Assessment of Squalene-Adenosine Nanoparticles in Two Rodent Models of Cardiac Ischemia-Reperfusion

Reperfusion injuries after a period of cardiac ischemia are known to lead to pathological modifications or even death. Among the different therapeutic options proposed, adenosine, a small molecule with platelet anti-aggregate and anti-inflammatory properties, has shown encouraging results in clinical trials. However, its clinical use is severely limited because of its very short half-life in the bloodstream. To overcome this limitation, we have proposed a strategy to encapsulate adenosine in squalene-based nanoparticles (NPs), a biocompatible and biodegradable lipid. Thus, the aim of this study was to assess, whether squalene-based nanoparticles loaded with adenosine (SQAd NPs) were cardioprotective in a preclinical cardiac ischemia/reperfusion model. Obtained SQAd NPs were characterized in depth and further evaluated in vitro. The NPs were formulated with a size of about 90 nm and remained stable up to 14 days at both 4 °C and room temperature. Moreover, these NPs did not show any signs of toxicity, neither on HL-1, H9c2 cardiac cell lines, nor on human PBMC and, further retained their inhibitory platelet aggregation properties. In a mouse model with experimental cardiac ischemia-reperfusion, treatment with SQAd NPs showed a reduction of the area at risk, as well as of the infarct area, although not statistically significant. However, we noted a significant reduction of apoptotic cells on cardiac tissue from animals treated with the NPs. Further studies would be interesting to understand how and through which mechanisms these nanoparticles act on cardiac cells.</p

Can one measure C-odd asymmetry in e+e- --> pi+pi-

C-odd asymmetry can be studied from an accurate measurement of the angular distribution due to the interference between the S- and P-waves in e+e- --> pi+ pi- at order alpha^3. The asymmetry is dominated by the pion rescattering diagram which is enhanced by the presence of the ln(s/m^2_e), and is quite large (10% at theta=30^0 and sqrt{s} < M_{f_2}) compared to alpha/pi=0.3%. This process can also be used for alternatively measuring the size of the rescattering term and the phase of the S-wave amplitude, but does not help to solve the present discrepancy between the hadronic spectral functions from e+e- and tau-decay data.Comment: 4 pages, 2 figures, 1 Table (revised version

Squalene-Adenosine Nanoparticles: Ligands of Adenosine Receptors or Adenosine Prodrug?

Adenosine receptors (ARs) represent key drug targets in many human pathologies, including cardiovascular, neurologic, and inflammatory diseases. To overcome the very rapid metabolization of adenosine, metabolically stable AR agonists and antagonists were developed. However, few of these molecules have reached the market due to efficacy and safety issues. Conjugation of adenosine to squalene to form squalene-adenosine (SQAd) nanoparticles (NPs) dramatically improved the pharmacological efficacy of adenosine, especially for neuroprotection in stroke and spinal cord injury. However, the mechanism by which SQAd NPs displayed therapeutic activity remained totally unknown. In the present study, two hypotheses were discussed: 1) SQAd bioconjugates, which constitute the NP building blocks, act directly as AR ligands; or 2) adenosine, once released from intracellularly processed SQAd NPs, interacts with these receptors. The first hypothesis was rejected, using radioligand displacement assays, as no binding to human ARs was detected, up to 100 µM SQAd, in the presence of plasma. Hence, the second hypothesis was examined. SQAd NPs uptake by HepG2 cells, which was followed using radioactive and fluorescence tagging, was found to be independent of equilibrative nucleoside transporters but rather mediated by low-density lipoprotein receptors. Interestingly, it was observed that after cell internalization, SQAd NPs operated as an intracellular reservoir of adenosine, followed by a sustained release of the nucleoside in the extracellular medium. This resulted in a final paracrine-like activation of the AR pathway, evidenced by fluctuations of the second messenger cAMP. This deeper understanding of the SQAd NPs mechanism of action provides a strong rational for extending the pharmaceutical use of this nanoformulation.Medicinal Chemistr

Brumes et brouillards de Bleak House à Heart of Darkness

This article analyses the ways in which air is combined to water to generate mist or fog in three novels of the Victorian period (Bleak House, Tess of the d’Urbervilles and Heart of Darkness). In these novels, mist and fog are recurrent and deeply ambivalent tropes. The article will first raise the following question : to what extent does the representation of fog and mist take part in the representation of the « Britishness » of the place described ? It will focus on the different interpretations of these tropes by drawing comparisons between short excerpts of the novels. It will notably draw a link between mist or fog and a double process of mythification and mystification. It concludes by suggesting that, being signifiers of blurriness, the mists and fogs depicted in the novels are characterised by the unstable or drifting quality of their meaning

Brumes et brouillards de Bleak House à Heart of Darkness

This article analyses the ways in which air is combined to water to generate mist or fog in three novels of the Victorian period (Bleak House, Tess of the d’Urbervilles and Heart of Darkness). In these novels, mist and fog are recurrent and deeply ambivalent tropes. The article will first raise the following question : to what extent does the representation of fog and mist take part in the representation of the « Britishness » of the place described ? It will focus on the different interpretations of these tropes by drawing comparisons between short excerpts of the novels. It will notably draw a link between mist or fog and a double process of mythification and mystification. It concludes by suggesting that, being signifiers of blurriness, the mists and fogs depicted in the novels are characterised by the unstable or drifting quality of their meaning

INTERPRÉTATION DES PHÉNOMÈNES ACOUSTOÉLECTRIQUES PAR UNE THÉORIE LINÉAIRE

Nous appliquons l'hypothèse émise par B. W. Haaki et R. W. Dixon aux composés III V et nous montrons que la plupart des phénomènes acoustoélectriques peuvent s'interpréter à partir de la théorie de D. L. White. L'amplification de l'onde de potentiel associée aux vibrations mécaniques provoque le piégeage d'une partie des porteurs libres. La densité des porteurs libres responsables de l'amplification acoustoélectrique décroît et un quasi-équilibre peut être atteint.We apply the assumption assumed by B. W. Haaki and R. W. Dixon to the III V compounds and we show that most of the acoustoelectric phenomena may be explained by D. L. White's theory. The amplification of the potential wave associated to the lattice vibration involves the trapping of a fraction of the carriers. The density of free carriers which is responsible of the acoustoelectric amplification decreases and a quasi equilibrium may be obtained