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Rheumatology (Oxford, England) May 2023Oxylipins modulate inflammation via complex pathways. The oxylipin profile in gout remains unexplored. In this study, we systemically profiled oxylipins in young men and...
OBJECTIVE
Oxylipins modulate inflammation via complex pathways. The oxylipin profile in gout remains unexplored. In this study, we systemically profiled oxylipins in young men and identified new oxylipin biomarkers for clinical use in differentiating gout from hyperuricaemia.
MATERIAL AND METHODS
Oxylipin profiling was performed in 90 men (30 very early onset gout, 30 asymptomatic hyperuricaemia [HU] and 30 normouricaemia [NU], all aged <20 years) divided into discovery and validation sample sets. The dataset was analysed based on orthogonal projection to latent structure-discriminant analysis. Correlation network and pathway enrichment were conducted to reveal potential oxylipin-involved pathways of gout. Candidate oxylipins were further evaluated and optimized in the validation cohort, and differential oxylipin biomarkers combined with or without serum urate were applied to construct diagnostic models.
RESULTS
In discovery stage, 21 differential oxylipins in the gout vs HU comparisons and 14 differential oxylipins in the gout vs NU comparisons were discovered. Correlation network analysis was performed and 14(S)-HDHA (14S-hydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid) was identified as a hub metabolite in both comparisons. Seven down-regulated oxylipins in the gout vs HU group and five down-regulated oxylipins in the gout vs NU group were validated. Diagnostic models were constructed with the above oxylipins, with 14(S)-HDHA alone having an area under the curve of 1 (95% CI, 1, 1) in both comparisons.
CONCLUSIONS
Young men with very early onset gout have distinct oxylipin spectrums, especially those derived from arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid. Differential oxylipins could serve as candidate serum biomarkers in differentiating gout from hyperuricaemia.
Topics: Male; Humans; Adolescent; Oxylipins; Docosahexaenoic Acids; Hyperuricemia; Biomarkers; Gout
PubMed: 36111871
DOI: 10.1093/rheumatology/keac507 -
Neuroscience Letters Nov 2022Despite known pathological hallmarks of Alzheimer's Disease (AD) including neuronal loss, gliosis (inflammation), beta-amyloid plaque deposition and neurofibrillary...
Despite known pathological hallmarks of Alzheimer's Disease (AD) including neuronal loss, gliosis (inflammation), beta-amyloid plaque deposition and neurofibrillary tangle accumulation in the brain, little is known about inflammation resolution in early AD pathogenesis. In the brain, inflammation and resolution pathways are mediated by free oxylipins which are mostly bound (i.e. esterified), and therefore must be released (i.e. become free) to exert bioactivity. Recently, we showed reductions in brain esterified pro-resolving oxylipins in a transgenic rat model of AD (TgF344-AD rat) at 15 months of age, suggesting deficits in the source and availability of free pro-resolving oxylipins. In the present study, we tested whether these changes are discernable earlier in the disease process, i.e., at age of 10 months. We observed significant reductions in esterified pro-resolving 8(9)-epoxyeicosatrienoic acid (8(9)-EpETrE), 13-hydroxyoctadecatrienoic acid (13-HOTrE) and 15-hydroxyeicosapentaenoic acid (15-HEPE) oxylipins, and in pro-inflammatory 13-hydroxy-octadecadienoic acid (13-HODE), 20-hydroxy-eicosatetraenoic acid (20-HETE), 15-deoxy-prostaglandin J2 (15-deoxy-PGJ2) and prostaglandin E2 (PGE2) oxylipins in male and/or female transgenic AD rats compared to wildtype controls. These findings point to a deficit in esterified pro-resolving lipid mediators in the early stages of AD, concident with. changes in esterified lipid mediators involved in promoting inflammation.
Topics: Animals; Male; Female; Rats; Alzheimer Disease; Rats, Transgenic; Oxylipins; Brain; Inflammation; Disease Models, Animal
PubMed: 36270451
DOI: 10.1016/j.neulet.2022.136921 -
Clinical Nutrition (Edinburgh, Scotland) Jan 2024The relationship between lipid mediators and severe obesity remains unclear. Our study investigates the impact of severe obesity on plasma concentrations of oxylipins...
BACKGROUND
The relationship between lipid mediators and severe obesity remains unclear. Our study investigates the impact of severe obesity on plasma concentrations of oxylipins and fatty acids and explores the consequences of weight loss.
METHODS
In the clinical trial identifier NCT05554224 study, 116 patients with severe obesity and 63 overweight/obese healthy controls matched for age and sex (≈2:1) provided plasma. To assess the effect of surgically induced weight loss, we requested paired plasma samples from 44 patients undergoing laparoscopic sleeve gastrectomy one year after the procedure. Oxylipins were measured using ultra-high-pressure liquid chromatography coupled to a triple quadrupole mass spectrometer via semi-targeted lipidomics. Cytokines and markers of interorgan crosstalk were measured using enzyme-linked immunosorbent assays.
RESULTS
We observed significantly elevated levels of circulating fatty acids and oxylipins in patients with severe obesity compared to their metabolically healthier overweight/obese counterparts. Our findings indicated that sex and liver disease were not confounding factors, but we observed weak correlations in plasma with circulating adipokines, suggesting the influence of adipose tissue. Importantly, while weight loss restored the balance in circulating fatty acids, it did not fully normalize the oxylipin profile. Before surgery, oxylipins derived from lipoxygenase activity, such as 12-HETE, 11-HDoHE, 14-HDoHE, and 12-HEPE, were predominant. However, one year following laparoscopic sleeve gastrectomy, we observed a complex shift in the oxylipin profile, favoring species from the cyclooxygenase pathway, particularly proinflammatory prostanoids like TXB2, PGE2, PGD2, and 12-HHTrE. This transformation appears to be linked to a reduction in adiposity, underscoring the role of lipid turnover in the development of metabolic disorders associated with severe obesity.
CONCLUSIONS
Despite the reduction in fatty acid levels associated with weight loss, the oxylipin profile shifts towards a predominance of more proinflammatory species. These observations underscore the significance of seeking mechanistic approaches to address severe obesity and emphasize the importance of closely monitoring the metabolic adaptations after weight loss.
Topics: Humans; Fatty Acids; Obesity; Obesity, Morbid; Overweight; Oxylipins; Weight Loss
PubMed: 38101315
DOI: 10.1016/j.clnu.2023.12.002 -
International Journal of Molecular... Jan 2020Plants as immovable organisms sense the stressors in their environment and respond to them by means of dedicated stress response pathways. In response to stress,... (Review)
Review
Plants as immovable organisms sense the stressors in their environment and respond to them by means of dedicated stress response pathways. In response to stress, jasmonates (jasmonic acid, its precursors and derivatives), a class of polyunsaturated fatty acid-derived phytohormones, play crucial roles in several biotic and abiotic stresses. As the major immunity hormone, jasmonates participate in numerous signal transduction pathways, including those of gene networks, regulatory proteins, signaling intermediates, and proteins, enzymes, and molecules that act to protect cells from the toxic effects of abiotic stresses. As cellular hubs for integrating informational cues from the environment, jasmonates play significant roles in alleviating salt stress, drought stress, heavy metal toxicity, micronutrient toxicity, freezing stress, ozone stress, CO stress, and light stress. Besides these, jasmonates are involved in several developmental and physiological processes throughout the plant life. In this review, we discuss the biosynthesis and signal transduction pathways of the JAs and the roles of these molecules in the plant responses to abiotic stresses.
Topics: Cyclopentanes; Gene Expression Regulation, Plant; Oxylipins; Plant Growth Regulators; Plant Proteins; Plants; Stress, Physiological
PubMed: 31963549
DOI: 10.3390/ijms21020621 -
Scientific Reports May 2021To investigate the pathophysiologic characteristics of diabetic complications, we identified differences in plasma metabolites in subjects with type 2 diabetes (T2DM)...
To investigate the pathophysiologic characteristics of diabetic complications, we identified differences in plasma metabolites in subjects with type 2 diabetes (T2DM) with or without diabetic macular edema (DME) and a disease duration > 15 years. An cohort of older T2DM patients with prolonged disease duration was established, and clinical information and biospecimens were collected following the guidelines of the National Biobank of Korea. DME phenotypes were identified by ophthalmologic specialists. For metabolomics studies, propensity matched case and control samples were selected. To discover multi-biomarkers in plasma, non-targeted metabolite profiling and oxylipin profiling in the discovery cohort were validated in an extended cohort. From metabolomic studies, 5 amino acids (asparagine, aspartic acid, glutamic acid, cysteine, and lysine), 2 organic compounds (citric acid and uric acid) and 4 oxylipins (12-oxoETE, 15-oxoETE, 9-oxoODE, 20-carboxy leukotriene B4) were identified as candidate multi-biomarkers which can guide DME diagnosis among non-DME subjects. Receiver operating characteristic curves revealed high diagnostic value of the combined 5 amino acids and 2 organic compounds (AUC = 0.918), and of the 4 combined oxylipins (AUC = 0.957). Our study suggests that multi-biomarkers may be useful for predicting DME in older T2DM patients.
Topics: Aged; Amino Acids; Biomarkers; Cohort Studies; Diabetes Mellitus, Type 2; Female; Gas Chromatography-Mass Spectrometry; Humans; Macular Edema; Male; Metabolomics; Oxylipins
PubMed: 33958610
DOI: 10.1038/s41598-021-88104-y -
The Journal of Nutrition Mar 2021Differences in health effects of dietary α-linolenic acid (ALA) and DHA are mediated at least in part by differences in their effects on oxylipins. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Differences in health effects of dietary α-linolenic acid (ALA) and DHA are mediated at least in part by differences in their effects on oxylipins.
OBJECTIVES
Time course and sex differences of plasma oxylipins in response to ALA- compared with DHA-rich supplements were examined.
METHODS
Healthy men and women, aged 19-34 y and BMI 18-28 kg/m2, were provided with capsules containing ∼4 g/d of ALA or DHA in a randomized double-blind crossover study with >6-wk wash-in and wash-out phases. Plasma PUFA and oxylipin (primary outcome) concentrations at days 0, 1, 3, 7, 14, and 28 of supplementation were analyzed by GC and HPLC-MS/MS, respectively. Sex differences, supplementation and time effects, and days to plateau were analyzed.
RESULTS
ALA supplementation doubled ALA concentrations, but had no effects on ALA oxylipins after 28 d, whereas DHA supplementation tripled both DHA and its oxylipins. Increases in DHA oxylipins were detected as early as day 1, and a plateau was reached by days 5-7 for 11 of 12 individual DHA oxylipins and for total DHA oxylipins. Nine individual DHA oxylipins reached a plateau in females with DHA supplementation, compared with only 4 in males. A similar time course and sex difference pattern occurred with EPA and its oxylipins with DHA supplementation. DHA compared with ALA supplementation also resulted in higher concentrations of 4 individual arachidonic acids, 1 linoleic acid, and 1 dihomo-γ-linolenic acid oxylipin, despite not increasing the concentrations of these fatty acids, further demonstrating that oxylipins do not always reflect their precursor PUFA.
CONCLUSIONS
DHA compared with a similar dose of ALA has greater effects on both n-3 and n-6 oxylipins in young, healthy adults, with differences in response to DHA supplementation occurring earlier and being greater in females. These findings can help explain differences in dietary effects of ALA and DHA.This study was registered at clinicaltrials.gov as NCT02317588.
Topics: Adult; Cross-Over Studies; Dietary Supplements; Docosahexaenoic Acids; Double-Blind Method; Eicosapentaenoic Acid; Female; Humans; Male; Oxylipins; Sex Factors; Time Factors; Young Adult; alpha-Linolenic Acid
PubMed: 33097936
DOI: 10.1093/jn/nxaa294 -
International Journal of Molecular... Feb 2023The jasmonic acid (JA) signaling pathway plays important roles in plant defenses, development, and the synthesis of specialized metabolites synthesis. Transcription... (Review)
Review
The jasmonic acid (JA) signaling pathway plays important roles in plant defenses, development, and the synthesis of specialized metabolites synthesis. Transcription factor MYC2 is a major regulator of the JA signaling pathway and is involved in the regulation of plant physiological processes and specialized metabolite synthesis. Based on our understanding of the mechanism underlying the regulation of specialized metabolite synthesis in plants by the transcription factor MYC2, the use of synthetic biology approaches to design MYC2-driven chassis cells for the synthesis of specialized metabolites with high medicinal value, such as paclitaxel, vincristine, and artemisinin, seems to be a promising strategy. In this review, the regulatory role of MYC2 in JA signal transduction of plants to biotic and abiotic stresses, plant growth, development and specialized metabolite synthesis is described in detail, which will provide valuable reference for the use of MYC2 molecular switches to regulate plant specialized metabolite biosynthesis.
Topics: Arabidopsis Proteins; Arabidopsis; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Plants; Transcription Factors; Plant Physiological Phenomena; Cyclopentanes; Oxylipins; Gene Expression Regulation, Plant
PubMed: 36834921
DOI: 10.3390/ijms24043511 -
Journal of Lipid Research Dec 2018Eicosanoids and related metabolites (oxylipins) possess potent signaling properties, elicit numerous important physiologic responses, and serve as biomarkers of disease....
Eicosanoids and related metabolites (oxylipins) possess potent signaling properties, elicit numerous important physiologic responses, and serve as biomarkers of disease. In addition to their presence in free form, a considerable portion of these bioactive lipids is esterified to complex lipids in cell membranes and plasma lipoproteins. We developed a rapid and sensitive method for the analysis of esterified oxylipins using alkaline hydrolysis to release them followed by ultra-performance LC coupled with mass spectrometric analysis. Detailed evaluation of the data revealed that several oxylipins are susceptible to alkaline-induced degradation. Nevertheless, of the 136 metabolites we examined, 56 were reproducibly recovered after alkaline hydrolysis. We classified those metabolites that were resistant to alkaline-induced degradation and applied this methodology to quantify metabolite levels in a macrophage cell model and in plasma of healthy subjects. After alkaline hydrolysis of lipids, 34 metabolites could be detected and quantified in resting and activated macrophages, and 38 metabolites were recovered from human plasma at levels that were substantially greater than in free form. By carefully selecting internal standards and taking the observed experimental limitations into account, we established a robust method that can be reliably employed for the measurement of esterified oxylipins in biological samples.
Topics: Animals; Chromatography, High Pressure Liquid; Eicosanoids; Humans; Hydrolysis; Macrophages; Mice; Oxylipins; RAW 264.7 Cells; Tandem Mass Spectrometry
PubMed: 30323111
DOI: 10.1194/jlr.D089516 -
Marine Drugs Jun 2020The chemical ecology of marine diatoms has been the subject of several studies in the last decades, due to the discovery of oxylipins with multiple simultaneous... (Review)
Review
The chemical ecology of marine diatoms has been the subject of several studies in the last decades, due to the discovery of oxylipins with multiple simultaneous functions including roles in chemical defence (antipredator, allelopathic and antibacterial compounds) and/or cell-to-cell signalling. Diatoms represent a fundamental compartment of marine ecosystems because they contribute to about 45% of global primary production even if they represent only 1% of the Earth's photosynthetic biomass. The discovery that they produce several toxic metabolites deriving from the oxidation of polyunsaturated fatty acids, known as oxylipins, has changed our perspectives about secondary metabolites shaping plant-plant and plant-animal interactions in the oceans. More recently, their possible biotechnological potential has been evaluated, with promising results on their potential as anticancer compounds. Here, we focus on some recent findings in this field obtained in the last decade, investigating the role of diatom oxylipins in cell-to-cell communication and their negative impact on marine biota. Moreover, we also explore and discuss the possible biotechnological applications of diatom oxylipins.
Topics: Animals; Biotechnology; Diatoms; Ecosystem; Oceans and Seas; Oxylipins
PubMed: 32629777
DOI: 10.3390/md18070342 -
International Journal of Molecular... Aug 2022Sensory circumventricular organs (sCVOs) are pivotal brain structures involved in immune-to-brain communication with a leaky blood-brain barrier that detect circulating...
Sensory circumventricular organs (sCVOs) are pivotal brain structures involved in immune-to-brain communication with a leaky blood-brain barrier that detect circulating mediators such as lipopolysaccharide (LPS). Here, we aimed to investigate the potential of sCVOs to produce n-3 and n-6 oxylipins after LPS-stimulation. Moreover, we investigated if norepinephrine (NE) co-treatment can alter cytokine- and oxylipin-release. Thus, we stimulated rat primary neuroglial sCVO cultures under n-3- or n-6-enriched conditions with LPS or saline combined with NE or vehicle. Supernatants were assessed for cytokines by bioassays and oxylipins by HPLC-MS/MS. Expression of signaling pathways and enzymes were analyzed by RT-PCR. Tumor necrosis factor (TNF)α bioactivity and signaling, IL-10 expression, and cyclooxygenase (COX)2 were increased, epoxide hydroxylase (Ephx)2 was reduced, and lipoxygenase 15-(LOX) was not changed by LPS stimulation. Moreover, LPS induced increased levels of several n-6-derived oxylipins, including the COX-2 metabolite 15d-prostaglandin-J2 or the Ephx2 metabolite 14,15-DHET. For n-3-derived oxylipins, some were down- and some were upregulated, including 15-LOX-derived neuroprotectin D1 and 18-HEPE, known for their anti-inflammatory potential. While the LPS-induced increase in TNFα levels was significantly reduced by NE, oxylipins were not significantly altered by NE or changes in TNFα levels. In conclusion, LPS-induced oxylipins may play an important functional role in sCVOs for immune-to-brain communication.
Topics: Animals; Circumventricular Organs; Cyclooxygenase 2; Cytokines; Fatty Acids, Omega-3; Lipopolysaccharides; Norepinephrine; Oxylipins; Rats; Tandem Mass Spectrometry; Tumor Necrosis Factor-alpha
PubMed: 35955879
DOI: 10.3390/ijms23158745