The gut lactic acid bacteria metabolite, 10-oxo-cis-6,trans-11-octadecadienoic acid, suppresses inflammatory bowel disease in mice by modulating the NRF2 pathway and GPCR-signaling.

Various gut bacteria, including Lactobacillus plantarum, possess several enzymes that produce hydroxy fatty acids (FAs), oxo FAs, conjugated FAs, and partially saturated FAs from polyunsaturated FAs as secondary metabolites. Among these derivatives, we identified 10-oxo-cis-6,trans-11-octadecadienoic acid (γKetoC), a γ-linolenic acid (GLA)-derived enon FA, as the most effective immunomodulator, which inhibited the antigen-induced immunoactivation and LPS-induced production of inflammatory cytokines. The treatment with γKetoC significantly suppressed proliferation of CD4+ T cells, LPS-induced activation of bone marrow-derived dendritic cells (BMDCs), and LPS-induced IL-6 release from peritoneal cells, splenocytes, and CD11c+ cells isolated from the spleen. γKetoC also inhibited the release of inflammatory cytokines from BMDCs stimulated with poly-I:C, R-848, or CpG. Further in vitro experiments using an agonist of GPR40/120 suggested the involvement of these GPCRs in the effects of γKetoC on DCs. We also found that γKetoC stimulated the NRF2 pathway in DCs, and the suppressive effects of γKetoC and agonist of GPR40/120 on the release of IL-6 and IL-12 were reduced in Nrf2-/- BMDCs. We evaluated the role of NRF2 in the anti-inflammatory effects of γKetoC in a dextran sodium sulfate-induced colitis model. The oral administration of γKetoC significantly reduced body weight loss, improved stool scores, and attenuated atrophy of the colon, in wild-type C57BL/6 and Nrf2+/- mice with colitis. In contrast, the pathology of colitis was deteriorated in Nrf2-/- mice even with the administration of γKetoC. Collectively, the present results demonstrated the involvement of the NRF2 pathway and GPCRs in γKetoC-mediated anti-inflammatory responses.

N-oleoyl alanine attenuates nicotine reward and spontaneous nicotine withdrawal in mice.

BACKGROUND: As nicotine dependence represents a longstanding major public health issue, new nicotine cessation pharmacotherapies are needed. Administration of N-oleoyl glycine (OlGly), an endogenous lipid signaling molecule, prevents nicotine-induced conditioned place preference (CPP) through a peroxisome proliferator-activated receptor-alpha (PPARα) dependent mechanism, and also ameliorated withdrawal signs in nicotine-dependent mice. Pharmacological evidence suggests that the methylated analog of OlGly, N-oleoyl alanine (OlAla), has an increased duration of action and may offer translational benefit. Accordingly, OlAla was assessed in nicotine CPP and dependence assays as well as its pharmacokinetics compared to OlGly. METHODS: ICR female and male mice were tested in nicotine-induced CPP with and without the PPARα antagonist GW6471. OlAla was also assessed in nicotine-dependent mice following removal of nicotine minipumps: somatic withdrawal signs, thermal hyper-nociception and altered affective behavior (i.e., light/dark box). Finally, plasma and brain were collected after administration of OlGly or OlAla and analyzed by high-performance liquid chromatography tandem mass spectrometry. RESULTS: OlAla prevented nicotine-induced CPP, but this effect was not blocked by GW6471. OlAla attenuated somatic and affective nicotine withdrawal signs, but not thermal hyper-nociception in nicotine-dependent mice undergoing withdrawal. OlAla and OlGly showed similar time-courses in plasma and brain. CONCLUSIONS: The observation that both molecules showed similar pharmacokinetics argues against the notion that OlAla offers increased metabolic stability. Moreover, while these structurally similar lipids show efficacy in mouse models of reward and dependence, they reduce nicotine reward through distinct mechanisms.

Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity.

Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously1. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter2,3, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively4,5. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands6-8. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP-PKA-CREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours.

Effect of Oleoylethanolamide-Based Dietary Supplement on Systemic Inflammation in the Development of Alimentary-Induced Obesity in Mice.

The complex effect of oleoylethanolamide-based dietary supplement (OEA-DS) was studied in a model of diet-induced obesity in mice. Physiological, biochemical, and immunohistochemical methods were used to reveal differences in the changes in the weight of experimental animals, morphological changes in the spleen tissues, and changes in the cytokine expression profile in the spleen, blood plasma, and macrophage cell culture. First, it is shown that a hypercaloric diet high in carbohydrates and cholesterol led to the development of systemic inflammation, accompanied by organ morphological changes and increased production of proinflammatory cytokines. In parallel, the use of OEA-DS reduced the intensity of cellular inflammatory reactions, accompanied by a decrease in markers of cellular inflammation and proliferation, such as CD68, Iba-1, and Ki67 in the spleen tissue, and stabilized the level of proinflammatory cytokines (IL-1ß, IL-6, TNFα) both in animals and in cell culture. In addition, in the macrophage cell culture (RAW264.7), it was shown that OEA-DS also suppressed the production of reactive oxygen species and nitrites in LPS-induced inflammation. The results of this study indicate the complex action of OEA-DS in obesity, which includes a reduction of systemic inflammation.

Oleoylethanolamide Treatment Modulates Both Neuroinflammation and Microgliosis, and Prevents Massive Leukocyte Infiltration to the Cerebellum in a Mouse Model of Neuronal Degeneration.

Neurodegenerative diseases involve an exacerbated neuroinflammatory response led by microglia that triggers cytokine storm and leukocyte infiltration into the brain. PPARα agonists partially dampen this neuroinflammation in some models of brain insult, but neuronal loss was not the triggering cause in any of them. This study examines the anti-inflammatory and immunomodulatory properties of the PPARα agonist oleoylethanolamide (OEA) in the Purkinje Cell Degeneration (PCD) mouse, which exhibits striking neuroinflammation caused by aggressive loss of cerebellar Purkinje neurons. Using real-time quantitative polymerase chain reaction and immunostaining, we quantified changes in pro- and anti-inflammatory markers, microglial density and marker-based phenotype, and overall leukocyte recruitment at different time points after OEA administration. OEA was found to modulate cerebellar neuroinflammation by increasing the gene expression of proinflammatory mediators at the onset of neurodegeneration and decreasing it over time. OEA also enhanced the expression of anti-inflammatory and neuroprotective factors and the Pparα gene. Regarding microgliosis, OEA reduced microglial density-especially in regions where it is preferentially located in PCD mice-and shifted the microglial phenotype towards an anti-inflammatory state. Finally, OEA prevented massive leukocyte infiltration into the cerebellum. Overall, our findings suggest that OEA may change the environment to protect neurons from degeneration caused by exacerbated inflammation.

"To brain or not to brain": evaluating the possible direct effects of the satiety factor oleoylethanolamide in the central nervous system.

Introduction: Oleoylethanolamide (OEA), an endogenous N-acylethanolamine acting as a gut-to-brain signal to control food intake and metabolism, has been attracting attention as a target for novel therapies against obesity and eating disorders. Numerous observations suggested that the OEA effects might be peripherally mediated, although they involve central pathways including noradrenergic, histaminergic and oxytocinergic systems of the brainstem and the hypothalamus. Whether these pathways are activated directly by OEA or whether they are downstream of afferent nerves is still highly debated. Some early studies suggested vagal afferent fibers as the main route, but our previous observations have contradicted this idea and led us to consider the blood circulation as an alternative way for OEA's central actions. Methods: To test this hypothesis, we first investigated the impact of subdiaphragmatic vagal deafferentation (SDA) on the OEA-induced activation of selected brain nuclei. Then, we analyzed the pattern of OEA distribution in plasma and brain at different time points after intraperitoneal administration in addition to measuring food intake. Results: Confirming and extending our previous findings that subdiaphragmatic vagal afferents are not necessary for the eating-inhibitory effect of exogenous OEA, our present results demonstrate that vagal sensory fibers are also not necessary for the neurochemical effects of OEA. Rather, within a few minutes after intraperitoneal administration, we found an increased concentration of intact OEA in different brain areas, associated with the inhibition of food intake. Conclusion: Our results support that systemic OEA rapidly reaches the brain via the circulation and inhibits eating by acting directly on selected brain nuclei.

Oleoylethanolamide attenuates the stress-mediated potentiation of rewarding properties of cocaine associated with an increased TLR4 proinflammatory response.

The lipid-derived messenger oleoylethanolamide (OEA) has been involved in multiple physiological functions including metabolism and the immune response. More recently, OEA has been observed to affect reward-related behavior. Stress is a major risk factor for drug use and a predictor of drug relapse. In the laboratory, social stress has been largely studied using the social defeat (SD) model. Here, we explored the effects of different OEA administration schedules on the increased rewarding properties of cocaine induced by SD. In addition, we evaluated the anti-inflammatory action of OEA pretreatment in TLR4 expression caused by SD in the cerebellum, a novel brain structure that has been involved in the development of cocaine addiction. Adult OF1 mice were assigned to an experimental group according to the stress condition (exploration or SD) and treatment (OEA before SD, OEA before conditioning or subchronic OEA treatment). Mice were administered with OEA i.p (10 mg/kg) 10 min previously to the corresponding event. Three weeks after the last SD encounter, conditioned place preference (CPP) was induced by a subthreshold cocaine dose (1 mg/kg). As expected, socially defeated mice presented greater vulnerability to the cocaine reinforcing effects and expressed CPP. Conversely, this effect was not observed under a non-stressed condition. Most importantly, we observed that OEA pretreatment before SD or before conditioning prevented cocaine CPP in defeated mice. Biochemical analysis showed that OEA administration before SD decreased proinflammatory TLR4 upregulation in the cerebellum caused by social stress. In summary, our results suggest that OEA may have a protective effect on stress-induced increased cocaine sensitivity by exerting an anti-inflammatory action.

Update on Anti-Inflammatory Molecular Mechanisms Induced by Oleic Acid.

In 2010, the Mediterranean diet was recognized by UNESCO as an Intangible Cultural Heritage of Humanity. Olive oil is the most characteristic food of this diet due to its high nutraceutical value. The positive effects of olive oil have often been attributed to its minor components; however, its oleic acid (OA) content (70-80%) is responsible for its many health properties. OA is an effective biomolecule, although the mechanism by which OA mediates beneficial physiological effects is not fully understood. OA influences cell membrane fluidity, receptors, intracellular signaling pathways, and gene expression. OA may directly regulate both the synthesis and activities of antioxidant enzymes. The anti-inflammatory effect may be related to the inhibition of proinflammatory cytokines and the activation of anti-inflammatory ones. The best-characterized mechanism highlights OA as a natural activator of sirtuin 1 (SIRT1). Oleoylethanolamide (OEA), derived from OA, is an endogenous ligand of the peroxisome proliferator-activated receptor alpha (PPARα) nuclear receptor. OEA regulates dietary fat intake and energy homeostasis and has therefore been suggested to be a potential therapeutic agent for the treatment of obesity. OEA has anti-inflammatory and antioxidant effects. The beneficial effects of olive oil may be related to the actions of OEA. New evidence suggests that oleic acid may influence epigenetic mechanisms, opening a new avenue in the exploration of therapies based on these mechanisms. OA can exert beneficial anti-inflammatory effects by regulating microRNA expression. In this review, we examine the cellular reactions and intracellular processes triggered by OA in T cells, macrophages, and neutrophils in order to better understand the immune modulation exerted by OA.

Evaluation of the composition and antimicrobial activities of essential oils from four species of Lamiaceae Martinov native to Iran.

In this study the essential oils obtained from four different plant species belonging to the Lamiaceae family were extracted by means of hydrodistillation and their composition and antimicrobial activity were evaluated. About 66 components were identified by using gas chromatography-mass spectrometry (GC-MS), and among all, thymol (67.7%), oleic acid (0.5-62.1%), (-)-caryophyllene oxide (0.4-24.8%), α-pinene (1.1-19.4%), 1,8-cineole (0.2-15.4%), palmitic acid (0.32-13.28%), ( +)spathulenol (11.16%), and germacrene D (0.3-10.3%) were the most abundant in all the species tested (i.e. Thymus daenensis, Nepeta sessilifolia, Hymenocrater incanus, and Stachys inflata). In particular, only the composition of essential oils from H. incanus was completely detected (99.13%), while that of the others was only partially detected. Oxygenated monoterpenes (75.57%) were the main compounds of essential oil from T. daenensis; sesquiterpenes hydrocarbons (26.88%) were the most abundant in S. inflata; oxygenated sesquiterpenes (41.22%) were mainly detected in H. incanus essential oil, while the essential oil from N. sessilifolia was mainly composed of non-terpene and fatty acids (77.18%). Due to their slightly different composition, also the antibacterial activity was affected by the essential oil tested. Indeed, the highest antibacterial and antifungal activities were obtained with the essential oil from T. daenensis by means of the inhibition halo (39 ± 1 and 25 ± 0 mm) against Gram-positive strains such as Staphylococcus aureus and Aspergillus brasiliensis. The minimal inhibitory concentration (MIC) and minimal bactericidal/fungicidal concentration (MBC/MFC) of the essential oils obtained from the four species varied from 16 to 2000 µg/mL and were strictly affected by the type of microorganism tested. As an example, the essential oils from H. incanus and S. inflata were the most effective against the Gram-negative bacterium Pseudomonas aeruginosa (MIC 16 and 63 µg/ml, respectively), which is considered one of the most resistant bacterial strain. Therefore, the essential oils obtained from the four species contained a suitable phytocomplexes with potential applications in different commercial area such as agriculture, food, pharmaceutical and cosmetic industries. Moreover, these essential oils can be considered a valuable natural alternative to some synthetic antibiotics, thanks to their ability to control the growth of different bacteria and fungi.

Exploring the effect of estrogen on Candida albicans hyphal cell wall glycans and ergosterol synthesis.

Increased levels of 17-ß estradiol (E2) due to pregnancy in young women or to hormonal replacement therapy in postmenopausal women have long been associated with an increased risk of yeast infections. Nevertheless, the effect underlying the role of E2 in Candida albicans infections is not well understood. To address this issue, functional, transcriptomic, and metabolomic analyses were performed on C. albicans cells subjected to temperature and serum induction in the presence or absence of E2. Increased filament formation was observed in E2 treated cells. Surprisingly, cells treated with a combination of E2 and serum showed decreased filament formation. Furthermore, the transcriptomic analysis revealed that serum and E2 treatment is associated with downregulated expression of genes involved in filamentation, including HWP1, ECE1, IHD1, MEP1, SOD5, and ALS3, in comparison with cells treated with serum or estrogen alone. Moreover, glucose transporter genes HGT20 and GCV2 were downregulated in cells receiving both serum and E2. Functional pathway enrichment analysis of the differentially expressed genes (DEGs) suggested major involvement of E2 signaling in several metabolic pathways and the biosynthesis of secondary metabolites. The metabolomic analysis determined differential secretion of 36 metabolites based on the different treatments' conditions, including structural carbohydrates and fatty acids important for hyphal cell wall formation such as arabinonic acid, organicsugar acids, oleic acid, octadecanoic acid, 2-keto-D-gluconic acid, palmitic acid, and steriacstearic acid with an intriguing negative correlation between D-turanose and ergosterol under E2 treatment. In conclusion, these findings suggest that E2 signaling impacts the expression of several genes and the secretion of several metabolites that help regulate C. albicans morphogenesis and virulence.

The Effect of Oleoylethanolamide (OEA) Add-On Treatment on Inflammatory, Oxidative Stress, Lipid, and Biochemical Parameters in the Acute Ischemic Stroke Patients: Randomized Double-Blind Placebo-Controlled Study.

Methods: Sixty patients with a mean age of 68.60 ± 2.10 comprising 29 females (48.33%), who were admitted to an academic tertiary care facility within the first 12 hours poststroke symptoms onset or last known well (LKW), in case symptom onset time is not clear, were included in this study. AIS was confirmed based on a noncontrast head CT scan and also neurological symptoms. Patients were randomly and blindly assigned to OEA of 300 mg/day (n = 20) or 600 mg/day (n = 20) or placebo (n = 20) in addition to the standard AIS treatment for three days. A blood sample was drawn at 12 hours from symptoms onset or LKW as the baseline followed by the second blood sample at 72 hours post symptoms onset or LKW. Blood samples were assessed for inflammatory and biochemical parameters, oxidative stress (OS) biomarkers, and lipid profile. Results: Compared to the baseline, there is a significant reduction in the urea, creatinine, triglyceride, high-density lipoprotein, cholesterol, alanine transaminase, total antioxidant capacity, malondialdehyde (MDA), total thiol groups (TTG), interleukin-6 (IL-6), and C-reactive protein levels on the follow-up blood testing in the OEA (300 mg/day) group. In patients receiving OEA (600 mg/day) treatment, there was only a significant reduction in the MDA level comparing baseline with follow-up blood testing. Also, the between-group analysis revealed a statistically significant difference between patients receiving OEA (300 mg/day) and placebo in terms of IL-6 and TTG level reduction when comparing them between baseline and follow-up blood testing. Conclusion: OEA in moderate dosage, 300 mg/day, add-on to the standard stroke treatment improves short-term inflammatory, OS, lipid, and biochemical parameters in patients with AIS. This effect might lead to a better long-term neurological prognosis.

Attenuation of oleoylethanolamide-induced reduction of alcohol consumption in adult rats exposed intermittently to alcohol during adolescence.

Oleoylethanolamide (OEA) is an endogenous N-acylethanolamine that reduces both food and alcohol intake through the activation of peripheral sensory nerves in the gut. These effects are opposite to those of anandamide, a main endogenous cannabinoid type 1 receptor (CB1R) agonist. The present study aims to characterize the impact of intermittent and voluntary alcohol intoxications (using the two-bottle choice paradigm) during adolescence on inhibitory actions of OEA and the CB1R antagonist/inverse agonist SR141716A on voluntary alcohol intake in adulthood. In the present study we show that both OEA (5 mg/kg) and SR141716A (3 mg/kg) reduce alcohol drinking in adult rats using a two-bottle choice paradigm. These effects lasted for 24 h and were not additive when both compounds were co-administered. However, when OEA and SR141716A were administered to adult rats with a history of intermittent alcohol exposure during adolescence (from postnatal day 31 to 55), the effects of OEA were attenuated. Moreover, the co-administration of OEA and SR141716A was not as effective as the administration of SR141716A alone. These data suggest that adolescent exposure to alcohol alters the inhibitory actions of OEA on alcohol drinking, which results in the loss of a protective mechanism that might account for the long-term effects of alcohol exposure in the adolescence. The implications for the vulnerability to alcohol addiction is discussed.

Dietary oleamide attenuates obesity induced by housing mice in small cages.

Physical inactivity due to prolonged sedentary behavior induces obesity. Therefore, we investigated whether housing mice in small cages to mimic sedentary behavior induced obesity and whether dietary oleamide (cis-9,10-octadeceneamide) suppressed the induced obesity. A single oral administration of oleamide (50 mg/kg) to mice resulted in the accumulation of the exogenous oleamide in abdominal visceral fat. Next, mice were housed in small cages and oleamide (50 mg/kg/d) was orally administered for 12 weeks. Housing mice in small cages impaired glucose tolerance and increased food efficiency. It also increased body weight and abdominal fat mass. Dietary oleamide improved the impairment and inhibited their increase in mice housed in small cages. Furthermore, dietary oleamide suppressed the mRNA expression of inflammation-related factors in the abdominal fat of mice housed in small cages. Hence, these results indicate that although housing mice in small cages induces obesity and increases abdominal fat mass, dietary oleamide suppresses the obesity.

Fatty acids secreted from head and neck cancer induce M2-like Macrophages.

Tumor-infiltrating monocytes can mature into Macrophages that support tumor survival or that display antitumor properties. To explore mechanisms steering Macrophage maturation, we assessed the effects of supernatants from squamous cell carcinoma cell lines (FaDu and SCC) on monocyte-derived Macrophage maturation. Purified monocytes were incubated in medium or medium supplemented with supernatants from FaDu and SCC9 or the leukemia monocytic cell line, THP-1. Macrophages were examined for markers of maturation (CD14, CD68), activation (HLA-DR, CD86, IL15R), scavenger receptor (CD36), toll-like receptor (TLR4), M2 marker (CD206), immune checkpoint (PD-L1), and intracellular chemokine expression (IP-10). Compared to other conditions, cells incubated with FaDu or SCC9 supernatants displayed enhanced survival, down-regulation of cell surface HLA-DR, CD86, IL-15R, CD36, and intracellular IP-10 expression, and increased cell surface PD-L1, CD14, and CD206 expression. Despite expressing TLR4 and CD14, Macrophages matured in tumor supernatants failed to respond to stimulation with the canonical TLR4 agonist, LPS. These changes were accompanied by a decrease in intracellular phospho-p38 expression in tumor supernatant conditioned Macrophages. Depletion of fatty acids from tumor supernatants or treatment of cell cultures with an inhibitor of fatty acid oxidation, Etomoxir, reversed a number of these phenotypic changes induced by tumor supernatants. Additionally, Macrophages incubated with either palmitic acid or oleic acid developed similar phenotypes as cells incubated in tumor supernatants. Together, these data suggest that fatty acids derived from tumor cells can mediate the maturation of Macrophages into a cell type with limited pro-inflammatory characteristics.

Palmitic acid-induced defects in cell cycle progression and cytokinesis in Neuro-2a cells.

Obesity is associated with elevated levels of free fatty acids (FFAs). Excessive saturated fatty acids (SFAs) exhibit significant deleterious cytotoxic effects in many types of cells. However, the effects of palmitic acid (PA), the most common circulating SFA, on cell cycle progression in neuronal cells have not been well-examined. The aim of this study was to examine whether PA affects the proliferation and cell cycle progression in mouse neuroblastoma Neuro-2a (N2a) cells. Our studies found that 200 µM PA significantly decreased DNA synthesis and mitotic index in N2a cells as early as 4 h following treatment. 24 h treatment with 200 µM PA significantly decreased the percentage of diploid (2 N) cells while dramatically increasing the percentage of tetraploid (4 N) cells as compared to the BSA control. Moreover, our studies found that 24 h treatment with 200 µM PA increased the percentage of binucleate cells as compared to the BSA control. Our studies also found that unsaturated fatty acids (UFAs), including linoleic acid, oleic acid, α-linolenic acid, and docosahexaenoic acid, were able to abolish PA-induced decrease of 2 N cells, increase of 4 N cells, and accumulation of binucleate cells. Taken together, these results suggest that PA may affect multiple aspects of the cell cycle progression in N2a cells, including decreased DNA synthesis, G2/M arrest, and cytokinetic failure, which could be abolished by UFAs.Abbreviations: 4-PBA, 4-Phenylbutyric Acid; ALA, α-linolenic acid; BrdU, 5-bromo-2'-deoxyuridine; DAPI, 4',6-diamidino-2-phenylindole; ER, endoplasmic reticulum; FFA, free fatty acids; FITC, fluorescein isothiocyanate; LA, linoleic acid; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; N2a, Neuro-2a; NAC, N-acetyl cysteine; OA, oleic acid; PA, palmitic acid; pHH3, Phosphorylation of histone H3; PI, propidium iodide; SFA, saturated fatty acids; PUFA, polyunsaturated fatty acids; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; UFA, unsaturated fatty acids.

Elaidic acid induced NLRP3 inflammasome activation via ERS-MAPK signaling pathways in Kupffer cells.

Trans fatty acids (TFA) in food can cause liver inflammation. Activation of NOD-like receptor protein-3 (NLRP3) inflammasome is a key factor in the regulation of inflammation. Accumulating evidence suggests that ERS-induced NLRP3 inflammasome activation underlies the pathological basis of various inflammatory diseases, but the precise mechanism has not been fully elucidated. Therefore, this paper focused on TFA, represented by elaidic acid (EA), to investigate the mechanism of liver inflammation. Levels of mRNA and protein were detected by RT-qPCR and Western blotting, the release of proinflammatory cytokines was measured by ELISA, and intracellular Ca2+ levels were determined by flow cytometer using Fluo 4-AM fluorescent probes. Our research indicated that EA induced the endoplasmic reticulum stress (ERS) response in Kupffer cells (KCs), accompanied by the activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which resulted in NLRP3 inflammasome formation, and eventually increased the release of inflammatory factors. NLRP3 inflammasome activation was inhibited when KCs were pretreated with ERS inhibitors (4-PBA) and MAPK selective inhibitors. Furthermore, when ERS was blocked, the MAPK pathway was inhibited.

A Duet Between Histamine and Oleoylethanolamide in the Control of Homeostatic and Cognitive Processes.

In ballet, a pas de deux (in French it means "step of two") is a duet in which the two dancers perform ballet steps together. The suite of dances shares a common theme of partnership. How could we better describe the fine interplay between oleoylethanolamide (OEA) and histamine, two phylogenetically ancient molecules controlling metabolic, homeostatic and cognitive processes? Contrary to the pas de deux though, the two dancers presumably never embrace each other as a dancing pair but execute their "virtuoso solo" constantly exchanging interoceptive messages presumably via vagal afferents, the blood stream, the neuroenteric system. With one exception, which is in the control of liver ketogenesis, as in hepatocytes, OEA biosynthesis strictly depends on the activation of histaminergic H1 receptors. In this review, we recapitulate our main findings that evidence the interplay of histamine and OEA in the control of food consumption and eating behaviour, in the consolidation of emotional memory and mood, and finally, in the synthesis of ketone bodies. We will also summarise some of the putative underlying mechanisms for each scenario.

Antimicrobial activity of sophorolipids produced by Starmerella bombicola against phytopathogens from cherry tomato.

BACKGROUND: Phytopathogenic microorganisms are the main cause of plant diseases, generating significant economic losses for the agricultural and food supply chain. Cherry tomatoes (Solanum lycopersicum var. cerasiforme) are very perishable plants and highly demanding in the use of pesticides; therefore, alternative solutions such as biosurfactants have aroused as a potent substituent. The main objective of the present study was to investigate the antimicrobial activity of sophorolipids against the phytopathogens Botrytis cinerea, Sclerotium rolfsii, Rhizoctonia solani and Pythium ultimum. RESULTS: The biosurfactant inhibited the mycelial growth in vitro with a minimum concentration of 2 mg mL-1 . The application of sophorolipids at 1, 2 and 4 mg mL-1 in detached leaves of tomato before the inoculation of the fungus B. cinerea was the best treatment, reducing leaf necrosis by up to 76.90%. The use of sophorolipids for washing tomato fruits before the inoculation of B. cinerea was able to inhibit the development of gray mold by up to 96.27%. CONCLUSION: The results for tomato leaves and fruits revealed that the biosurfactant acts more effectively when used preventively. Sophorolipids are stable molecules that show promising action for the potential replacement of pesticides in the field and the post-harvest process against the main tomato phytopathogens. © 2021 Society of Chemical Industry.

Cytotoxic Impact of N-Oleoylethanolamine on Bone Cancer Cells.

BACKGROUND: Cancer is a complex disease that derives from the uncontrolled proliferation of cells. Bone cancer is a type of prevalent cancer that occurs both in young and adults. Bone cancer is most common in the long bones of the pelvis, arms and legs. Statistically, more than 200 cases of osteosarcoma have been reported annually in our country. Classical treatment with chemotherapeutics remains ineffective in the cure of this cancer type. Recent studies have shown that ceramide induces apoptosis at its increased levels in the cells. Thus, many studies have been conducted to cause the accumulation of ceramide molecules in the cell by different ways to induce apoptosis. NOE (Noleoylethanolamine) is a specific inhibitor of ceramidase enzymes that hydrolyze intracellular ceramides and prevent apoptosis. OBJECTIVE: This study investigates the cytotoxic and apoptosis-inducing activities of NOE on human osteosarcoma Saos-2 cells. METHODS: Cytotoxic effects were investigated by MTT colorimetric assay. For the detection of morphological and ultrastructural indicators of apoptosis, confocal and TEM techniques were used. RESULTS: Our finding indicated that NOE is effective in the inhibition of the growth of Saos-2 cells. Confocal and TEM findings showed morphological and ultrastructural changes as chromatin condensation, fragmentation of nuclei and mitochondria as well as damaged cytoskeleton and cell shrinkage. CONCLUSION: The results revealed that NOE exerts its cytotoxicity on Saos-2 cells through changing the ultrastructure and morphology of cells with clear apoptotic sparks.