Fatty Amide Research Articles

Impact of Stress on the Endocannabinoid System: A [11C]-CURB Positron Emission Tomography Study in Early Psychosis: Les effets du stress sur le système endocannabinoïde : étude par tomographie par émission de positons avec l'indicateur radioactif [11C-CURB] dans la psychose précoce.

Stress and traumatic experiences are well-established risk factors for psychiatric disorders. Stressful events can induce symptoms of anxiety and depression and may lead to overt psychosis, especially when there is an innate biological vulnerability. This study explores the role of the stress-regulating endocannabinoid system, specifically the activity of the enzyme fatty acid amid hydrolase (FAAH), a key regulatory enzyme for endocannabinoids, in association with stress by analysing data from healthy individuals and patients with psychosis. We performed a post-hoc exploratory analysis on 65 positron emission tomography scans using the selective FAAH radioligand [11C]CURB, encompassing 30 patients with psychosis (6 female) and 35 healthy controls (19 female). The study aimed to examine the association between FAAH activity and stressful life events, assessed through the Recent Life Events, Survey of Life Experiences, and Hassles and Uplifts Scale. There was a significant difference regarding the number of recent stressors with higher levels in patients compared to healthy subjects (Survey of Life Experiences: t = 4.88, p < 0.001, hassles: t = 3.14, p = 0.003), however there was no significant relationship of brain FAAH activity and stressful life events in any of the applied scales across groups (Recent Life Events: F1,57 = 0.07, p = 0.80; Survey of Life Experiences: F1,57 = 1.75, p = 0.19; hassles: F1,56 = 1.06, p = 0.31). Linear mixed models performed separately for each group revealed that there was a positive association between FAAH activity and Recent Life Events in patients with psychosis only (F1,25 = 8.07, p = 0.009). Our data reveal a significant disparity in recent stressors between the two groups, and a correlation between brain FAAH activity and stressful life events in patients with psychosis only. This suggests a complex interplay between stress and the endocannabinoid system.

Reusable Iron-Copper Catalyzed Cross-Coupling of Primary Amides with Aryl and Alkyl Halides: Access to N-Arylamides as Potential Antibacterial and Anticancer Agents.

We present, for the first time, an efficient ligand-free iron-copper catalyzed cross-coupling reaction involving a variety of aryl, heteroaryl halides (including chlorides, bromides, and iodides), and alkyl bromides with diverse aryl and aliphatic primary amides, conducted under solvent-minimized conditions. This economically competitive protocol successfully yielded the corresponding cross-coupling products, N-arylamides and N-alkylamides, in good to excellent yields with broad substrate scope (65 examples) and tolerance to several sensitive functionalities (including heterocycles). No conventional work-up is required for this protocol, and the developed method is applicable for gram-scale synthesis. Notably, the catalyst is inexpensive, environmentally friendly, and can be reused at least four times with minimal loss of catalytic activity. A series of experiments, including X-ray photoelectron spectroscopy (XPS), UV spectroscopy, cyclic voltammetry (CV), electron paramagnetic resonance (EPR), and X-ray diffraction (XRD) were conducted to identify the oxidation state of active catalytic species and radical clock experiment was performed using a radical probe to investigate the reaction mechanism. Furthermore, we evaluated the antibacterial and anticancer properties of selected synthesized products (3ii, 3xii, and 3xxxx) in-vitro. The results indicated that the prepared compounds exhibited promising antibacterial and anticancer activities (MTT and Molecular Docking).

Phytochemical Composition and Antioxidant Properties of Canarium odontophyllum (Sarawak Olive): A Seasonal Fruit from Borneo, East Malaysia.

BackgroundCanarium species are reported rich of polyphenol, alkaloids, flavones, and saponins compounds. Canarium odontophyllum from Borneo's variety, on the other hand is remaining unclear especially on the antioxidant activity towards radicals. PurposeTo investigate phytochemical composition and antioxidant properties of C. odontophyllum. MethodsAntioxidant properties were evaluated using 2,2-diphenyl-1-picrylhydrazyl-hydrate (DPPH) assay, 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) assay, and ferric-reducing antioxidant power (FRAP) assay with different polarity of extraction solvents (methanol, acetone and hexane). The phytochemical composition was determined by Liquid Chromatography Mass Spectrometry Quadrupole Time of Flight (LCMS-QTOF). ResultsAcetone showed the highest scavenging activity in the DPPH (0.0307 mg/ml) and FRAP (3.926 mg/ml) assays, while hexane exhibited the highest activity in the ABTS assay (0.119 mg/ml). The LCMS-QTOF chromatogram identified 22 potential compounds. Among these, the major compounds oleamide (10.49%) and emmotin A (7.23%) have previously been reported to exhibit antioxidant activity. Other health-beneficial compounds were also found, such as palmitic amide (2.46%), deoxymiroestrol (6.23%), and N-Cyclohexanecarbonylpentadecylamine (48.92%), which are important in preventing metal corrosion, regulating hormones, and distinguishing between N-palmitoylethanolamine-hydrolyzing acid amidase (NPAA) and fatty acid amide hydrolase (FAAH), respectively. ConclusionThe results indicate that C. odontophyllum shows a promising potential an alternative drug in pharmaceutical developments.

Promising Inhibitors of Endocannabinoid Degrading Enzymes Sharing a Carbamate Scaffold.

Carbamate has been extensively used as a scaffold in the recent era of drug discovery and is a common structural motif of many approved drugs. The carbamate moiety's unique amide-ester hybrid (-O-CO-NH-) feature offers the designing of specific drug-target interactions. Despite the discovery of numerous carbamate derivatives that act on the endocannabinoid system (ECS), the development of clinically effective carbamates remains a challenge. In this review, we highlight the therapeutic potential of carbamate inhibitors of endocannabinoid degrading enzymes as a breakthrough in discovering neurotherapeutic drugs. We discuss the design strategies and medicinal chemistry aspects involved in developing carbamate-based molecular architectures that modulate the endocannabinoid signaling pathway by interfering with fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), and α/β-Hydrolase domain-containing 6 (ABHD6). Additionally, we highlight the dual activity profile of carbamates against FAAH and MAGL, FAAH and cholinesterase, and FAAH and TRPV1 channels. Furthermore, we illustrate the pharmacophores of O-functionalized carbamates and N-cyclic carbamates that are crucial for FAAH and MAGL inhibitory activities, respectively.

Cafeteria Diet Abstinence Induces Depressive Behavior and Disrupts Endocannabinoid Signaling in Dopaminergic Areas: A Preclinical Study.

Alterations of dopamine (DA) transmission in the brain reward system can be associated with an addictive-like state defined as food addiction (FA), common in obese individuals. Subjects affected by FA experience negative feelings when abstinent from their preferred diet and may develop mood disorders, including depression, sustained by alterations in brain DA pathways. This study aims to investigate the impact of long-term abstinence from a palatable diet on depressive-like behavior in rats, exploring neurochemical alterations in monoamine and endocannabinoid signaling in DA-enriched brain regions, including ventral tegmental area, dorsolateral striatum, substantia nigra and medial prefrontal cortex. Rats underwent exposure and subsequent abstinence from a palatable cafeteria diet. During abstinence, animals were treated with fatty acid amide hydrolase (FAAH) inhibitor PF-3845 (10 mg/kg, intraperitoneal administration every other day). Lastly, animals were subjected to a forced swimming test, and their brains were dissected and processed for high-performance liquid chromatography measurement of monoamines and western blot analyses of markers of the endocannabinoid machinery. After the withdrawal from the palatable diet, animals showed depressive-like behavior, coupled with significant variations in the concentration of brain monoamines and in the expression of endocannabinoid signalling machinery proteins in cited brain areas. Treatment with PF-3845 exerted an antidepressant- like effect and restored part of the alterations in monoaminergic and endocannabinoid systems. Overall, our results suggest that abstinence from a cafeteria diet provokes emotional disturbances linked to neuroadaptive changes in monoamines and endocannabinoid signalling in brain areas partaking to DA transmission that could partially be restored by the enhancement of endocannabinoid signalling through FAAH inhibition.

Alterations of endocannabinoid signaling and microglia reactivity in the retinas of AD-like mice precede the onset of hippocampal β-amyloid plaques.

Extra-cerebral manifestations of Alzheimer's disease (AD) develop in the retina, which is, therefore, considered a "window to the brain". Recent studies demonstrated the dysregulation of the endocannabinoid (eCB) system (ECS) in AD brain. Here, we explored the possible alterations of ECS and the onset of gliosis in the retina of AD-like mice. Tg2576 (TG) mice overexpressing the amyloid precursor protein (APP) were used at the age of 12 months, when hippocampal β-amyloid plaques had not been developed yet. Analysis of retinal gliosis showed a significant increase in the number of IBA1 (+) microglia cells in TG versus wild type (WT). Gliosis was not associated with retinal β-amyloid plaques, evident retinal degenerative signatures, or excitotoxicity; instead, oxidative stress burden was observed as increased acrolein levels. Analysis of the ECS (receptors/metabolic enzymes) through western blotting (WB) revealed the up-regulation of cannabinoid receptor 2 (CB2) and monoacylglycerol lipase (MAGL), the enzyme responsible for the degradation of 2-arachidonoylglycerol (2-AG), in TG retinas. Fluorescence intensity analysis of anti-CB2 and anti-MAGL immuno-stained cryosections was consistent with WB, showing their up-regulation throughout the retinal layers. No statistically significant differences were found for the other enzymes/receptors of the ECS under study. However, linear regression analysis for individual animals showed a significant correlation between CB2 and fatty acid amide hydrolase (FAAH), diacylglycerol lipase α/β (DAGLα/β), and APP; instead, a significant negative correlation was found between MAGL and APP. Finally, ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) demonstrated a significant reduction of 2-AG in TG retinas (~0.34 ng/mg) compared to WT (~1.70 ng/mg), while a trend toward increase was found for the other eCB anandamide (AEA). Overall, our data indicate that gliosis and ECS dysregulation-in particular of CB2, MAGL and 2-AG-occur in the retina of AD-like mice before retinal degeneration and development of hippocampal β-amyloid plaques.

Copper-Catalyzed γ-C(sp3)-H Lactamization and Iminolactonization.

Despite extensive efforts to develop γ-lactamization reactions for pyrrolidinone synthesis using either cyclometallation, C-H insertion, or radical C-H abstraction strategies, γ-lactamization reactions of aliphatic amides using practical catalysts and common protecting groups remain extremely rare. Herein we report copper-catalyzed γ-C(sp3)-H lactamization and iminolactonization of tosyl-protected aliphatic amides using inexpensive Selectfluor as the sole oxidant. A switchable selectivity of γ-lactams or γ-iminolactones can be obtained by using two different sets of reaction conditions. Notably, structurally diverse spiro-, fused-, and bridged-lactams and iminolactones, as well as isoindolinones are accessible by this method. Further derivatization of the γ-lactam products enables the synthesis of a range of biologically important motifs, including γ-amino acids, δ-amino alcohols, and pyrrolidines.

Copper‐Catalyzed γ‐C(sp3)−H Lactamization and Iminolactonization

AbstractDespite extensive efforts to develop γ‐lactamization reactions for pyrrolidinone synthesis using either cyclometallation, C−H insertion, or radical C−H abstraction strategies, γ‐lactamization reactions of aliphatic amides using practical catalysts and common protecting groups remain extremely rare. Herein we report copper‐catalyzed γ‐C(sp3)−H lactamization and iminolactonization of tosyl‐protected aliphatic amides using inexpensive Selectfluor as the sole oxidant. A switchable selectivity of γ‐lactams or γ‐iminolactones can be obtained by using two different sets of reaction conditions. Notably, structurally diverse spiro‐, fused‐, and bridged‐lactams and iminolactones, as well as isoindolinones are accessible by this method. Further derivatization of the γ‐lactam products enables the synthesis of a range of biologically important motifs, including γ‐amino acids, δ‐amino alcohols, and pyrrolidines.

Endocannabinoid dysregulation and PTSD in urban adolescents: Associations with anandamide concentrations and FAAH genotype.

The endocannabinoid system, which regulates fear- and anxiety-related behaviors, is dysregulated in adults with posttraumatic stress disorder (PTSD), as indicated by higher circulating anandamide (AEA) concentrations. The C385A (rs324420) polymorphism in the fatty acid amide hydrolase (FAAH) gene, which catabolizes AEA, is linked to higher AEA concentrations and greater PTSD symptoms in adults. Given that adolescence is a critical period during which trauma and psychiatric disorders emerge, understanding this relationship in youth is essential. This study examines PTSD symptoms, AEA concentrations, and FAAH genotype in a diverse adolescent sample. This study included 102 Detroit-area adolescents (M ± SD = 13.33 ± 2.21 years, 54.9% female) and their parents/guardians. The sample consisted of 40.2% White Non-Hispanic, 34.3% Black Non-Hispanic, 6.9% White Hispanic, 4.9% Asian/Pacific Islander, and 12.7% Biracial adolescents. Trauma exposure and PTSD symptoms were assessed using the UCLA PTSD Reaction Index for DSM-5. Plasma concentrations of AEA were measured by liquid chromatography-tandem mass spectrometry, and FAAH genotype was determined from saliva samples and high-throughput screening. The majority (90%) of adolescents reported trauma exposure, and 20% met PTSD criteria. Higher AEA concentrations were associated with more severe PTSD symptoms (p = 0.009), especially hyperarousal. The FAAH A-allele (present in 52.5% of participants) was associated with higher AEA concentrations (2.11 ± 0.69 pmol/ml, p = 0.013) and greater PTSD severity (22.65 ± 15.931, p = 0.027), particularly those with the reexperiencing cluster, compared to the CC genotype (1.79 ± 0.66 pmol/ml and 15.87 ±+ 13.043, respectively). Elevated AEA concentrations and the FAAH A-allele were associated with greater PTSD symptom severity in urban adolescents. These findings suggest endocannabinoid dysregulation may play a role in adolescent PTSD, highlighting the need for further research and targeted interventions.

Automatic classification of fatty acid amide hydrolase polymorphism genotype based on EEG signal

Automatic classification of fatty acid amide hydrolase polymorphism genotype based on EEG signal

Comparative Multi-Omics Survey Reveals Novel Specialized Metabolites and Biosynthetic Gene Clusters Under GacS Control in Pseudomonas donghuensis Strain SVBP6.

In Pseudomonas donghuensis SVBP6, isolated from an agricultural field, the well-conserved Gac-Rsm pathway upregulates biosynthesis of the antifungal compound 7-hydroxytropolone (7-HT). However, 7-HT does not fully explain the strain's Gac-Rsm-dependent antimicrobial activity. Here, we combined comparative transcriptomic, proteomic, and metabolomic approaches to identify novel GacS-dependent biosynthetic gene clusters (BGC) and/or extracellular specialized metabolites. Our data revealed a broad impact of GacS on gene expression and extracellular metabolite profile of SVBP6. At both the mRNA and polypeptide levels, specialized metabolism was the main affected functional category in the gacS mutant. The major extracellular MS/MS spectral families promoted by GacS were fatty acid amides, fatty acids, and alkaloids. GacS was required for the production of the antimicrobial compound pseudoiodinine and to activate expression of the corresponding BGC. We also detected GacS-dependent production of 2,3,4-trihydro-β-carboline-1-one, which may add to the antimicrobial arsenal of SVBP6. Furthermore, transcriptomics and proteomics pinpointed several GacS-activated BGCs that had escaped in silico genome mining tools. Altogether, comparative multi-omics analyses of gacS loss-of-function mutants in Pseudomonas isolates are a promising strategy to uncover bioactive metabolites and/or their BGCs. Discovery of novel natural products is important for harnessing the potential of microbiota to improve crop plant growth and health.

FAAH Inhibition Reverses Depressive-like Behavior and Sex-Specific Neuroinflammatory Alterations Induced by Early Life Stress.

Early life stress (ELS) increases predisposition to major depressive disorder (MDD), with neuroinflammation playing a crucial role. This study investigated the long-term effects of the fatty acid amide hydrolase (FAAH) inhibitor URB597 on ELS-induced depressive-like behavior and messenger RNA (mRNA) of pro-inflammatory cytokines in the medial prefrontal cortex (mPFC) and CA1 regions. We also assessed whether these gene expression alterations were present at the onset of URB597 treatment during late adolescence. ELS induced a depressive-like phenotype in adult male and female rats, which was reversed by URB597. In the mPFC, ELS downregulated nuclear factor kappa B1 (nfκb1) in both sexes, while URB597 normalized this expression exclusively in males. In females, ELS downregulated interleukin (il) 6 and tumor necrosis factor alpha (tnfα) but upregulated il1β and corticotropin-releasing factor (crf); URB597 normalized il6, il1β, and crf. In the CA1, ELS downregulated il1β and tnfα in males and upregulated il1β expression in females, which was reversed by URB597. Some of these effects began in late adolescence, including mPFC-nfκb1 expression in both sexes, mPFC-il6 and mPFC-il1β in females, CA1-il1β and CA1-tnfα in males, and CA1-il1β in females. These findings highlight URB597 as a therapeutic approach for reversing ELS-induced depressive-like behavior by associating with changes in the gene expression of neuroinflammatory cytokines, with notable sex differences.

Insights into the Chemical Exposome during Pregnancy: A Non-Targeted Analysis of Preterm and Term Births.

Human-made chemicals are ubiquitous, leading to chronic exposure to complex mixtures of potentially harmful substances. We investigated chemical exposures in pregnant women in New York City by applying a non-targeted analysis (NTA) workflow to 95 paired prenatal urine and serum samples (35 pairs of preterm birth) collected as part of the New York University Children's Health and Environment Study. We analyzed all samples using liquid chromatography coupled with Orbitrap high-resolution mass spectrometry in both positive and negative electrospray ionization modes, employing full scan and data-dependent MS/MS fragmentation scans. We detected a total of 1524 chemical features for annotation, with 12 chemicals confirmed by authentic standards. Two confirmed chemicals dodecyltrimethylammonium and N,N-dimethyldecylamine N-oxide appear to not have been previously reported in human blood samples. We observed a statistically significant differential enrichment between urine and serum samples, as well as between preterm and term birth (p < 0.0001) in serum samples. When comparing between preterm and term births, an exogenous contaminant, 1,4-cyclohexanedicarboxylic acid (tentative), showed a statistical significance difference (p = 0.003) with more abundance in preterm birth in serum. An example of chemical associations (12 associations in total) observed was between surfactants (tertiary amines) and endogenous metabolites (fatty acid amides).

Differential Lipid Signatures of Lumbar and Cisternal Cerebrospinal Fluid.

The molecular composition of cerebrospinal fluid (CSF) is often used as a key indicator of biochemical alterations within distinct brain and spinal cord fluid compartments. The CSF protein content in lumbar CSF samples is widely employed as a biomarker matrix for diagnosing brain-related pathological conditions. CSF lipid profiles may serve as promising complementary diagnostics, but it remains unresolved if the lipid distribution is consistent along the neuroaxis. The lipid composition was determined with liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) in cisternal CSF obtained from healthy subjects undergoing preventive surgery of an unruptured aneurism (n = 11) and lumbar CSF obtained from individuals referred for the clinical evaluation of cognitive dysfunction but subsequently cleared and deemed healthy (n = 19). We reveal discernible variations in lipid composition along the neuroaxis, with a higher overall lipid concentration in cisternal CSF, although with different relative distributions of the various lipid classes in the two compartments. The cisternal CSF contained elevated levels of most lipid classes, e.g., sphingomyelins, lysophosphatidylcholines, plasmenylphosphatidylcholines, phosphatidic acids, and triacylglycerols, whereas a few select lipids from the classes of fatty acids, phosphatidylcholines, amides and plasmenylphosphatidylethanolamines were, oppositely, elevated in the lumbar CSF pool. The distinct lipid distribution along the neuroaxis illustrates that the molecular constituents in these two CSF compartments are not uniform. These findings emphasize the necessity of establishing a lumbar lipid index for the accurate interpretation of the cranial CSF lipid profile.

Research Progress in the Synthesis of N-Acyl Amino Acid Surfactants: A Review

This paper reviews the research progress in the synthesis of N-acyl amino acid surfactants, including chemical synthesis methods, enzymatic synthesis methods, chemo-enzymatic methods, and fermentation methods. Chemical synthesis is currently the main route for laboratory and industrial synthesis, including methods such as direct dehydration condensation of fatty acids, amidation of fatty acid anhydrides, carbonyl addition of fatty amides, amidation of fatty acid activated esters, amidation of fatty acid methyl esters, amidation of oils and fats, hydrolysis of fatty nitriles, and Schotten–Baumann condensation. Enzymatic synthesis has the advantages of mild reaction conditions and being green and pollution-free, but the yield is relatively low. The chemo-enzymatic method combines the advantages of enzymatic and chemical methods, but it has not been widely promoted. Fermentation methods have low production costs and are environmentally friendly but the technology is not yet mature. This paper elaborates on the principles, advantages, and disadvantages of each synthesis method and provides an outlook on future research directions.

Fatty acid amide hydrolase gene inactivation induces hetero-cellular potentiation of microglial function in the 5xFAD mouse model of Alzheimer's disease.

Neuroinflammation has recently emerged as a crucial factor in Alzheimer's disease (AD) etiopathogenesis. Microglial cells play an important function in the inflammatory response; specifically, the emergence of disease-associated microglia (DAM) has offered new insights into the conflicting perspectives on the detrimental or beneficial roles of microglia. We previously showed that modulating the endocannabinoid tone by fatty acid amide hydrolase (FAAH) inactivation renders beneficial effects in an amyloidosis context, paradoxically accompanied by an exacerbated neuroinflammatory response and the enrichment of DAM population. Here, we aim to elucidate the role of microglial cells in FAAH-lacking mice in the 5xFAD mouse model of AD by using RNA-sequencing analysis, molecular determinations, and morphological studies by using in vivo multiphoton microscopy. FAAH-lacking AD mice displayed upregulated inflammatory genes and exhibited a DAM genetic profile. Conversely, genes linked to AD were downregulated. Depleting microglia using PLX5622 revealed that plaque-associated microglia in FAAH-deficient AD mice had a more stable, ramified morphology and increased Aβ uptake, leading to reduced plaque growth compared to control mice. Importantly, FAAH expression was negligible in microglial cells, thus suggesting a role for FAAH in the cellular interplay in the central nervous system. Our findings show that Faah gene inactivation triggers a hetero-cellular enhancement of microglial function that was paradoxically paralleled by an exacerbated inflammatory response. Taken together, the present data highlight FAAH as a potential therapeutic target in AD.

Comparative Metabolomics to Unravel the Biochemical Mechanism Associated with Rancidity in Pearl Millet (Pennisetum glaucum L.).

Despite being a highly nutritious and resilient cereal, pearl millet is not popular among consumers and food industries due to the short shelf-life of flour attributed to rapid rancidity development. The biochemical mechanism underlying rancidity, a complex and quantitative trait, needs to be better understood. The present study aims to elucidate the differential accumulation of metabolites in pearl millet that impact the rancidity process. Metabolite profiling was conducted on ten pearl millet genotypes with varying levels of rancidity-comprising high, low, and medium rancid genotypes-utilizing liquid chromatography and high-resolution mass spectrometry (LC-HRMS) at different accelerated ageing conditions. Through non-targeted metabolomic analysis, crucial metabolites associated with rancidity were identified across various biochemical pathways, including fatty acids, glycerophospholipids, sphingolipids, glycerol lipids, flavonoids, alkaloids, and terpenoids. Notably, metabolites such as fatty aldehydes, fatty alcohols, fatty esters, fatty acyls, fatty esters, and fatty amides were significantly elevated in high rancid genotypes, indicating their involvement in the rancidity process. These fatty acids-related metabolites further break down into saturated and unsaturated fatty acids. Four key fatty acids-stearic, palmitic, linoleic and linolenic acid-were quantified in the ten pearl millet genotypes, confirming their role in rancidity development. This investigation promises novel insights into utilizing metabolomics to understand the biochemical processes and facilitate precision breeding for developing low-rancidity pearl millet lines.

A human gut Faecalibacterium prausnitzii fatty acid amide hydrolase.

Undernutrition in Bangladeshi children is associated with disruption of postnatal gut microbiota assembly; compared with standard therapy, a microbiota-directed complementary food (MDCF) substantially improved their ponderal and linear growth. Here, we characterize a fatty acid amide hydrolase (FAAH) from a growth-associated intestinal strain of Faecalibacterium prausnitzii cultured from these children. This enzyme, expressed and purified from Escherichia coli, hydrolyzes a variety of N-acylamides, including oleoylethanolamide (OEA), neurotransmitters, and quorum sensing N-acyl homoserine lactones; it also synthesizes a range of N-acylamides, notably N-acyl amino acids. Treating germ-free mice with N-oleoylarginine and N-oleolyhistidine, major products of FAAH OEA metabolism, markedly affected expression of intestinal immune function pathways. Administering MDCF to Bangladeshi children considerably reduced fecal OEA, a satiety factor whose levels were negatively correlated with abundance and expression of their F. prausnitzii FAAH. This enzyme, structurally and catalytically distinct from mammalian FAAH, is positioned to regulate levels of a variety of bioactive molecules.

3-O-Ethyl Ascorbic Acid and Cannabigerol in Modulating the Phospholipid Metabolism of Keratinocytes.

Phospholipids and their metabolites play an important role in maintaining the membrane integrity and the metabolic functions of keratinocytes under physiological conditions and in the regeneration process after exposure to high-energy UVB radiation. Therefore, in the search for compounds with a protective and regenerative effect on keratinocyte phospholipids, the effectiveness of two antioxidant compounds has been tested: a stable derivative of ascorbic acid, 3-O-ethyl ascorbic acid (EAA) and cannabigerol (CBG), both of which are primarily located in the membrane structures of keratinocytes. In addition, this study has demonstrated that EAA and CBG, especially in a two-component combination, enhance the antioxidant properties of keratinocytes and reduce lipid peroxidation assessed at the level of MDA (malondialdehyde)/neuroprostanes. Moreover, by reducing the activity of enzymes that metabolise phospholipids, free PUFAs (polyunsaturated fatty acids) and endocannabinoids (PLA2; phospholipase A2, COX1/2; cyclooxygenases 1/2, LOX-5; lipoxygenase 5, FAAH; fatty acid amide hydrolase, MAGL; monoacylglycerol lipase), antioxidants have been found to regulate the levels of endocannabinoids (AEA; anandamide, 2-AG; 2-arachidonoylglycerol, PEA; palmitoylethanolamide) and eicosanoids (PGD2; prostaglandin D2, PGE2; prostaglandin E2, 15-d-PGJ2; 15-deoxy-Δ12,14-prostaglandin J2, 15-HETE; 15-hydroxyeicosatetraenoic acid), that are enhanced by UVB radiation. The metabolic effect of both groups of PUFA metabolites is mainly related to the activation of G protein-related receptors (CB1/2; cannabinoid receptor 1 and 2, PPARγ; peroxisome proliferator-activated receptor gamma, TRPV1; transient receptor potential cation channel subfamily V member 1), the expression of which is reduced under the influence of EAA, CBG, and especially the two-component combination. It promotes the regeneration of keratinocyte metabolism disrupted by UVB, particularly in relation to redox balance and inflammation.

Early life stress induces decreased expression of CB1R and FAAH and epigenetic changes in the medial prefrontal cortex of male rats.

Several studies in both animal models and in humans have provided substantial evidence that early life stress (ELS) induces long-term changes in behavior and brain function, making it a significant risk factor in the aetiology of various mental disorders, including anxiety and depression. In this study, we tested the hypothesis that ELS in male rats (i) leads to increased anxiety and depressive-like symptoms; and (ii) that these behavioral changes are associated with functional alterations in the endocannabinoid system of the medial prefrontal cortex (mPFC). We further assessed whether the predicted changes in the gene expression of two key components of the endocannabinoid system, cannabinoid receptor 1 (CB1R) and the fatty acid amide hydrolase (FAAH), are regulated by epigenetic mechanisms. Behavioral profiling revealed that the proportion of behaviorally affected animals was increased in ELS exposed male rats compared to control animals, specifically showing symptoms of anhedonia and impaired social behavior. On the molecular level we observed a decrease in CB1R and FAAH mRNA expression in the mPFC of adult ELS exposed animals. These gene expression changes were accompanied by reduced global histone 3 acetylation in the mPFC, while no significant changes in DNA methylation and no significant changes of histone-acetylation at the promoter regions of the analyzed genes were detected. Taken together, our data provide evidence that ELS induces a long-term reduction of CB1R and FAAH expression in the mPFC of adult male rats, which may partially contribute to the ELS-induced changes in adult socio-emotional behavior.