatic compounds. Twenty‐six flavour compounds were statistically closely related to the floral origin of the honeys (P ≤ 0.05). The flavour index was evaluated progressively in heated honeys, whereas in fresh honeys it showed a minimal value. © 2003 Society of Chemical Industry