D-mannose suppresses macrophage IL-1β production

D-mannose is a monosaccharide approximately a hundred times less abundant than glucose in human blood. Previous studies demonstrated that supraphysiological levels of D-mannose inhibit tumour growth and stimulate regulatory T cell differentiation. It is not known whether D-mannose metabolism affects the function of non-proliferative cells, such as inflammatory macrophages. Here, we show that D-mannose suppresses LPS-induced macrophage activation by impairing IL-1β production. In vivo, mannose administration improves survival in a mouse model of LPS-induced endotoxemia as well as decreases progression in a mouse model of DSS-induced colitis. Phosphomannose isomerase controls response of LPS-activated macrophages to D-mannose, which impairs glucose metabolism by raising intracellular mannose-6-phosphate levels. Such alterations result in the suppression of succinate-mediated HIF-1α activation, imposing a consequent reduction of LPS-induced Il1b expression. Disclosing an unrecognized metabolic hijack of macrophage activation, our study points towards safe D-mannose utilization as an effective intervention against inflammatory conditions

Rat pial microvascular responses to melatonin during bilateral common carotid artery occlusion and reperfusion

The present study assessed the in vivo rat pial microvascular responses induced by melatonin during brain hypoperfusion and reperfusion (RE) injury. Pial microcirculation of male Wistar rats was visualized by fluorescence microscopy through a closed cranial window. Hypoperfusion was induced by bilateral common carotid artery occlusion (BCCAO, 30 min); thereafter, pial microcirculation was observed for 60 min. Arteriolar diameter, permeability increase, leukocyte adhesion to venular walls, perfused capillary length (PCL), and capillary red blood cell velocity (V(RBC) ) were investigated by computerized methods. Melatonin (0.5, 1, 2 mg/kg b.w.) was intravenously administered 10 min before BCCAO and at the beginning of RE. Pial arterioles were classified in five orders according to diameter, length, and branchings. In control group, BCCAO caused decrease in order 2 arteriole diameter (by 17.5 ± 3.0% of baseline) that was reduced by 11.8 ± 1.2% of baseline at the end of RE, accompanied by marked leakage and leukocyte adhesion. PCL and capillary V(RBC) decreased. At the end of BCCAO, melatonin highest dosage caused order 2 arteriole diameter reduction by 4.6 ± 2.0% of baseline. At RE, melatonin at the lower dosages caused different arteriolar responses. The highest dosage caused dilation in order 2 arteriole by 8.0 ± 1.5% of baseline, preventing leakage and leukocyte adhesion, while PCL and V(RBC) increased. Luzindole (4 mg/kg b.w.) prior to melatonin caused order 2 arteriole constriction by 12.0 ± 1.5% of baseline at RE, while leakage, leukocyte adhesion, PCL and V(RBC) were not affected. Prazosin (1 mg/kg b.w.) prior to melatonin did not significantly change melatonin's effects. In conclusion, melatonin caused different responses during hypoperfusion and RE, modulating pial arteriolar tone likely by MT1 and MT2 melatonin receptors while preventing blood-brain barrier changes through its free radical scavenging action

TOURISM INTEGRATED RELATIONAL AND ENVIRONMENTALLY SUSTAINABLE IN THE MEDITERRANEAN: AN UTOPIA OR A NECESSARY STRATEGY FOR DEVELOPMENT?

ABSTRACT: A first question we can ask is this: The European Community will be able, despite the diversity of cultural and religious traditions of various civilizations that make up the mosaic Euro-Mediterranean Partnership, to recover the values deep and genuine so well exposed by Fernand Braudel, in order to counter the current dominance of the processes of globalization and the effect of spatial concentration in accordance with the rules of the so-called free market (land, buildings, services and infrastructure for the mobility)? New entry into the Community to bring greater security (only apparent) in investments for companies and families (which also affect tourism and the mainly residential on seasonal o the investment on brick), which is used to launch forms of speculation in marginal areas but especially with coastal environmental resources. These initial concentrations are in need of infrastructure networks and therefore proposes the mechanism of traffic and vehicle contract which, if you manage to have a minimal economic and social return, leading inevitably to a congestion and pollution of the area, and to a diffuse spatial to depletion of environmental resources available. At this point there is a certain abandonment and speculative greed will find more beaches, and perhaps there will only groups of residents or desertification will return in time to dominate (maybe it was not possible to produce historical values). On environmental resources and local communities which will be the effects? This is a model of sustainable tourism development? What is happening in Egypt and Morocco? A second question is: These processes undoubtedly involve, in addition to private operators including national and local governments and then the various systems of organization and management of the territory, the different types of plans and programs and procedures for evaluation and participation. There is a creeping globalization that can influence the behavior of the different actors involved (unfortunately also the so-called cultural and professional circles) and in the name of profit and financial unifies the different cultural and religious traditions? The ultimate goal is improving the quality of life for all (or a few in different parts of the world) but what the environmental effects and irreversibility on free use of resources and real participatory democracy? The European Community as it might encourage virtuous behavior inside and in the relationship? Should be the most developed countries to change their pattern of behavior and development, not statements of principle but with real effectiveness, and therefore propose the economic and financial partnership provided that the reference models are those of tourism integrated, relational and environmentally sustainable. If we see what is happening in Italy (including Sicily) we certainly can not say that we give an example. A third question is: If we consider tourism as a necessity of freedom, to nomadism, knowledge of people and different environments, then not locked it on the management company, in a hasty desire to offer more consumer can, in a new urban environments and building of poor quality or artificial, but help to spread freely in local communities and in nature (in security and knowledge) to become an integral and non-fictional superstructure, improving mobility and maritime railway in Euro-Mediterranean Basin, with their inter-nodes and places of rest and services, environmentally sustainable and capable of integration, retraining and catching, the architectural and urban contexts existing historic

LA SOSTENIBILITÀ DELL’USO DEL SUOLO, LA VAS E LA GESTIONE DEL TERRITORIO, CON ALCUNI RIFERIMENTI ALLA REGIONE VENETO ED ALLA SICILIA

Sommario Il problema nazionale, ma soprattutto meridionale ed in particolare della Regione Sicilia, della necessità di un approccio olistico, etico, civico ed interdisciplinare alla formazione di piani e programmi d’interesse pubblico, porta alla necessità di una formazione complessa scientifica ed umanistica. In particolare è strategico intersecare l’atteggiamento formativo ed applicativo delle progettualità ingegneristico-architettoniche con quello dei sistemi di conoscenza, valutazione sociale, economica ed ambientale, delle strutture organizzative e della programmazione economica. Occorrono competenze interdisciplinari con riferimento alle problematiche degli indicatori territoriali, ambientali e socio-economici per la costruzione del processo di conoscenza, interpretazione, valutazione delle condizioni esistenti e per la costruzione degli scenari di sviluppo locale sostenibile e la loro verifica di compatibilità nel sistema di pianificazione e programmazione multilivello. E’ un sistema complesso, articolato su tre livelli principali, la cui cerniera nell’integrazione fra pianificazione fisica del territorio e programmazione strategica socio-economica, dovrà essere una provincia regionale, più efficace ed efficiente, ridando forza e qualità al governo pubblico e partecipato del territorio. Occorre riorganizzare il processo di pianificazione-programmazione-attuazione e monitoraggio del sistema pubblico multilivello ed il sistema di conoscenza-interpretazione-valutazione-partecipazione-decisione-attuazione, proponendo un modello operativo di riferimento. Definire indicatori territoriali, ambientali e socio-economici per la costruzione di un DataWarehouse, comprendente un Sistema Informativo Territoriale Regionale (SITR), un Sistema di Supporto alle Decisioni (DSS) ed una procedura, definita mediante un PERT, che possa connettere le diverse fasi, con tempi ed obiettivi di riferimento, nodi critici di copianificazione, verifica e concertazione, d’informazione e partecipazione democratica. Occorrerà: Organizzare e gestire SIT, uffici di piano e programmazione con nuclei operativi interdisciplinari, supportati dalla consulenza esterna di centri di ricerca universitari ed associazioni pubbliche e private, d’ausilio alle politiche sia nelle fasi interattive di problem setting che in quelle di problem solving. Definire il ruolo centrale regionale nel sistema integrato multilivello nazionale ed internazionale, per la formazione dei quadri strutturali e strategici interni ed esterni. Stabilire le procedure di copianificazione dei sistemi urbani locali ai fini della qualità e sostenibilità insediativa delle comunità locali con la garanzia della forma strutturale di medio e lungo periodo fornita dalla formazione d’Unioni di Comuni. Tutelare le forme di pianificazione del paesaggio, sulla base degli indirizzi regionali, in coerenza con i valori culturali, materiali ed immateriali locali e con i mosaici colturali e delle naturalità, espresse e potenziali. Predisporre progetti integrati locali e d’area vasta, all’interno di scenari programmati nel piano territoriale strategico, in coerenza con gli indirizzi programmatori ed i quadri strutturali e strategici regionali ed internazionali. Definire la Valutazione di Sostenibilità territoriale ed ambientale, Valsat o Vas, riferita agli indicatori ambientali d’area vasta e di contesto, all’efficacia ed efficienza del sistema degli interventi previsti, ai criteri di sostenibilità territoriale, ambientale e socio-economica e della qualità territoriale-urbanistica ed ambientale-paesaggistica. Approccio Prevalente: Metodologic

BCAM and LAMA5 Mediate the Recognition between Tumor Cells and the Endothelium in the Metastatic Spreading of KRAS Mutant Colorectal Cancer

PURPOSE: KRAS mutations confer adverse prognosis to CRC and no targeted therapies have shown efficacy in this patient subset. Paracrine, nongenetic events induced by KRAS mutant tumor cells are expected to result in specific deregulation and/or relocation of tumor microenvironment (TME) proteins, which in principle can be exploited as alternative therapeutic targets. EXPERIMENTAL DESIGN: A multimodal strategy combining ex-vivo/in vitro phage display screens with deep-sequencing and bioinformatics was applied to uncover TME-specific targets in KRAS mutant hepatic metastasis from CRC. Expression and localization of BCAM and LAMA5 were validated by immunohistochemistry in preclinical models of human hepatic metastasis and in a panel of human specimens (n=71). The anti-metastatic efficacy of two BCAM-mimic peptides was evaluated in mouse models. The role of BCAM in the interaction of KRAS mutant CRC cells with TME cells was investigated by adhesion assays. RESULTS: BCAM and LAMA5 were identified as molecular targets within both tumor cells and TME of KRAS mutant hepatic metastasis from CRC, where they were specifically overexpressed. Two BCAM-mimic peptides inhibited KRAS mutant hepatic metastasis in preclinical models. Genetic suppression and biochemical inhibition of either BCAM or LAMA5 impaired adhesion of KRAS mutant CRC cells specifically to endothelial cells while adhesion to pericytes and hepatocytes was unaffected. CONCLUSIONS: These data show that the BCAM/LAMA5 system plays a functional role in the metastatic spreading of KRAS mutant CRC by mediating tumor-TME interactions, and as such represents a valuable therapeutic candidate for this large, currently untreatable patient group