1,721,627 research outputs found
Monoglyceride lipase: Structure and inhibitors
Full text linkMonoglyceride lipase (MGL), the main enzyme responsible for the hydrolytic deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG), is an intracellular serine hydrolase that plays critical roles in many physiological and pathological processes, such as pain, inflammation, neuroprotection and cancer. The crystal structures of MGL that are currently available provide valuable information about how this enzyme might function and interact with site-directed small-molecule inhibitors. On the other hand, its conformational equilibria and the contribution of regulatory cysteine residues present within the substrate-binding pocket or on protein surface remain open issues. Several classes of MGL inhibitors have been developed, from early reversible ones, such as URB602 and pristimerin, to carbamoylating agents that react with the catalytic serine, such as JZL184 and more recent O-hexafluoroisopropyl carbamates. Other inhibitors that modulate MGL activity by interacting with conserved regulatory cysteines act through mechanisms that deserve to be more thoroughly investigated
Compounds, compositions and therapeutic uses of oleoylethanolamide-like compounds and modulators of PPARalpha. numero di brevetto WO2005002524
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Endocannabinoid Anandamide Mediates the Effect of Skeletal Muscle Sphingomyelins on Human Energy Expenditure
Full text linkContext:
Skeletal muscle endocannabinoids and sphingolipids (particularly sphingomyelins) are inversely associated with sleeping energy expenditure (SLEEP) in humans. The endocannabinoid system may increase sphingolipid synthesis via cannabinoid receptor-1.
Objective:
To investigate in human skeletal muscle whether endocannabinoids are responsible for the effect of sphingomyelins on SLEEP.
Design:
Muscle endocannabinoid [anandamide (AEA), 2-arachidonoylglycerol (2-AG)], endocannabinoid congeners [oleoylethanolamide (OEA), palmitoylethanolamide (PEA)], and sphingomyelin content were measured with liquid chromatography/mass spectrometry. SLEEP was assessed in a whole-room indirect calorimeter. Mediation analyses tested whether the inverse associations between sphingomyelins and SLEEP depended on endocannabinoids and endocannabinoid-related OEA and PEA.
Setting:
Inpatient study.
Participants:
Fifty-three Native Americans who are overweight.
Main Outcome Measure:
SLEEP.
Results:
AEA (r = 0.45, P = 0.001), 2-AG (r = 0.47, P = 0.0004), OEA (r = 0.27, P = 0.05), and PEA (r = 0.53, P 0.31, all P 0.05).
Conclusions:
In skeletal muscle, AEA is responsible for the sphingomyelin effect on SLEEP, indicating that endocannabinoids and sphingomyelins may jointly reduce human whole-body energy metabolism
N-Acylethanolamine Acid Amidase (NAAA): Structure, Function, and Inhibition
Full text linkN-Acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase primarily found in the endosomal-lysosomal compartment of innate and adaptive immune cells. NAAA catalyzes the hydrolytic deactivation of palmitoylethanolamide (PEA), a lipid-derived peroxisome proliferator-activated receptor-α (PPAR-α) agonist that exerts profound anti-inflammatory effects in animal models. Emerging evidence points to NAAA-regulated PEA signaling at PPAR-α as a critical control point for the induction and the resolution of inflammation and to NAAA itself as a target for anti-inflammatory medicines. The present Perspective discusses three key aspects of this hypothesis: the role of NAAA in controlling the signaling activity of PEA; the structural bases for NAAA function and inhibition by covalent and noncovalent agents; and finally, the potential value of NAAA-targeting drugs in the treatment of human inflammatory disorders
Development of Fragment‐Based n‐FABS NMR Screening Applied to the Membrane Enzyme FAAH
Full text linkDespite the recognized importance of membrane proteins as pharmaceutical targets, the reliable identification of fragment hits that are able to bind these proteins is still a major challenge. Among different ¹⁹F NMR spectroscopic methods, n-fluorine atoms for biochemical screening (n-FABS) is a highly sensitive technique that has been used efficiently for fragment screening, but its application for membrane enzymes has not been reported yet. Herein, we present the first successful application of n-FABS to the discovery of novel fragment hits, targeting the membrane-bound enzyme fatty acid amide hydrolase (FAAH), using a library of fluorinated fragments generated based on the different local environment of fluorine concept. The use of the recombinant fusion protein MBP-FAAH and the design of compound 11 as a suitable novel fluorinated substrate analogue allowed n-FABS screening to be efficiently performed using a very small amount of enzyme. Notably, we have identified 19 novel fragment hits that inhibit FAAH with a median effective concentration (IC₅₀) in the low mM-μM range. To the best of our knowledge, these results represent the first application of a ¹⁹F NMR fragment-based functional assay to a membrane protein
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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