No abstract

Atherosclerosis arises from leukocyte infiltration and thickening of the artery walls and constitutes a major component of vascular disease pathology, but the molecular events underpinning this process are not fully understood. Proteins containing an Asn-Gly-Arg (NGR) motif readily undergo deamidation of asparagine to generate isoDGR structures that bind to integrin αvβ3 on circulating leukocytes. Here we report the identification of isoDGR motifs in human atherosclerotic plaque components including extracellular matrix (ECM) proteins fibronectin and tenascin C, which have been strongly implicated in human atherosclerosis. We further demonstrate that deamidation of NGR motifs in fibronectin and tenascin C leads to increased adhesion of the monocytic cell line U937 and enhanced binding of primary human monocytes, except in the presence of a αvβ3-blocking antibody or the αv-selective inhibitor cilengitide. In contrast, under the same deamidating conditions monocyte-macrophages displayed only weak binding to the alternative ECM component vitronectin which lacks NGR motifs. Together, these findings confirm a critical role for isoDGR motifs in mediating leukocyte adhesion to the ECM via integrin αvβ3 and suggest that protein deamidation may promote the pathological progression of human atherosclerosis by enhancing monocyte recruitment to developing plaques.

Objectives: The aim of the present study was to compare the efficacy of a nano form of amphotericin B deoxycholate with that of conventional amphotericin B deoxycholate for the treatment of visceral leishmaniasis. Methods:We have formulated nanoparticles (10-20 nM) from amphotericin B deoxycholate (1 -2 mM) by applying high-pressure (150 argon) milling homogenization and have tested their efficacy in a J774A cell line and in hamsters. Parasite survival and tissue burden in spleen were evaluated for nanoamphotericin B and conventional amphotericin B. Both nano-amphotericin B and conventional amphotericin B were injected intraperitoneally at 5 mg/kg per day for 5 days.Results: The inhibition of amastigotes in the splenic tissue with nano-amphotericin B was significantly more than with conventional amphotericin B (92.18% versus 74.57%, P 5 0.005). Similarly, the suppression of parasite replication in the spleen was also found to be significant (99.18% versus 97.17%, P 5 0.05). In a cytotoxicity test, nano-amphotericin B against the J774A cell line had a CC 50 of 12.67 mg/L in comparison with 10.61 mg/L for amphotericin B, far higher than the doses used for ED 50 .Conclusions: Nanoparticles of amphotericin B had significantly greater efficacy than conventional amphotericin B. This formulation may have a favourable safety profile, and if production costs are low, it may prove to be a feasible alternative to conventional amphotericin B.