Anti-Inflammatory Activity of a CB2 Selective Cannabinoid Receptor Agonist: Signaling and Cytokines Release in Blood Mononuclear Cells

The endocannabinoid system (ECS) exerts immunosuppressive effects, which are mostly mediated by cannabinoid receptor 2 (CBR2), whose expression on leukocytes is higher than CBR1, mainly localized in the brain. Targeted CBR2 activation could limit inflammation, avoiding CBR1-related psychoactive effects. Herein, we evaluated in vitro the biological activity of a novel, selective and high-affinity CBR2 agonist, called JT11, studying its potential CBR2-mediated anti-inflammatory effect. Trypan Blue and MTT assays were used to test the cytotoxic and anti-proliferative effect of JT11 in Jurkat cells. Its pro-apoptotic activity was investigated analyzing both cell cycle and poly PARP cleavage. Finally, we evaluated its impact on LPS-induced ERK1/2 and NF-kB-p65 activation, TNF-α, IL-1β, IL-6 and IL-8 release in peripheral blood mononuclear cells (PBMCs) from healthy donors. Selective CB2R antagonist SR144528 and CBR2 knockdown were used to further verify the selectivity of JT11. We confirmed selective CBR2 activation by JT11. JT11 regulated cell viability and proliferation through a CBR2-dependent mechanism in Jurkat cells, exhibiting a mild pro-apoptotic activity. Finally, it reduced LPS-induced ERK1/2 and NF-kB-p65 phosphorylation and pro-inflammatory cytokines release in human PBMCs, proving to possess in vitro anti-inflammatory properties. JT11 as CBR2 ligands could enhance ECS immunoregulatory activity and our results support the view that therapeutic strategies targeting CBR2 signaling could be promising for the treatment of chronic inflammatory diseases.     

On using an automatic scheme for obtaining the convex hull defining inequalities of a Weismantel 0–1 knapsack constraint

In this short note we obtain the full set of inequalities that define the convex hull of a 0–1 knapsack constraint presented in Weismantel (1997). For that purpose we use our O(n) procedures for identifying maximal cliques and non-dominated extensions of consecutive minimal covers and alternates, as well as our schemes for coefficient increase based tightening cover induced inequalities and coefficient reduction based tightening general 0–1 knapsack constraints.     

<Emphasis Type="Italic">k</Emphasis>–Pyramidal One–Factorizations

We consider one–factorizations of complete graphs which possess an automorphism group fixing k ≥ 0 vertices and acting regularly (i.e., sharply transitively) on the others. Since the cases k = 0 and k = 1 are well known in literature, we study the case k≥ 2 in some detail. We prove that both k and the order of the group are even and the group necessarily contains k − 1 involutions. Constructions for some classes of groups are given. In particular we extend the result of [7]: let G be an abelian group of even order and with k − 1 involutions, a one–factorization of a complete graph admitting G as an automorphism group fixing k vertices and acting regularly on the others can be constructed.     

Computational approaches to shed light on molecular mechanisms in biological processes

Computational approaches based on Molecular Dynamics simulations, Quantum Mechanical methods and 3D Quantitative Structure-Activity Relationships were employed by computational chemistry groups at the University of Milano-Bicocca to study biological processes at the molecular level. The paper reports the methodologies adopted and the results obtained on Aryl hydrocarbon Receptor and homologous PAS proteins mechanisms, the properties of prion protein peptides, the reaction pathway of hydrogenase and peroxidase enzymes and the defibrillogenic activity of tetracyclines.     

Yttrium Geothermometry Applied to Garnets from Different Metamorphic Grades Analysed by EPMA and µ-PIXE Techniques

We present a multi-analytical and multi-instrumental approach to a petrologic study of garnets from metapelites characterized by different metamorphic grades. The comparison between major, minor and trace element (Y) distribution in garnets crystallized at different temperatures was performed by electron microprobe (EDS and WDS) and the Proton Induced X-ray Emission microprobe (μ-PIXE). Two garnet samples were selected from metapelite rocks at different metamorphic grades from the tectonic unit of Stilo, Calabrian–Peloritanian Arc, Southern Italy. Quantitative spot analysis profiles and compositional X-ray maps of major elements and yttrium are reported. The major element zoning of garnets is mostly characterized by a smoothed and gradual concentric variation of all elements from core to rim. The Y concentration reveals a marked zoning with its distribution decreasing from about 7000 ppm to about 100 ppm from core to rim, respectively. The precise determination of the Y content by μ-PIXE technique allowed us to better define the rock thermal history, by applying the Y geothermometer. In particular, a common starting temperature of about 450 °C was calculated for the beginning of the garnet growth from all over the unit, but different temperatures in the range from 520 °C to 670 °C were estimated for the peak event in garnets from different areas, in agreement with the P–T values given by the main rock mineral assemblages, reflecting a different metamorphic grade.     

Asymmetric synthesis of (R)- and (S)-4-methyloctanoic acids. A new route to chiral fatty acids with remote stereocenters

The enantioselective synthesis of both enantiomers of 4-methyloctanoic acid, one major aggregation pheromone component of the rhinoceros beetles of the genus Oryctes and an important aroma compound, is described. The key step of the synthesis is based on a stereospecific alkylation with an alcohol-protected alkyl iodide using a pseudoephedrine derivative as a chiral auxiliary followed by subsequent removal of the auxiliary. Both enantiomers are obtained in excellent yields and enantioselectivities (93–94% ee). The strategy outlined allows preparation of a wide variety of enantiopure methyl-branched saturated and unsaturated fatty acids.     

Transformation of incidence structures and sharply multiply transitive permutation sets

In this note we generalize the transformation process introduced in [8]. This generalization allows to find the nonplanar nearfield discovered by H.Karzel and W.Kerby, [5], [6], and the affine Andrè planes.Dedicated to Prof. A.Barlotti and to Prof. L.A.Rosati on their 70th birthdayWork performed under the auspicies of G.N.S.A.G.A. and supported by 40% grants of M.U.R.S.T.     

Nilpotent 1‐factorizations of the complete graph

For which groups G of even order 2n does a 1‐factorization of the complete graph K_2n exist with the property of admitting G as a sharply vertex‐transitive automorphism group? The complete answer is still unknown. Using the definition of a starter in G introduced in 4 , we give a positive answer for new classes of groups; for example, the nilpotent groups with either an abelian Sylow 2‐subgroup or a non‐abelian Sylow 2‐subgroup which possesses a cyclic subgroup of index 2. Further considerations are given in case the automorphism group G fixes a 1‐factor. © 2005 Wiley Periodicals, Inc. J Combin Designs