Synthesis and preliminary pharmacological characterisation of a new class of nitrogen-containing bisphosphonates (N-BPs)

A new series of bisphosphonates bearing either the nitrogen-containing NO-donor furoxan (1,2,5-oxadiazole 2-oxide) system or the related furazan (1,2,5-oxadiazole) in lateral chain has been developed. pK_a values and affinity for hydroxyapatite were determined for all the compounds. The products were able to inhibit osteoclastogenesis on RAW 246.7 cells at 10 μM concentration. The most active compounds were further assayed on human PBMC cells and on rat microsomes. Unlike most nitrogen-containing bisphosphonates which target farnesyl pyrophosphate synthase, experimental and theoretical investigations suggest that the activity of our derivatives may be related to different mechanisms. The furoxan derivatives were also tested for their ability to relax rat aorta strips in view of their potential NO-dependent vasodilator properties.     

Crystal structure of the blue multicopper oxidase from the white-rot fungus Trametes trogii complexed with p-toluate

A multicopper oxidase, the fungal laccase glycoenzyme from the white-rot basidiomycete fungus Trametes (Funalia) trogii, was crystallized and its crystal structure was solved at 1.58 Å using molecular replacement techniques.Model refinement resulted in R-factor and R-free values of 17.4% and 19.0%, respectively. The T. trogii laccase structural model reveals the presence of a ligand bound to the T1 active site which resembles a p-toluate molecule, such bound compound is most probably a fungal metabolite. The p-toluate is bound into the T1 active site of the laccase forming, with one of the carboxylate oxygens, a H-bond with His455, one of the T1 copper ion ligands, whereas the methyl group presents hydrophobic interactions within a pocket composed by Phe331, Phe336, Pro390 and Val162.The coordination geometries, the bond distances and the oxidation states of the T1 and T2/T3 copper active sites are analyzed and discussed in terms of the enzymatic mechanism and catalytic functionality.     

Laminin-332 (Laminin-5) is the major motility ligand for B cell chronic lymphocytic leukemia.

Cell adhesion and motility are central aspects in the pathophysiology of B cell chronic lymphocytic leukemia (B-CLL), but the role of specific extracellular matrix proteins is still to be completely unveiled. Purified peripheral blood neoplastic cells of B-CLL patients migrated poorly on laminins-111,-411,-511, but showed pronounced motility on laminin (LM)-332 in a high percentage of cases. B-CLL cell motility on LM-332 was mediated by the alpha3beta1 integrin and was preferentially observed in cells carrying a mutated IgV(H) gene profile. Within normal lymph nodes, LM-332 was circumscribed around blood vessels and to areas corresponding to marginal zones, where it was deposited in a pattern reminiscent of reticular fibers. Conversely, in B-CLL involved lymph nodes, a positive LM-332 reticular mesh was diffusely evident, throughout the disrupted nodal architecture. In the present study we identified LM-332 as a crucial motility-promoting factor for B-CLL lymphocytes and as a potential constituent favoring the dissemination of B-CLL lymphocytes through vascular basement membranes and possibly lymph node compartments.     

Spiral valve parasites of blue and common thresher sharks as indicators of shark feeding behaviour and ecology

This study documented the parasite faunas of the spiral valves of blue sharks Prionace glauca (L. 1758) and common thresher sharks Alopias vulpinus (Bonnaterre, 1788) caught in the California Current Large Marine Ecosystem (CCLME) north of the Mexican border. The spiral valves of 18 blue and 19 thresher sharks caught in the CCLME from 2009 to 2013 were examined for parasites. Seven parasite taxa were found in blue sharks and nine in threshers. The tetraphyllidean cestode Anthobothrium sp. (78% prevalence) was the most common parasite in blue sharks, and the phyllobothriid cestode Paraorygmatobothrium sp. (90% prevalence) was the most common in threshers. An adult nematode of the genus Piscicapillaria was found in threshers for the first time and may be a new species. Adult individuals of Hysterothylacium sp. were found in both shark species. The adult acanthocephalan Rhadinorhynchus cololabis and remains of the parasitic copepod Pennella sp. – both parasites of Pacific saury, Cololabis saira – were found in the intestines of threshers, indicating recent feeding on saury. This study paves the way for a more comprehensive examination, including more samples and a wider variety of shark species, to provide a greater understanding of shark feeding behaviour and possibly provide information on shark population biology.     

Evolution of the metal hyperaccumulation and hypertolerance traits

To succeed in life, living organisms have to adapt to the environmental issues to which they are subjected. Some plants, defined as hyperaccumulators, have adapted to metalliferous environments, acquiring the ability to tolerate and accommodate high amounts of toxic metal into their shoot, without showing symptoms of toxicity. The determinants for these traits and their mode of action have long been the subject of research, whose attention lately moved to the evolution of the hypertolerance and hyperaccumulation traits. Genetic evidence indicates that the evolution of both traits includes significant evolutionary events that result in species-wide tolerant and accumulating backgrounds. Different edaphic environments are responsible for subsequent refinement, by local adaptive processes, leading to specific strategies and various degrees of hypertolerance and hyperaccumulation, which characterize metallicolous from non-metallicolous ecotypes belonging to the same genetic unit. In this review, we overview the most updated concepts regarding the evolution of hyperaccumulation and hypertolerance, highlighting also the ecological context concerning the plant populations displaying this fascinating phenomenon.     

C‐terminal tails mimicking bioactive intermediates cause different plasma degradation patterns and kinetics in neuropeptides γ‐MSH, α‐MSH,and neurotensin

Peptides are attractive drugs because of their specificity and minimal off‐target effects. Short half‐lives are within their major drawbacks, limiting actual use in clinics. The golden standard in therapeutic peptide development implies identification of a minimal core sequence, then modified to increase stability through several strategies, including the introduction of nonnatural amino acids, cyclization, and lipidation. Here, we investigated plasma degradations of hormone sequences all composed of a minimal active core peptide and a C‐terminal extension. We first investigated pro‐opimelanocortin (POMC) γ2/γ3‐MSH hormone behavior and extended our analysis to POMC‐derived α‐melanocyte stimulating hormone/adrenocorticotropic hormone signaling neuropeptides and neurotensin. We demonstrated that in all the three cases analyzed in this study, few additional residues mimicking the natural sequence alter both peptide stability and the mechanism(s) of degradation of the minimal conserved functional pattern. Our results suggest that the impact of extensions on the bioactivity of a peptide drug has to be carefully evaluated throughout the optimization process.