Interplay Between Endocannabinoid System and Neurodegeneration: Focus on Polypharmacology

Pharmacological treatment of complex pathologies, such as neurodegenerative diseases still represents a major challenge, due to the networked pathways involved in their onset and progression that may require equally complex therapeutic approaches. Polypharmacology, based on the simultaneous modulation of multiple targets involved in the disease, may offer the potential to increase effectiveness and reduce the drawbacks related to the use of drug combinations. Clearly, this approach requires both the knowledge of the systems responsible for disease development and the discovery of new attractive targets to be exploited to design a multitarget drug. Over the last years, an ever increasing interest has focused on the endocannabinoid system, implicated in the modulation of several physiological functions, among which neuroinflammation, a crucial process for most neurodegenerative diseases. In this respect, the cannabinoid receptor subtype 2 represents a promising therapeutic target, being overexpressed in microglia cells and thus involved in neuroinflammation. The indirect modulation of this system through the inhibition of the main enzymes responsible for endocannabinoids metabolism, namely fatty acid amide hydrolase and monoacylglycerol lipase, may also significantly affect neurodegenerative processes. The aim of this review is to give an overview of the opportunities posed by the endocannabinoid system for neurodegenerative diseases management, mainly focusing on the potential for a multitarget strategy

Foliar treatment of esca-proper affected vines with nutrients and bioactivators

Foliar treatment with nutrients and bioactivators was carried out in two vineyards affected with esca proper in 2004 and 2005. Changes in the foliar symptoms and in the quality of berries without lesions from treated symptomatic vines were assessed. Treated vines unexpectedly had a higher incidence and a greater severity of symptomatic leaves than untreated plants, most likely because physiological processes were stimulated by the treatments, possibly also because treatments facilitated the movement of toxins produced by the wood fungi of esca. However it cannot be excluded that the increase in foliar symptoms was due to the forced nutrition causing an imbalance between the various elements, and altering the mechanisms that vines use for the remission of foliar symptoms. This supposition seemed corroborated by the observation that treated vines diseased with esca proper had a weaker defense response than untreated diseased vines, and that treated diseased vines had lower levels of nitrogen and microelements, which are respectively involved in osmoregulation and as cofactors of enzymes involved in the defense response of the plant. The main quality parameters of berries without lesions from treated and untreated symptomatic vines were very similar

Innovative approach for a classic target: fragment screening on trypanothione reductase reveals new opportunities for drug design

Trypanothione reductase (TR) is a key factor in the redox homeostasis of trypanosomatid parasites, critical for survival in the hostile oxidative environment generated by the host to fight infection. TR is considered an attractive target for the development of new trypanocidal agents as it is essential for parasite survival but has no close homolog in humans. However, the high efficiency and turnover of TR challenging targets since only potent inhibitors, with nanomolar IC50, can significantly affect parasite redox state and viability. To aid the design of effective compounds targeting TR, we performed a fragment-based crystal screening at the Diamond Light Source XChem facility using a library optimized for follow-up synthesis steps. The experiment, allowing for testing over 300 compounds, resulted in the identification of 12 new ligands binding five different sites. Interestingly, the screening revealed the existence of an allosteric pocket close to the NADPH binding site, named the "doorstop pocket" since ligands binding at this site interfere with TR activity by hampering the "opening movement" needed to allow cofactor binding. The second remarkable site, known as the Z-site, identified by the screening, is located within the large trypanothione cavity but corresponds to a region not yet exploited for inhibition. The fragments binding to this site are close to each other and have some remarkable features making them ideal for follow-up optimization as a piperazine moiety in three out of five fragments

Effect of Esca on the Quality of Berries, Musts and Wines

Variations in the composition of berries, musts and wines in three groups of vines: 1. vines with foliar esca symptoms; 2. asymptomatic esca diseased vines; and 3. healthy vines, were studied in 2001 and 2002 in two “Trebbiano d’Abruzzo” vineyards in the Abruzzi region, Italy, to determine the effect of esca. Vines were grouped by foliar symptoms that had been recorded in annual inspections for 10 years: symptomatic vines by definition showed foliar symptoms in the sampling years (2001 and 2002); asymptomatic esca diseased vines showed no symptoms during the sampling years though they were known to be diseased because they had had foliar symptoms in at least one previous annual inspections; healthy vines were those with no symptoms at any time during the 10-year survey. The quality of berries, musts and wines obtained from vines with trunk renewal that had been restored, and of healthy unrenewed vines was compared in another vineyard of the same cultivar. Fairly similar results were obtained over the two sampling years, with a strong reduction in sugar levels of the must from symptomatic vines, leading to a lower ethanol content in the wine made from that must. These findings confirmed those of the preliminary investigation carried out in 2000. The yield pressed from symptomatic vines also had significantly higher levels of malic acid (causing higher total acidity), and of total nitrogen, potassium and total polyphenols. Berries from symptomatic vines had much higher levels of trans-resveratrol, possibly because of the spots on the leaves and berries. Small and non-significant differences between the yields of healthy vines and asymptomatic diseased vines were found, suggesting a slight loss in the quality of musts and wines from asymptomatic diseased vines. The yield of trunk-renewed vines was similar to that of healthy unrenewed vines, despite an increase of trans-resveratrol in the berries and of total nitrogen in the must of the trunk-renewed vines

Selectivity in multiple multicomponent reactions: Types and synthetic applications

Multiple multicomponent reactions reach an unparalleled level of connectivity, leading to highly complex adducts. Usually, only one type of transformation involving the same set of reactants takes place. However, in some occasions this is not the case. Selectivity issues then arise, and different scenarios are analyzed. The structural pattern of the reactants, the reaction design and the experimental conditions are the critical factors dictating selectivity in these processes

Nutritional status of vines afected with esca proper

A vineyard of the cv. Trebbiano d’Abruzzo located in Abruzzo, Italy,  was monitored for more than ten years to distinguish healthy vines not only from vines with the visual leaf symptoms of esca, but also from those vines that were esca-infected but did not produce any visual symptoms for one or more growing seasons. In the period 2004–2006, leaves and berries were collected at four phenological growth stages from three groups of vines: healthy vines, infected vines showing esca symptoms, and infected vines that did not show symptoms. The macro and micro-elements of the leaves and berries, and the quality parameters of the must were determined. Esca did not seem to affect nutrient uptake in the vines. Nevertheless there were some differences in the nutrient levels of the leaves between healthy and diseased vines consistent with the degradation of the leaf blade caused by esca. Berries from symptomatic vines were less ripe at the time of harvesting and therefore had higher levels of mineral elements. These berries also had higher levels of nitrogen, which are thought to be associated with the defence response of diseased vines to esca, as are higher levels of iron in the leaves of diseased vines. The study confirmed earlier findings that fruit composition did not differ greatly between healthy and diseased-but-asymptomatic vines. In the three-year study period there were differences in the incidence of leaf symptoms and differences in nutrient levels attributable to fertiliser applications and rainfall. These differences suggested that the amount of mineral nutrients affected the onset of esca symptoms: a higher availability of nutrients in a growing season increased the proportion of diseased vines with symptoms and lowered the proportion of diseased vines without symptoms, whereas in a growing season with the lower levels of  water and potassium, the yield was reduced, but this was accompanied by an increase in the proportion of diseased vines without symptoms. It is suggested that a higher availability of nutrients for diseased vines lowers the resistance of these vines and, by improving the nutrition not only of the vines themselves but also of the esca fungi, increase fungal virulence, as a result of which there is a greater incidence of diseased vines showing leaf symptoms

The Prickle Effect Comes From Fabrics Made of South American Camelid (Alpaca and Lama) Fibers. Mechanical and/or Genetic Solutions.

In this paper we intends to analyze the physical attributes that determine the comfort of fabrics made of South American Camelid fibers (Lama and Alpaca), the effect on their value and their possible mechanical and/or genetic solutions. While emphasis has always been on mean fiber diameter, the fiber frequency exceeding 30 microns has a key role in quality. This is essential for light fabrics, where the effect of prickle plays a critical part in consumer´s choice. Yet the genetic solution of the problem lies in the slow selection response. Dehairing provides an immediate solution, though excessive fiber breakage should be addressed. It is concluded that the textile fiber quality of South American Camelids is promissory if the presence of objectionable fibers is solved, resulting in a tolerable frequency for consumers (<3%). This process could be explored via genetic selection or applying dehairing technology. This implies a true paradigm shift with regard to the classic textile processing of Alpaca and Lama fibers. This would enhance the fiber softness to touch, together with other important features that would render the fiber price more competitive