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Phospholipase A₂ (PLA₂) enzymes are considered the primary source of arachidonic acid for cyclooxygenase (COX)-mediated biosynthesis of prostaglandins. Here, we show that a distinct pathway exists in brain, where monoacylglycerol Upase (MAGL) hydrolyzes the endocannabinoid 2-arachidonoylglycerol to generate a major arachidonate precursor pool for neuroinflammatory prostaglandins. MAGL-disrupted animals show neuroprotection in a parkinsonian mouse model. These animals are spared the hemorrhaging caused by COX inhibitors in the gut, where prostaglandins are instead regulated by cytosolic PLA₂ . These findings identify MAGL as a distinct metabolic node that couples endocannabinoid to prostaglandin signaling networks in the nervous system and suggest that inhibition of this enzyme may be a new and potentially safer way to suppress the proinflammatory cascades that underlie neurodegenerative disorders.

Endocannabinoids (eCBs) are involved in buffering threat and stress responses. Elevation of circulating eCBs in humans was reported to strengthen inhibition (i.e., extinction) of threat responses and to reduce effects of stressors. However, it remains unclear whether the acquisition of threat responses involves a physiological change in circulating eCBs. Here, we demonstrate in male human volunteers that the plasma concentration of the eCB N-arachidonoylethanolamine (AEA) and its metabolite arachidonic acid (AA) are increased during acquisition of threat responses. Furthermore, elevated responses to a learned threat cue (e.g., rating of fear) were associated with individual increases in plasma concentration of the eCB 2-arachidonoylglycerol (2-AG). In complementing these observations, we found individual increases in AEA associated with elevated neural responses during threat learning in the amygdala. Our results thereby suggest that physiological increases in circulating eCB levels are part of a response mechanism to learned threats.

Elevated arachidonic acid metabolism (AAM) has been linked to the progression of non-alcoholic fatty liver disease (NAFLD). However, the specific role of AAM-related genes (AAMRGs) in NAFLD remains poorly understood. To investigate the involvement of AAMRGs in NAFLD, this study analyzed datasets GSE89632 and GSE135251 from the Gene Expression Omnibus (GEO) and Molecular Signatures Database (MSigDB). Differential expression analysis revealed 2256 differentially expressed genes (DEGs) between NAFLD and control liver tissues. Cross-referencing these DEGs with AAMRGs identified nine differentially expressed AAMRGs (DE-AAMRGs). Least absolute shrinkage and selection operator (LASSO) and univariate logistic regression analyses pinpointed five biomarkers—CYP2U1, GGT1, PLA2G1B, GPX2, and PTGS1—demonstrating significant diagnostic potential for NAFLD, as validated by receiver operating characteristic (ROC) analysis. These biomarkers were implicated in pathways related to AAM and arachidonate transport. An upstream regulatory network, involving transcription factors (TFs) and MicroRNAs (miRNAs), was constructed to explore the regulatory mechanisms of these biomarkers. In vivo validation using a NAFLD mouse model revealed liver histopathological changes, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot (WB) analyses confirmed the upregulation of biomarker expression, particularly PTGS1, in NAFLD. The bioinformatic analysis identified five AAM-related biomarkers, enhancing the understanding of NAFLD pathogenesis and offering potential diagnostic targets.

Arachidonic acid (AA)-derived lipid mediators play pivotal roles in inflammation and its resolution. While glycolysis is a key metabolic pathway determining macrophage polarization, the crosstalk between specific AA metabolites and glycolytic reprogramming remains poorly understood. In this study, we explore whether certain AA metabolites modulate macrophage function through covalent protein modification, with therapeutic implications for myocardial ischemia-reperfusion injury. Unlike conventional specialized pro-resolving mediators (SPMs) that primarily act via receptors, here we identify an endogenous electrophilic AA metabolite, 15-keto-prostaglandin F2α (15KPF), that covalently modifies pyruvate kinase M2 (PKM2) at Cys49. Such interaction enhanced tetramerization, suppressed the axis, redirected energy metabolism from glycolysis to mitochondrial respiration, and promoted pro-resolving M2 macrophage polarization. Mutated (C49S) failed to inhibit STAT3 signaling and blocked the effect of 15KPF on M1 to M2 phenotype switch. Moreover, 15KPF reduced infarct size and preserved myocardial integrity in model. Taken together, covalent 15-keto-PGF2α- conjugation represents a self-regulatory mechanism linking AA metabolism to glycolysis to drive macrophage metabolic-inflammatory reprogramming. This pathway positions 15KPF as a promising therapeutic candidate for inflammatory and metabolic diseases, including ischemia-reperfusion injury, and distinguishes it from synthetic allosteric PKM2 activators such as TEPP-46.

Oxylipins are bioactive oxidation products derived from n-6 and n-3 polyunsaturated fatty acids (PUFAs) in the linoleic acid and α-linolenic desaturation pathways. This study determined if carbohydrate intake during prolonged and intensive cycling countered post-exercise increases in n-6 and n-3 PUFA-derived oxylipins. The research design utilized a randomized, crossover, counterbalanced approach with cyclists (N = 20, overnight fasted state, 7:00 am start) who engaged in four 75-km time trials while ingesting two types of bananas (Cavendish, Mini-yellow), a 6% sugar beverage, and water only. Carbohydrate intake was set at 0.2 g/kg every 15 minutes, and blood samples were collected pre-exercise and 0 h-, 0.75 h-,1.5 h-, 3 h-, 4.5 h-, 21 h-, 45 h-post-exercise. Oxylipins were measured with a targeted liquid chromatography-multiple reaction monitoring mass spectrometric method. Significant time effects and substantial fold-increases (immediately post-exercise/pre-exercise) were measured for plasma levels of arachidonic acid (ARA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and 43 of 45 oxylipins. Significant interaction effects (4 trials x 8 time points) were found for plasma ARA (P<0.001) and DHA (P<0.001), but not EPA (P = 0.255), with higher post-exercise values found in the water trial compared to the carbohydrate trials. Significant interaction effects were also measured for 12 of 45 oxylipins. The data supported a strong exercise-induced increase in plasma levels of these oxylipins during the water trial, with carbohydrate ingestion (both bananas types and the sugar beverage) attenuating oxylipin increases, especially those (9 of 12) generated from the cytochrome P-450 (CYP) enzyme system. These trials differences were especially apparent within the first three hours of recovery from the 75-km cycling bout. Prolonged and intensive exercise evoked a transient but robust increase in plasma levels of oxylipins, with a significant attenuation effect linked to acute carbohydrate ingestion for 28% of these, especially those generated through the CYP enzyme system. ClinicalTrials.gov, U.S. National Institutes of Health, NCT02994628.

Arachidonic acid (AA) metabolism plays essential roles in inflammation, tissue regeneration, immune regulation, and tumorigenesis. However, the prognostic significance of genetic variants in AA metabolism genes for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains unclear. We analyzed 56 AA metabolism-related genes in 866 HBV-HCC patients using Cox proportional hazards regression, with Bayesian false discovery probability and false positive report probability for multiple testing correction. Two independent SNPs, CYP2A6 rs28399433 A > C (HR = 1.30, 95% CI = 1.07–1.58, P  = 0.008) and ABHD12 rs3827014 C > T (HR = 0.69, 95% CI = 0.52–0.93, P  = 0.013), were identified. A genetic score combining protective alleles showed a dose-dependent association with improved overall survival ( P t rend <0.001), with significant multiplicative interactions with smoking ( P interaction =0.016) and alcohol consumption ( P interaction =0.049), and additive interactions for smoking (RERI = 0.65, 95% CI = 0.10–1.19) and BCLC stage B/C (RERI = 1.25, 95% CI = 0.17–2.33). Functional validation with luciferase reporter assays demonstrated allele-specific effects on gene expression ( P  < 0.001). Lower CYP2A6 and higher ABHD12 levels in HCC tissues compared to normal were observed in the UALCAN database ( P  = 6.43 × 10⁻⁷ for CYP2A6 ; P  < 1.00 × 10⁻¹² for ABHD12 ) and in 103 paired tumor/normal tissues. Survival analysis using the KMplot database indicated that decreased CYP2A6 and increased ABHD12 expression were associated with poorer survival ( P  < 0.001 and P  = 0.008, respectively). These findings suggest that functional variants in CYP2A6 and ABHD12 may serve as novel survival biomarkers for HBV-HCC by regulating gene expression.

Arachidonic acid (C20: 4n-6, AA) plays a fundamental role in fish physiology, influencing growth, survival and stress resistance. However, imbalances in dietary AA can have detrimental effects on fish health and performance. Optimal AA requirements for rainbow trout have not been established. This study aimed to elucidate the effects of varying dietary AA levels on survival, growth, long-chain polyunsaturated fatty acid (LC-PUFA) biosynthetic capacity, oxylipin profiles, lipid peroxidation, and stress resistance of rainbow trout fry. Over a period of eight weeks, 4000 female rainbow trout fry at the resorptive stage (0.12 g) from their first feeding were fed diets with varying levels of AA (0.6%, 1.1% or 2.5% of total fatty acids) while survival and growth metrics were closely monitored. The dietary trial was followed by an acute confinement stress test. Notably, while the fatty acid profiles of the fish reflected dietary intake, those fed an AA-0.6% diet showed increased expression of elongase5, highlighting their inherent ability to produce LC-PUFAs from C18 PUFAs and suggesting potential AA or docosapentaenoic acidn-6 (DPAn-6) biosynthesis. However, even with this biosynthetic capacity, the trout fed reduced dietary AA had higher mortality rates. The diet had no effect on final weight (3.38 g on average for the three diets). Conversely, increased dietary AA enhanced eicosanoid production from AA, suggesting potential inflammatory and oxidative consequences. This was further evidenced by an increase in non-enzymatic lipid oxidation metabolites, particularly in the AA-2.5% diet group, which had higher levels of phytoprostanes and isoprostanes, markers of cellular oxidative damage. Importantly, the AA-1.1% diet proved to be particularly beneficial for stress resilience. This was evidenced by higher post-stress turnover rates of serotonin and dopamine, neurotransmitters central to the fish's stress response. In conclusion, a dietary AA intake of 1.1% of total fatty acids appears to promote overall resilience in rainbow trout fry.

The diacylglycerol lipases (DAGLs) hydrolyse diacylglycerol to generate 2-arachidonoylglycerol (2-AG), the most abundant ligand for the CB1 and CB2 cannabinoid receptors in the body. DAGL-dependent endocannabinoid signalling regulates axonal growth and guidance during development, and is required for the generation and migration of new neurons in the adult brain. At developed synapses, 2-AG released from postsynaptic terminals acts back on presynaptic CB1 receptors to inhibit the secretion of both excitatory and inhibitory neurotransmitters, with this DAGL-dependent synaptic plasticity operating throughout the nervous system. Importantly, the DAGLs have functions that do not involve cannabinoid receptors. For example, 2-AG is the precursor of arachidonic acid in a pathway that maintains the level of this essential lipid in the brain and other organs. This pathway also drives the cyclooxygenase-dependent generation of inflammatory prostaglandins in the brain, which has recently been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. Remarkably, we still know very little about the mechanisms that regulate DAGL activity—however, key insights can be gleaned by homology modelling against other α/β hydrolases and from a detailed examination of published proteomic studies and other databases. These identify a regulatory loop with a highly conserved signature motif, as well as phosphorylation and palmitoylation as post-translational mechanisms likely to regulate function.

Background The human intestine and its microbiota is the most common infection site for soil-transmitted helminths (STHs), which affect the well-being of ~ 1.5 billion people worldwide. The complex cross-kingdom interactions are not well understood. Results A cross-sectional analysis identified conserved microbial signatures positively or negatively associated with STH infections across Liberia and Indonesia, and longitudinal samples analysis from a double-blind randomized trial showed that the gut microbiota responds to deworming but does not transition closer to the uninfected state. The microbiomes of individuals able to self-clear the infection had more alike microbiome assemblages compared to individuals who remained infected. One bacterial taxon ( Lachnospiracae ) was negatively associated with infection in both countries, and 12 bacterial taxa were significantly associated with STH infection in both countries, including Olsenella (associated with reduced gut inflammation), which also significantly reduced in abundance following clearance of infection. Microbial community gene abundances were also affected by deworming. Functional categories identified as associated with STH infection included arachidonic acid metabolism; arachidonic acid is the precursor for pro-inflammatory leukotrienes that threaten helminth survival, and our findings suggest that some modulation of arachidonic acid activity in the STH-infected gut may occur through the increase of arachidonic acid metabolizing bacteria. Conclusions For the first time, we identify specific members of the gut microbiome that discriminate between moderately/heavily STH-infected and non-infected states across very diverse geographical regions using two different statistical methods. We also identify microbiome-encoded biological functions associated with the STH infections, which are associated potentially with STH survival strategies, and changes in the host environment. These results provide a novel insight of the cross-kingdom interactions in the human gut ecosystem by unlocking the microbiome assemblages at taxonomic, genetic, and functional levels so that advances towards key mechanistic studies can be made.

Scoparone (6,7-dimethoxycoumarin) is a simple coumarin from botanical drugs of Artemisia species used in Traditional Chinese Medicine and Génépi liquor. However, its bioavailability to the brain and potential central effects remain unexplored. We profiled the neuropharmacological effects of scoparone upon acute and subchronic intraperitoneal administration (2.5–25 mg/kg) in Swiss mice and determined its brain concentrations and its effects on the endocannabinoid system (ECS) and related lipids using LC–ESI–MS/MS. Scoparone showed no effect in the forced swimming test (FST) but, administered acutely, led to a bell-shaped anxiogenic-like behavior in the elevated plus-maze test and bell-shaped procognitive effects in the passive avoidance test when given subchronically and acutely. Scoparone rapidly but moderately accumulated in the brain (Cmax < 15 min) with an apparent first-order elimination (95% eliminated at 1 h). Acute scoparone administration (5 mg/kg) significantly increased brain arachidonic acid, prostaglandins, and N -acylethanolamines (NAEs) in the FST. Conversely, subchronic scoparone treatment (2.5 mg/kg) decreased NAEs and increased 2-arachidonoylglycerol. Scoparone differentially impacted ECS lipid remodeling in the brain independent of serine hydrolase modulation. Overall, the unexpectedly potent central effects of scoparone observed in mice could have toxicopharmacological implications for humans.