Arachidonic acid-derived lipid mediators in multiple sclerosis pathogenesis: fueling or dampening disease progression?

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), characterized by neuroinflammation, demyelination, and neurodegeneration. Considering the increasing prevalence among young adults worldwide and the disabling phenotype of the disease, a deeper understanding of the complexity of the disease pathogenesis is needed to ultimately improve diagnosis and personalize treatment opportunities. Recent findings suggest that bioactive lipid mediators (LM) derived from ω-3/-6 polyunsaturated fatty acids (PUFA), also termed eicosanoids, may contribute to MS pathogenesis. For example, disturbances in LM profiles and especially those derived from the ω-6 PUFA arachidonic acid (AA) have been reported in people with MS (PwMS), where they may contribute to the chronicity of neuroinflammatory processes. Moreover, we have previously shown that certain AA-derived LMs also associated with neurodegenerative processes in PwMS, suggesting that AA-derived LMs are involved in more pathological events than solely neuroinflammation. Yet, to date, a comprehensive overview of the contribution of these LMs to MS-associated pathological processes remains elusive. MAIN BODY: This review summarizes and critically evaluates the current body of literature on the eicosanoid biosynthetic pathway and its contribution to key pathological hallmarks of MS during different disease stages. Various parts of the eicosanoid pathway are highlighted, namely, the prostanoid, leukotriene, and hydroxyeicosatetraenoic acids (HETEs) biochemical routes that include specific enzymes of the cyclooxygenases (COXs) and lipoxygenases (LOX) families. In addition, cellular sources of LMs and their potential target cells based on receptor expression profiles will be discussed in the context of MS. Finally, we propose novel therapeutic approaches based on eicosanoid pathway and/or receptor modulation to ultimately target chronic neuroinflammation, demyelination and neurodegeneration in MS. SHORT CONCLUSION: The eicosanoid pathway is intrinsically linked to specific aspects of MS pathogenesis. Therefore, we propose that novel intervention strategies, with the aim of accurately modulating the eicosanoid pathway towards the biosynthesis of beneficial LMs, can potentially contribute to more patient- and MS subtype-specific treatment opportunities to combat MS.

Decreased oxidative stress and altered urinary oxylipidome by intravenous omega-3 fatty acid emulsion in a randomized controlled trial of older subjects hospitalized for COVID-19.

Proinflammatory bioactive lipid mediators and oxidative stress are increased in coronavirus disease 2019 (COVID-19). The randomized controlled single-blind trial COVID-Omega-F showed that intravenous omega-3 polyunsaturated fatty acids (n-3 PUFA) shifted the plasma lipid signature of COVID-19 towards increased proresolving precursor levels and decreased leukotoxin diols, associated with a beneficial immunodulatory response. The present study aimed to determine the effects of n-3 PUFA on the urinary oxylipidome and oxidative stress in COVID-19. From the COVID-Omega-F trial, 20 patients hospitalized for COVID-19 had available serial urinary samples collected at baseline, after 24-48 h, and after completing 5 days treatment with one daily intravenous infusion (2 mL/kg) of either placebo (NaCl; n = 10) or a lipid emulsion containing 10 g of n-3 PUFA per 100 mL (n = 10). Urinary eicosanoids and isoprostanes were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Erythrocytes obtained at the different time-points from n = 10 patients (n = 5 placebo and n = 5 n-3 PUFA) were used for determination of reactive oxygen species. Intravenous n-3 PUFA emulsion administration altered eicosanoid metabolites towards decreased levels for mediators of inflammation and thrombosis, and increased levels of the endothelial function mediator prostacyclin. Furthermore, non-enzymatic metabolism was skewed towards n-3 PUFA-derived metabolites with potential anti-inflammatory and pro-resolving effects. The oxidative stress marker 15-F2t-isoprostane was significantly lower in patients receiving n-3 PUFA treatment, who also exhibited significantly decreased erythrocyte oxidative stress compared with placebo-treated patients. These findings point to additional beneficial effects of intravenous n-3 PUFA emulsion treatment through a beneficial oxylipin profile and decreased oxidative stress in COVID-19.

Lipid profiling reveals the presence of unique lipid mediators in human milk from healthy and mastitic subjects.

Milk lipids are an important energy source for infants, but the composition of milk lipids has not yet been clarified in detail. In this study, we analyzed free fatty acids and their metabolites in milk from humans and cows. In comparison to cow milk, human milk showed a higher content of free fatty acids including polyunsaturated fatty acids, especially ω-3 fatty acids and their metabolites. Polyunsaturated fatty acids were enriched at an early period of lactation, while saturated fatty acids did not change significantly over the period. Moreover, human milk contained high levels of ω-3 fatty acid metabolites, particularly 18-hydroxyeicosapentaenoic acid, an eicosapentaenoic acid-derived metabolite with anti-inflammatory activity. In comparison with human normal milk, thromboxane B2 and protectin D1 levels were significantly elevated in milk from individuals with mastitis, suggesting that these lipid mediators could be potential biomarkers of obstructive mastitis. Overall, the unique lipid profile of human milk supports the efficacy of breast-feeding for supply of more nutritional and bioactive lipids in comparison to artificial or cow milk to infants, in whom digestive and absorptive functions are still immature.

The function of specialized pro-resolving endogenous lipid mediators, vitamins, and other micronutrients in the control of the inflammatory processes: Possible role in patients with SARS-CoV-2 related infection.

Inflammation is an essential protective response against harmful stimuli, such as invading pathogens, damaged cells, or irritants. Physiological inflammation eliminates pathogens and promotes tissue repair and healing. Effective immune response in humans depends on a tightly regulated balance among inflammatory and anti-inflammatory mechanisms involving both innate and adaptive arms of the immune system. Excessive inflammation can become pathological and induce detrimental effects. If this process is not self-limited, an inappropriate remodeling of the tissues and organs can occur and lead to the onset of chronic degenerative diseases. A wide spectrum of infectious and non-infectious agents may activate the inflammation, via the release of mediators and cytokines by distinct subtypes of lymphocytes and macrophages. Several molecular mechanisms regulate the onset, progression, and resolution of inflammation. All these steps, even the termination of this process, are active and not passive events. In particular, a complex interplay exists between mediators (belonging to the group of Eicosanoids), which induce the beginning of inflammation, such as Prostaglandins (PGE2), Leukotrienes (LT), and thromboxane A2 (TXA2), and molecules which display a key role in counteracting this process and in promoting its proper resolution. The latter group of mediators includes: ω-6 arachidonic acid (AA)-derived metabolites, such as Lipoxins (LXs), ω -3 eicosapentaenoic acid (EPA)-derived mediators, such as E-series Resolvins (RvEs), and ω -3 docosahexaenoic (DHA)-derived mediators, such as D-series Resolvins (RvDs), Protectins (PDs) and Maresins (MaRs). Overall, these mediators are defined as specialized pro-resolving mediators (SPMs). Reduced synthesis of these molecules may lead to uncontrolled inflammation with possible harmful effects. ω-3 fatty acids are widely used in clinical practice as rather inexpensive, safe, readily available supplemental therapy. Taking advantage of this evidence, several researchers are suggesting that SPMs may have beneficial effects in the complementary treatment of patients with severe forms of SARS-CoV-2 related infection, to counteract the "cytokine storm" observed in these individuals. Well-designed and sized trials in patients suffering from COVID-19 with different degrees of severity are needed to investigate the real impact in the clinical practice of this promising therapeutic approach.

Anti-allergic actions of a Chinese patent medicine, huoxiangzhengqi oral liquid, in RBL-2H3 cells and in mice.

CONTEXT: Huoxiangzhengqi oral liquid (HXZQ-OL), a traditional Chinese medicine formula, has antibacterial, anti-inflammation and gastrointestinal motility regulation effects. OBJECTIVE: The study investigates the anti-allergic activity and underlying mechanism of HXZQ-OL. MATERIALS AND METHODS: IgE/Ag-mediated RBL-2H3 cells were used to evaluate the anti-allergic activity of HXZQ-OL (43.97, 439.7 and 4397 µg/mL) in vitro. The release of cytokines and eicosanoids were quantified using ELISA. RT-qPCR was used to measure the gene expression of cytokines. The level of intracellular Ca2+ was measured with Fluo 3/AM. Immunoblotting analysis was performed to investigate the mechanism of HXZQ-OL. In the passive cutaneous anaphylaxis (PCA), BALB/c mice (5 mice/group) were orally administrated with HXZQ-OL (263.8, 527.6 and 1055 mg/kg/d) or dexamethasone (5 mg/kg/d, positive control) for seven consecutive days. RESULTS: HXZQ-OL not only inhibited degranulation of mast cells (IC50, 123 µg/mL), but also inhibited the generation and secretion of IL-4 (IC50, 171.4 µg/mL), TNF-α (IC50, 88.4 µg/mL), LTC4 (IC50, 52.9 µg/mL) and PGD2 (IC50, 195.8 µg/mL). Moreover, HXZQ-OL suppressed the expression of IL-4 and TNF-α mRNA, as well as the phosphorylation of Fyn, Lyn and multiple downstream signalling proteins including MAPK and PI3K/NF-κB pathways. In addition, HXZQ-OL (527.5 mg/kg) attenuated the IgE-mediated PCA with 55% suppression of Evans blue exudation in mice. CONCLUSIONS: HXZQ-OL attenuated the activation of mast cell and PCA. Therefore, HXZQ-OL might be used as an alternative treatment for allergic diseases.

Baccharin and p-coumaric acid from green propolis mitigate inflammation by modulating the production of cytokines and eicosanoids.

ETHNOPHARMACOLOGICAL RELEVANCE: Green propolis is produced by Apis mellifera honeybees using Baccharis dracunculifolia D.C. (Asteraceae) as substrate. This Southern Brazilian native plant and green propolis have been used in traditional medicine to treat gastric diseases, inflammation and liver disorders. AIM OF THE STUDY: Investigate the effects of baccharin (Bac) or p-coumaric acid (pCA) isolated from B. dracunculifolia D.C. (Asteraceae) over the inflammation induced by lipopolysaccharide (LPS) in vivo. MATERIALS AND METHODS: Inflammation was induced by LPS injection into air-pouches in mice, which were subsequently treated with Bac or pCA. Lavage fluid was collected from air pouches for the quantification of cellular influx via microscopy, and quantification of inflammatory mediators via colorimetric methods, ELISA and liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: LPS-induced inflammation increased cellular influx and increased the levels of parameters related to vascular permeability and edema formation, such as nitric oxide (NO) and protein extravasation. Moreover, LPS increased the levels of cytokines and eicosanoids in the air-pouches. Importantly, both Bac and pCA suppressed the infiltration of neutrophils, production of NO and protein extravasation. Notably, the compounds promote differential regulation of cytokine and eicosanoid production. CONCLUSIONS: Our results suggest that Bac from green propolis directly affects inflammation by inhibiting the production of cytokines and eicosanoids, while pCA may exert direct, but also indirect effects on inflammation by stimulating the production of regulatory effectors such as interkeukin-10 in vivo.

Omega-3 fatty acids protect from colitis via an Alox15-derived eicosanoid.

An increased omega-3 polyunsaturated fatty acid (n-3 PUFA) tissue status can lead to a significant formation of anti-inflammatory lipid mediators and effective reduction in inflammation and tissue injury in murine colitis. Arachidonic acid lipoxygenases (ALOX) have been implicated in the pathogenesis of inflammatory bowel disease as well as in the formation of pro- and anti-inflammatory lipid mediators. To explore the role of Alox15 in the protective response found in fat1 transgenic mice with endogenously increased n-3 PUFA tissue status fat1 transgenic mice were crossed with Alox15-deficient animals and challenged in the dextran sulfate sodium (DSS)- and the 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis model. Transgenic fat1 mice rich in endogenous n-3 PUFAs were protected from colitis. However, additional systemic inactivation of the Alox15 gene counteracted this protective effect. To explore the molecular basis for this effect Alox15 lipid metabolites derived from n-3 PUFA were analyzed in the different mice. Alox15 deficiency suppressed the formation of n-3 PUFA-derived 15-hydroxy eicosapentaenoic acid (15-HEPE). In contrast, treating mice with intraperitoneal injections of 15S-HEPE protected wild-type mice from DSS- and TNBS-induced colitis. These data suggest that the anti-colitis effect of increased n-3 PUFA in the transgenic fat1 mouse model is mediated in part via Alox15-derived 15-HEPE formation.

The need for precision nutrition, genetic variation and resolution in Covid-19 patients.

The health of the individual and the population in general is the result of interaction between genetics and various environmental factors, of which diet/nutrition is the most important. The focus of this paper is on the association of high n-6 PUFA or low n-3 PUFA due to genetic variation and/or dietary intake, with changes in specialized pro-resolving mediators (SPMs), cytokine storm, inflammation-resolution and Covid-19. Human beings evolved on a diet that was balanced in the n-6 and n-3 essential fatty acids with a ratio of n-6/n-3 of 1-2/1 whereas today this ratio is 16/1. Such a high ratio due to high amounts of n-6 fatty acids leads to a prothrombotic and proinflammatory state and is associated with obesity, diabetes, cardiovascular disease, and some forms of cancer. In addition to the high intake of n-6 fatty acids that increases inflammation there is genetic variation in the biosynthesis of n-6 linoleic acid (LA) to arachidonic acid (ARA) and of linolenic (ALA) to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Present day humans have two common FADS haplotypes that differ dramatically in their ability to generate long-chain fatty acids. The more efficient, evolutionary derived haplotype increases the efficiency of synthesizing essential long-chain fatty acids from precursors and could have provided an advantage in environments with limited access to dietary long-chain fatty acids ARA, EPA and DHA. In the modern world this haplotype has been associated with lifestyle-related diseases, such as cardiovascular disease, obesity, diabetes, all of which are characterized by increased levels of inflammation. African Americans and Latino populations have increased susceptibility and higher death rates from SARS-CoV-2 than whites. These populations are characterized by increased numbers of persons (about 80%) that are fast metabolizers, leading to increased production of ARA, as well as poor intake of fruits and vegetables. The combinations of fast metabolism and high n-6 intake increases their inflammatory status and possibly susceptibility of SARS-CoV-2. In vitro and human studies indicate that the specialized pro-resolving mediators (SPM) produced from the n-3, EPA and DHA influence the resolution of inflammation, allowing the tissues to return to function and homeostasis. The SPMs each counter-regulate cytokine storms, as well as proinflammatory lipid mediators via NFκB and inflammasome down regulation and reduce the proinflammatory eicosanoids produced from ARA. The nutritional availability of dietary n-3 fatty acids from marine oils enriched with SPM intermediate precursors, along with increasing local biosynthesis of SPMs to functional concentrations may be an approach of value during SARS-CoV2 infections, as well as in prevention, and shortening their recovery from infections. It is evident that populations differ in their genetic variants and their frequencies and their interactions with the food they eat. Gene-nutrient interactions is a very important area of study that provides specific dietary advice for individuals and subgroups within a population in the form of Precision Nutrition. Nutritional science needs to focus on Precision Nutrition, genetic variants in the population and a food supply composed of Nutrients that have been part of our diet throughout evolution, which is the diet that our genes are programmed to respond.

PPAR Gamma: From Definition to Molecular Targets and Therapy of Lung Diseases.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily that regulate the expression of genes related to lipid and glucose metabolism and inflammation. There are three members: PPARα, PPARß or PPARγ. PPARγ have several ligands. The natural agonists are omega 9, curcumin, eicosanoids and others. Among the synthetic ligands, we highlight the thiazolidinediones, clinically used as an antidiabetic. Many of these studies involve natural or synthetic products in different pathologies. The mechanisms that regulate PPARγ involve post-translational modifications, such as phosphorylation, sumoylation and ubiquitination, among others. It is known that anti-inflammatory mechanisms involve the inhibition of other transcription factors, such as nuclear factor kB(NFκB), signal transducer and activator of transcription (STAT) or activator protein 1 (AP-1), or intracellular signaling proteins such as mitogen-activated protein (MAP) kinases. PPARγ transrepresses other transcription factors and consequently inhibits gene expression of inflammatory mediators, known as biomarkers for morbidity and mortality, leading to control of the exacerbated inflammation that occurs, for instance, in lung injury/acute respiratory distress. Many studies have shown the therapeutic potentials of PPARγ on pulmonary diseases. Herein, we describe activities of the PPARγ as a modulator of inflammation, focusing on lung injury and including definition and mechanisms of regulation, biological effects and molecular targets, and its role in lung diseases caused by inflammatory stimuli, bacteria and virus, and molecular-based therapy.

Dietary Technologies to Optimize Healing from Injury-Induced Inflammation.

Inflammation is an acute adaptive response to injury. However, if the initial inflammatory response to an injury is not completely healed, it becomes chronic low-level inflammation that is strongly associated with many chronic disease states, including metabolic (obesity and diabetes), cardiovascular, auto-immune, and neurogenerative disorders as well as cancer. The healing process is far more complex than the initiation of inflammation. Within that complexity of healing is a sequence of events that are under profound dietary control and can be defined by specific blood markers. Those molecular events of the healing process that are under significant dietary control are termed as the Resolution Response. The purpose of this review is to describe the molecular components of the Resolution Response and how different dietary factors can either optimize or inhibit their actions. In particular, those dietary components that optimize the Resolution Response include a calorie-restricted, protein-adequate, moderate-carbohydrate, low-fat diet referred to as the Zone diet, omega-3 fatty acids, and polyphenols. The appropriate combination of these dietary interventions constitutes the foundation of Pro-Resolution Nutrition. The effect of these dietary components the actions of NF-κB, AMPK, eicosanoids, and resolvins are described in this review, as well as ranges of appropriate blood markers that indicate success in optimizing the Resolution Response by dietary interventions.

Cassia sieberiana DC. leaves modulate LPS-induced inflammatory response in THP-1 cells and inhibit eicosanoid-metabolizing enzymes.

ETHNOPHARMACOLOGICAL RELEVANCE: According to ethnobotanical surveys, Cassia sieberiana DC. (1825) is a particularly reputed species in African folk Medicine, namely due to the application of its leaves and roots for the treatment of diseases and symptomatology that appear to be related with an inflammatory background. In contrast with the roots of the plant, the leaves remain to be investigated, which prompted us to further detail mechanisms underlying their anti-inflammatory properties, by using in vitro models of disease. AIM OF THE STUDY: Considering its use in the amelioration and treatment of conditions that frequently underlie an inflammatory response, C. sieberiana leaves extract was prioritized amongst a collection of extracts obtained from plants collected in Guinea-Bissau. As such, this work aims to deliver experimental data on the anti-inflammatory properties of C. sieberiana leaf and to establish possible associations with its chemical composition, thus providing a rationale on its use in folk Medicine. MATERIALS AND METHODS: The chemical profile of an hydroethanol extract obtained from the leaves of the plant was established by HPLC-DAD-ESI/MSn in order to identify bioactives. The extract and its main compound were tested towards a series of inflammatory mediators, both in enzymatic and cell-based models. The capacity to interfere with the eicosanoid-metabolizing enzymes 5-lipoxygenase (5-LOX), cyclooxygenase-1 (COX-1) and -2 (COX-2) was evaluated in cell-free systems, while the effects in interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α) levels produced by THP-1 derived macrophages were assessed through ELISA. RESULTS: HPLC-DAD-ESI/MSn analysis of the extract elucidated a chemical profile qualitatively characterized by a series of anthraquinones, particularly rhein derivatives, and nine flavonols, most of which 3-O-glycosylated. Considering the concentrations of the identified compounds, quercetin was detached as the main component. Effects of the hydroethanol extract obtained from C. sieberiana leaves against key enzymes of the arachidonic acid cascade were recorded, namely a concentration-dependent inhibition against 5-LOX, at concentrations ranging from 16 to 250 µg mL-1 and a selective inhibitory action upon COX-2 (IC50 = 3.58 µg mL-1) in comparison with the isoform COX-1 (IC50 = 9.10 µg mL-1). Impact on inflammatory cytokines was also noted, C. sieberiana leaf extract significantly decreasing IL-6 levels in THP-1 derived macrophages at 250 and 500 µg mL-1. In contrast, TNF-α levels were found to be increased in the same model. Quercetin appears to partially account for the observed effects, namely due to the significant inhibitory effects on the activity of the arachidonic acid metabolizing enzymes COX-2 and 5-LOX. CONCLUSIONS: The anti-inflammatory effects herein reported provide a rationale for the use of C. sieberiana leaves in African folk practices, such as in the treatment of arthritis, rheumatism and body aches. Considering the occurrence of flavonoidic and anthraquinonic constituents, as well as the observed anti-inflammatory properties of quercetin, recorded effects must be related with the presence of several bioactives.

Ginger and turmeric lipid-solubles attenuate heated oil-induced hepatic inflammation via the downregulation of NF-kB in rats.

PURPOSE: Reusing deep-fried vegetable oils multiple times is a common practice to save costs, and their chronic consumption may cause hepatic dysfunction. In this investigation, we assessed the modulatory effects of ginger and turmeric lipid-solubles that may migrate to oils during heating on the hepatic inflammatory response in rats. METHODS: Male Wistar rats were fed with; 1) control {native canola (N-CNO) or native sunflower (N-SFO)} oil, 2) heated (heated canola {(H-CNO) or heated sunflower (H-SFO)} oil, and 3) heated oil with ginger or turmeric {heated canola with ginger (H-CNO + GI) or heated canola oil with turmeric (H-CNO + TU), heated sunflower oil with ginger (H-SFO + GI) or heated sunflower oil with turmeric (H-SFO + TU)} for 120 days. Hepatic inflammatory response comprising eicosanoids, cytokines, and NF-kB were assessed. RESULTS: Compared to respective controls, feeding heated oils significantly (p < 0.05); 1) increased eicosanoids (PGE2, LTB4, and LTC4) and cytokines (TNF-α, MCP-1, IL-1ß, and IL-6), 2) increased nuclear translocation of NF-kB in the liver, and 3) increased the hepatic expression of 5-LOX, COX-2, BLT-1, and EP-4. However, feeding oils heated with ginger or turmeric positively countered the changes induced by consumption of heated oils. CONCLUSIONS: Consumption of repeatedly heated oil may cause hepatic dysfunction by inducing inflammatory stress through NF-kB upregulation. Lipid-solubles from ginger and turmeric that may migrate to oil during heating prevent the hepatic inflammatory response triggered by heated oils in rats.

Extracellular vesicles of MSCs and cardiomyoblasts are vehicles for lipid mediators.

Recent works reported the relevance of cellular exosomes in the evolution of different pathologies. However, most of these studies focused on the ability of exosomes to convey mi-RNA from cell to cell. The level of knowledge concerning the transport of lipid mediators by these nanovesicles is more than fragmented. The role of lipid mediators in the inflammatory signaling is fairly well described, in particular concerning the derivatives of the arachidonic acid (AA), called eicosanoïds or lipid mediators. The aim of the present work was to study the transport of these lipids within the extracellular vesicles of rat bone marrow mesenchymal stem cells (BM-MSC) and the cardiomyoblast cell line H9c2. We were able to characterize, for the first time, complete profiles of oxilipins within these nanovesicles. We studied also the impact on these profiles, of the polyunsaturated fatty acids (PUFAs) know to be precursors of the inflammatory signaling molecules (AA, eicosapentaenoic acid EPA and Docosahexaenoic acid DHA), at physiological concentrations. By growing the progenitor cells under PUFAs supplementation, we provide a comprehensive assessment of the beneficial effect of ω-3 PUFA therapy. Actually, our results tend to support the resolving role of the inflammation that stromal cell-derived extracellular vesicles can have within the cardiac microenvironment.

Eicosanoids seasonally impact pulmonary function in asthmatic patients with Japanese cedar pollinosis.

BACKGROUND: Condition of asthma in patients with asthma and concomitant seasonal allergic rhinitis (SAR) deteriorates during the Japanese cedar pollen (JCP) season. However, the underlying mechanisms remain unclear. METHODS: We analyzed seasonal variations in eicosanoid levels in the airways of patients with asthma and concomitant SAR sensitized to JCP (N = 29, BA-SAR-JCP group) and those not sensitized (N = 13, BA-AR-non-JCP group) during the JCP season. The association between changes in eicosanoid concentrations and pulmonary function was assessed. Exhaled breath condensate (EBC) was collected, and pulmonary function tests were performed during the JCP and non-JCP seasons. The cysteinyl leukotriene (CysLT), thromboxane B2 (TXB2), prostaglandin D2-methoxime (PGD2-MOX), and leukotriene B4 (LTB4) levels in the collected EBC were measured via enzyme-linked immunosorbent immunoassays. RESULTS: The log CysLT levels significantly increased in the BA-SAR-JCP group during the JCP season compared with the non-JCP season (1.78 ± 0.55, 1.39 ± 0.63 pg/mL, mean ± standard deviation, respectively, p = 0.01) and those in the BA-AR-non-JCP group during the JCP season (1.39 ± 0.38 pg/mL, p = 0.04). Moreover, the log TXB2 levels seemed to increase. However, the log LTB4 and log PGD2-MOX levels did not increase. The changes in the log CysLT levels during the two seasons were negatively correlated to forced expiratory volume in one second (FEV1) in the BA-SAR-JCP group (r = -0.52, p < 0.01). CONCLUSIONS: In the BA-SAR-JCP group, seasonal increases in eicosanoid levels in the airway likely promoted deterioration in pulmonary function despite optimal maintenance treatment.

Taoren-dahuang herb pair reduces eicosanoid metabolite shifts by regulating ADORA2A degradation activity in ischaemia/reperfusion injury rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Peach kernel (taoren: TR) is the dried mature seed of peach, Prunus persica (L.) Batsch, which belongs to the Rosaceae family. Rhubarb (dahuang: DH) is the dried root and rhizome of rhubarb (Rheum palmatum L., Rheum officinale Baill., or Rheum tanguticum Maxim. ex Balf.). TR-DH (TD) is a traditional Chinese medicine herb pair that promotes blood circulation and removes blood stasis. In recent years, TD has shown definite benefits in the cardio-cerebrovascular system, but its specific mechanism is not very clear. AIM OF STUDY: The purpose of this study was to explore the mechanism by which TD affects cerebral ischaemia/reperfusion (I/R) injury and to optimize the mixture ratio. METHODS: The affected metabolic pathways in rat brain tissues after I/R were analysed by network pharmacology and verified with animal pharmacological experiments. RESULTS: TD had a certain therapeutic effect on cerebral I/R injury. TD with a TR:DH ratio of 1:1 had the best therapeutic effect. Metabolic pathway analysis showed that the protective mechanism of TD against I/R injury involves mainly regulation of brain tissue ADORA2A protein levels and action on the arachidonic acid (AA) pathway. CONCLUSION: TD can ameliorate cerebral I/R injury by regulating ADORA2A degradation in the AA metabolic pathway to attenuate AA metabolic dysfunction and the inflammatory response.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters hepatic polyunsaturated fatty acid metabolism and eicosanoid biosynthesis in female Sprague-Dawley rats.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent aryl hydrocarbon receptor (AhR) agonist that elicits a broad spectrum of dose-dependent hepatic effects including lipid accumulation, inflammation, and fibrosis. To determine the role of inflammatory lipid mediators in TCDD-mediated hepatotoxicity, eicosanoid metabolism was investigated. Female Sprague-Dawley (SD) rats were orally gavaged with sesame oil vehicle or 0.01-10 µg/kg TCDD every 4 days for 28 days. Hepatic RNA-Seq data was integrated with untargeted metabolomics of liver, serum, and urine, revealing dose-dependent changes in linoleic acid (LA) and arachidonic acid (AA) metabolism. TCDD also elicited dose-dependent differential gene expression associated with the cyclooxygenase, lipoxygenase, and cytochrome P450 epoxidation/hydroxylation pathways with corresponding changes in ω-6 (e.g. AA and LA) and ω-3 polyunsaturated fatty acids (PUFAs), as well as associated eicosanoid metabolites. Overall, TCDD increased the ratio of ω-6 to ω-3 PUFAs. Phospholipase A2 (Pla2g12a) was induced consistent with increased AA metabolism, while AA utilization by induced lipoxygenases Alox5 and Alox15 increased leukotrienes (LTs). More specifically, TCDD increased pro-inflammatory eicosanoids including leukotriene LTB4, and LTB3, known to recruit neutrophils to damaged tissue. Dose-response modeling suggests the cytochrome P450 hydroxylase/epoxygenase and lipoxygenase pathways are more sensitive to TCDD than the cyclooxygenase pathway. Hepatic AhR ChIP-Seq analysis found little enrichment within the regulatory regions of differentially expressed genes (DEGs) involved in eicosanoid biosynthesis, suggesting TCDD-elicited dysregulation of eicosanoid metabolism is a downstream effect of AhR activation. Overall, these results suggest alterations in eicosanoid metabolism may play a key role in TCDD-elicited hepatotoxicity associated with the progression of steatosis to steatohepatitis.

Oils' Impact on Comprehensive Fatty Acid Analysis and Their Metabolites in Rats.

Fatty acids, especially polyunsaturated, and their metabolites (eicosanoids) play many pivotal roles in human body, influencing various physiological and pathological processes. The aim of the study was to evaluate the effect of supplementation with edible oils diverse in terms of fatty acid composition on fatty acid contents, activities of converting their enzymes, and on lipoxygenase metabolites of arachidonic and linoleic acids (eicosanoids) in rat serum. Female Sprague-Dawley rats divided into seven groups were used in the study. Animals from six groups were fed one of oils daily (carotino oil, made up by combining of red palm oil and canola oil, linseed oil, olive oil, rice oil, sesame oil, or sunflower oil). One group received a standard diet only. Fatty acids were determined using gas chromatography with flame ionization detection. Eicosanoids-hydroxyeicosatetraenoic (HETE) and hydroxyoctadecadienoic acids (HODE) were extracted using a solid-phase extraction method and analyzed with HPLC. Vegetable oils given daily to rats caused significant changes in serum fatty acid profile and eicosanoid concentrations. Significant differences were also found in desaturases' activity, with the linseed and olive oil supplemented groups characterized by the highest D6D and D5D activity. These findings may play a significant role in various pathological states.

Assessment of the Effect of Sorafenib on Omega-6 and Omega-3 Epoxyeicosanoid Formation in Patients with Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death. The multikinase inhibitor sorafenib is widely used for systemic therapy in advanced HCC. Sorafenib might affect epoxyeicosanoids, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of epoxides derived from long-chain polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding diols. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) showed that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this pilot study, we assessed the effect of sorafenib treatment on the presence of lipid mediators, such as EETs, in blood of the patients with HCC using the lipidomics technology. We found a significant increase in 11,12-EET and 14,15-EET levels in HCC patients treated with sorafenib. Furthermore, while not significant in this small sample set, the data presented indicate that sorafenib can also increase the level of omega-3 DHA-derived 19,20-EDP. While the effect on EETs might hamper the anti-tumor effect of sorafenib, we hypothesize that supplementation of DHA in sorafenib-treated HCC patients could increase the level of 19,20-EDP and thereby enhance its anti-tumor effect.

Synthesis and function of fatty acids and oxylipins, with a focus on Caenorhabditis elegans.

Polyunsaturated fatty acids (PUFAs) exhibit a diverse range of important biological functions in most biological systems. These PUFAs can be oxygenated via enzymatic or free radical-mediated reactions to form bioactive oxygenated lipid mediators termed oxylipins. Eicosanoids are broad class of oxylipins that are transient and locally synthesized signalling molecules, including prostaglandins, leukotrienes, lipoxins and thromboxanes, which mediate various physiological responses, such as inflammation. In addition to arachidonic acid-derived eicosanoids, current developments in lipidomic methodologies have brought attention to vast number of oxylipins produced from other PUFAs, including omega-3. Although, the molecular mechanisms of how PUFAs and oxylipins contribute to majority of the fundamental biological processes are largely unclear, a model organism Caenorhabditis elegans remains a powerful model for exploring lipid metabolism and functions of PUFAs and oxylipins. For instance, the ability of C. elegans to modify fatty acid composition with dietary supplementation and genetic manipulation enables the dissection of the roles of omega-3 and omega-6 PUFAs in many biological processes that include aging, reproduction, and neurobiology. However, much remains to be elucidated concerning the roles of oxylipins, but thus far, C. elegans is well-known for the synthesis of vast set of cytochrome (CYP) eicosanoids. These CYP eicosanoids are extremely susceptible to changes in the relative bioavailability of the different PUFAs, thus providing a better insight into complex mechanisms connecting essential dietary fatty acids to various biological processes. Therefore, this review provides an overview of the synthesis and function of PUFAs and oxylipins in mammals. It also focusses on what is known regarding the production of PUFAs and oxylipins in C. elegans and their functions.

A combined in vivo and in vitro approach to evaluate the influence of linseed oil or sesame oil and their combination on innate immune competence and eicosanoid metabolism processes in common carp (Cyprinus carpio).

This study aimed to evaluate the influence of dietary pure linseed oil or sesame oil or a mixture on innate immune competence and eicosanoid metabolism in common carp (Cyprinus carpio). Carp of 100.4 ±â€¯4.7 g were fed to satiation twice daily for 6 weeks with four diets prepared from three lipid sources (CLO; LO; SO; SLO). On day 42, plasma was sampled for immune parameter analyses, and kidney and liver tissues were dissected for gene expression analysis. On day 45, HKL and PBMCs from remaining fish were isolated and exposed to E. coli LPS at a dose of 10 µg/mL for 24 h. Results show that the SLO diet enhanced feed utilisation (P = 0.01), while no negative effects on growth or survival were observed in plant oil-fed fish compared to those fed a fish-oil based diet. Plant oil diets did not alter lysozyme and peroxidase activities or gene expression levels. Moreover, the diets did not affect the expression levels of some genes involved in eicosanoid metabolism processes (pla, pge2, lox5). Lys expression in HKL in vitro following exposure to LPS was up-regulated in LO-fed fish, while expression levels of pge2 were higher in SLO fish than in other groups (P < 0.05). The highest value for peroxidase activity in HKL exposed to LPS was found in the SLO-fed group (P < 0.05). In conclusion, our results indicate that dietary plant oils did not induce any negative effects on fish growth, survival, and immune competence status. Moreover, a dietary combination of SO and LO improved the feed utilisation efficiency and seemed more effective in inducing a better immunomodulatory response to LPS through a more active eicosanoid metabolism process.