14 research outputs found

    N-Acylethanolamine Acid Amidase (NAAA): Structure, Function, and Inhibition

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    N-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

    NAAA-regulated lipid signaling governs the transition from acute to chronic pain

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    Chronic pain affects 1.5 billion people worldwide but remains woefully undertreated. Understanding the molecular events leading to its emergence is necessary to discover disease-modifying therapies. Here we show that N-acylethanolamine acid amidase (NAAA) is a critical control point in the progression to pain chronicity, which can be effectively targeted by small-molecule therapeutics that inhibit this enzyme. NAAA catalyzes the deactivating hydrolysis of palmitoylethanolamide, a lipid-derived agonist of the transcriptional regulator of cellular metabolism, peroxisome proliferator-activated receptor-α (PPAR-α). Our results show that disabling NAAA in spinal cord during a 72-h time window following peripheral tissue injury halts chronic pain development in male and female mice by triggering a PPAR-α-dependent reprogramming of local core metabolism from aerobic glycolysis, which is transiently enhanced after end-organ damage, to mitochondrial respiration. The results identify NAAA as a crucial control node in the transition to chronic pain and a molecular target for disease-modifying medicines

    Chemical composition, antifungal properties and seed treatment potential of essential oil fractions of Callistemon citrinus against two seed-borne fungi of rice: Alternaria padwickii and Bipolaris oryzae

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    The use of plant extracts with antifungal effects is a plausible alternative solution which is increasingly attracting the attention of researchers worldwide, to address the multiple limitations associated with the use of synthetic agrochemicals. The antifungal potential of essential oils (EO) fractions of Callistemon citrinus, were investigated in vitro by the supplemented media method against Bipolaris oryzae and Alternaria padwickii, two seed-borne fungi of rice in Cameroon. The EO fractions obtained by hydrodistillation of the plant’s fresh and dry leaves inhibited to varying degrees the mycelia growth of the two pathogens. The EO’s fractions obtained from dry leaves were more active than those extracted from fresh leaves. Fractions of EO showed fungicidal effects, with minimum inhibitory concentrations (MIC) varying between 3616 and 7232 μg/ml. The dry leaves EO fraction DF2 exhibited the strongest antifungal activity (MIC = 3616 μg/ml), followed by the fresh leaves fraction FF2 (MIC = 4520 μg/ml) and the total dry leaves EO DM (MIC = 4520 μg/ml), against B. oryzae. Those fractions (DF2, FF2 and DM) also exhibited the highest MIC (MIC = 4520 μg/ml) against Alternaria padwickii. The GC-SM analysis of EO fractions showed that, the antifungal activity was inversely associated to the content of the major bioactive compound 1,8-cineole; 60.67, 66.36 and 86.39% 86.39%; and proportional to α-terpineol; 13.39, 10.52 and 3.5%; for EO fractions DF2, FF2 and MD DM, respectively. Seed treatment of three of rice varieties with fractions DF2, FF2 and DM respectively at the doses of 1.5, 2 and 3.5%, reduced the seed to seedling transmission rate of B. oryzae by 100% and increased the germination rate of these seeds between 2 and 12%. Our results suggest the use of EO from C. citrinus as biofungicides for the treatment of rice seeds infected with B. oryzae and A. padwickii

    Cannabinoid CB2 receptors mediate the anxiolytic-like effects of monoacylglycerol lipase inhibition in a rat model of predator-induced fear

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    The endocannabinoid system is a key regulator of the response to psychological stress. Inhibitors of monoacylglycerol lipase (MGL), the enzyme that deactivates the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG), exert anxiolytic-like effects in rodent models via 2-AG-dependent activation of CB1 cannabinoid receptors. In the present study, we examined whether the MGL inhibitor JZL184 might modulate persistent predator-induced fear in rats, a model that captures features of human post-traumatic stress disorder. Exposure to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a volatile chemical that is innately aversive to some rodent species, produced in male rats a long-lasting anxiety-like state that was measured 7 days later in the elevated plus maze test. Systemic administration of JZL184 [4, 8 and 16 mg/kg, intraperitoneal (IP)] 4 h before testing caused dose-dependent inhibition of MGL activity and elevation of 2-AG content in brain tissue. Concomitantly, the inhibitor suppressed TMT-induced fear behaviors with a median effective dose (ED50) of 4 mg/kg. A similar behavioral response was observed with another MGL inhibitor, KML29 (4 and 16 mg/kg, IP). Surprisingly, the effect of JZL184 was prevented by co-administration of the CB2 inverse agonist AM630 (5 mg/kg, IP), but not the CB1 inverse agonist rimonabant (1 mg/kg, IP). Supporting mediation of the response by CB2 receptors, the CB2 agonist JWH133 (0.3, 1 and 3 mg/kg, IP) also produced anxiolytic-like effects in TMT-stressed rats, which were suppressed by AM630. Notably, (i) JWH133 was behaviorally ineffective in animals that had no prior experience with TMT; and (ii) CB2 mRNA levels in rat prefrontal cortex were elevated 7 days after exposure to the aversive odorant. The results suggest that JZL184 attenuates the behavioral consequences of predator stress through a mechanism that requires 2-AG-mediated activation of CB2 receptors, whose transcription may be induced by the stress itself
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