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      Endocannabinoids, related compounds and their metabolic routes.

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          Abstract

          Endocannabinoids are lipid mediators able to bind to and activate cannabinoid receptors, the primary molecular targets responsible for the pharmacological effects of the Δ9-tetrahydrocannabinol. These bioactive lipids belong mainly to two classes of compounds: N-acylethanolamines and acylesters, being N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), respectively, their main representatives. During the last twenty years, an ever growing number of fatty acid derivatives (endocannabinoids and endocannabinoid-like compounds) have been discovered and their activities biological is the subject of intense investigations. Here, the most recent advances, from a therapeutic point of view, on endocannabinoids, related compounds, and their metabolic routes will be reviewed.

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          Most cited references182

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          Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors

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            Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides.

            Endogenous neuromodulatory molecules are commonly coupled to specific metabolic enzymes to ensure rapid signal inactivation. Thus, acetylcholine is hydrolysed by acetylcholine esterase and tryptamine neurotransmitters like serotonin are degraded by monoamine oxidases. Previously, we reported the structure and sleep-inducing properties of cis-9-octadecenamide, a lipid isolated from the cerebrospinal fluid of sleep-deprived cats. cis-9-Octadecenamide, or oleamide, has since been shown to affect serotonergic systems and block gap-junction communication in glial cells (our unpublished results). We also identified a membrane-bound enzyme activity that hydrolyses oleamide to its inactive acid, oleic acid. We now report the mechanism-based isolation, cloning and expression of this enzyme activity, originally named oleamide hydrolase, from rat liver plasma membranes. We also show that oleamide hydrolase converts anandamide, a fatty-acid amide identified as the endogenous ligand for the cannabinoid receptor, to arachidonic acid, indicating that oleamide hydrolase may serve as the general inactivating enzyme for a growing family of bioactive signalling molecules, the fatty-acid amides. Therefore we will hereafter refer to oleamide hydrolase as fatty-acid amide hydrolase, in recognition of the plurality of fatty-acid amides that the enzyme can accept as substrates.
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              Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis.

              Tumor cells display progressive changes in metabolism that correlate with malignancy, including development of a lipogenic phenotype. How stored fats are liberated and remodeled to support cancer pathogenesis, however, remains unknown. Here, we show that the enzyme monoacylglycerol lipase (MAGL) is highly expressed in aggressive human cancer cells and primary tumors, where it regulates a fatty acid network enriched in oncogenic signaling lipids that promotes migration, invasion, survival, and in vivo tumor growth. Overexpression of MAGL in nonaggressive cancer cells recapitulates this fatty acid network and increases their pathogenicity-phenotypes that are reversed by an MAGL inhibitor. Impairments in MAGL-dependent tumor growth are rescued by a high-fat diet, indicating that exogenous sources of fatty acids can contribute to malignancy in cancers lacking MAGL activity. Together, these findings reveal how cancer cells can co-opt a lipolytic enzyme to translate their lipogenic state into an array of protumorigenic signals. PAPERFLICK:
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                Author and article information

                Journal
                Molecules
                Molecules (Basel, Switzerland)
                1420-3049
                1420-3049
                Oct 24 2014
                : 19
                : 11
                Affiliations
                [1 ] Department of Experimental Medicine & Surgery, Tor Vergata University of Rome, 00133 Rome, Italy. filomena.fezza@uniroma2.it.
                [2 ] Department of Experimental Medicine & Surgery, Tor Vergata University of Rome, 00133 Rome, Italy. bari@med.uniroma2.it.
                [3 ] Department of Movement, Human and Health Sciences, Foro Italico University of Rome, 00128 Rome, Italy. rit.flo@libero.it.
                [4 ] Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli (NA), Italy. emanuelatalamonti.86@libero.it.
                [5 ] Department of Experimental Medicine & Surgery, Tor Vergata University of Rome, 00133 Rome, Italy. monica.feole@hotmail.it.
                [6 ] European Center for Brain Research/IRCCS Santa Lucia Foundation, 00143 Rome, Italy. m.maccarrone@unicampus.it.
                Article
                molecules191117078
                10.3390/molecules191117078
                25347455
                9cd6b361-15f7-4aac-aa42-dd7df31ba2d8
                History

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