Nutraceuticals: opening the debate for a regulatory framework

Currently, nutraceuticals do not have a specific definition distinct from those of other food-derived categories, such as food supplements, herbal products, pre- and probiotics, functional foods, and fortified foods. Many studies have led to an understanding of the potential mechanisms of action of pharmaceutically active components contained in food that may improve health and reduce the risk of pathological conditions while enhancing overall well-being. Nevertheless, there is a lack of clear information and, often, the claimed health benefits may not be properly substantiated by safety and efficacy information or in vitro and in vivo data, which can induce false expectations and miss the target for a product to be effective, as claimed. An officially shared and accepted definition of nutraceuticals is still missing, as nutraceuticals are mostly referred to as pharma-foods, a powerful toolbox to be used beyond the diet but before the drugs to prevent and treat pathological conditions, such as in subjects who may not yet be eligible for conventional pharmaceutical therapy. Hence, it is of utmost importance to have a proper and unequivocal definition of nutraceuticals and shared regulations. It also seems wise to assess the safety, mechanism of action and efficacy of nutraceuticals with clinical data. A growing demand exists for nutraceuticals, which seem to reside in the grey area between pharmaceuticals and food. Nonetheless, given specific legislation from different countries, nutraceuticals are experiencing challenges with safety and health claim substantiation

Synthesis, Structural Analysis, and Biological Evaluation of Thioxoquinazoline Derivatives as Phosphodiesterase 7 Inhibitors

PDE7 inhibitors regulate pro-inflammatory and immune T-cell functions, and are a potentially novel class of drugs especially useful in the treatment of a wide variety of immune and inflammatory disorders. Starting from our lead family of thioxoquinazolines, we designed, synthesized, and characterized a novel series of thioxoquinazoline derivatives. Many of these compounds showed inhibitory potencies at sub-micromolar levels against the catalytic domain of PDE7A1 and at the micromolar level against PDE4D2. Cell-based studies showed that these compounds not only increased intracellular cAMP levels, but also had interesting anti-inflammatory properties within a therapeutic window. The in silico data predict that these compounds are capable of the crossing the blood–brain barrier. The X-ray crystal structure of the PDE7A1 catalytic domain in complex with compound 15 at a resolution of 2.4 Å demonstrated that hydrophobic interactions at the active site pocket are a key feature. This structure, together with molecular modeling, provides insight into the selectivity of the PDE inhibitors and a template for the discovery of new PDE7 or PDE7/PDE4 dual inhibitors

In Saccharomyces cerevisiae, the Inositol Polyphosphate Kinase Activity of Kcs1p Is Required for Resistance to Salt Stress, Cell Wall Integrity, and Vacuolar Morphogenesis

A problem for inositol signaling is to understand the significance of the kinases that convert inositol hexakisphosphate to diphosphoinositol polyphosphates. This kinase activity is catalyzed by Kcs1p in the yeast Saccharomyces cerevisiae. A kcs1Delta yeast strain that was transformed with a specifically "kinase-dead" kcs1p mutant did not synthesize diphosphoinositol polyphosphates, and the cells contained a fragmented vacuolar compartment. Biogenesis of the yeast vacuole also required another functional domain in Kcs1p, which contains two leucine heptad repeats. The kinase activity of Kcs1p was also found to sustain cell growth and integrity of the cell wall and to promote adaptive responses to salt stress. Thus, the synthesis of diphosphoinositol polyphosphates has wide ranging physiological significance. Furthermore, we showed that these phenotypic responses to Kcs1p deletion also arise when synthesis of precursor material for the diphosphoinositol polyphosphates is blocked in arg82Delta cells. This metabolic block was partially bypassed, and the phenotype was partially rescued, when Kcs1p was overexpressed in the arg82Delta cells. This was due, in part, to the ability of Kcs1p to phosphorylate a wider range of substrates than previously appreciated. Our results show that diphosphoinositol polyphosphate synthase activity is essential for biogenesis of the yeast vacuole and the cell's responses to certain environmental stresses.Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington's disease

Huntington's disease is a devastating neurodegenerative condition for which there is no therapy to slow disease progression. The particular vulnerability of striatal medium spiny neurons to Huntington's pathology is hypothesized to result from transcriptional dysregulation within the cAMP and CREB signaling cascades in these neurons. To test this hypothesis, and a potential therapeutic approach, we investigated whether inhibition of the striatal-specific cyclic nucleotide phosphodiesterase PDE10A would alleviate neurological deficits and brain pathology in a highly utilized model system, the R6/2 mouse