Low doses of 3-aminobenzamide, a poly(ADP-ribose) polymerase inhibitor, stimulate angiogenesis by regulating expression of urokinase type plasminogen activator and matrix metalloprotease 2

Abstract Background: Poly(ADP-Ribose) polymerase (PARP) activity has been demonstrated fundamental in many cellular processes, including DNA repair, cell proliferation and differentiation. In particular, PARP activity has been recently found to affect proliferation, migration, and tube formation of human umbilical vein endothelial cells. In recent times, PARP inhibitors have entered in clinical trials to potentiate cancer treatments by preventing DNA repair, but little is known about the effects performed by different drug concentrations on neoangiogenesis, an essential step in tumor growth. Methods: Human umbilical vein endothelial cells were treated with 3 aminobenzamide (3ABA), a PARP inhibitor, and tested for several different cellular parameters. Results: Here we present in vitro evidence that a low concentration of 3ABA (50 μM), stimulates angiogenesis by decreasing fibrinolytic activity, carried out by urokinase-type plasminogen activator (uPA), and by enhancing matrix metalloprotease-2 (MMP-2) gelatinolytic activity, in fibroblast growth factor-2-stimulated endothelial cells. These unbalanced pathways modify in vitro angiogenic steps, inhibiting chemoinvasion and stimulating tubulogenic activity. Conclusions: Our results suggest that the proangiogenic effect of low concentrations of 3ABA alerts on the efficacy of PARP inhibitors to potentiate anticancer therapy. Moreover, they indicate that endothelial chemoinvasion and tubulogenesis depend on distinct proteolytic pathways

Brain uptake of an anti-ischemic agent by nasal administration of microparticles

N6-cyclopentyladenosine (CPA) has neuronal anti-ischemic properties, but it is not absorbed into the brain from the bloodstream, where it shows poor stability and induces side effects. Microparticulate drug delivery systems designed for CPA nasal administration and constituted by mannitol or chitosan, were prepared by spray-drying and characterized. Mannitol-lecithin microparticles showed high CPA dissolution rate, whereas chitosan microparticles controlled its release rate. In vitro mucoadhesion studies indicated that CPA-loaded chitosan microparticles had higher mucoadhesive properties compared to mannitol particles. Ex vivo studies on sheep nasal mucosa showed that mannitol microparticles promoted CPA permeation across the mucosa, whereas chitosan microparticles controlled CPA permeation rate in comparison with CPA raw material. In vivo studies were carried out on rats. No CPA was detected in rat cerebrospinal fluid (CSF) and brain sections after intravenous administration. In contrast, after nasal administration of loaded microparticles CPA was found in the CSF at concentrations ranging from high nM to µM values and up to two order of magnitude higher than those obtained at systemic level. CPA was also found in the olfactory bulb at concentrations around 0.1 ng/mg of tissue. These results can open new perspectives for the employment of CPA against brain damages following stroke

Cannabinoid ReceptorActivation Induces Apoptosis through Tumor Necrosis Factor A Mediated Ceramide De novo Synthesis in Colon Cancer Cells,

PURPOSE: Cannabinoids have been recently proposed as a new family of potential antitumor agents. The present study was undertaken to investigate the expression of the two cannabinoid receptors, CB1 and CB2, in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation. EXPERIMENTAL DESIGN: Cannabinoid receptor expression was investigated in both human cancer specimens and in the DLD-1 and HT29 colon cancer cell lines. The effects of the CB1 agonist arachinodyl-2'-chloroethylamide and the CB2 agonist N-cyclopentyl-7-methyl-1-(2-morpholin-4-ylethyl)-1,8-naphthyridin-4(1H)-on-3-carboxamide (CB13) on tumor cell apoptosis and ceramide and tumor necrosis factor (TNF)-alpha production were evaluated. The knockdown of TNF-alpha mRNA was obtained with the use of selective small interfering RNA. RESULTS: We show that the CB1 receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB2 receptor. The activation of the CB1 and, more efficiently, of the CB2 receptors induced apoptosis and increased ceramide levels in the DLD-1 and HT29 cells. Apoptosis was prevented by the pharmacologic inhibition of ceramide de novo synthesis. The CB2 agonist CB13 also reduced the growth of DLD-1 cells in a mouse model of colon cancer. The knockdown of TNF-alpha mRNA abrogated the ceramide increase and, therefore, the apoptotic effect induced by cannabinoid receptor activation. CONCLUSIONS: The present study shows that either CB1 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells. Our data unveiled, for the first time, that TNF-alpha acts as a link between cannabinoid receptor activation and ceramide production

N. 6 Schede di catalogo: n. 7.6 Vescovo Lazzaro, Breviario Armeno; n. 7.7 Copista e miniatore ignoti, Evangeliario armeno; n. 7.8 Officina mesopotamica, Mattoni di fondazione con iscrizione cuneiforme; n. 7.18 Ambito veneziano (?), Lavanda dei piedi; n. 7.19 Ambito Italia centrale (?), San Carlo Borromeo e San Filippo Neri; n. 8.6 Attilio Spaccarelli, Coppa con scene dionisiache

La mostra presenta al pubblico – per la prima volta in modo organico – la raccolta vasta e sorprendente che i coniugi statunitensi George Washington Wurts ed Henriette Tower misero insieme a cavallo fra XIX e XX secolo e donarono poi allo Stato italiano, per l’esattezza al museo di Palazzo Venezia, dove tuttora è conservata. Alla base della mostra vi è comunque anche l’idea di restituire il contesto della raccolta Wurts, ovvero quella particolare forma di collezionismo che tra Ottocento e Novecento si legò così intimamente all’Italia, fino a concretizzarsi spesso nella donazione allo Stato di singole opere o di intere raccolte. La mostra illustra le dinamiche del collezionismo, soprattutto anglo-americano, e del mercato internazionale, sullo sfondo dei radicali cambiamenti vissuti in quegli anni dalla giovane nazione italiana e dalla sua nuova capitale, Roma. La costruzione del Vittoriano, iniziato nel 1885 e inaugurato nel 1911 nell’occasione dell’Esposizione che celebrava il cinquantenario dell’Unità d’Italia, diviene l’emblema che caratterizza la città all’alba del Novecento