Effects of MgSO4 Alone or Associated with 4-PBA on Behavior and White Matter Integrity in a Mouse Model of Cerebral Palsy: A Sex- and Time-Dependent Study

Cerebral palsy (CP) is defined as permanent disorders of movement and posture. Prematurity and hypoxia–ischemia (HI) are risk factors of CP, and boys display a greater vulnerability to develop CP. Magnesium sulfate (MgSO₄) is administered to mothers at risk of preterm delivery as a neuroprotective agent. However, its effectiveness is only partial at long term. To prolong MgSO₄ effects, it was combined with 4-phenylbutyrate (4-PBA). A mouse model of neonatal HI, generating lesions similar to those reported in preterms, was realized. At short term, at the behavioral and cellular levels, and in both sexes, the MgSO₄/4-PBA association did not alter the total prevention induced by MgSO₄ alone. At long term, the association extended the MgSO₄ preventive effects on HI-induced motor and cognitive deficits. This might be sustained by the promotion of oligodendrocyte precursor differentiation after HI at short term, which led to improvement of white matter integrity at long term. Interestingly, at long term, at a behavioral level, sex-dependent responses to HI were observed. This might partly be explained by early sex-dependent pathological processes that occur after HI. Indeed, at short term, apoptosis through mitochondrial pathways seemed to be activated in females but not in males, and only the MgSO₄/4-PBA association seemed to counter this apoptotic process.     

Biomaterial surface properties modulate in vitro rat calvaria osteoblasts response: Roughness and or chemistry?

The aim of this study was a better understanding of the regulation mechanisms of in vitro osteoblast activity on biomaterials. Rat osteoblast behaviour on different surfaces was studied. Surfaces with different roughness (and a similar surface chemistry) or with different surface chemistry (and a similar roughness) were compared. Cellular morphology was observed by scanning electron microscopy and cell adhesion was quantified using an image analysis system. Osteoblast proliferation was quantified by a MTT test and total protein content and alkaline phosphatase (ALP) activity were evaluated by spectrophotometry. Data were compared by statistical analysis.

Results showed that NiTi surface roughness did not influence osteoblasts morphology, adhesion, total protein content and ALP activity whereas it modulated cell proliferation. Roughness was shown to stimulate cell proliferation. For smooth surfaces exhibiting two different chemical compositions, adhesion rate was found to be higher on Thermanox® than on NiTi whereas proliferation was shown to be smaller. ALP activity was also modulated by surface chemistry. Thus, cell adhesion and ALP activity were found to be more governed by surface chemistry than by roughness whereas cell proliferation was shown to be modulated by roughness (this effect increasing during cell culture) and by chemistry (this effect remaining stable in time) together. Total protein content and cell morphology were found to be independent of both parameters (roughness and chemistry). Effects of surface chemistry were discussed in terms of wettability and electron acceptor/donor properties of the surfaces of interest. Immunofluorescence images of adhesion proteins could not demonstrate differences between the three surfaces.     

Methinylogation Approach in Chiral Pharmacophore Design: from Alkynyl‐ to Allenyl‐carbinol Warheads against Tumor Cells

Extension of a structure–activity relationship study of the antitumor cytotoxicity of lipidic dialkynylcarbinols (DACs) is envisaged by formal methinylogation of one of the ethyndiyl moieties of the DAC warhead into the corresponding allenylalkynylcarbinol (AllAC) counterpart. External AllACs were directly obtained by methinylation of the parent DACs with formaldehyde in either the racemic or scalemic series. Isomers containing external progargyl and propynyl motifs were also prepared. Internal AllACs were obtained as racemic statistical mixtures of stereoisomers in two steps from the key C₅‐DAC rac‐TIPS‐C≡C‐CH(OH)‐C≡CH and aldehydes. Kinetic resolution of the (S)‐C₅‐DAC in 97 % ee and (R)‐C₅‐DAC in 99 % ee was achieved by sequential lipase‐mediated acetylation/hydrolysis using the Candida antartica lipase (Novozyme 435). The four internal AllAC stereoisomers were prepared by asymmetric methinylation with (R)‐ or (S)‐diphenylprolinol as chiral auxiliary. Cytotoxicity assays on HCT116 cancer cells showed that the most active (eutomeric) external or internal AllAC exhibits an S configuration, a fatty chain length of n=12, and a 50 % inhibitory concentration IC₅₀≈1.0 μm .     

Effects of the Methanol Extract of Basella alba L (Basellaceae) on Steroid Production in Leydig Cells

In this study, Leydig cells were purified from 70 day-old Sprague Dawley male rats and incubated with 10 and 100 μg/mL of methanol extract of Basella alba (MEBa) for 4 hours followed by the evaluation of cell viability, steroid (testosterone and estradiol) production, and the level of aromatase mRNA. Results showed that MEBa did not affect Leydig cell viability. At the concentration of 10 μg/mL, MEBa significantly stimulated testosterone and estradiol production (p < 0.01 and p < 0.03, respectively), and enhanced aromatase mRNA level (p < 0.04). These observations suggest that MEBa directly stimulated testosterone, estradiol and aromatase mRNA levels in isolated Leydig cells.     

Targeting G Protein-Coupled Receptors with Magnetic Carbon Nanotubes: The Case of the A3 Adenosine Receptor

The A₃ adenosine receptor (AR) is a G protein-coupled receptor (GPCR) overexpressed in the membrane of specific cancer cells. Thus, the development of nanosystems targeting this receptor could be a strategy to both treat and diagnose cancer. Iron-filled carbon nanotubes (CNTs) are an optimal platform for theranostic purposes, and the use of a magnetic field can be exploited for cancer magnetic cell sorting and thermal therapy. In this work, we have conjugated an A₃AR ligand on the surface of iron-filled CNTs with the aim of targeting cells overexpressing A₃ARs. In particular, two conjugates bearing PEG linkers of different length were designed. A docking analysis of A₃AR showed that neither CNT nor linker interferes with ligand binding to the receptor; this was confirmed by in vitro preliminary radioligand competition assays on A₃AR. Encouraged by this result, magnetic cell sorting was applied to a mixture of cells overexpressing or not the A₃AR in which our compound displayed indiscriminate binding to all cells. Despite this, it is the first time that a GPCR ligand has been anchored to a magnetic nanosystem, thus it opens the door to new applications for cancer treatment.     

Flavin Conjugates for Delivery of Peptide Nucleic Acids

Oligonucleotides and their analogues, such as peptide nucleic acids (PNAs), can be used in chemical strategies to artificially control gene expression. Inefficient cellular uptake and inappropriate cellular localization still remain obstacles in biological applications, however, especially for PNAs. Here we demonstrate that conjugation of PNAs to flavin resulted in efficient internalization into cells through an endocytic pathway. The flavin–PNAs exhibited antisense activity in the sub‐micromolar range, in the context of a treatment facilitating endosomal escape. Increased endosomal release of flavin conjugates into the cytoplasm and/or nucleus was shown by chloroquine treatment and also—when the flavin–PNA was conjugated to rhodamine, a mild photosensitizer—upon light irradiation. In conclusion, an isoalloxazine moiety can be used as a carrier and attached to a cargo biomolecule, here a PNA, for internalization and functional cytoplasmic/nuclear delivery. Our findings could be useful for further design of PNAs and other oligonucleotide analogues as potent antisense agents.     

C2 Arylated Benzo[b]thiophene Derivatives as Staphylococcus aureus NorA Efflux Pump Inhibitors

An innovative and straightforward synthesis of second‐generation 2‐arylbenzo[b]thiophenes as structural analogues of INF55 and the first generation of our laboratory‐made molecules was developed. The synthesis of C2‐arylated benzo[b]thiophene derivatives was achieved through a method involving direct arylation, followed by simple structural modifications. Among the 34 compounds tested, two of them were potent NorA pump inhibitors, which led to a 16‐fold decrease in the ciprofloxacin minimum inhibitory concentration (MIC) against the SA‐1199B strain at concentrations of 0.25 and 0.5 μg mL^?1 (1 and 1.5 μm , respectively). This is a promising result relative to that obtained for reserpine (MIC=20 μg mL^?1), a reference compound amongst NorA pump inhibitors. These molecules thus represent promising candidates to be used in combination with ciprofloxacin against fluoroquinolone‐resistant strains.     

Influence of an Alkoxy Group on Bis-Triazinyl-Pyridines for Selective Extraction of Americium(III)

The extraction of americium(III), curium(III), and lanthanides(III) from nitric acid by 2,6-bis-(5,6-dimethyl-[1,2,4]-triazin-3-yl)-pyridine and 2,6-bis-(5,6-dimethyl-[1,2,4]-triazin-3-yl)-4-methoxypyridine was studied. The physico-chemical properties of these ligands, such as the protonation and complexation constants, were also determined to describe the influence of different substituent groups. The selectivity of substituted-BTP was confirmed both in complexation and in solvent extraction experiments. The presence of an alkoxy-group in position 4 of the pyridine decreases the BTP selectivity. Influence of a long alkyl chain on protonation and complexation constants was also studied with 2,6-bis-(5,6-dimethyl-[1,2,4]-triazin-3-yl)-4-dodecyloxypyridine.     

Influence of the spinning conditions on the structure and properties of polyamide 12/carbon nanotube composite fibers

The inclusion of nanoparticles in polymer fibers is potentially useful for improving or bringing new properties such as mechanical strength, electrical conductivity, piezoresistivity, and flame retardancy. In this study, composite fibers made of polyamide 12 and multiwall carbon nanotubes were investigated. The fibers were spun via a melt‐spinning process and stretched at different draw ratios. The influence of several spinning factors, including spinning speed, extrusion rate, and draw ratio were investigated and correlated to the structure and properties of the fibers. X‐ray diffraction analyses and mechanical tests indicated that the spinning speed barely affected the structure and mechanical properties of the fibers under tension. The spinning speed, however, is critical for future industrial applications because it determines the possible production rates. By contrast, drawing during spinning or after spinning strongly affected the polymer chain alignment and fiber mechanical properties. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009