Search Results (20)

Inflammation is a complicated physiological process that contributes to a variety of disorders including osteoarthritis (OA) and rheumatoid arthritis (RA). Endocannabinoids and the endocannabinoid system (ECS) play a pivotal role in the physiological response to pain and inflammation. A clinical study to investigate the role of the endocannabinoid system and related lipids in pain and inflammation in OA and RA was performed. In total, 80 subjects, namely, 25 patients with RA, 18 with OA, and 37 healthy participants, were included. Sixteen endocannabinoids and congeners, as well as 129 oxylipins, were quantified in plasma using specific, quantitative LC-MS/MS assays. The endocannabinoid analysis revealed significantly lower levels of 2-arachidonoylglycerol (2-AG) in RA and OA patients compared to healthy participants. In contrast, the EC levels of the ethanolamide group (anandamide, docosahexaenoyl-EA, palmitoleoyl-EA, and other ethanolamides) were higher in the RA study cohort and to a lesser extent also in the OA cohort. This analysis of oxylipins revealed lower levels of the pro-resolving lipid 9-oxo-octadecadienoic acid (9-oxoODE) and the ω-3 fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) in RA compared to all other study cohorts. 2-AG is a key regulator of nociception and inflammation, and its relatively low levels might be a mechanistic contributor to residual pain and inflammation in RA and OA. Several changes in pro- and anti-inflammatory lipid mediators were detected, including lower levels of EPA and DHA in RA, which might reveal the potential for nutritional supplementation with these anti-inflammatory fatty acids. Full article

Background/Objectives: Neuroinflammation, a hallmark of Alzheimer’s disease (AD), is characterized by elevated levels of inflammatory signaling molecules, including cytokines and eicosanoids, as well as increased microglial reactivity, and is augmented by gut microbiota dysbiosis via the gut–brain axis. We conducted a pilot experiment to elucidate the anti-inflammatory effects of dietary omega-3 polyunsaturated fatty acid (ω-3 PUFA) eicosapentaenoic acid (EPA) on the gut microbiota and neuroinflammation. Methods: Female APP/PS1 mice (TG) and non-transgenic littermates (WT), 13–14 months old, were fed a diet supplemented with 0.3% EPA or control chow for 3 weeks. The gut microbiota composition, hippocampal and plasma eicosanoids levels, platelet activation, and microglial phagocytosis, as well as the brain and retinal genes and protein expression, were analyzed. Results: EPA supplementation decreased the percentage of Bacteroidetes and increased bacteria of the phylum Firmicutes in APP/PS1 and WT mice. Inflammatory lipid mediators were elevated in the hippocampus of the TG mice, accompanied by a reduction in the endocannabinoid docosahexaenoyl ethanolamide (DHEA). Dietary EPA did not affect hippocampal lipid mediators, but reduced the levels of arachidonic-derived 5-HETE and N-arachidonoylethanolamine (AEA) in WT plasma. Moreover, EPA supplementation decreased major histocompatibility complex class II (MHCII) gene expression in the retina in both genotypes, and MHCII+ cells in the hippocampus of TG mice. Conclusions: This pilot study showed that short-term EPA supplementation shaped the gut microbiota by increasing butyrate-producing bacteria of the Firmicutes phylum and decreasing Gram-negative LPS-producing bacteria of the Bacteroidetes phylum, and downregulated the inflammatory microglial marker MHCII in two distinct regions of the central nervous system (CNS). Further investigation is needed to determine whether EPA-mediated effects on the microbiome and microglial MHCII have beneficial long-term effects on AD pathology and cognition. Full article

Background/Objectives: Milk is one of the main sources of nutrition in people’s daily diet, but the fat in milk raises health concerns in consumers. Here, we aimed to elucidate the impact of Buffalo milk and Holstein cow milk consumption on blood lipid health through metabolomics analysis. Methods: Golden hamsters were administered Murrah Buffalo milk (BM) or Holstein cow milk (HM), and the body weight and serum lipid indicators were tested and recorded. The hamsters receiving equal amounts of physiological saline were used as the negative control (NC). Serum and fecal samples were collected, and LC-MS was used to identify the metabolites in the samples. Results: The results showed that both the BM and HM groups exhibited a significant reduction in body weight compared to that of the NC group from day 9, and the serum TG, TC, and LDL-C levels were significantly lower than those of the NC group. Further analysis identified 564 and 567 metabolites in the serum and fecal samples shared in the BM and HM groups and significantly different from those in the NC group, which were mainly enriched in the pathways related to lipid metabolism, such as fatty acid biosynthesis, arachidonic acid metabolism, and primary bile acid biosynthesis. Correlation analysis further suggested that milk intake can increase the levels of Muramic Acid, Oleoyl Ethanolamide, Seratrodast, Chenodeoxycholic Acid, Docosahexaenoic Acid Ethyl Ester, and Deoxycholic Acid in the serum and gut microbiota, which may affect TG, TC, HDL-C, and LDL-C in the serum, and thereby benefit the body’s lipid health. Conclusions: The results further confirmed that milk intake has a beneficial effect on blood lipid health by altering multiple metabolites in the serum and the gut. This study provides novel evidence that milk consumption is beneficial to health and is a reference for guiding people to a healthy diet. Full article

Neuroinflammation is a symptom of different neurodegenerative diseases, and growing interest is directed towards active drug development for the reduction of its negative effects. The anti-inflammatory activity of polyunsaturated fatty acids, eicosapentaenoic (EPA), docosahexaenoic (DHA), and their amide derivatives was largely investigated on some neural cells. Herein, we aimed to elucidate the protective role of both EPA and DHA and the corresponding N-ethanolamides EPA-EA and DHA-EA on neonatal mouse Olfactory Ensheathing Cells (OECs) after exposition to lipopolysaccharide (LPS)-induced neuroinflammation. To verify their anti-inflammatory effect and cell morphological features on OECs, the expression of IL-10 cytokine, and cytoskeletal proteins (vimentin and GFAP) was evaluated by immunocytochemical procedures. In addition, MTT assays, TUNEL, and mitochondrial health tests were carried out to assess their protective effects on OEC viability. Our results highlight a reduction in GFAP and vimentin expression in OECs exposed to LPS and treated with EPA or DHA or EPA-EA or DHA-EA in comparison with OECs exposed to LPS alone. We observed a protective role of EPA and DHA on cell morphology, while the amides EPA-EA and DHA-EA mainly exerted a superior anti-inflammatory effect compared to free acids. Full article

Identification of disease and therapeutic biomarkers remains a significant challenge in the early diagnosis and effective treatment of juvenile idiopathic arthritis (JIA). In this study, plasma metabolomic profiling was conducted to identify disease-related metabolic biomarkers associated with JIA. Plasma samples from treatment-naïve JIA patients and non-JIA reference patients underwent global metabolomic profiling across discovery (60 JIA, 60 non-JIA) and replication (49 JIA, 38 non-JIA) cohorts. Univariate analysis identified significant metabolites (q-value ≤ 0.05), followed by enrichment analysis using ChemRICH and metabolic network mapping with MetaMapp and Cytoscape. Receiver operating characteristic (ROC) analysis determined the top discriminating biomarkers based on area under the curve (AUC) values. A total of over 800 metabolites were measured, consisting of 714 known and 155 unknown compounds. In the discovery cohort, 587 metabolites were significantly altered in JIA patients compared with the reference population (q < 0.05). In the replication cohort, 288 metabolites were significantly altered, with 78 overlapping metabolites demonstrating the same directional change in both cohorts. JIA was associated with a notable increase in plasma levels of sphingosine metabolites and fatty acid ethanolamides and decreased plasma levels of sarcosine, iminodiacetate, and the unknown metabolite X-12462. Chemical enrichment analysis identified cycloparaffins in the form of naproxen and its metabolites, unsaturated lysophospholipids, saturated phosphatidylcholines, sphingomyelins, ethanolamines, and saturated ceramides as the top discriminating biochemical clusters. ROC curve analysis identified 11 metabolites classified as highly discriminatory based on an AUC > 0.90, with the top discriminating metabolite being sphinganine-1-phosphate (AUC = 0.98). This study identifies specific metabolic changes in JIA, particularly within sphingosine metabolism, through both discovery and replication cohorts. Plasma metabolomic profiling shows promise in pinpointing JIA-specific biomarkers, differentiating them from those in healthy controls and Crohn’s disease, which may improve diagnosis and treatment. Full article

Linoleic acid (LA) is required for neuronal development. We have previously demonstrated sex-specific changes in cardiovascular and hepatic function in rat offspring from mothers consuming a high-LA diet, with some effects associated with reduced LA concentration in the postnatal diet. At this time, the impact of a high-maternal-LA diet on offspring brain development and the potential for the postnatal diet to alter any adverse changes are unknown. Rat offspring from mothers fed low- (LLA) or high-LA (HLA) diets during pregnancy and lactation were weaned at postnatal day 25 (PN25) and fed LLA or HLA diets until sacrifice in adulthood (PN180). In the offspring’s brains, the postnatal HLA diet increased docosapentaenoate in males. The maternal HLA diet increased LA, arachidonate, docosapentaenoate, C18:0 dimethylacetal (DMA), C16:0 DMA, C16:0 DMA/C16:0, and C18:0 DMA/C18:0, but decreased eoicosenoate, nervoniate, lignocerate, and oleate in males. Maternal and postnatal HLA diets reduced oleate and vaccenate and had an interaction effect on myristate, palmitoleate, and eicosapentaenoate in males. In females, maternal HLA diet increased eicosadienoate. Postnatal HLA diet increased stearate and docosapentaenoate. Maternal and postnatal HLA diets had an interaction effect on oleate, arachidate, and docosahexaenoic acid (DHA)/omega (n)-6 docosapentaenoic acid (DPA) in females. Postnatal HLA diet decreased DHA/n-6 DPA in males and females. Postnatal HLA diet increased plasma endocannabinoids (arachidonoyl ethanolamide and 2-arachidonoyl glycerol), as well as other N-acyl ethanolamides and testosterone. HLA diet alters brain fatty acids, plasma endocannabinoids, and plasmalogen concentrations in a development-specific and sex-specific manner. Full article

A glioma is a type of tumor that acts on the Central Nervous System (CNS) in a highly aggressive manner. Gliomas can occasionally be inaccurately diagnosed and treatments have low efficacy, meaning that patients exhibit a survival of less than one year after diagnosis. Due to factors such as intratumoral cell variability, inefficient chemotherapy drugs, adaptive resistance development to drugs and tumor recurrence after resection, the search continues for new drugs that can inhibit glioma cell growth. As such, analogues of endocannabinoids, such as fatty acid amides (FAAs), represent interesting alternatives for inhibiting tumor growth, since FAAs can modulate several metabolic pathways linked to cancer and, thus, may hold potential for managing glioblastoma. The aim of this study was to investigate the in vitro effects of two fatty ethanolamides (FAA1 and FAA2), synthetized via direct amidation from andiroba oil (Carapa guianensis Aublet), on C6 glioma cells. FAA1 and FAA2 reduced C6 cell viability, proliferation and migratory potential in a dose-dependent manner and were not toxic to normal retina glial cells. Both FAAs caused apoptotic cell death through the loss of mitochondrial integrity (ΔΨm), probably by activating cannabinoid receptors, and inhibiting the PI3K/Akt pathway. In conclusion, FAAs derived from natural products may have the potential to treat glioma-type brain cancer. Full article

Modifying the food structure allows a nutrient to be delivered differently, which can modify not only its digestion process but also its subsequent metabolism. In this study, rats received 3 g of omelette daily containing docosahexaenoic acid (DHA) as crude oil or previously encapsulated with whey proteins, whereas a control group received a DHA-free omelette. The results showed that DHA encapsulation markedly induced a different feeding behaviour so animals ate more and grew faster. Then, after four weeks, endocannabinoids and other N-acyl ethanolamides were quantified in plasma, brain, and heart. DHA supplementation strongly reduced endocannabinoid derivatives from omega-6 fatty acids. However, DHA encapsulation had no particular effect, other than a great increase in the content of DHA-derived docosahexaenoyl ethanolamide in the heart. While DHA supplementation has indeed shown an effect on cannabinoid profiles, its physiological effect appears to be mediated more through more efficient digestion of DHA oil droplets in the case of DHA encapsulation. Thus, the greater release of DHA and other dietary cannabinoids present may have activated the cannabinoid system differently, possibly more locally along the gastrointestinal tract. However, further studies are needed to evaluate the synergy between DHA encapsulation, fasting, hormones regulating food intake, and animal growth. Full article

Neovascular age-related macular degeneration (nAMD) is a common and multifactorial disease in the elderly that may lead to irreversible vision loss; yet the pathogenesis of AMD remains unclear. In this study, nontargeted metabolomics profiling using ultra-performance liquid chromatography coupled with Q-Exactive Orbitrap mass spectrometry was applied to discover the metabolic feature differences in both faeces and serum samples between Chinese nonobese subjects with and without nAMD. In faecal samples, a total of 18 metabolites were significantly altered in nAMD patients, and metabolic dysregulations were prominently involved in glycerolipid metabolism and nicotinate and nicotinamide metabolism. In serum samples, a total of 29 differential metabolites were founded, involved in caffeine metabolism, biosynthesis of unsaturated fatty acids, and purine metabolism. Two faecal metabolites (palmitoyl ethanolamide and uridine) and three serum metabolites (4-hydroxybenzoic acid, adrenic acid, and palmitic acid) were selected as potential biomarkers for nAMD. Additionally, the significant correlations among dysregulated neuroprotective, antineuroinflammatory, or fatty acid metabolites in faecal and serum and IM dysbiosis were found. This comprehensive metabolomics study of faeces and serum samples showed that alterations in IM-mediated neuroprotective metabolites may be involved in the pathophysiology of AMD, offering IM-based nutritional therapeutic targets for nAMD. Full article

Microglia, the resident immune cells of the central nervous system, play important roles in brain homeostasis as well as in neuroinflammation, neurodegeneration, neurovascular diseases, and traumatic brain injury. In this context, components of the endocannabinoid (eCB) system have been shown to shift microglia towards an anti-inflammatory activation state. Instead, much less is known about the functional role of the sphingosine kinase (SphK)/sphingosine-1-phosphate (S1P) system in microglia biology. In the present study, we addressed potential crosstalk of the eCB and the S1P systems in BV2 mouse microglia cells challenged with lipopolysaccharide (LPS). We show that URB597, the selective inhibitor of fatty acid amide hydrolase (FAAH)—the main degradative enzyme of the eCB anandamide—prevented LPS-induced production of tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β), and caused the accumulation of anandamide itself and eCB-like molecules such as oleic acid and cis-vaccenic acid ethanolamide, palmitoylethanolamide, and docosahexaenoyl ethanolamide. Furthermore, treatment with JWH133, a selective agonist of the eCB-binding cannabinoid 2 (CB₂) receptor, mimicked the anti-inflammatory effects of URB597. Interestingly, LPS induced transcription of both SphK1 and SphK2, and the selective inhibitors of SphK1 (SLP7111228) and SphK2 (SLM6031434) strongly reduced LPS-induced TNFα and IL-1β production. Thus, the two SphKs were pro-inflammatory in BV2 cells in a non-redundant manner. Most importantly, the inhibition of FAAH by URB597, as well as the activation of CB₂ by JWH133, prevented LPS-stimulated transcription of SphK1 and SphK2. These results present SphK1 and SphK2 at the intersection of pro-inflammatory LPS and anti-inflammatory eCB signaling, and suggest the further development of inhibitors of FAAH or SphKs for the treatment of neuroinflammatory diseases. Full article

Chronic neuropathic pain resulting from peripheral nerve damage is a significant clinical problem, which makes it imperative to develop the mechanism-based therapeutic approaches. Enhancement of endogenous cannabinoids by blocking their hydrolysis has been shown to reduce inflammation and neuronal damage in a number of neurological disorders and neurodegenerative diseases. However, recent studies suggest that inhibition of their hydrolysis can shift endocannabinoids 2-arachidonoyl glycerol (2-AG) and anandamide (AEA) toward the oxygenation pathway mediated by cyclooxygenase-2 (COX-2) to produce proinflammatory prostaglandin glycerol esters (PG-Gs) and prostaglandin ethanolamides (PG-EAs). Thus, blocking both endocannabinoid hydrolysis and oxygenation is likely to be more clinically beneficial. In this study, we used the chronic constriction injury (CCI) mouse model to explore the therapeutic effects of simultaneous inhibition of AEA hydrolysis and oxygenation in the treatment of neuropathic pain. We found that the fatty acid amide hydrolase (FAAH) inhibitor PF04457845 and the substrate-selective COX-2 inhibitor LM4131 dose-dependently reduced thermal hyperalgesia and mechanical allodynia in the CCI mice. In addition to ameliorating the pain behaviors, combined treatment with subeffective doses of these inhibitors greatly attenuated the accumulation of inflammatory cells in both sciatic nerve and spinal cord. Consistently, the increased proinflammatory cytokines IL-1β, IL-6, and chemokine MCP-1 in the CCI mouse spinal cord and sciatic nerve were also significantly reduced by combination of low doses of PF04457845 and LM4131 treatment. Therefore, our study suggests that simultaneous blockage of endocannabinoid hydrolysis and oxygenation by using the substrate-selective COX-2 inhibitor, which avoids the cardiovascular and gastrointestinal side effects associated with the use of general COX-2 inhibitors, might be a suitable strategy for the treatment of inflammatory and neuropathic pain. Full article

At present, the study of the neurotropic activity of polyunsaturated fatty acid ethanolamides (N-acylethanolamines) is becoming increasingly important. N-docosahexaenoylethanolamine (synaptamide, DHEA) is a highly active metabolite of docosahexaenoic acid (DHA) with neuroprotective, synaptogenic, neuritogenic, and anti-inflammatory properties in the nervous system. Synaptamide tested in the present study was obtained using a chemical modification of DHA isolated from squid Berryteuthis magister liver. The results of this study demonstrate the effects of synaptamide on the astroglial response to injury in the acute (1 day) and chronic (7 days) phases of mild traumatic brain injury (mTBI) development. HPLC-MS study revealed several times increase of synaptamide concentration in the cerebral cortex and serum of experimental animals after subcutaneous administration (10 mg/kg/day). Using immunohistochemistry, it was shown that synaptamide regulates the activation of GFAP- and S100β-positive astroglia, reduce nNOS-positive immunostaining, and stimulates the secretion of neurotrophin BDNF. Dynamics of superoxide dismutase production in synaptamide treatment confirm the antioxidant efficacy of the test compound. We found a decrease in TBI biomarkers such as GFAP, S100β, and IL-6 in the blood serum of synaptamide-treated experimental animals using Western blot analysis. The results indicate the high therapeutic potential of synaptamide in reducing the severity of the brain damage consequences. Full article

Oleoylethanolamide and palmitoylethanolamide are members of the fatty acid ethanolamide family, also known as acylethanolamides. Their physiological effects, including glucose homeostasis, anti-inflammation, anti-anaphylactic, analgesia, and hypophagia, have been reported. They have affinity for different receptor proteins, including nuclear receptors such as PPARα, channels such as TRPV1, and membrane receptors such as GPR119 and GPR55. In the present review, the pathophysiological functions of fatty acid ethanolamides have been discussed from the perspective of receptor pharmacology and drug discovery. Full article

Inflammation is a key element in the pathobiology of neurodegenerative diseases and sees the involvement of different neuronal and non-neuronal cells as players able to respond to inflammatory signals of immune origin. Palmitoylethanolamide (PEA) is an endogenous potent anti-inflammatory agent, in which activity is regulated by N-acylethanolamine acid amidase (NAAA), that hydrolyzes saturated or monounsaturated fatty acid ethanolamides, such as PEA. In this research, an in vitro study was performed on different neuronal (SH-SY5Y) and non-neuronal cell lines (C6, BV-2, and Mo3.13) subjected to NAAA enzyme silencing and treated with PEA ultra-micronized (PEA-um) (1, 3, and 10 μM) to increase the amount of endogenous PEA available for counteract neuroinflammation provoked by stimulation with lipopolysaccharide (LPS) (1 μg/mL) and interferon gamma (INF-γ )(100 U/mL). Cell viability was performed by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) staining, suggesting a protective effect of PEA-um (3 and 10 μM) on all cell lines studied. Western Blot analysis for inflammatory markers (Inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2)) was carried out in control and NAAA-silenced cells, highlighting how the concomitant treatment of the neuronal and non-neuronal cells with PEA-um after NAAA genic downregulation is satisfactory to counteract neuroinflammation. These in vitro findings support the protective role of endogenous PEA availability in the neuronal field, bringing interesting information for a translational point of view. Full article

Over the last decades a renewed interest in n−3 very long polyunsaturated fatty acids (PUFAs), derived mainly from fish oils in the human diet, has been observed because of their potential effects against cancer diseases, including breast carcinoma. These n−3 PUFAs mainly consist of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that, alone or in combination with anticancer agents, induce cell cycle arrest, autophagy, apoptosis, and tumor growth inhibition. A large number of molecular targets of n−3 PUFAs have been identified and multiple mechanisms appear to underlie their antineoplastic activities. Evidence exists that EPA and DHA also elicit anticancer effects by the conversion to their corresponding ethanolamide derivatives in cancer cells, by binding and activation of different receptors and distinct signaling pathways. Other conjugates with serotonin or dopamine have been found to exert anti-inflammatory activities in breast tumor microenvironment, indicating the importance of these compounds as modulators of tumor epithelial/stroma interplay. The objective of this review is to provide a general overview and an update of the current n−3 PUFA derivative research and to highlight intriguing aspects of the potential therapeutic benefits of these low-toxicity compounds in breast cancer treatment and care. Full article