Integrin-mediated adhesive properties of neutrophils are reduced by hyperbaric oxygen therapy in patients with chronic non-healing wound.

In recent years, several studies suggested that the ability of hyperbaric oxygen therapy (HBOT) to promote healing in patients with diabetic ulcers and chronic wounds is due to the reduction of inflammatory cytokines and to a significant decrease in neutrophils recruitment to the damaged area. α4 and ß2 integrins are receptors mediating the neutrophil adhesion to the endothelium and the comprehension of the effects of hyperbaric oxygenation on their expression and functions in neutrophils could be of great importance for the design of novel therapeutic protocols focused on anti-inflammatory agents. In this study, the α4 and ß2 integrins' expression and functions have been evaluated in human primary neutrophils obtained from patients with chronic non-healing wounds and undergoing a prolonged HBOT (150 kPa per 90 minutes). The effect of a peptidomimetic α4ß1 integrin antagonist has been also analyzed under these conditions. A statistically significant decrease (68%) in ß2 integrin expression on neutrophils was observed during the treatment with HBO and maintained one month after the last treatment, while α4 integrin levels remained unchanged. However, cell adhesion function of both neutrophilic integrins α4ß1 and ß2 was significantly reduced 70 and 67%, respectively), but α4ß1 integrin was still sensitive to antagonist inhibition in the presence of fibronectin, suggesting that a combined therapy between HBOT and integrin antagonists could have greater antinflammatory efficacy.

Role of nociceptin/orphanin FQ in thermoregulation.

Nociceptin/Orphanin FQ (N/OFQ) is a 17-amino acid peptide that binds to the nociceptin receptor (NOP). N/OFQ and NOP receptors are expressed in numerous brain areas. The generation of specific agonists, antagonists and receptor-deficient mice or rats has enabled progress in elucidating the biological functions of N/OFQ. These tools have been employed to identify the biological significance of the N/OFQ system and how it interacts with other endogenous systems to regulate several body functions. The present review focuses on the role of N/OFQ in the regulation of body temperature and its relationship with energy balance. Critical evaluation of the literature data suggests that N/OFQ, acting through the NOP receptor, may cause hypothermia by influencing the complex thermoregulatory system that operates as a federation of independent thermoeffector loops to control body temperature at the hypothalamic level. Furthermore, N/OFQ counteracts hyperthermia elicited by cannabinoids or µ-opioid agonists. N/OFQ-induced hypothermia is prevented by ω-conotoxin GVIA, an N-type calcium channel blocker. Hypothermia induced by N/OFQ is considered within the framework of the complex action that this neuropeptide exerts on energy balance. Energy stores are regulated through the complex neural controls exerted on both food intake and energy expenditure. In laboratory rodents, N/OFQ stimulates consummatory behavior and decreases energy expenditure. Taken together, these studies support the idea that N/OFQ contributes to the regulation of energy balance by acting as an "anabolic" neuropeptide as it elicits effects similar to those produced in the hypothalamus by other neuropeptides such as orexins and neuropeptide Y.

Antiangiogenic effect of dual/selective alpha(5)beta(1)/alpha(v)beta(3) integrin antagonists designed on partially modified retro-inverso cyclotetrapeptide mimetics.

Recent evidence highlighted the role of alpha(5)beta(1) integrin in angiogenesis and in regulating alpha(v)beta(3) integrin function. As a consequence, selective alpha(5)beta(1) integrin inhibitors or dual alpha(5)beta(1)/alpha(v)beta(3) integrin inhibitors are considered promising candidates for the development of cancer therapeutic agents. In this paper, we describe the synthesis and pharmacological characterization of a minilibrary of cyclotetrapeptide mimetics containing a PMRI Arg-Gly-Asp sequence. In particular, c[(R)-betaPhepsi(NHCO)Asppsi(NHCO)Gly-Arg] (3) displayed a good activity in inhibiting the alpha(v)beta(3) integrin-mediated cell adhesion of fibronectin or vitronectin, as well as the adhesion of fibronectin to the alpha(5)beta(1) integrin. Interestingly, the diastereomeric compound c[(S)-betaPhepsi(NHCO)Asppsi(NHCO)Gly-Arg] (2) maintained a good efficacy in inhibiting alpha(5)beta(1) integrin while gaining a certain selectivity over alpha(v)beta(3) integrin. These two integrin antagonists significantly inhibited bFGF-induced human endothelial cell tube formation at submicromolar concentrations. Conformational analysis and Molecular Docking calculations suggest that the different alpha(5)beta(1) versus alpha(v)beta(3) selectivity of 2 and 3 can be rationalized on the basis of the alternative display of the aromatic side chain adjacent to Asp.

Imidazo[2,1-b]thiazole system: a scaffold endowing dihydropyridines with selective cardiodepressant activity.

The synthesis, characterization, and functional in vitro assays in cardiac tissues and smooth muscle (vascular and nonvascular) of a number of 4-imidazo[2,1- b]thiazole-1,4-dihydropyridines are reported. The binding properties for the novel compounds have been investigated and the interaction with the binding site common to other aryl-dihydropyridines has been demonstrated. Interestingly, the novel 4-aryl-dihydropyridines are L-type calcium channel blockers with a peculiar pharmacological behavior. Indeed, the imidazo[2,1- b]thiazole system is found to confer to the dihydropyridine scaffold an inotropic and/or chronotropic cardiovascular activity with a high selectivity toward the nonvascular tissue. Finally, molecular modeling studies were undertaken for the most representative compounds with the aim of describing the binding properties of the new ligands at molecular level and to rationalize the found structure-activity relationship data. Due to the observed pharmacological behavior of our compounds, they might be promising agents for the treatment of specific cardiovascular pathologies such as cardiac hypertrophy and ischemia.

Opioid peptide response to spinal cord stimulation in chronic critical limb ischemia.

Twelve patients with chronic critical limb ischemia in whom a spinal cord stimulation (SCS) system had been implanted for at least one year had increased microvascular flow and achieved healing of trophic acral lesions. After switching off the system, the clinical improvement persisted for 10 days and the neurohormonal pattern showed high plasma values of beta-endorphin and Met-enkephalin, normal dynorphin B, endothelin-1 and catecholamines, and low nitric oxide. Met-enkephalin levels were further increased (P < 0.01) immediately after switching on the electrical stimulation again. The persistence of high plasma opioid levels after switching off the spinal cord stimulation explains the absence of subjective complaints and suggests an involvement of opioids in the regulation and improvement of the microcirculation.

Synthesis and pharmacological evaluation of 6-piperidino- and 6-piperazinoalkyl-2(3H)-benzothiazolones as mixed sigma/5-HT(1A) ligands.

In an effort to produce new pharmacological probes with mixed sigma/5-HT(1A) affinity, we have synthesized a series of 12 original 6-piperidino- or piperazino-alkyl-2(3H)-benzothiazolones and their receptor binding profile (sigma, 5-HT(1A), 5-HT(2A), 5-HT(3), D(2), H(1), and M(1)) was determined. The best mixed sigma/5-HT(1A) affinity profile was found within the piperidine series with 4-benzyl substitution associated to linker methylene chain n=2 (K(i) 5 and 4nM, respectively). Moreover, a highly selective sigma2 ligand was obtained with a 3,4-dichlorobenzyl substitution associated to n=4 (K(i) 2nM, selectivity ratio sigma1/sigma2=70).