In this study we investigated the role of CB1 receptor signaling in angiogenesis and the therapeutic exploitation of CB1 inactivation as an antiangiogenic strategy. We started from the observation that CB1 receptor expression is induced during angiogenesis and that the endocannabinoid anandamide stimulated bFGFinduced angiogenesis in the nanomolar physiologic range. To define the functional involvement of CB1 receptor signaling during angiogenesis, 2 different strategies have been carried out: siRNAmediated knockdown and pharmacologic antagonism of CB1 receptors. CB1 receptors inactivation resulted in the inhibition of bFGF-induced endothelial proliferation, migration, and capillary-like tube formation, through prosurvival and migratory pathways involving ERK, Akt, FAK, JNK, Rho, and MMP-2. To corroborate the potential therapeutic exploitation of CB1 blockade as an antiangiogenic strategy, we performed in vivo assays founding that CB1 blockade was able to inhibit bFGF-induced neovascular growth in the rabbit cornea assay. A relevant finding was the ability to reduce ocular pathologic neo-vascularization in mouse oxygen-induced retinopathy. These results demonstrate that CB1 signaling participates to the proliferative response elicited by proangiogenic growth factors in angiogenesis and that for this reason CB1 receptor could represent a novel target for the treatment of diseases where excessive neoangiogenesis is the underlying pathology. IntroductionThe endocannabinoid system, composed of 2 cannabinoid receptors CB1 and CB2, their endogenous ligands (endocannabinoids, eg, anandamide), and the enzymes for their metabolism, has been pointed out to be implicated in several pathophysiologic conditions ranging from neurologic and psychiatric diseases to eating, cardiovascular, reproductive disorders, and cancer. [1][2][3] The main effects of endocannabinoids rely on the activation of CB1, a 7-transmembranedomain protein belonging to the G ␣i protein-coupled receptor family (GPCR). 4 CB1 receptors are highly expressed in the central nervous system, especially in the cortex, cerebellum, hippocampus, and basal ganglia, and their involvement in processes of memory and learning, in diseases affecting movement, mood, and anxiety and in conditions related to altered brain reward mechanisms, has been ascertained. 5 Noteworthy, CB1 receptors are expressed also by a variety of peripheral tissues and cells and in the last years a role in several physiologic functions and pathologies is emerging. CB1 deficiency was reported to be associated to age-related osteoporosis 6 and preterm birth in mice, 7 highlighting a role for CB1 signaling in bone metabolism and in early pregnancy events. On the other hand, CB1 receptor antagonism and/or inactivation through genetic engineering as in CB1-deficient mouse strains, 8 were shown to be useful in several pathologies in which the endocannabinoid system is unbalanced or CB1 more than expressed (eg, obesity, metabolic syndrome, diabetes, Alzheimer disease). 9-11 Indeed, CB1 inactivation e...

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Fresh juice from bergamot (Citrus bergamia Risso) has been studied to evaluate the polyphenolic composition by HPLC-DAD analysis and total polyphenols content by UV method. The main constituent, Naringin, has been selected as analytical and biological marker of the juice. Juice has been loaded onto maltodextrin matrix by spray-drying. The produced maltodextrin/juice powder (BMP) showed neither significant change in total polyphenols content nor decrease in antioxidant properties with respect to fresh juice. Moreover, BMP displayed high in vitro dissolution rate of the bioactive constituents in water and in simulated biological fluids. BMP appears as promising functional raw material for food, nutraceutical and pharmaceutical products. With this aim, a formulation study to develop tablets (BMT) for oral administration has been also performed. The produced solid oral dosage form preserved high polyphenols content, showed complete disaggregation in few minutes and satisfying dissolution rate of the bioactive constituents in simulated biological fluids.

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ObjectiveN6-isopentenyladenosine (iPA) is an intermediate of the mevalonate pathway that exhibits various anti-cancer effects. However, studies on its anti-inflammatory activity are scarce and underlying molecular mechanisms are unknown. Therefore, we aimed to investigate the ability of iPA to exert anti-inflammatory effects in the human cystic fibrosis (CF) cell model of exacerbated inflammation.Materials and methodsTNFα-stimulated CF cells CuFi-1 and its normal counterpart NuLi-1 were pre-treated with increasing concentrations of iPA and cell viability and proliferation were assessed by MTT and BrdU assays. The effect of iPA on IL-8 and RANTES secretion was determined by ELISA, and the activation and expression of signaling molecules and selenoproteins were studied by Western blot. To assess the direct effect of iPA on NFκB activity, luciferase assay was performed on TNFα-stimulated HEK293/T cells transfected with a NFκB reporter plasmid.ResultsWe demonstrated for the first time that iPA prevents IL-8 and RANTES release in TNFα-stimulated CF cells and this effect is mediated by increasing the expression of the direct NFκB inhibitor IκBα and decreasing the levels of STAT3. Consistent with this, we showed that iPA inhibited TNFα-mediated NFκB activation in HEK/293T cells. Finally, we also found that iPA improved the levels of glutathione peroxidase 1 and thioredoxin reductase 1 only in CF cells suggesting its ability to maintain sufficient expression of these anti-oxidant selenoproteins.ConclusionsOur findings indicate that iPA can exert anti-inflammatory activity especially in the cases of excessive inflammatory response as in CF.

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