Functional Dysregulations in CA1 Hippocampal Networks of a 3-Hit Mouse Model of Schizophrenia

For a better translation from treatment designs of schizophrenia to clinical efficiency, there is a crucial need to refine preclinical animal models. In order to consider the multifactorial nature of the disorder, a new mouse model associating three factors (genetic susceptibility—partial deletion of the MAP6 gene, early-life stress—maternal separation, and pharmacological treatment—chronic Δ-9-tetrahydrocannabinol during adolescence) has recently been described. While this model depicts a schizophrenia-like phenotype, the neurobiological correlates remain unknown. Synaptic transmission and functional plasticity of the CA1 hippocampal region of male and female 3-hit mice were therefore investigated using electrophysiological recordings on the hippocampus slice. While basal excitatory transmission remained unaffected, NMDA receptor (NMDAr)-mediated long-term potentiation (LTP) triggered by theta-burst (TBS) but not by high-frequency (HFS) stimulation was impaired in 3-hit mice. Isolated NMDAr activation was not affected or even increased in female 3-hit mice, revealing a sexual dimorphism. Considering that the regulation of LTP is more prone to inhibitory tone if triggered by TBS than by HFS, the weaker potentiation in 3-hit mice suggests a deficiency of intrinsic GABA regulatory mechanisms. Indeed, NMDAr activation was increased by GABA_A receptor blockade in wild-type but not in 3-hit mice. This electrophysiological study highlights dysregulations of functional properties and plasticity in hippocampal networks of 3-hit mice, one of the mechanisms suspected to contribute to the pathophysiology of schizophrenia. It also shows differences between males and females, supporting the sexual dimorphism observed in the disorder. Combined with the previously reported study, the present data reinforce the face validity of the 3-hit model that will help to consider new therapeutic strategies for psychosis.     

Modified Galacto- or Fuco-Clusters Exploiting the Siderophore Pathway to Inhibit the LecA- or LecB-Associated Virulence of Pseudomonas aeruginosa

Galacto- and fuco-clusters conjugated with one to three catechol or hydroxamate motifs were synthesised to target LecA and LecB lectins of Pseudomonas aeruginosa (PA) localised in the outer membrane and inside the bacterium. The resulting glycocluster–pseudosiderophore conjugates were evaluated as Trojan horses to cross the outer membrane of PA by iron transport. The data suggest that glycoclusters with catechol moieties are able to hijack the iron transport, whereas those with hydroxamates showed strong nonspecific interactions. Mono- and tricatechol galactoclusters ( G1C and G3C ) were evaluated as inhibitors of infection by PA in comparison with the free galactocluster ( G0 ). All of them exhibited an inhibitory effect between 46 to 75 % at 100 μM, with a higher potency than G0 . This result shows that LecA localised in the outer membrane of PA is involved in the infection mechanism.     

Cover Feature: A Comparative Study of in vitro Assays for Predicting the Nonspecific Binding of PET Imaging Agents in vivo (ChemMedChem 7/2020)

Nonspecific binding (NSB) is a key parameter in optimizing PET imaging tracers. We compared the ability to predict NSB of three available methods: LIMBA, rat f_u,brain, and CHI(IAM). Even though NSB is often associated with lipophilicity, we observed that logD does not correlate with any of these assays, clearly indicating that lipophilicity, while influencing NSB, is insufficient to predict it. A cross-comparison of the methods showed that all three correlate and are useful predictors of NSB. The three assays, however, rank the molecules slightly differently, illustrating the challenge of comparing molecules within a narrow chemical space. We also noted that CHI(IAM) values more effectively predict V_NS, a measure of in vivo NSB in the human brain. CHI(IAM) measurements might be a closer model of the actual physicochemical interaction between PET tracer candidates and cell membranes, and seems to be the method of choice for the optimization of in vivo NSB.     

Hydrolytic degradation of poly(l‐lactic acid)/poly(methyl methacrylate) blends

The hydrolytic degradation of poly(l ‐lactic acid)/poly(methyl methacrylate) (PLLA/PMMA) blends was carried out by the immersion of thin films in buffer solutions (pH = 7.24) in a shaking water bath at 60 °C for 38 days. The PLA/PMMA blends (0/100; 30/70; 50/50; 70/30; 100/0) were obtained by melt blending using a Brabender internal mixer and shaped into thin films of about 150 µm in thickness. Considering that PMMA does not undergo hydrolytic degradation, that of PLLA was followed via evolution of PLA molecular weight (recorded by size exclusion chromatography), thermal parameters (differential scanning calorimetry (DSC)) and morphology of the films (scanning transmission electron microscopy). The results reveal a completely different degradation pathway of the blends depending on the polymethacrylate/polyester weight ratio. DSC data suggest that, during hydrolysis at higher PMMA content, the polyester amorphous chains, more sensitive to water, are degraded before being able to crystallize, while at higher PLLA content, the crystallization is favoured leading to a sample more resistant to hydrolysis. In other words, and quite unexpectedly, increasing the content of water‐sensitive PLLA in the PLLA/PMMA blends does not mean de facto faster hydrolytic degradation of the resulting materials. © 2018 Society of Chemical Industry     

Synthesis and Anticancer Properties of Oxazepines Related to Azaisoerianin and IsoCoQuines

In this article, we report the synthesis and biological properties of a series of novel oxazepines related to isoCA-4 having significant antitumor properties. Among them, three oxazepin-9-ol derivatives display a nanomolar or a sub-nanomolar cytotoxicity level against five human cancer cell lines (HCT116, U87, A549, MCF7, and K562). It was demonstrated that the lead compound in this series inhibits tubulin assembly with an IC₅₀ value of 1 μM and totally arrests the cellular cycle in the G2/M phase at the low concentration of 5 nM in HCT116 and K562 cells. Molecular modeling studies perfectly corroborates these promising results.     

Temperature stability of a pure metakaolin based K-geopolymer: Part 2. Variations in the mesoporous network and its rehydration stability

The thermal behavior of a model MK-based K-geopolymer was investigated between room temperature and 1400°C in order to evaluate its potentiality for high-temperature applications. The purpose of our study was to monitor the behavior of a geopolymer during a temperature rise in order to better understand its variations with respect to temperature. The works from the present paper focus only changes in the porous network; it follows a first part devoted to variations in the mineral matrix. The results obtained here show that the geopolymer material preserves its porous integrity up to 800°C, while maintaining the reversibility of water exchanges corresponding to about 25 weight percent. Together with the results of part 1, the findings of this study allow us to affirm that geopolymer materials are only very little affected by temperatures up to 800°C, or even 900°C (keeping its mesoporous amorphous structure).     

Synthesis and Microstructural Characterization of Substoichiometric Ti2Al(CxNy) Solid Solutions and Related Ti2AlCx and Ti2AlN End‐Members

Ti, TiC, Al and AlN powders were mixed to synthesize Ti₂Al(C_xN_y) (x + y < 1) solid solutions, Ti₂AlC_x (x < 1) and Ti₂AlN‐related end‐members by hot isostatic pressing at 1400°C/80 MPa for 4 h. For the pure carbides, it is demonstrated that single‐phased samples can only be obtained when about 15% of substoichiometry on the carbon site is applied. Such a result likely implies that Ti₂AlC_x can only exist in a narrow range of carbon composition. Ti₂AlN nitride can be synthesized with y = 1. Assuming that vacancy content varies linearly from 0 to 0.15 going from Ti₂AlN to Ti₂AlC_0.85 in the solid solutions, element concentrations have been calculated to synthesize different solid solutions. Thus, it is demonstrated that single‐phased and fully dense Ti₂Al(C_0.23N_0.71), Ti₂Al(C_0.45N_0.45), and Ti₂Al(C_0.66N_0.22) carbonitrides can be synthesized.     

Biomonitoring of the adverse effects induced by the chronic exposure to lead and cadmium on kidney function: usefulness of alpha-glutathione S-transferase

A successful prevention of renal diseases induced by occupational exposure to lead (Pb) and/or cadmium (Cd) largely relies on the capability to detect nephrotoxic effects at a stage when they are still reversible or at least not yet compromising renal function. Hence, the aim of this cross-sectional study was to evaluate the usefulness of a set of early biological markers of oxidative stress or nephrotoxicity for the biomonitoring of workers occupationally exposed to Pb and/or Cd in a non-ferrous metal smelter, and gender, age, socioeconomic status, smoking habits, and drug use-matched control individuals. In exposed subjects, mean levels of Pb in blood and urine were also 387.1+/-99.1 microg Pb/L (1.868+/-0.478 micromol Pb/L) and 217.7+/-117.7 microg Pb/g creatinine (1.051+/-0.568 micromol Pb/g creatinine), and mean levels of Cd in blood and urine were 3.26+/-2.11 microg Cd/L (0.029+/-0.019 micromol Cd/L) and 2.51+/-1.89 microg Cd/g creatinine (0.022+/-0.017 micromol Cd/g creatinine), suggesting thereby relatively low occupational exposure levels. Statistically significant variations in zinc protoporphyrin, malondialdehyde, retinol binding protein, alpha-glutathione S-transferase, and urinary protein levels were reported between the two groups, and were closely correlated with Pb and/or Cd exposure levels. Variations in alphaGST levels were closely associated with Pb exposure. Taken together, these results suggest the use of alpha-glutathione S-transferase excretion in urine as a hallmark of early changes in the proximal tubular integrity.     

Contaminant levels in sediments and asteroids (Asterias rubens L., Echinodermata) from the Belgian coast and Scheldt estuary: polychlorinated biphenyls and heavy metals

The Southern Bight of the North Sea is particularly exposed to anthropogenic contamination, due to heavy urbanisation and industrialisation of its catchment area. The present work focuses on polychlorinated biphenyl (PCB) and metal contamination of the marine environment along and off the Belgian coast. Its objectives were to compare the concentrations of seven PCB congeners and four heavy metals in the sediments (a repository for anthropogenic contaminants) and in the asteroid Asterias rubens (a recognized bioindicator species). Nineteen sampling stations were considered between the mouth of the Scheldt Estuary and the southern limit of the Belgian coast (asteroids were found in 10 out of the 19 stations). PCB and metal concentrations measured in sediments and asteroids were in the range of values reported in previous studies. Stations under direct influence of the Scheldt were the most impacted by the considered contaminants. Metal concentrations varied according to the grain-size fraction considered. In asteroids, PCBs and metals were found to be selectively distributed among body compartments, and pyloric caeca were found to most efficiently discriminate between sampling stations contamination levels. PCB and metal analysis of sediments provided a physicochemical evaluation of the contamination, whereas analysis of asteroids introduced a biological dimension to the approach by taking into account bioavailability of the contaminants.