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Food sources in order of decreasing concentration of palmitoyl ethanolamide (PEA).

Food sources in order of decreasing concentration of palmitoyl ethanolamide (PEA).

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Virtually every cellular process is affected by diet and this represents the foundation of dietary management to a variety of small animal disorders. Special attention is currently being paid to a family of naturally occurring lipid amides acting through the so-called autacoid local injury antagonism, i.e., the ALIA mechanism. The parent molecule o...

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... many other food sources of PEA were progressively discovered, like, for example, tomatoes, alfalfa (Medicago sativa), potatoes, carrots, walnuts, peanuts, wheat flour, barley, tuna fish, and vegetable oils [23][24][25][26]. Moreover, high levels of PEA were also found in human, bovine, and elk milk [25,[28][29][30] (Table 1). Interestingly, a high and increasing amount of PEA has recently been found in milk samples from mothers belonging to underserved populations, where milk represents a food of primary importance to avoid infant malnutrition [31]. ...

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... N-stearoylethanolamide (NSE) is a lipid-signaling molecule from Nacylethanolamines (NAEs) family. NAEs are produced "on demand" from their precursors N-acylphosphatidylethanolamines (NAPE) in response to tissue injury and stress to restore homeostatic balance and prevent further damage [1]. NAEs are the derivatives of ethanolamine and fatty acids with different length and saturation of acyl chain, which determine their biological activity. ...
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Background N-stearoylethanolamine (NSE) is a bioactive lipid amine with a wide range of biological activities. Anti-inflammatory properties of NSE were previously confirmed on multiple animal models. However, the molecular mechanisms of anti-inflammatory action of NSE remain unclear. In the current study, we examined the involvement of nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) in the NF-kB –dependent pathway of anti-inflammatory action of NSE using different methodological approaches. Methods Molecular modeling calculated the possibility of NSE binding PPAR. Ex vivo experiment, using selective agonist of PPARα/γ - LY-171883 and antagonist of PPARγ - GW9662, examined the role of PPARα/γ in the NSE’s effect on nuclear NF-kB translocation in LPS-activated rat peritoneal macrophages. Finally, the NSE’s action on mRNA level of PPARγ-dependent genes was studied in the liver of insulin-resistant rats. Results The results of molecular docking showed that NSE could bind to PPARγ and compete for the binding site with antagonist GW9662 and agonist LY-171883. These data was supported by in vitro study where pre-treatment with NSE prevented further LPS-induced NF-kB translocation into the nuclei of rat peritoneal macrophages. NSE treatment before GW9662 and LPS addition normalized the level of NF-kB translocation and IL-1β content. This finding confirmed a competitive binding of NSE with GW9662 for the ligand-binding domain of PPARγ. Additional in vivo study showed that NSE administration changed the mRNA expression of several PPARγ target genes, including SLC27A1 encoding fatty acid transport protein-1 and IL1RN - interleukin-1 receptor antagonist in insulin resistant rats. Conclusion NSE suppressed nuclear translocation of NF-κB in LPS-stimulated peritoneal macrophages via PPARγ and changed hepatic mRNA expression of PPARγ target genes (SLC27A1, IL1RN) in insulin resistant rats.
... The term "autacoid" comes from the Greek "autos" (self) and "acos" (healing or remedy) and refers to cell-produced factors that act locally near their site of synthesis [2]. In particular, the autacoid mechanism of ALIAmides serves auto-protective purposes through the down-modulation of cell hyperactivity (mainly immune cells), thus controlling inflammatory responses and limiting tissue damage [3]. It was originally observed that the ALIAmide parent molecule, palmitoylethanolamide (PEA), down-modulates rat mast cell behavior after challenge [1,4], as later confirmed in companion animals [5][6][7]. ...
... Besides PEA, ALIAmides currently comprise several lipid compounds, ranging from Adelmidrol (the diethanolamide derivative of azelaic acid) to palmitoylglucosamine (PGA), oleoylethanolamide, and many others ( Figure 2). Their respective mechanisms of action have been (and still are being) investigated and appear to be profoundly interconnected to the parent compound PEA, which is by far the most studied ALIAmide [3,32,33]. A brief overview of their molecular mechanisms will be given in the following paragraphs. ...
... A large body of evidence has been accumulating on the prohomeostatic functions of ALIAmides in several diseases sustained by non-resolving inflammatory and neuroinflammatory responses. The findings have been reviewed by several excellent papers, to which the reader is encouraged to refer [3,[32][33][34][35][36][37]. After addressing a few general key points on ALIAmides, here we will focus exclusively on the main studies performed on small animals. ...
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ALIAmides are a family of fatty acid amides whose name comes from their mechanism of action, i.e., the Autacoid Local Injury Antagonism (ALIA). Actually, the ALIAmide parent molecule, palmitoylethanolamide (PEA), is locally produced on demand from a cell membrane precursor in order to control immune-inflammatory cell responses, avert chronic non-resolving inflammation, and limit the resulting clinical signs. ALIAmide sister compounds, such as Adelmidrol and palmitoylglucosamine, share mechanisms of action with PEA and may also increase endogenous levels of PEA. Provided that their respective bioavailability is properly addressed (e.g., through decreasing the particle size through micronization), exogenously administered ALIAmides thus mimic or sustain the prohomeostatic functions of endogenous PEA. The aim of the present paper is to review the main findings on the use of ALIAmides in small animals as a tribute to the man of vision who first believed in this “according-to-nature” approach, namely Francesco della Valle. After briefly presenting some key issues on the molecular targets, metabolism, and pharmacokinetics of PEA and related ALIAmides, here we will focus on the preclinical and clinical studies performed in dogs and cats. Although more data are still needed, ALIAmides may represent a novel and promising approach to small animal health.
... N-palmitoyl-D-glucosamine (PGA) is a natural amide of palmitic acid and glucosamine that shares the anti-inflammatory properties with its endogenous analog palmitoylethanolamide (PEA) and those of glucosamine [7]. PGA belongs to the ALIAmide family (ALIA, autacoid local injury antagonism), a class of both synthetic and endogenous fatty acid amides that display a wide range of homeostatic effects in response to increased oxidative stress and cell damage, including anti-inflammatory and pain-relieving effects [8]. In particular, PEA has repeatedly been shown to improve clinical and histological signs of colitis in different murine models [9,10]. ...
... In agreement with previous studies demonstrating that PGA negatively regulates TLR-4 signaling enhanced by intestinal inflammation and neuropathic pain [8,14], our results show that micronized PGA dose-dependently reduced TLR-4 expression in the colonic mucosa of colitis mice, suggesting that this may contribute to its potent anti-inflammatory activity. The sequel of events triggered by TLR-4 activation, including NF-kB and NLRP3 activation, and the release of IL-1β, IL-6, and TNF-α, are considered the most involved in persistent intestinal inflammation triggering and maintenance during colitis [8,14], and HIV-1 Tat-induced diarrhea [33]. ...
... In agreement with previous studies demonstrating that PGA negatively regulates TLR-4 signaling enhanced by intestinal inflammation and neuropathic pain [8,14], our results show that micronized PGA dose-dependently reduced TLR-4 expression in the colonic mucosa of colitis mice, suggesting that this may contribute to its potent anti-inflammatory activity. The sequel of events triggered by TLR-4 activation, including NF-kB and NLRP3 activation, and the release of IL-1β, IL-6, and TNF-α, are considered the most involved in persistent intestinal inflammation triggering and maintenance during colitis [8,14], and HIV-1 Tat-induced diarrhea [33]. In this context, PPAR-α agonists, such as PEA, may mediate TLR-4 down-regulation and efficiently suppress the inflammatory process similar to the evidence observed in vitro [15], clinical studies [34], endotoxin induced-uveitis rat model, and DSS-induced colitis mice model [21,35]. ...
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Similar to canine inflammatory enteropathy, inflammatory bowel disease (IBD) is a chronic idiopathic condition characterized by remission periods and recurrent flares in which diarrhea, visceral pain, rectal bleeding/bloody stools, and weight loss are the main clinical symptoms. Intestinal barrier function alterations often persist in the remission phase of the disease without ongoing inflammatory processes. However, current therapies include mainly anti-inflammatory compounds that fail to promote functional symptoms-free disease remission, urging new drug discoveries to handle patients during this step of the disease. ALIAmides (ALIA, autacoid local injury antagonism) are bioactive fatty acid amides that recently gained attention because of their involvement in the control of inflammatory response, prompting the use of these molecules as plausible therapeutic strategies in the treatment of several chronic inflammatory conditions. N-palmitoyl-D-glucosamine (PGA), an under-researched ALIAmide, resulted in being safe and effective in preclinical models of inflammation and pain, suggesting its potential engagement in the treatment of IBD. In our study, we demonstrated that micronized PGA significantly and dose-dependently reduces colitis severity, improves intestinal mucosa integrity by increasing the tight junction proteins expression, and downregulates the TLR-4/NLRP3/iNOS pathway via PPAR-α receptors signaling in DNBS-treated mice. The possibility of clinically exploiting micronized PGA as support for the treatment and prevention of inflammation-related changes in IBD patients would represent an innovative, effective, and safe strategy.
... PEA exerts its effects by modulating histamine release and microglial state. PEA reduces mast cell degranulation (through the autacoid local injury antagonism mechanism [24]). PEA also confers neuroprotection in the CNS by shifting microglia from the M1 pro-inflammatory phenotype to M2 anti-inflammatory phenotype [25]. ...
... Its action on PPAR-↵ is responsible for an increased expression of the type 2 cannabinoid receptor (CB2) and the activation of transient receptor potential vanilloid 1 (TRPV1). Moreover, PEA acts through an entourage effect, increasing the availability of endocannabinoid anandamide (AEA) and 2-arachydonoylglycerol (2-AG), which, in turn, directly interacts with CB2, TRPV1, and cannabinoid receptor type 1 (CB1) [24]. Both mechanisms can contribute to olfactory and memory effects. ...
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Background: This study investigated whether treatment with Palmitoylethanolamide and Luteolin (PEA-LUT) led to improvement in quantitative or qualitative measures of olfactory dysfunction or relief from mental clouding in patients affected by Long-COVID. Methods: Patients with Long-COVID and olfactory dysfunction were allocated to groups based on presence or absences of prior exposure to olfactory training. Patients were then randomized to receive PEA-LUT alone or in combination with olfactory training. Olfactory function and memory were assessed at monthly intervals using self-report measures and quantitative threshold. Results: A total of 69 patients (43 women, 26 men) with age average 40.6 +10.5 were recruited. PEA-LUT therapy was associated with significant improvement of validated odor identification scores at baseline versus each subsequent month; assessment at 3 months showed average improvement of 10.7 + 2.6, CI 95%: 6-14 (p <0.0001). Prevalence of parosmia was 79.7%, with significant improvement from baseline to 3 months (p <0.0001). Mental clouding was detected in 37.7% of cases, with reduction in severity from baseline to three months (p= 0.02). Conclusions. In patients with Long-Covid and chronic olfactory loss, a regimen including oral PEA-LUT and olfactory training ameliorated olfactory dysfunction and memory. Further investigations are necessary to discern biomarkers, mechanisms, long-term outcomes.
... The strength points of PEA naïve along with hypothetical weakness have been exposed in several reviews, on the base of experimental data and clinical issues [8][9][10][11][12][13][14]. Micronized and ultramicronized palmitoylethanolamide (m-PEA and um-PEA) have been used for preclinical and clinical studies to overcome the concern of PEA bioavailability. ...
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Background: Palmitoylethanolamide is reported to solve pain and neuroinflammation in different models of chronic and neurodegenerative diseases. Some concerns have been illustrated for cautiously interpreting the available literature on the topic. Specifically, there is a lack of evidence about palmitoylethanolamide and female chronic pelvic pain. Concerns will be best solved by randomized trials. The present study was aimed at finding the best responders to micronized palmitoylethanolamide in female patient with chronic pelvic pain, using the existing literature at individual patient level, to help further randomized trial planning. Methods: After a systematic research, eligible studies (the ones enrolled female patients treated for chronic pelvic pain or for dyspareunia, dysuria, dyschezia, and dysmenorrhea with or without chronic pelvic pain) were assessed at individual patient data level. Conditional probabilities were calculated to assess variables conditioning the rates of good responders (pain score points more or equal to 3 reduction), poor responders (2 pain score reduction), and nonresponders at a three-month follow-up. Results: Only cases treated with palmitoylethanolamide comicronized with polydatin for a short period can be assessed. Good responders are more than 50%. In chronic pelvic pain, there is a 19.0% conditional probability to find good responders among patients with pain score at enrolment of 6 to 8 and of 6.8% to find poor responders among patients with a pain score at enrolment of 6 to 8. Painful disease does not matter on responders' rates. Conclusion: Best responders to comicronized palmitoylethanolamide/polydatin are patients with pain score higher than 6 at enrolment, irrespective of other variables.
... PEA is an endogenous lipid compound, i.e., the amide of ethanolamide and palmitic acid. It was first isolated from soy lecithin and was shown to be produced 'on demand' by mammals in response to stressful conditions [38]. The first observation in this regard came from the infarcted canine myocardium [39]. ...
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Chronic pain management requires increasing doses of opioids, the milestone of painkillers, which may result in the onset of tolerance with exacerbated side effects. Maintaining stable analgesia with low doses of opioids is thus imperative. N-palmitoylethanolamine (PEA) is an endogenous lipid compound endowed with pain-relieving as well as anti-inflammatory properties. The ultramicronized formulation of PEA was recently demonstrated to be able to modulate morphine’s effects, delaying tolerance and improving efficacy. To evaluate the possible application to other opioids, in this study, we analysed the capacity of ultramicronized PEA to regulate analgesia and tolerance induced by oxycodone and tramadol. Pre-emptive and continuative treatment with ultramicronized PEA (30 mg kg−1, daily, per os) delayed the onset of opioid tolerance and enhanced opioid analgesia when it was acutely administered in association with tramadol (20 mg kg−1, daily, subcutaneously) or oxycodone (0.5 mg kg−1, daily, subcutaneously). Moreover, PEA exerted antinociceptive effects on tolerant rats, suggesting the use of PEA together with opioids for stable, long-lasting analgesia. To that purpose, the oxycodone dose needed to be increased from 0.3 mg kg−1 (day 1) up to 1 mg kg−1 (day 31) in the oxycodone + vehicle group; the tramadol dose was progressively enhanced from 15 mg kg−1 to 50 mg kg−1 in 31 days in the tramadol + vehicle group. Acute oral co-treatment with PEA (120 mg kg−1) achieved the same analgesia without increasing the dose of both opioids. The behavioural effects of PEA on opioid chronic treatment paralleled a decrease in astrocyte activation in the dorsal horn of the spinal cord (a marker of the development of opioid tolerance) and with a modulation of mRNA expression of IL-6 and serpin-A3. In conclusion, pre- and co-administration of ultramicronized PEA delayed the development of tramadol tolerance, potentiating either oxycodone or tramadol analgesia and allowing a long-lasting analgesic effect with a low opioid dose regimen. The use of PEA is suggested for clinical purposes to support the opioid-based management of persistent pain.
... For example, dogs with chronic enteropathies have recently been found to have increased or decreased plasma levels of PEA, 2-AG and AEA, depending on the single compound and the specific enteropathy, i.e., whether it was food-, antibiotic-or immunosuppressive-responsive or belonged to the protein-losing subtype [145]. Moreover, levels of PEA are increased in colon biopsies from patients with coeliac disease and dogs with IBD as well as experimentally induced gut inflammation [100,[146][147][148], while markedly decreased in animals fed unbalanced diets [149][150][151]. Interestingly, in mice with genetic deletion of NAE biosynthetic enzyme, a marked inflammatory tone was observed in the basal state, which was believed to result from the observed decline in the levels of PEA [152]. ...
... Main distribution of the investigated eCBome receptors in the gastrointestinal (GI) tract of either dogs (grey), cats (yellow) or both species (green). Modified from[98,100]. ...
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There is growing evidence that perturbation of the gut microbiome, known as “dysbiosis”, is associated with the pathogenesis of human and veterinary diseases that are not restricted to the gastrointestinal tract. In this regard, recent studies have demonstrated that dysbiosis is linked to the pathogenesis of central neuroinflammatory disorders, supporting the existence of the so-called microbiome-gut-brain axis. The endocannabinoid system is a recently recognized lipid signaling system and termed endocannabinoidome monitoring a variety of body responses. Accumulating evidence demonstrates that a profound link exists between the gut microbiome and the endocannabinoidome, with mutual interactions controlling intestinal homeostasis, energy metabolism and neuroinflammatory responses during physiological conditions. In the present review, we summarize the latest data on the microbiome-endocannabinoidome mutual link in health and disease, focalizing the attention on gut dysbiosis and/or altered endocannabinoidome tone that may distort the bidirectional crosstalk between these two complex systems, thus leading to gastrointestinal and metabolic diseases (e.g., idiopathic inflammation, chronic enteropathies and obesity) as well as neuroinflammatory disorders (e.g., neuropathic pain and depression). We also briefly discuss the novel possible dietary interventions based not only on probiotics and/or prebiotics, but also, and most importantly, on endocannabinoid-like modulators (e.g., palmitoylethanolamide) for intestinal health and beyond.
... Palmitic acid was implicated in the pathogenesis of human IBD [46], and its role in intestinal health has been discussed, this fatty acid having been implicated as a ligand of Toll-like receptors (TLR4) [47], whereas down-or upregulation of TLR expressions are found in different canine CE conditions [48,49]. It is also important at this point to consider that membrane phospholipid composition also influences the balance of lipid mediators involved in intestinal diseases; therefore, mediators from palmitic acid, such as palmitoylethanolamide [50,51] and, from PUFA, for example, docosahexanoyl serotonin [52], can be influenced by the change in the precursor's levels in the membrane. ...
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Canine chronic enteropathies (CEs) are inflammatory processes resulting from complex interplay between the mucosal immune system, intestinal microbiome, and dietary components in susceptible dogs. Fatty acids (FAs) play important roles in the regulation of physiologic and metabolic pathways and their role in inflammation seems to be dual, as they exhibit pro–inflammatory and anti–inflammatory functions. Analysis of red blood cell (RBC) membrane fatty acid profile represents a tool for assessing the quantity and quality of structural and functional molecular components. This study was aimed at comparing the FA membrane profile, determined by Gas Chromatography and relevant lipid parameter of 48 CE dogs compared with 68 healthy dogs. In CE patients, the levels of stearic (p < 0.0001), dihomo–gamma–linolenic, eicosapentaenoic (p = 0.02), and docosahexaenoic (p = 0.02) acids were significantly higher, and those of palmitic (p < 0.0001) and linoleic (p = 0.0006) acids were significantly lower. Non-responder dogs presented higher percentages of vaccenic acid (p = 0.007), compared to those of dogs that responded to diagnostic trials. These results suggest that lipidomic status may reflect the “gut health”, and the non–invasive analysis of RBC membrane might have the potential to become a candidate biomarker in the evaluation of dogs affected by CE.
... Among these compounds, great attention had been focused on PEA, an AEA congener. PEA is an endogenous lipid compound, an amide of ethanolamide and palmitic acid, firstly isolated from soy lecithin [205]. ...
... For over a decade, this N-acylethanolamine was considered the progenitor of a class of substances (ALIAmides) that share the ability to appease the excess reactivity of nonneuronal and mast cells via the so-called Autacoid Local Injury Antagonism (ALIA) effect [205][206][207][208]. It is now well-established that PEA mimics several endocannabinoid-driven actions, even though it does not bind directly to cannabinoid receptors but other receptors belonging to the endocannabinoidome [205,209,210]. ...
... For over a decade, this N-acylethanolamine was considered the progenitor of a class of substances (ALIAmides) that share the ability to appease the excess reactivity of nonneuronal and mast cells via the so-called Autacoid Local Injury Antagonism (ALIA) effect [205][206][207][208]. It is now well-established that PEA mimics several endocannabinoid-driven actions, even though it does not bind directly to cannabinoid receptors but other receptors belonging to the endocannabinoidome [205,209,210]. PEA has been detected in several regions of the spinal cord and brain, including the cortex, hippocampus, cerebellum, and thalamus/hypothalamus, of several mammals [211][212][213]. ...
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Canine and feline cognitive dysfunction syndrome is a common neurodegenerative disorder of old age and a natural model of human Alzheimer’s disease. With the unavoidable expanding life expectancy, an increasing number of small animals will be affected. Although there is no cure, early detection and intervention are vitally important to delay cognitive decline. Knowledge of cellular and molecular mechanisms underlying disease onset and progression is an equally decisive factor for developing effective approaches. Uncontrolled neuroinflammation, orchestrated in the central nervous system mainly by astrocytes, microglia, and resident mast cells, is currently acknowledged as a hallmark of neurodegeneration. This has prompted scientists to find a way to rebalance the altered crosstalk between these cells. In this context, great emphasis has been given to the role played by the expanded endocannabinoid system, i.e., endocannabinoidome, because of its prominent role in physiological and pathological neuroinflammation. Within the endocannabinoidome, great attention has been paid to palmitoylethanolamide due to its safe and pro-homeostatic effects. The availability of new ultramicronized formulations highly improved the oral bioavailability of palmitoylethanolamide, paving the way to its dietary use. Ultramicronized palmitoylethanolamide has been repeatedly tested in animal models of age-related neurodegeneration with promising results. Data accumulated so far suggest that supplementation with ultramicronized palmitoylethanolamide helps to accomplish successful brain aging.
... N-stearoylethanolamide (NSE) is a member of endogenous class of lipid signaling molecules -Nacylethanolamides (NAEs). NAEs are produced "on demand" from their precursors N-acylated phosphatidylethanolamide (NAPE) in response to tissue injury and stress to restore homeostatic balance and prevent further damage [ 1 ]. NAEs are the derivatives of ethanolamide and fatty acids with different length and saturation of acyl chain that determinate their biological activity. ...
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N-stearoylethanolamide (NSE)– a cannabinoid-like compound with wide range of biological activity. Anti-inflammatory properties of NSE have been indicated on different animal models of pathological conditions. However, the molecular mechanisms of anti-inflammatory action of NSE remain unclear. In the current study, the involvement of PPARγ in the NF-kB -dependent anti-inflammatory action of NSE was evaluated using different methodological approach. First method - molecular modeling, evaluated the possibility of NSE to bind with PPAR. Then, in ex vivo experiment, using selective synthetic agonist of PPARα/γ LY-171883 and selective antagonist of PPARγ - GW9662, the role of PPARα /PPARγ in the NSE’s effect on nuclear NF-kB translocation was examined in LPS-activated rat peritoneal macrophages. Finally, the NSE action on the mRNA level of several PPARγ- dependent genes was studied in liver of insulin-resistant rats. The molecular docking results showed that NSE could bind to PPARγ and compete for the binding with antagonist GW9662 and agonist LY171883 in the active site of PPARγ. It also has been found that NSE prevented the LPS-induced NF-kB translocation into the nuclei of rat peritoneal macrophages during pre-treatment with NSE before LPS application. When NSE was added before GW9662 and LPS treatment, the level of NF-kB translocation and IL-1β content reduced to control cells’ levels. These data confirmed a competitive binding of NSE with GW9662 for the ligand-binding domen of PPARγ. In addition, NSE administration to insulin resistant rats changed the mRNA expression of several PPARγ target gens, including FATP1 and IL1-ra.