122 research outputs found
Synthesis and pharmacological evaluation of new biphenylic derivatives as CB2 receptor ligands
No full textTargeting type-2 cannabinoid receptor (CB2) is considered a feasible strategy to develop new drugs for the treatment of diseases like neuropathic pain, chronic inflammation, neurodegenerative disorders and cancer. Such drugs are devoid of the undesired central side effects that are typically mediated by the CB1 receptor. In this work we synthesized 18 biphenylic carboxamides as new CB2-selective ligands and evaluated their pharmacological profiles. The functional activity of these compounds is strongly influenced by the nature of the substituent at position 4' and 5 of the biphenyl scaffold. Position 5 seems to be responsible for the agonist or inverse agonist behaviour independently of the substituent in position 4', with the exception of the methoxyl group which transforms both full agonists and inverse agonists into neutral antagonists. This study provides a novel complete toolbox of CB2 functional modulators that derive from the same chemical scaffold. Such probes may be useful to investigate the biological role of CB2 receptors in cellular assays
Anticancer activity of anandamide in human cutaneous melanoma cells
No full textCannabinoids are implicated in the control of cell proliferation, but little is known about the role of the endocannabinoid system in human malignant melanoma. This study was aimed at characterizing the in vitro antitumor activity of anandamide (AEA) in A375 melanoma cells. The mRNA expression of genes that code for proteins involved in the metabolism and in the mechanism of AEA action was assessed by RT-PCR. Cell viability was tested using WST-1 assay and the apoptotic cell death was determined by measuring caspase 3/7 activities. A375 cells express high levels of fatty acid amide hydrolase (FAAH), cyclooxygenase (COX)-2, cannabinoid receptor 1 (CB1), transient receptor potential cation channel subfamily V member 1 (TRPV1) and G-protein-coupled receptor 55 (GPR55) genes. AEA induced a concentration-dependent cytotoxicity with an IC50 of 5.8±0.7 µM and such an effect was associated to a caspase-dependent apoptotic pathway. AEA cytotoxicity was potentiated by FAAH inhibition (2-fold increase, p<0.05) and mitigated by COX-2 or lipoxygenase (LOX) inhibition (5- and 3-fold decrease, respectively; p<0.01). Blocking CB1 receptors partially decreased AEA cytotoxicity, whereas selective antagonism on the TRPV1 barely affected the mechanism of AEA action. Finally, methyl-β-cyclodextrin, a membrane cholesterol depletory, completely reversed the cytotoxicity induced by the selective GPR55 agonist, O-1602, and AEA. Overall, these findings demonstrate that AEA induces cytotoxicity against human melanoma cells in the micromolar range of concentrations through a complex mechanism, which involves COX-2 and LOX-derived product synthesis and CB1 activation. Lipid raft modulation, probably linked to GPR55 activation, might also have a role
Synthetic cannabinoid receptor agonists and antagonists: implication in CNS disorders
No full textSince the discovery of the cannabinoid receptors, numerous studies associate the endocannabinoid system with several physiological and pathological processes including cancer, appetite, fertility, memory, neuropathic and inflammatory pain, obesity, and neurodegenerative diseases. Over the last two decades, several researches have been dedicated extensively on the cannabinoid receptors ligands since the direct activation of cannabinoid receptors results in several beneficial effects, in the brain and in the periphery
Beyond the Direct Activation of Cannabinoid Receptors: New Strategies to Modulate the Endocannabinoid System in CNS-Related Diseases
No full textBackground: Anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are signalling lipids which belong to the class of endocannabinoids (ECs) and exert their actions by activating cannabinoid receptor type-1 (CB1) and type-2 (CB2). These receptors are involved in many physiological and pathological processes in the central nervous system (CNS) and in peripheral organs. Despite many potent and selective ligands for cannabinoid receptors have been generated over the last two decades, this class of compounds achieved only a very limited therapeutic success, mainly because of the CB1- mediated side effects.
Methods: The compounds and results presented in this review article have been gathered from an extensive research in public databases for patents, clinical trials and scientific literature. Reference to patent numbers, clinical trial registry numbers, websites and scientific articles is provided in the text and/or in the reference section.
Results: Over the last 10-15 years, many inhibitors for the main EC hydrolytic enzymes fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), α,β-hydrolase domain-6 (ABHD6) and -12 (ABHD12) have been synthesized and characterized in vitro and in vivo. Additionally, other targets have been explored for the modulation of the endocannabinoid system (ECS). Among them, several novel inhibitors for COX-2, diacylglycerol lipases and the putative endocannabinoid membrane transporter have been described in the literature. Polypharmacological approaches which combine mild or reversible inhibition of at least two of these targets are also under investigation.
Conclusions: The ECS offers several therapeutic opportunities beyond the direct activation of cannabinoid receptors. The modulation of EC levels in vivo represents an interesting therapeutic perspective for several CNS-related diseases. Based on the literature and patent literature this review provides an overview of the different classes of inhibitors for FAAH, MAGL, ABHDs and COX-2 used as tool compounds and for clinical development with a special focus on CNS-related diseases
I benefici delle certificazioni ISO 14001 ed EMAS nel settore delle carni in Italia: un’analisi empirica
No full textIl settore dell'alimentazione di origine animale occupa una posizione di rilievo nell'economia e nella cultura di molteplici nazioni. Anche in Italia, il settore della carne, con un valore economico di circa 30 miliardi di euro, riesce a rappresentare 1/6 dell’intero comparto alimentare italiano.
Tuttavia, si rileva come le attività di produzione della carne abbiano un impatto significativo praticamente su tutti gli aspetti ambientali. Ne consegue la necessità di adottare misure concrete per garantire la sostenibilità, un imperativo per le organizzazioni di questo settore e non solo. Infatti, sempre più̀ aziende stanno adottando politiche ambientali, grazie all’utilizzo delle certificazioni.
L'obiettivo di questa ricerca è stato analizzare la diffusione delle certificazioni ISO 14001 ed EMAS nel settore delle carni in Italia e la correlazione con il posizionamento economico finanziario delle imprese, per valutarne i potenziali benefici.
L'analisi, sviluppata con l’utilizzo del database Orbis, si è concentrata sulle grandi aziende produttrici di carne italiane, identificate tramite i codici NACE 1011, 1012 e 1013.
Dai risultati ottenuti, sull’analisi di 179 aziende target, 32 risultano certificate ISO 14001, 16 risultano registrate EMAS e 12 posseggono entrambe le certificazioni. Inoltre, l'analisi dei dati finanziari ha rivelato che le aziende certificate ISO 14001 e registrate EMAS presentano indicatori reddituali più elevati rispetto a quelle senza certificazione. Le aziende che possiedono entrambe le certificazioni mostravano indicatori reddituali superiori sia rispetto a quelle con una sola certificazione, sia rispetto a quelle senza certificazioni.
La correlazione positiva osservata tra la certificazione ambientale e i dati finanziari lascia interpretare come la redditività dell’impresa possa rappresentare un elemento di valorizzazione delle tematiche ambientali. Questo risultato richiede ulteriori approfondimenti per comprendere meglio la relazione di causa ed effetto tra le due variabili
Reactive oxygen species in human inner ear perilymph
No full textConclusions: The results reported here provide the first evidence of the production of superoxide, a biologically relevant reactive oxygen species (ROS), in human inner ear perilymph (hIP) in pathological conditions, by the activity of the xanthine dehydrogenase/xanthine oxidase (XA/XO) enzyme system. Objective: To investigate the presence of ROS in hIP. Methods: Since damage and apoptosis of inner ear hair cells may occur as a result of ROS-mediated injury, we investigated the presence and production of ROS in 105 hIP samples; 98 collected from patients affected by profound sensorineural hearing loss, during surgery for cochlear implantation, and 7 controls, collected from patients affected by otosclerosis, in case of spontaneous leakage after stapedotomy. ROS production was investigated by spectrophotometric analysis and polyacrylamide gel electrophoresis (SDS-PAGE). Results: In hIP samples tested by cytochrome c reduction kinetics, the average superoxide production was 27.34 mmoles per mg of total protein, against 0.36 in controls. Some of these hIP samples, analyzed by cytochrome c reduction kinetics in the presence of xanthine, were found to be positive for ROS-producing XA/XO enzyme. These results were supported by SDS-PAGE analysis
DEPENDENCE OF ELECTROMIGRATION NOISE ON GEOMETRICAL AND STRUCTURAL CHARACTERISTICS IN ALUMINUM-BASED RESISTORS
No full textLow frequency noise measurements have been performed on Al-Si resistors, subjected to high current density (j = 2 x 10(6) A/cm2), in order to investigate the dependence of the electromigration noise on the structural and geometrical parameters. To this end five groups of samples have been used, each characterized by a different value of the average grain size D. The power spectral density S(v) of the voltage fluctuations across the samples has been measured using test patterns with different widths w and lengths l. It has been found that S(v) shows an exponential dependence on the grain dimension and a linear dependence on the shape factor F = l/w. The model previously proposed for noise generation has been integrated to take into account the observed dependence of S(v) on D and F
Functionalization of β-caryophyllene generates novel polypharmacology in the endocannabinoid system
No full textThe widespread dietary plant sesquiterpene hydrocarbon β-caryophyllene (1) is a CB2 cannabinoid receptor-specific agonist showing anti-inflammatory and analgesic effects in vivo. Structural insights into the pharmacophore of this hydrocarbon, which lacks functional groups other than double bonds, are missing. A structure-activity study provided evidence for the existence of a well-defined sesquiterpene hydrocarbon binding site in CB2 receptors, highlighting its exquisite sensitivity to modifications of the strained endocyclic double bond of 1. While most changes on this element were detrimental for activity, ring-opening cross metathesis of 1 with ethyl acrylate followed by amide functionalization generated a series of new monocyclic amides (11a, 11b, 11c) that not only retained the CB2 receptor functional agonism of 1 but also reversibly inhibited fatty acid amide hydrolase (FAAH), the major endocannabinoid degrading enzyme, without affecting monoacylglycerol lipase (MAGL) and α,β hydrolases 6 and 12. Intriguingly, further modification of this monocyclic scaffold generated the FAAH- and endocannabinoid substrate-specific cyclooxygenase-2 (COX-2) dual inhibitors 11e and 11f, which are probes with a novel pharmacological profile. Our study shows that by removing the conformational constraints induced by the medium-sized ring and by introducing functional groups in the sesquiterpene hydrocarbon 1, a new scaffold with pronounced polypharmacological features within the endocannabinoid system could be generated. The structural and functional repertoire of cannabimimetics and their yet poorly understood intrinsic promiscuity may be exploited to generate novel probes and ultimately more effective drugs
Tissue location of resistance in apple to the rosy apple aphid established by electrical penetration graphs
No full textA study of the constitutive resistance of the apple cultivar Florina, Malus domestica Borkh. (Rosaceae), to the rosy apple aphid, Dysaphis plantaginea (Passerini) (Homoptera Aphididae), was performed for the first time by the electrical penetration graph (DC-EPG) system, using the susceptible apple cultivar Smoothe as control. All experiments were conducted with apterous adult virginoparae. The results showed a constitutive resistance in Florina due to a much longer period before the first probe reflecting surface factors. Some weak indications were found for pre-phloem resistance and initiating phloem access was not affected as inferred from equal time to show phloem salivation. However, the complete absence of phloem ingestion indicates a major resistance factor in the phloem sieve elements, most likely in the sieve element sap. Surface factors could have affected tissue related variables and this should be studied further. Anyhow, the strong constitutive resistance in Florina, either on the surface alone or in the phloem as well, effectively prevented reliable experiments on induced resistance, previously detected by molecular methods
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