Fatty Amide Research Articles

Physiological effects of fatty acid amides in experimental peripheral neuropathy with pharmacological blockade of GPR55 receptors

Objective. To study the effect of fatty acid amides during pharmacologic blockade of GPR55 receptors on nociceptive sensitivity and gait patterns in rats in normal and experimental peripheral neuropathy.Materials and methods. The study was carried out on male Wister rats (n=125), divided into 18 groups. The role of fatty acid amides in blockade of GPR55 receptors by administration of the antagonist O-1918 on nociceptive responses and gait parameters in healthy rats and in animals after the formation of neuropathy (NP) was studied.Results. It was found that administration of O-1918 to healthy rats and rats with neuropathy at a dose of 1 mg/kg resulted in a statistically significant decrease in the values of nociceptive reactions and gait parameters. In healthy rats and animals after ligation of the sciatic nerve against the background of blockade of GPR55 receptors PGlyA had a pronounced antinociceptive effect, which was confirmed by a significant increase in the values of nociceptive sensitivity, as well as normalization of gait.Conclusion. The analgesic effect after administration of PEA and SEA is probably the result of the interaction of the above FAAs with membrane orphan receptors. At the same time, the antinociceptive effect of PGlyA probably results from the activation of receptors belonging to another class, presumably vanilloid receptors of the first type.

Labour and premature delivery differentially affect the expression of the endocannabinoid system in the human placenta

Plasma concentrations of N-arachidonyletholamine (AEA), N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA) increase at term and can predict when a woman is likely to go into labour. We hypothesised that increased plasma AEA concentrations in women in preterm and term labour might also be increased and have a function in the placenta at the end of pregnancy. Here we examined the expression of the N-acylethanolamine-modulating enzymes fatty acid amide hydrolase (FAAH) and N-acyl-phosphatidylethanolamine-specific phospholipase-D (NAPE-PLD) and of the cannabinoid receptors (CB1 and CB2) in the placenta and their activation in an in vitro model of the third-trimester placenta to determine if those expressions change with labour and have functional significance. Expression of CB1, CB2, FAAH and NAPE-PLD was examined by immunohistochemistry (IHC) and RT-qPCR in placental samples obtained from four patient groups: preterm not in labour (PTNL), term not in labour (TNL), preterm in labour (PTL) and term in labour (TL). Additionally, the effects of AEA on a third-trimester human cell line (TCL-1) were evaluated. All ECS components were present in the third-trimester placenta, with NAPE-PLD and CB2 being the key modulated proteins in terms of expression. Functionally, AEA reduced TCL-1 cell numbers through the actions of the CB2 receptor whilst CB1 maintained placental integrity through the expression of the transcription regulators histone deacetylase 3, thyroid hormone receptor β 1 and the modulation of 5α reductase type 1. The placenta in the third trimester and at term is different from the placenta in the first trimester with respect to the expression of CB1, CB2, FAAH and NAPE-PLD, and the expression of these proteins is affected by labour. These data suggest that early perturbation of some ECS components in the placenta may cause AEA-induced PTL and thus PTB.

Pioneering first-in-class FAAH-HDAC inhibitors as potential multitarget neuroprotective agents.

Aiming to simultaneously modulate the endocannabinoid system (ECS) functions and the epigenetic machinery, we selected the fatty acid amide hydrolase (FAAH) and histone deacetylase (HDAC) enzymes as desired targets to develop potential neuroprotective multitarget-directed ligands (MTDLs), expecting to achieve an additive or synergistic therapeutic effect in oxidative stress-related conditions. We herein report the design, synthesis, and biological evaluation of the first-in-class FAAH-HDAC multitarget inhibitors. A pharmacophore merging strategy was applied, yielding 1-phenylpyrrole-based compounds 4a-j. The best-performing compounds (4c, 4f, and 4h) were tested for their neuroprotective properties in oxidative stress models, employing 1321N1 human astrocytoma cells and SHSY5 human neuronal cells. In our preliminary studies, compound 4h stood out, showing a balanced nanomolar inhibitory activity against the selected targets and outperforming the standard antioxidant N-acetylcysteine in vitro. Together with 4f, 4h was also able to protect 1321N1 cells from tert-butyl hydroperoxide or glutamate insult. Our study may provide the basis for the development of novel MTDLs targeting the ECS and epigenetic enzymes.

Discovery of Novel Diamides Scaffold Containing Monofluoro-acrylamides Activating the Insect Ryanodine Receptor.

The research and development of organofluorine chemistry has flourished; in particular, monofluoroalkene has aroused considerable interest from medicinal and organic chemists. It is a significant attempt to introduce monofluoroalkene into agrochemicals. In this study, monofluoroalkene was introduced into diamide molecules and inserted between the aliphatic amide and benzene ring, and 44 compounds have been successfully synthesized. The bioassay results showed that compounds with monofluoro-acrylamide moiety (Z-isomers) had excellent larvicidal activity against lepidopteran pests at 5 mg·L-1. The LC50 values of compounds B16, B18, and B21 against Mythimna separata were 1.02, 1.32, and 0.78 mg·L-1, respectively. 3D-QSAR analysis including the CoMFA model and the CoMSIA model was conducted to illustrate the contributions of steric, electrostatic, hydrophobic, and hydrogen bond fields on the bioactivity. Moreover, typical symptoms caused by chlorantraniliprole including dehydration, shrinkage, and blackening were also observed on the test larvae treated with monofluoro-acrylamide diamide compounds. M. separata central neurons calcium imaging experiment of compound B18 indicated that the monofluoro-acrylamide diamide compounds were potential insect ryanodine receptor activators. The molecular docking was performed in the CHL binding domain of Plutella xylostella RyR and revealed that the predicted binding mode of compound B21 was slightly different from that of CHL. The MM|GBSA dG Bind values of B21 and CHL with P. xylostella RyR were respectively -85.797 and -95.641 kcal·mol-1. The present work explored the insecticidal properties of a new diamide scaffold containing a monofluoro-acrylamide fragment and extended the application of monofluoroalkene in the agrochemical field.

Functional Variation in the FAAH Gene Is Directly Associated with Subjective Well-Being and Indirectly Associated with Problematic Alcohol Use.

Fatty acid amide hydrolase (FAAH) is an enzyme that degrades anandamide, an endocannabinoid that modulates mesolimbic dopamine release and, consequently, influences states of well-being. Despite these known interactions, the specific role of FAAH in subjective well-being remains underexplored. Since well-being is a dynamic trait that can fluctuate over time, we hypothesized that we could provide deeper insights into the link between FAAH and well-being using longitudinal data. To this end, we analyzed well-being data collected three years apart using the WHO (Ten) Well-Being Index and genotyped a functional polymorphism in the FAAH gene (rs324420, Pro129Thr) in a sample of 2822 individuals. We found that the A-allele of rs324420, which results in reduced FAAH activity and elevated anandamide levels, was associated with lower well-being scores at both time points (Wave I, B: -0.52, p = 0.007; Wave II, B: -0.41, p = 0.03, adjusted for age and sex). A subsequent phenome-wide association study (PheWAS) affirmed our well-being findings in the UK Biobank (N = 126,132, alternative C-allele associated with elevated happiness, p = 0.008) and revealed an additional association with alcohol dependence. In our cohort, using lagged longitudinal mediation analyses, we uncovered evidence of an indirect association between rs324420 and problematic alcohol use (AUDIT-P) through the pathway of lower well-being (indirect effect Boot: 0.015, 95% CI [0.003, 0.030], adjusted for AUDIT in Wave I). We propose that chronically elevated anandamide levels might influence disruptions in the endocannabinoid system-a biological contributor to well-being-which could, in turn, contribute to increased alcohol intake, though multiple factors may be at play. Further genetic studies and mediation analyses are needed to validate and extend these findings.

Synthesis and characterization of long‐chain (C20 ~ C48) fatty acid amides (FAAms) from soybean oil and alkyl amines for phase change material applications

AbstractBio‐based organic phase change materials (PCMs) have drawn attention considering their great value in environmental sustainability as a latent heat storage strategy. In this study, bio‐based fatty acid amides (FAAms) were synthesized directly from soybean oil and different amines through a solvent‐free reaction with a non‐toxic catalyst (DABCO). The chemical and thermal properties were confirmed by FT‐IR, NMR, DSC, and TGA measurements. The effects of oil saturation and chain length were investigated. FAAms were successfully synthesized from most of the primary alkyl amines with high purity and yield. Fifteen different FAAms exhibit high latent heat (up to 202 J/g) with a single‐phase transition peak. A general trend of increasing enthalpy of fusion, narrower phase transition temperature range, higher melting temperature, and better thermal stability was found with increasing FAAms chain length. An opposite trend was observed for some long‐chain FAAms (C > 42). Overall, a wide choice of green, organic PCMs with comparable thermal properties to petroleum based PCMs is provided in this work. Those FAAms with high working temperatures (>100°C) could expand the application of organic PCM to different fields such as steam generation, textile, rubber industry, etc.

Ternary Mixture of Pentanamide in Solvent Analogy with Halogenated Phenol: Experimental, Theoretical, and In Silico Biological Studies.

This research describes the preparation of mixtures of new halogen-substituted phenol derivatives and their effects due to linkages with a fatty amide (pentanamide). The molecules were optimized using DFT, and the vibrational and electronic analysis was done subsequently. The energies of frontier molecular orbitals (FMOs) were used to estimate the global chemical reactivity parameters as we suggest that hydrogen-bonded networks may have contributed to the stability and reactivity of the compound. In addition to the experimental investigation, dielectric parameters were calculated. Fukui functions were analyzed to study the chemical reactivity. To get insight into interactions of σ → π* orbitals, natural bond orbital calculations were done. Additionally, surface analysis of the MEP and Hirshfeld charges were performed at the equivalent DFT levels. The research also indicated that both (interaction region indicator) IRI and (electron delocalize range) EDR would proficiently identify chemical-bonding and weak interaction regions, providing a significant advantage in exploring diverse chemical systems and reactions. This indicated that compounds could diffuse through noncovalent interactions, including intramolecular hydrogen bonding. Dielectric relaxation studies taken at five distinct molar ratios identified significant dielectric properties such as ε', ε″, ε0, and ε∞. The PA with FP, CP, BP, and IP molecules has potential antiviral and antioxidant benefits for carbonic anhydrase, with favorable drug-like features and diverse biological benefits. Pharmacological effects were forecasted using the PASS server, and these molecules exhibited favorable pharmacokinetic properties.

Effect of wax additives on asphalt rheological behavior as road paving material

In response to the growing demand for sustainable and high-performance roads, various asphalt additives have been developed and introduced to pavement construction. The increasing practice of warm mix in asphalt industry advances the usage of wax additives. However, the concern of wax content poses challenges to the application of wax additives in asphalt pavement via wet process. To address this concern, this study comprehensively investigates the influence of wax content on asphalt binder through rheological and chemical characterization. Specifically, three types of wax additives (Fischer-Tropsch wax, fatty acid amide wax and 64# paraffin wax) were selected at two dosages (2 wt% and 4 wt%) incorporating into four types of asphalt binder (virgin asphalt, SBS modified asphalt, asphalt rubber and high-viscosity & high-elasticity asphalt) to formulate various wax modified asphalts. Rheological properties were characterized to assess the engineering performance. Wax content and chemical mechanisms were characterized to investigate wax modification. Results show that incorporating wax additives enhances the engineering performance of asphalt binders but is difficult to meet wax content requirement. Fischer-Tropsch and fatty acid amide waxes are effective in improving rutting and fatigue resistance, whereas paraffin wax has an overall negative effect. Wax modification promotes the asphalt wax crystallization, leading to a further increased wax content and compromised low-temperature performance on asphalt binders, where modified asphalts can alleviate this adverse effect. Wax additives compromise low-temperature performance of virgin asphalt, but minimally impact modified asphalt. Careful wax content consideration is vital for virgin binders, while more flexibility of adjusting wax additive dosage is beneficial for enhancing overall of modified asphalt. This study is anticipated to prompt the understanding the influence of wax content on asphalt binder and benefit the industrial application of wax additives.

Design, Synthesis, and Insecticidal Evaluation of N-Pyridylpyrazole Amide Derivatives Containing 4,5-Dihydroisoxazole Amide as Potential Ryanodine Receptor Activators.

Using the 4,5-dihydroisoxazol amide structure to expand the aliphatic amide moiety of chlorantraniliprole, a series of 28 novel N-pyridylpyrazolecarboxamide derivatives containing 4,5-dihydroisoxazol amide fragment were designed and synthesized. All target compounds had been properly characterized and confirmed by 1H NMR, 13C NMR, and HRMS, and the effects were evaluated against Mythimna separata (M. separata) and Plutella xylostella (P. xylostella). The bioassay results indicated that most of the target compounds exhibited good insecticidal activities against M. separata and P. xylostella at 50 mg/L; especially, compound A4 showed an LC50 value of 3.27 mg/L against M. separata. Calcium imaging experiments indicated that the target compound A4 had a similar mechanism of action to chlorantraniliprole, causing an increase in the cytoplasmic Ca2+ concentration. The molecular docking revealed the possible binding mode of compound A4 with a ryanodine receptor.

Profile of pro- and anti-inflammatory cytokines during injection of fatty acid amides with ethanolamine and glycine in modeling peripheral neuropathy

The effect of fatty acid amides during the blockade of membrane orphan GPR18, GPR55 and nuclear PPARα receptors on the level of pro- and anti-inflammatory cytokines in rats with experimental peripheral neuropathy was studied. It has been proven that the anti-inflammatory action of PEA and SEA in experimental animals with neuropathy is carried out through nuclear PPARα receptors. However, PGlyA has no anti-inflamatory effects in a rat model of peripheral neuropathy.

Homogenizer-intensified amidation of free fatty acids in waste cooking oil for biodiesel production

Biodiesel production from waste cooking oil is a viable alternative both to satisfy renewable energy demand and utilize a low-cost feedstock. However, a preparatory procedure is required to reduce free fatty acid contained in waste cooking oil to a specific value which is time- and energy-extensive. Herein, a fast and non-catalytic amidation reaction performs at room temperature is established as an alternative method to reduce the free fatty acid level. The effect of the molar ratio of waste cooking oil to monoethanolamine, reaction time and rotational speed of homogenizer were investigated on the conversion of free fatty acid to alkanolamide compounds. The highest conversion of 95.9 ± 0.02% was achieved in presence of a molar ratio of 1:1.5, reaction time of 0.5 min and rotational speed of 5000 rpm. Further, a homogenizer was used to facilitate the transesterification reaction using an alkaline catalyst at room temperature. The conversion of waste cooking oil to biodiesel of 91.4 ± 0.2% was achieved after 5 min of reaction time. In terms of processing parameters, the non-catalytic amidation and alkaline base catalytic transesterification reaction assisted by a homogenizer device is a time-saved process as it could save 92% and 94% of reaction time compared to one- and two-steps method and was performed in ambient condition.

Cannabinoid receptor gene CNR1 is downregulated in subcortical brain samples and upregulated in blood samples of individuals with schizophrenia: A participant data systematic meta-analysis.

Cannabis use leads to symptom exacerbation in schizophrenia patients, and endocannabinoid ligands have been studied as tentative schizophrenia therapeutics. Here, we aimed to characterise the connection between schizophrenia and the cannabinoid receptor 1 gene (CNR1) and explore possible mechanisms affecting its expression in schizophrenia. We performed a participant data systematic meta-analysis of CNR1 gene expression and additional endocannabinoid system genes in both brain (subcortical areas) and blood samples. We integrated eight brain sample datasets (overall 316 samples; 149 schizophrenia and 167 controls) and two blood sample datasets (overall 90 samples; 53 schizophrenia and 37 controls) while following the PRISMA meta-analysis guidelines. CNR1 was downregulated in subcortical regions and upregulated in blood samples of patients with schizophrenia. CNR2 and genes encoding endocannabinoids synthesis and degradation did not show differential expression in the brain or blood, except fatty acid amide hydrolase (FAAH), which showed a downregulation trend in blood. In addition, the brain expression levels of CNR1 and three GABA receptor genes, GABRA1, GABRA6 and GABRG2, were positively correlated (R = .57, .36, .54; p = 2.7 × 10-14 , 6.9 × 10-6 and 1.1 × 10-12 , respectively). Brain CNR1 downregulation and the positive correlation with three GABA receptor genes suggest an association with GABA neurotransmission and possible effects on negative schizophrenia symptoms. Further studies are required for clarifying the opposite CNR1 dysregulation in the brain and blood of schizophrenia patients and the potential of endocannabinoid ligands as schizophrenia therapeutics.

Palladium-Catalyzed Aerobic Oxidative Spirocyclization of Alkyl Amides with Maleimides via β-C(sp3)-H Activation.

An efficient method for the synthesis of bicyclic spirodiamine molecules via β-C(sp3)-H bond activation of aliphatic amides, followed by cyclization with maleimides, has been developed. The reaction proceeds through an amide-directed β-C(sp3)-H bond activation of alkyl amides and subsequent cyclization with maleimides. The methodology is highly compatible with a wide variety of maleimides. Amides derived from biologically active aliphatic and fatty acids were also found to be highly compatible with the protocol. A palladacycle was synthesized and found to be the active intermediate in this reaction. A plausible reaction mechanism was also proposed to account for this spirocyclization.

Investigating the effects of a FAAH inhibitor in the laterodorsal tegmental nucleus using a new ex vivo mouse preparation

As part of the brainstem reticular activating system, the laterodorsal tegmentum (LDT) is a central player in regulating sleep, arousal, and motivated behaviors including addiction. The neuronal lipids within the LDT that could regulate neuronal activity and LDT signaling are not fully characterized due, in part, to the complication of the presence of fatty acid amide hydrolases (FAAH). To determine the lipids in the LDT, mouse brain slices at different stages of brain development (16, 26 and 66 days) were exposed ex vivo to the FAAH inhibitor oleyl trifluoromethyl ketone (OTMK). Metabolomics and proteomic analyses were conducted on matched samples. Metabolomics analysis revealed differences between OTMK treated and untreated LDT. Furthermore, a distinct phenotype (proteomic profile) as a function of OTMK treatment was observed in LDT from adolescent (66 days) mice indicating an effect of treatment with OTMK at later stages of brain development. Our data indicate that this ex vivo preparation could facilitate screening of different FAAH inhibitors in mammalian tissues, and more importantly, this preparation should allow a deeper characterization of global mass spectrometry-based omics profiles within the LDT.

Codium fragile Suppresses PM2.5-Induced Cognitive Dysfunction by Regulating Gut-Brain Axis via TLR-4/MyD88 Pathway.

This study was conducted to evaluate the cognitive dysfunction improvement effect of aqueous extract of Codium fragile (AECF) by regulating the imbalance of the gut-brain axis in chronic particulate matter (PM)2.5-exposed mice. The physiological compounds of AECF were identified as hexadecanamide, oleamide, octadecanamide, stearidonic acid, and linolenic acid by the ultra-performance liquid chromatography-quadrupole time of flight mass spectrometry (UPLC Q-TOF MSE) analysis. To evaluate the effect of PM2.5 on the antioxidant system, superoxide dismutase (SOD) contents, reduced glutathione (GSH) contents, and malondialdehyde (MDA) contents were measured in colon and brain tissues. AECF significantly ameliorated the imbalance of the antioxidant systems. Also, AECF improved intestinal myeloperoxidase (MPO) activity, the abundance of the gut microbiome, short-chain fatty acids (SCFAs) contents, and tight junction protein expression against PM2.5-induced damage. In addition, AECF prevented PM2.5-induced inflammatory and apoptotic expression via the toll-like receptor-4 (TLR-4)/myeloid differentiation primary response 88 (MyD88) pathway in colon and brain tissues. Additionally, AECF enhanced the mitochondrial function, including the mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) contents in brain tissues. Furthermore, AECF regulated the cholinergic system, such as acetylcholine (ACh) contents, acetylcholinesterase (AChE) activity, and protein expression levels of AChE and choline acetyltransferase (ChAT) in brain tissues. To evaluate the effect of cognitive dysfunction caused by PM2.5-induced intestinal dysfunction, behavior tests such as Y-maze, passive avoidance, and Morris water maze tests were performed. From the results of the behavior tests, AECF ameliorated spatial learning and memory, short-term memory, and long-term learning and memory function. This study confirmed that AECF reduced PM2.5-induced cognitive dysfunction by regulating gut microbiome and inflammation, apoptosis, and mitochondrial function by enhancing the gut-brain axis. Based on these results, this study suggests that AECF, which contains fatty acid amides, might be a potential material for ameliorating PM2.5-induced cognitive dysfunction via gut-brain axis improvement.

Efficient hydrogenation of aliphatic acyclic amides to amines by bimetallic NiMo nitrides via heterogeneous catalysis

Primary amines are vital building blocks in pharmaceutical and polymer industry. The heterogeneous catalytic hydrogenation of aliphatic acyclic amides to amines is rather attractive but challenging due to low reactivity of aliphatic acyclic amides, and then rarely be reported. Herein, cheap bimetallic NiMo nitride catalysts were synthesized by hydrothermal method and firstly utilized to the efficient conversion of a wide range of aliphatic acyclic amides to amines, achieving 93.9 % conversion of hexanamide and 75.1 % yield to hexylamine. Characterizations such XRD, N2 Physical adsorption, TGA, Raman, XPS, SEM-EDX Mapping and (HR)TEM revealed that Ni2Mo3N is crucially important for the activation of hexanamide while the synergetic effect between Ni2Mo3N and Ni6Mo6C1.06 would further promote the conversion of hexanamide, and higher TOFs (145.9 h−1) and lower Ea (29.5 kJ mol−1) are achieved. The CO bond of the amide can be activated by the surface Lewis acid site of bimetallic NiMo nitrides, while the simultaneous dissociation of H2 to form H atoms is beneficial for hydrogenation. This catalyst is also found to be recyclable with stable catalytic performance upon consecutive runs. The present work provides a novel and unique option for the efficient conversion of aliphatic acyclic amides to amines, being a strong supplementary to those reported for the hydrogenation of cyclic-amides, secondary amides, and tertiary amides.

Sustainable polyurethane coatings based on functional Camelina oil-based polyols

Polyurethane (PU) coatings have garnered considerable attention across diverse applications and industries, owing to their versatile physiochemical attributes. Despite their widespread use, the environmental implications associated with their carbon footprint have raised concerns in recent years. To address this issue, we explored the potential of Camelina oil as a base chemical for synthesizing polyesteramide polyols as a viable alternative to petrochemical-based materials. Consequently, we formulated biocarbon-rich polyurethane coatings using the synthesized polyols. Initially, we synthesized a fatty amide intermediate through a transamidation reaction, involving the interaction of diethanolamine and triglyceride. Subsequently, we produced three distinct polyesteramide polyols using citric acid, itaconic acid, and phthalic acid. To confirm the formation of ester and amide linkages, we employed various structural analyses, including Nuclear Magnetic Resonance (NMR) and Fourier Transform Infrared (FTIR) spectroscopy, on the Camelina-oil-derived polyols. Furthermore, we utilized quantitative techniques such as titration to ascertain hydroxyl number, acid number, and amine value. Our structural analyses corroborated the establishment of ester linkage and the incorporation of OH functionality in Camelina oil, while titration results indicated a remarkable 1200 % surge in hydroxyl value. We subsequently employed the three polyesteramide polyols to fabricate polyurethane coatings, subjecting them to a battery of tests. The resultant biobased coatings were assessed using Dynamic Mechanical Analysis (DMA), Thermo-Gravimetric Analysis (TGA), and an array of surface characteristics such as gloss, hardness, impact resistance, water contact angle, and saline resistance. All tested samples exhibited satisfactory thermal stability, with the biocarbon content of the final PU coatings measuring at least 61.6 %. Moreover, our study demonstrates that the derived polyurethane coatings hold promise for non-wet applications, particularly in the realm of interior coatings.

Effects on Fetal Metabolic Programming and Endocannabinoid System of a Normocaloric Diet during Pregnancy and Lactation of Female Mice with Pregestational Obesity.

Fetal programming provides explanatory mechanisms for the currently high prevalence of gestational obesity. The endocannabinoid system (ECS) participates in the regulation of energy balance, and with a high-fat diet (HFD), it is overactivated. The aim of this study was to determine the effects of a nutritional intervention during pregnancy and lactation on obese female progenitors, on metabolic alterations of the offspring and on the involvement of ECS. Female mice (C57/BL/6-F0), 45 days old, and their offspring (males) were separated according to type of diet before and during gestation and lactation: CON-F1: control diet; HFD-F1 group: HFD (fat: 60% Kcal); INT-F1 group: HFD until mating and control diet (fat: 10% Kcal) afterward. Glucose tolerance and insulin sensitivity (IS) were tested at 2 and 4 months. At 120 days, mice were sacrificed, plasma was extracted for the determination of hormones, and livers for gene expression and the protein level determination of ECS components. INT-F1 group presented a lower IS compared to CON-F1, and normal levels of adiponectin and corticosterone in relation to the HFD-F1 group. The intervention increased hepatic gene expression for fatty-acid amide hydrolase and monoacylglycerol lipase enzymes; however, these differences were not observed at the protein expression level. Our results suggest that this intervention model normalized some hormonal parameters and hepatic mRNA levels of ECS components that were altered in the offspring of progenitors with pre-pregnancy obesity.

URB597 exerts neuroprotective effects against transient brain ischemia injury in mice by regulating autophagic flux and necroptosis

Ischemic stroke is a leading cause of death and disability, and medical treatments for ischemic stroke are very limited. URB597 is a potent and selective inhibitor of fatty acid amide hydrolase (FAAH). However, the effect of URB597 on ischemic stroke and the underlying molecular mechanisms remain little known. In this study, focal cerebral ischemia was induced by transient middle cerebral artery occlusion in mice. Our results showed that URB597 dose-dependently improved neurological function and reduced brain infarct volume and brain edema 24 h after brain ischemia. The most effective dose was 1 mg/kg and the therapeutic time window was within 3 h after ischemic stroke. To further investigate the underlying mechanism, necroptosis and autophagy flux were detected by Western blot and/or immunofluorescence staining with or without chloroquine, an autophagic flux inhibitor. Our results showed that URB597 promoted autophagic flux and reduced neuronal necroptosis after brain ischemia and these effects could be abolished by chloroquine. In addition, we found that peroxisome proliferator-activated receptor α (PPARα) antagonist GW6471 partly abolished the effect of URB597 against brain ischemia and URB597 upregulated the expressions of PPARα. In conclusion, URB597 exerts a neuroprotective effect in a dose- and time-dependent manner, and this effect may be related to its restoration of autophagic flux and inhibition of neuronal necroptosis. PPARα is involved in the neuroprotective effect of URB597. This study provides novel evidence that URB597 may be a promising agent for the clinical treatment of ischemic stroke.

Fatty Acid Amide Hydrolase, Neurodevelopment, and Alcohol: Illuminating the Intricacies of the Endocannabinoid System in Addiction Susceptibility

Fatty Acid Amide Hydrolase, Neurodevelopment, and Alcohol: Illuminating the Intricacies of the Endocannabinoid System in Addiction Susceptibility