Caspase-3 activation in human melanoma A375 cell line by a novel selective sigma-2 agonist.

Two novel 8-azabicyclo[3.2.1]octan-3-ol derivatives, 11a and 11b, with high affinity for sigma-2 receptors and a very good sigma-1/sigma-2 selectivity ratio were synthesized. In comparison with several well established sigma-2 selective ligands, 11 b showed a very low sigma-1 receptor affinity. Functional assays demonstrated that 11b acts as an agonist and in A-375 human melanoma cell line is able to lower levels of procaspase-3, thus confirming a potential major role for sigma-2 pure agonists in the treatment of rapid proliferating melanoma cells.

Biological properties of Cakile maritima Scop. (Brassicaceae) extracts.

OBJECTIVE: Cakile maritima scop. (CKM) is a herbaceous plant (Brassicaceae) growing also in high salinity environment. It is an annual plant growing in clumps or mounds in the sand on beaches and bluffs. MATERIALS AND METHODS: Stems, seeds, leaves and flowers of CKM were used to obtain 70% of ethanol extracts. The phenolic content of the different extracts was evaluated by the Folin-Ciocalteu method. The separation of phytochemical compounds was based on ultra-performance liquid chromatography coupled to mass spectrometry. Radical scavenging activity was determined by 1,1-diphenyl-2-picrylhydrazyl assay. The qualitative assay for the inhibition of α-glucosidase was quantified spectrophotometrically and the anti-inflammatory activity was determined in the U937 cell line by using gene expression of pro-inflammatory cytokines. Cell viability assay was done in U937, MM1S, and U266 cells by using the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. The antimicrobial activity was investigated by MIC determination, "double-triple combinations assay", and growth inhibition curves analysis, using the extracts individually or in various combination. Statistical analysis was performed by the Student's t-test and ANOVA. RESULTS: All parts of the plant exhibited a high antioxidant capacity as measured by DPPH assay. Furthermore, all extracts reduced (about 10 folds) the expression of inflammatory cytokines in macrophage following LPS treatment. As regards the antibacterial activity, only the seeds extract was able to inhibit both Gram-negative and Gram-positive bacteria when tested alone, whereas dual combinations of different extracts (leaves, flowers, stems and seeds) caused bacterial inhibition exhibiting a synergic action. Finally, we showed that the extracts did not exhibit cytotoxic effects in normal cells and that, surprisingly, it exhibited an anti-proliferative effect (inhibition ≈80%) in multiple myeloma U266 cells. CONCLUSIONS: Our study suggests that CKM possesses antioxidant, anti-inflammatory, antibacterial, anti-proliferative activities and such pleiotropic effects may be exploited under various pathological conditions.

Effect of hyaluronic acid and polysaccharides from Opuntia ficus indica (L.) cladodes on the metabolism of human chondrocyte cultures.

Conventional medications in articular disease are often effective for symptom relief, but they can also cause significant side effects and do not slow the progression of the disease. Several natural substances have been shown to be effective as non-steroidal anti-inflammatory drugs at relieving the symptoms of osteoarthritis (OA), and preliminary evidence suggests that some of these compounds may exert a favourable influence on the course of the disease. In this study, we assay the anti-inflammatory/chondroprotective effect of some lyophilised extracts obtained from Opuntia ficus indica (L.) cladodes and of hyaluronic acid (HA) on the production of key molecules released during chronic inflammatory events such as nitric oxide (NO), glycosaminoglycans (GAGs), prostaglandins (PGE(2)) and reactive oxygen species (ROS) in human chondrocyte culture, stimulated with proinflammatory cytokine interleukin-1 beta (IL-1 beta). Further the antioxidant effect of these extracts was evaluated in vitro employing the bleaching of the stable 1,1-diphenyl-2-picrylhydrazyl radical (DPPH test). All the extracts tested in this study showed an interesting profile in active compounds. Particularly some of these extracts were characterized by polyphenolic and polysaccharidic species. In vitro results pointed out that the extracts of Opuntia ficus indica cladodes were able to contrast the harmful effects of IL-1 beta. Our data showed the protective effect of the extracts of Opuntia ficus indica cladodes in cartilage alteration, which appears greater than that elicited by hyaluronic acid (HA) commonly employed as visco-supplementation in the treatment of joint diseases.

New benzomorphan derivatives of MPCB as MOP and KOP receptor ligands.

There is considerable interest in developing KOP Opioid receptor ligands as clinically useful analgesics. Moreover, compounds with mixed KOP receptor and mu-opioid peptide (MOP) receptor agonist/antagonist properties could have a better therapeutic potential. The benzomorphan-based synthetic ligands MPCB and CCB have been shown to bind KOP receptors with high affinity and selectivity. We report here a series of compounds synthesized to perform structure-affinity relationship (SAR) studies on MPCB. The aim of this study was to optimise KOP receptor-ligand interaction and to modulate MOP receptor selectivity. In the benzylamide analogue of MPCB (compound 9) the presence of a third aromatic nucleus, at an appropriate distance and conformation with respect to aromatic pharmacophoric residues, increased KOP receptor affinity by about 6-fold compared to MPCB (Ki = 35 nM and Ki = 240 nM, respectively). Instead, compound 28 with a tertiary amino group in the nitrogen substituent displayed a comparable KOP receptor affinity (Ki = 179 nM) but also high MOP receptor affinity (Ki = 45 nM). Thus, the present study shows that in benzomorphan-based ligands the presence of different functional groups in the nitrogen substituent, ranging from a positive charged amine to an additional aromatic ring, is able to promote the correct aligment of aromatic pharmacophoric residues with MOP and KOP receptor types. Evaluation of docking simulations of compounds 9 and 28 into the KOP and MOP receptor displayed selective ligand interactions with the important amino acid residues Tyr320 (TMVII) and Trp318 (TMVII), respectively.

"In vitro" differences among (R) and (S) enantiomers of profens in their activities related to articular pathophysiology.

An important group of non steroidal antinflammatory drugs (NSAIDs), which have been used for the symptomatic treatment of various forms of arthritis, are the 2-arylpropionic acid derivatives, 'profens'. By virtue of a chiral carbon atom on the propionic acid side chain, they exist as enantiomeric pairs. Whereas the S (+) enantiomer could be represented as an effective, but unselective COX inhibitor, the R (-) enantiomer could be much less active in this respect. However, recent findings suggest that certain pharmacological effects of profens cannot be attributed exclusively to the S (+) enantiomer. To obtain further insights into the pharmacological effects of profens, this study investigated the influence of pure enantiomers (S), (R), and racemic flurbiprofen and ketoprofen on the production of NO, MMP-3, PGE(2), ROS and GAGs, key molecules involved in cartilage destruction. Our results show that (S) flurbiprofen and ketoprofen decrease, at 1- and 10-microM concentrations, the interleukin-1beta induced cartilage destruction.

Design and synthesis of new bifunctional sigma-1 selective ligands with antioxidant activity.

Herein we report the synthesis of new bifunctional sigma-1 (σ1)-selective ligands with antioxidant activity. To achieve this goal, we combined the structure of lipoic acid, a universal antioxidant, with an appropriate sigma aminic moiety. Ligands 14 and 26 displayed high affinity and selectivity for σ1 receptors (Kiσ1 = 1.8 and 5.5 nM; Kiσ2/σ1 = 354 and 414, respectively). Compound 26 exhibited in vivo antiopioid effects on kappa opioid (KOP) receptor-mediated analgesia. In rat liver and brain mitochondria (RLM, RBM), this compound significantly reduced the swelling and the oxidation of thiol groups induced by calcium ions. Our results demonstrate that the tested compound has protective effects against oxidative stress.

Fournier's gangrene following a perianal abscess.

Fournier's disease is an uncommon form of gas gangrene involving the scrotum and perineum. Described by Fournier as an idiopathic condition, it must be recognized as a synergistic gangrene secondary, in most cases, to a focus of perianal infection. Urinary tract infection and local trauma follow as possible causal factors. Five cases complicating a perianal abscess observed in a period of 11 years have been treated with urgent aggressive surgical debridement and intensive care support. Full-thickness skin grafts were required in three patients. Hospital mortality occurred in one case. Although combination antibiotic therapy and correct postoperative wound management are potentially successful, the mainstay of treatment is complete excision of all necrotic tissue. Colostomy and urinary diversion are not mandatory. Treatment with hyperbaric oxygen is controversial.