1,3,4-Oxadiazoles by Ugi-Tetrazole and Huisgen Reaction

Easy to perform, functional group tolerant, and short syntheses of the privileged scaffold oxadiazole are highly desired. Here, a metal-free protocol for MCR-based synthesis of 2,5-disubstituted 1,3,4-oxadiazoles via a Ugi-tetrazole/Huisgen sequence was developed. Optimization and scope and limitations of this short and general sequence are described. The reaction was also successfully performed on a gram scale

Pd-Catalyzed de Novo Assembly of Diversely Substituted Indole-Fused Polyheterocycles

Here we describe a facile, tandem synthetic route for indolo[3,2-c]quinolinones, a class of natural alkaloid analogues of high biological significance. A Ugi four-component reaction with indole-2-carboxylic acid and an aniline followed by a Pd-catalyzed cyclization yields tetracyclic indoloquinolines in good to moderate yields. Commercially available building blocks yield highly diverse analogues in just two simple steps

Human transcriptome response after Mediterranean diet consumption

Trabajo presentado en el IV Congress of International Society of Nutrigenetics/Nutrigenomics ISNN, celebrado en Pamplona (España) del 18 al 20 de noviembre de 2010.[Introduction]: Despite the benefits associated with healthy diets, data on the mechanisms by which these benefits are promoted are scarce. Our aim was to explore the global transcriptomic response of biological pathways related to cardiovascular disease associated with traditional Mediterranean diet (TMD) intervention.[Methods]: The PREDIMED study is a large on-going, parallel, multicentre, randomized, controlled trial aimed at assessing the TMD effect on primary cardiovascular prevention. High cardiovascular risk participants were recruited and assigned to one of the following interventions: 1) TMD plus virgin olive oil (VOO); 2) TMD plus mixed nuts; or 3) low-fat diet (control group). In a sub sample of 30 volunteers of the PREDIMED-Barcelona Sur Centre, gene expression changes in peripheral mononuclear cells, after 3 months of intervention, were assessed by microarray analysis (Affymetrix) in which about 30,000 individual human genes were included. Crude and adjusted models for data analyses were performed separately in two different centres. Pearson´s correlation coefficients for log2ratio (post-intervention/pre-intervention value) and T-statistics were greater than 0.97. Gene ontology analyses were performed by Bioingenuity Software on genes with T-statistics ≥1.5 or ≥-1.5 after interventions.[Results]: Analyses of canonical pathways related with cardiovascular risk highlighted that: 1) MUFA versus PUFA rich diets (MUFA/PUFA ratio >3.5; TMD plus VOO and Low-fat) promoted changes in clusters of genes associated with cytokine and nuclear receptor signaling; and 2) TMD plus VOO promoted changes in blood pressure related pathways. In agreement with this, the greatest decrease in systolic and diastolic blood pressure levels were observed after TMD plus VOO diet.[Conclusions]: One of the mechanisms by which MUFA rich diets, and particularly a TMD rich in virgin olive oil, can exert their health benefits is through an enhancement of the global transcriptomic response in pathways related with cardiovascular risk

The Antioxidant Potential of the Mediterranean Diet in Patients at High Cardiovascular Risk: An In-Depth Review of the PREDIMED

Cardiovascular disease (CVD) is the leading global cause of death. Diet is known to be important in the prevention of CVD. The PREDIMED trial tested a relatively low-fat diet versus a high-fat Mediterranean diet (MedDiet) for the primary prevention of CVD. The resulting reduction of the CV composite outcome resulted in a paradigm shift in CV nutrition. Though many dietary factors likely contributed to this effect, this review focuses on the influence of the MedDiet on endogenous antioxidant systems and the effect of dietary polyphenols. Subgroup analysis of the PREDIMED trial revealed increased endogenous antioxidant and decreased pro-oxidant activity in the MedDiet groups. Moreover, higher polyphenol intake was associated with lower incidence of the primary outcome, overall mortality, blood pressure, inflammatory biomarkers, onset of new-onset type 2 diabetes mellitus (T2DM), and obesity. This suggests that polyphenols likely contributed to the lower incidence of the primary event in the MedDiet groups. In this article, we summarize the potential benefits of polyphenols found in the MedDiet, specifically the PREDIMED cohort. We also discuss the need for further research to confirm and expand the findings of the PREDIMED in a non-Mediterranean population and to determine the exact mechanisms of action of polyphenols

Social-ecological features of set nets small-scale fisheries in the context of Mediterranean marine protected areas

The small-scale fisheries (SSF) sector has attracted considerable attention over the last decade due to its major importance in sustaining the livelihoods of coastal communities worldwide, poverty alleviation, food security, social wealth and traditions. Despite this importance, quantitative and qualitative information on SSF is still largely lacking and when available, it tends to be scattered or very localized. SSF are also among the very few professional extractive activities generally allowed within Marine Protected Areas (MPAs), and are therefore expected to acquire further momentum in the near future in light of the projected increase of protected marine surface area due to international commitments. However, SSF associated with areas including MPAs may differ from those operating in unprotected contexts with regard to a range of socio-ecological aspects, thus potentially making management strategies currently in force unsuitable, and requiring the development of ad hoc local and regional policies. Here, we assessed the socio-ecological dimension of SSF operating within and around 11 Mediterranean MPAs, in six EU countries, with the aim of identifying relevant patterns that could inform policy and management relative to this fishing sector in view of the forthcoming increase of the marine surface area under protection. To do so, we have adopted a collaborative approach with fishers and combined a photo-sampling survey of 1,292 set net (mainly trammel-nets) fishing operations at landing with 149 semi-structured interviews with fishers, to gather information on features and catches of SSF fleets (e.g. vessel characteristics, gears, catch composition, catch and revenue per unit of effort). Overall, results highlighted: 1) multiple shared features emerging at regional level (i.e. among the 11 study areas), such as the predominant use of set nets, the major contribution of a limited number of species to the overall catch and revenue, the occurrence in the catch of threatened species and/or undersized individuals; 2) a variety of distinctive socio-ecological features differentiating local SSF communities such as the species mainly contributing to catch and revenue, species size distribution and fleet characteristics. In addition to presenting elements to inform common policies and strategies for SSF management in the context of MPAs, our study provides guidance for the development of a standard methodology for the full documentation of SSF in the Mediterranean Sea

The Combination of RAD001 and NVP-BEZ235 Exerts Synergistic Anticancer Activity against Non-Small Cell Lung Cancer In Vitro and In Vivo

The phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling axis has emerged as a novel target for cancer therapy. Agents that inhibit PI3K, mTOR or both are currently under development. The mTOR allosteric inhibitor, RAD001, and the PI3K/mTOR dual kinase inhibitor, BEZ235, are examples of these agents. We were interested in developing strategies to enhance mTOR-targeted caner therapy. In this study, we found that BEZ235 alone effectively inhibited the growth of rapamycin-resistant cancer cells. Interestingly, the combination of sub-optimal concentrations of RAD001 and BEZ235 exerted synergistic inhibition of the growth of human lung cancer cells along with induction of apoptosis and G1 arrest. Furthermore, the combination was also more effective than either agent alone in inhibiting the growth of lung cancer xenografts in mice. The combination showed enhanced effects on inhibiting mTOR signaling and reducing the expression of c-Myc and cyclin D1. Taken together, our results suggest that the combination of RAD001 and BEZ235 is a novel strategy for cancer therapy

The SUMO E3-ligase PIAS1 Regulates the Tumor Suppressor PML and Its Oncogenic Counterpart PML-RARA

The ubiquitin-like SUMO proteins covalently modify protein substrates and regulate their functional properties. In a broad spectrum of cancers, the tumor suppressor PML undergoes ubiquitin-mediated degradation primed by CK2 phosphorylation. Here we report that the SUMO E3-ligase inhibitor PIAS1 regulates oncogenic signaling through its ability to sumoylate PML and the PML-RARA oncoprotein of acute promyelocytic leukemia (APL). PIAS1-mediated SUMOylation of PML promoted CK2 interaction and ubiquitin/proteasome-mediated degradation of PML, attenuating its tumor suppressor functions. In addition, PIAS1-mediated SUMOylation of PML-RARA was essential for induction of its degradation by arsenic trioxide, an effective APL treatment. Moreover, PIAS1 suppression abrogated the ability of arsenic trioxide to trigger apoptosis in APL cells. Lastly, PIAS1 was also essential for PML degradation in non-small cell lung cancer cells, and PML and PIAS1 were inversely correlated in NSCLC cell lines and primary specimens. Together, our findings reveal novel roles for PIAS1 and the SUMOylation machinery in regulating oncogenic networks and the response to leukemia therapy

Multi-Level Targeting of the Phosphatidylinositol-3-Kinase Pathway in Non-Small Cell Lung Cancer Cells

Introduction: We assessed expression of p85 and p110a PI3K subunits in non-small cell lung cancer (NSCLC) specimens and the association with mTOR expression, and studied effects of targeting the PI3K/AKT/mTOR pathway in NSCLC cell lines. Methods: Using Automated Quantitative Analysis we quantified expression of PI3K subunits in two cohorts of 190 and 168 NSCLC specimens and correlated it with mTOR expression. We studied effects of two PI3K inhibitors, LY294002 and NVP-BKM120, alone and in combination with rapamycin in 6 NSCLC cell lines. We assessed activity of a dual PI3K/mTOR inhibitor