Background and purpose: Phenolic compounds exert cytoprotective effects; our purpose was to investigate whether the isosteric polyphenolic compounds clovamide and rosmarinic acid are neuroprotective. Experimental approach: Three in vitro models of neuronal death were selected: (i) differentiated SH-SY5Y human neuroblastoma cells exposed to tert-butylhydroperoxide (t-BOOH), for oxidative stress; (ii) differentiated SK-N-BE(2) human neuroblastoma cells treated with L-glutamate, for excitotoxicity; and (iii) differentiated SH-SY5Y human neuroblastoma cells exposed to oxygen-glucose deprivation/reoxygenation, for ischaemia-reperfusion. Cell death was evaluated by lactate dehydrogenase measurements in the cell media, while the mechanisms underlying the effects by measuring: (i) t-BOOH-induced glutathione depletion and increase in lipoperoxidation; and (ii) L-glutamate-induced intracellular Ca 2+ overload (fura-2 method) and inducible gene expression (c-fos, c-jun), by reverse transcriptase-PCR. The ability of compounds to modulate nuclear factor-kB and peroxisome proliferator-activated receptor-g activation was evaluated by Western blot in SH-SY5Y cells not exposed to harmful stimuli. Key results: Both clovamide and rosmarinic acid (10-100 mmol·L -1 ) significantly protected neurons against insults with similar potencies and efficacies. The EC50 values were in the low micromolar range (0.9-3.7 mmol·L -1 ), while the maximal effects ranged from 40% to -60% protection from cell death over untreated control at 100 mmol·L -1. These effects are mediated by the prevention of oxidative stress, intracellular Ca 2+ overload and c-fos expression. In addition, rosmarinic acids inhibited nuclear factor-kB translocation and increased peroxisome proliferator-activated receptor-g expression in SH-SY5Y cells not exposed to harmful stimuli. Conclusion and implications: Clovamide and rosmarinic acid are neuroprotective compounds of potential use at the nutritional/pharmaceutical interface.

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Abstract-The adaptive changes that develop in the pressure-overloaded left ventricular (LV) myocardium include cardiomyocyte hypertrophy and interstitial fibrosis. Although the former is known to depend to a sizeable extent on sympathetic (over)activity, little information exists whether the same applies to the latter, ie, whether excess catecholamine exposure contributes to the imbalance between collagen deposition by fibroblasts and degradation by matrix metalloproteases (MMPs), eventually leading to LV collagen accumulation. Sprague-Dawley rats were subjected to abdominal aortic banding (B) or sham operation (S) and treated with ␤-blockade (Bb, oral propranolol, 40 mg/kg per day), chemical sympathectomy (Sx, 6-hydroxydopamine, 150 mg/kg intraperitoneal twice per week) or vehicle (Vh). Ten weeks later, systolic blood pressure, LV weight, collagen abundance (computer-aided histology), zymographic matrix metalloproteinase (MMP)-2 activity and its specific tissue inhibitor concentration (TIMP-2) were measured. Both sympathectomy and ␤-blockade failed to attenuate the banding-induced blood pressure elevation but significantly attenuated the attendant LV hypertrophy. As expected, pressure-overload hypertrophy was associated with interstitial fibrosis (collagen: 4.37Ϯ1.23% BVh versus 1.23Ϯ0.44% SVh, PϽ0.05), which was abolished by sympathectomy (2.55Ϯ1.31%, Pϭnot significant versus SSx) but left unchanged by ␤-blockade (4.11Ϯ1.23%, PϽ0.05 versus both SBb and BSx). ␤-blockade, but not sympathectomy, was also associated with an increased TIMP-2/MMP-2 ratio (PϽ0.05), indicating reduced interstitial collagenolytic activity. In separate groups of banded and sham-operated rats, treatment with the ␣-receptor blocker doxazosin (10 mg/kg per day) displayed similar antifibrotic and biochemical effects as sympathectomy. Thus in the course of experimental pressure overload, the sympathetic nervous system plays a major pro-fibrotic role, which is mediated via ␣-adrenergic but not ␤-adrenergic receptors. Key Words: collagen Ⅲ extracellular matrix Ⅲ fibrosis Ⅲ heart failure Ⅲ hypertrophy Ⅲ sympathectomy T here is extensive evidence that sympathetic nerve overactivity consistently accompanies hypertension in its uncomplicated stage and even more so after the progressive development of left ventricular (LV) hypertrophy, dysfunction, and failure. 1,2 This has deleterious consequences on the severity of hypertension itself, because it produces peripheral vasoconstriction, as well as on the heart, because: (1) it favors activation of other potentially cardiotoxic neurohumoral systems (renin-angiotensin system, endothelin, etc) 3,4 ; (2) it increases myocardial oxygen consumption; and (3) it directly exerts toxic (pro-apoptotic, pro-necrotic) effects on the myocardium. 5-7 Accordingly, it is now firmly established that administration of ␤-adrenergic receptor blockers favorably affects hypertension and heart failure, 8 most likely via correction of the aforementioned pathophysiological alterations.However, although it is well documented ...

This work is a step forward toward synthetic nanosystems combining carbohydrate antigens and immunogenic peptides as potential carbohydrate-based vaccines.

We have synthesized and characterized nearly monodisperse and highly pure gold nanoparticles (2 and 5 nm) coated with non-immunoactive mono-and disaccharides, modelled after the capsular polysaccharide of serogroup A of the Neisseria meningitidis bacterium. We have used them to test their ability to induce immune cell responses as a consequence of their multivalency. The results indicate that they are indeed immunoactive and that immunoactivity is strongly dependent on size, and larger, 5 nm nanoparticles perform far better than smaller, 2 nm ones. Immune response (activation of macrophages) initiates with the whole nanoparticle recognition by the surface of antigen-presenting cells, independent of the saccharide oligomerization (or charge) on the nanoparticle surface. The induction of T cell proliferation and the increase of IL-2 levels, a consequence of the expression of MHC II involved in antigen presentation, require the presence of a disaccharide on the nanoparticle, not just a monosaccharide. A possible explanation is that, at this stage, the saccharides are detached from the gold surface. These results may provide leads for designing new saccharide-based, nanoparticle-conjugate vaccines.

In this study, a successful medicinal chemistry campaign that exploited virtual, biophysical, and biological investigations led to the identification of a novel class of IDO1 inhibitors based on a benzimidazole substructure. This family of compounds is endowed with an extensive bonding network in the protein active site, including the interaction with pocket C, a region not commonly exploited by previously reported IDO1 inhibitors. The tight packing of selected compounds within the enzyme contributes to the strong binding interaction with IDO1, to the inhibitory potency at the low nanomolar level in several tumoral settings, and to the selectivity toward IDO1 over TDO and CYPs. Notably, a significant reduction of L-Kyn levels in plasma, together with a potent effect on abrogating immunosuppressive properties of MDSC-like cells isolated from patients affected by pancreatic ductal adenocarcinoma, was observed, pointing to this class of molecules as a valuable template for boosting the antitumor immune system.

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Our data suggest that the CYP3A4 and CYP3A5 polymorphisms are unlikely to influence donepezil metabolism and/or clinical outcome. On the other hand, the ABCB1 polymorphisms may play a role in donepezil disposition and clinical outcome.