Traceability and authentication in agri-food production: A multivariate approach to the characterization ofthe Italian food excellence elephant garlic (Allium ampeloprasum L.), a vasoactive nutraceutical.

A research platform for food authentication was set up by combining stable isotope ratio analysis, metabolomics by gas and liquid mass-spectrometry and NMR investigations, chemometric analyses for food excellences. This multi-analytical approach was tested on samples of elephant garlic (Allium ampeloprasum L.), a species belonging to the same genus of common garlic (Allium ampeloprasum L.), mainly produced in southern Tuscany-(Allium ampeloprasum). The isotopic composition allowed the product to be geographically characterized. Flavonoids, like (+)-catechin, cinnamic acids, quercetin glycosides were identified. The samples showed also a significant amount of dipeptides, sulphur-containing metabolites and glutathione, the latter of which could be considered a molecular marker of the analyzed elephant garlic. For nutraceutical profiling to reach quality labels, extracts were investigated in specific biological assays, displaying interesting vasorelaxant properties in rat aorta by mediating nitric oxide release from the endothelium and exhibited positive inotropic and negative chronotropic effects in rat perfused heart.

Retinitis Pigmentosa and Retinal Degenerations: Deciphering Pathways and Targets for Drug Discovery and Development.

Inherited retinal diseases (IRDs) are a group of retinopathies generally caused by genetic mutations. Retinitis pigmentosa (RP) represents one of the most studied IRDs. RP leads to intense vision loss or blindness resulting from the degeneration of photoreceptor cells. To date, RP is mainly treated with palliative supplementation of vitamin A and retinoids, gene therapies, or surgical interventions. Therefore, a pharmacologically based therapy is an urgent need requiring a medicinal chemistry approach, to validate molecular targets able to deal with retinal degeneration. This Review aims at outlining the recent research efforts in identifying new drug targets for RP, especially focusing on the neuroprotective role of the Wnt/ß-catenin/GSK3ß pathway and apoptosis modulators (in particular PARP-1) but also on growth factors such as VEGF and BDNF. Furthermore, the role of spatiotemporally expressed G protein-coupled receptors (GPR124) in the retina and the emerging function of histone deacetylase inhibitors in promoting retinal neuroprotection will be discussed.

A Repurposing Approach for Uncovering the Anti-Tubercular Activity of FDA-Approved Drugs with Potential Multi-Targeting Profiles.

Tuberculosis (TB) is one of the top 10 causes of death worldwide. This scenario is further complicated by the insurgence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. The identification of appropriate drugs with multi-target affinity profiles is considered to be a widely accepted strategy to overcome the rapid development of resistance. The aim of this study was to discover Food and Drug Administration (FDA)-approved drugs possessing antimycobacterial activity, potentially coupled to an effective multi-target profile. An integrated screening platform was implemented based on computational procedures (high-throughput docking techniques on the target enzymes peptide deformylase and Zmp1) and in vitro phenotypic screening assays using two models to evaluate the activity of the selected drugs against Mycobacterium tuberculosis (Mtb), namely, growth of Mtb H37Rv and of two clinical isolates in axenic media, and infection of peripheral blood mononuclear cells with Mtb. Starting from over 3000 FDA-approved drugs, we selected 29 marketed drugs for submission to biological evaluation. Out of 29 drugs selected, 20 showed antimycobacterial activity. Further characterization suggested that five drugs possessed promising profiles for further studies. Following a repurposing strategy, by combining computational and biological efforts, we identified marketed drugs with relevant antimycobacterial profiles.

Dietary polyphenols rutin, taxifolin and quercetin related compounds target Leishmania amazonensis arginase.

Quercetin related compounds were tested against Leishmania amazonensis arginase, a potential target for the development of new approaches in treating leishmaniasis. The IC50 and kinetic analysis were performed to determine the dissociation constant Ki and the inhibition mechanism of the parasite's arginase enzyme. The best arginase inhibition was obtained from taxifolin (dihydroquercetin) with IC50 = 1.6 ± 0.1 µM. This study showed for the first time that rutin (IC50 = 10.4 ± 0.8 µM), and human metabolite quercetin-3-O-glucuronide (IC50 = 8.2 ± 0.4 µM), target L. amazonensis arginase. In addition, computational studies applying molecular docking simulations were performed to gain insight into the molecular basis for arginase inhibition by the competitive inhibitors. Our results suggest that these compounds could be exploited to develop new approaches for treating leishmaniasis through molecular nutrition supplement in a drug-based therapy.

Sujeitos da saúde, agentes do território: o agente comunitário de saúde na Atenção Básica ao imigrante / Sujetos de la salud, agentes del territorio: el agente comunitario de salud en la Atención Básica al inmigrante / Health subjects, territory agents: the community health agent in immigrant Primary Care

Com a intensificação e diversificação dos fluxos migratórios internacionais para o Brasil e a necessidade de inserção da população imigrante aos serviços públicos de saúde, novas dinâmicas se apresentam no contexto da Atenção Básica. Tendo como estudo de caso a população boliviana que utiliza os serviços da Unidade Básica de Saúde do Bom Retiro, em São Paulo, buscou-se compreender qual o papel dos agentes comunitários de saúde (ACS) para que o sistema público cumpra seu princípio de universalidade, oferecendo acesso às populações imigrantes e as incluindo. Por meio de entrevistas semiestruturadas, examinadas por meio da análise de conteúdo, pôde-se constatar que os agentes comunitários são essenciais para a garantia de inserção dos imigrantes ao serviço de Atenção Básica, pois são ao mesmo tempo sujeitos da promoção em saúde e agentes do território, construindo redes de vínculos que favorecem o cuidado integral.(AU)

Con la intensificación y la diversificación de los flujos migratorios internacionales para Brasil y la necesidad de inserción de la población inmigrante en los servicios públicos de salud, se presentan nuevas dinámicas en el contexto de la Atención Básica. Teniendo como estudio de caso la población boliviana que utiliza los servicios de la Unidad Básica de Salud de Bom Retiro, en São Paulo, se buscó entender cuál era el papel de los agentes comunitarios desalud para que el sistema público cumpla su principio de universalidad, ofreciendo acceso a las poblaciones inmigrantes e incluyéndolas. Por medio de entrevistas semiestructuradas, examinadas por medio del análisis de contenido, es posible constatar que los agentes comunitarios son esenciales para la garantía de inserción de los inmigrantes en el servicio de atención básica, puesto que son al mismo tiempo sujetos de la promoción de salud y agentes del territorio construyendo redes de vínculos que favorecen el cuidado integral.(AU)

With the intensification and diversification of international migratory flows to Brazil and the need to integrate the immigrant population into essential services, new dynamics are presented in the Primary Health Care. Considering the Bolivian population that uses the services of one Basic Health Unit in São Paulo , this work seeks to understand what the role of the community health agents is, in order to guarantee the principle of universality of the public health services offering access and including the immigrant populations. Through qualitative interviews, examined through content analysis, it was possible to verify that the community health agents appear as essential actors to guarantee the right of access to the health system. Hence, they are responsible for the promotion of health care and they are also the agents of the territory, building up social networks for the holistic care.(AU)

Targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors for developing effective antipsychotics: synthesis, biological characterization, and behavioral studies.

Combination of dopamine D3 antagonism, serotonin 5-HT1A partial agonism, and antagonism at 5-HT2A leads to a novel approach to potent atypical antipsychotics. Exploitation of the original structure-activity relationships resulted in the identification of safe and effective antipsychotics devoid of extrapyramidal symptoms liability, sedation, and catalepsy. The potential atypical antipsychotic 5bb was selected for further pharmacological investigation. The distribution of c-fos positive cells in the ventral striatum confirmed the atypical antipsychotic profile of 5bb in agreement with behavioral rodent studies. 5bb administered orally demonstrated a biphasic effect on the MK801-induced hyperactivity at dose levels not able to induce sedation, catalepsy, or learning impairment in passive avoidance. In microdialysis studies, 5bb increased the dopamine efflux in the medial prefrontal cortex. Thus, 5bb represents a valuable lead for the development of atypical antipsychotics endowed with a unique pharmacological profile for addressing negative symptoms and cognitive deficits in schizophrenia.

Synthesis and biological evaluation of novel allophenylnorstatine-based HIV-1 protease inhibitors incorporating high affinity P2-ligands.

A series of stereochemically defined cyclic ethers as P2-ligands were incorporated in an allophenylnorstatine-based isostere to provide a new series of HIV-1 protease inhibitors. Inhibitors 3b and 3c, containing conformationally constrained cyclic ethers, displayed impressive enzymatic and antiviral properties and represent promising lead compounds for further optimization.

Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavior.

Dopamine D(3) antagonism combined with serotonin 5-HT(1A) and 5-HT(2A) receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacological features of 5i are a high affinity for dopamine D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors, together with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c-fos expression in mesocorticolimbic areas, confirmed an atypical antipsychotic profile of 5i in vivo, characterized by the absence of catalepsy at antipsychotic dose.