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Brain : a Journal of Neurology Nov 2018Epilepsy therapy is based on drugs that treat the symptoms rather than the underlying mechanisms of the disease (epileptogenesis). There are no treatments for preventing...
Epilepsy therapy is based on drugs that treat the symptoms rather than the underlying mechanisms of the disease (epileptogenesis). There are no treatments for preventing seizures or improving disease prognosis, including neurological comorbidities. The search of pathogenic mechanisms of epileptogenesis highlighted that neuroinflammatory cytokines [i.e. interleukin-1β (IL-1β), tumour necrosis factor-α (Tnf-α)] are induced in human and experimental epilepsies, and contribute to seizure generation in animal models. A major role in controlling the inflammatory response is played by specialized pro-resolving lipid mediators acting on specific G-protein coupled receptors. Of note, the role that these pathways have in epileptogenic tissue remains largely unexplored. Using a murine model of epilepsy, we show that specialized pro-resolving mechanisms are activated by status epilepticus before the onset of spontaneous seizures, but with a marked delay as compared to the neuroinflammatory response. This was assessed by measuring the time course of mRNA levels of 5-lipoxygenase (Alox5) and 15-lipoxygenase (Alox15), the key biosynthetic enzymes of pro-resolving lipid mediators, versus Il1b and Tnfa transcripts and proteins. In the same hippocampal tissue, we found a similar delayed expression of two main pro-resolving receptors, the lipoxin A4 receptor/formyl peptide receptor 2 and the chemerin receptor. These receptors were also induced in the human hippocampus after status epilepticus and in patients with temporal lobe epilepsy. This evidence supports the hypothesis that the neuroinflammatory response is sustained by a failure to engage pro-resolving mechanisms during epileptogenesis. Lipidomic LC-MS/MS analysis showed that lipid mediator levels apt to resolve the neuroinflammatory response were also significantly altered in the hippocampus during epileptogenesis with a shift in the biosynthesis of several pro-resolving mediator families including the n-3 docosapentaenoic acid (DPA)-derived protectin D1. Of note, intracerebroventricular injection of this mediator during epileptogenesis in mice dose-dependently reduced the hippocampal expression of both Il1b and Tnfa mRNAs. This effect was associated with marked improvement in mouse weight recovery and rescue of cognitive deficit in the novel object recognition test. Notably, the frequency of spontaneous seizures was drastically reduced by 2-fold on average and the average seizure duration was shortened by 40% after treatment discontinuation. As a result, the total time spent in seizures was reduced by 3-fold in mice treated with n-3 DPA-derived protectin D1. Taken together, the present findings demonstrate that epilepsy is characterized by an inadequate engagement of resolution pathways. Boosting endogenous resolution responses significantly improved disease outcomes, providing novel treatment avenues.
Topics: Animals; Anticonvulsants; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; CD11b Antigen; Cytokines; Dinoprostone; Disease Models, Animal; Docosahexaenoic Acids; Encephalitis; Epilepsy; Gene Expression Regulation; Hippocampus; Kainic Acid; Leukotriene B4; Lipid Metabolism; Lipoxins; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic
PubMed: 30307467
DOI: 10.1093/brain/awy247 -
American Journal of Physiology. Heart... Aug 2014n-3 Polyunsaturated fatty acids (n-3 PUFA) have been shown to reduce inflammation and proliferation of pulmonary artery smooth muscle cells under pathophysiological...
n-3 Polyunsaturated fatty acids (n-3 PUFA) have been shown to reduce inflammation and proliferation of pulmonary artery smooth muscle cells under pathophysiological conditions. However, the anti-inflammatory effect of the newly synthesized docosapentaenoic acid monoacylglyceride (MAG-DPA) on key signaling pathways in pulmonary hypertension (PH) pathogenesis has yet to be assessed. The aim of the present study was to determine the effects of MAG-DPA on pulmonary inflammation and remodeling occurring in a rat model of PH, induced by a single injection of monocrotaline (MCT: 60 mg/kg). Our results demonstrate that MAG-DPA treatment for 3 wk following MCT injection resulted in a significant improvement of right ventricular hypertrophy (RVH) and a reduction in Fulton's Index (FI). Morphometric analyses revealed that the wall thickness of pulmonary arterioles was significantly lower in MCT + MAG-DPA-treated rats compared with controls. This result was further correlated with a decrease in Ki-67 immunostaining. Following MAG-DPA treatments, lipid analysis showed a consistent increase in DPA together with lower levels of arachidonic acid (AA), as measured in blood and tissue samples. Furthermore, in MCT-treated rats, oral administration of MAG-DPA decreased NF-κB and p38 MAPK activation, leading to a reduction in MMP-2, MMP-9, and VEGF expression levels in lung tissue homogenates. Altogether, these data provide new evidence regarding the mode of action of MAG-DPA in the prevention of pulmonary hypertension induced by MCT.
Topics: Animals; Arachidonic Acid; Arterioles; Fatty Acids, Unsaturated; Hypertension, Pulmonary; Inflammation; Lipid Metabolism; Lung; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Monoglycerides; NF-kappa B; Rats; Rats, Wistar; Vascular Endothelial Growth Factor A; Vascular Remodeling; p38 Mitogen-Activated Protein Kinases
PubMed: 24929859
DOI: 10.1152/ajpheart.00814.2013 -
PloS One 2023Factors for initiating hibernation are unknown, but the condition shares some metabolic similarities with consciousness/sleep, which has been associated with n-3 fatty...
Factors for initiating hibernation are unknown, but the condition shares some metabolic similarities with consciousness/sleep, which has been associated with n-3 fatty acids in humans. We investigated plasma phospholipid fatty acid profiles during hibernation and summer in free-ranging brown bears (Ursus arctos) and in captive garden dormice (Eliomys quercinus) contrasting in their hibernation patterns. The dormice received three different dietary fatty acid concentrations of linoleic acid (LA) (19%, 36% and 53%), with correspondingly decreased alpha-linolenic acid (ALA) (32%, 17% and 1.4%). Saturated and monounsaturated fatty acids showed small differences between summer and hibernation in both species. The dormice diet influenced n-6 fatty acids and eicosapentaenoic acid (EPA) concentrations in plasma phospholipids. Consistent differences between summer and hibernation in bears and dormice were decreased ALA and EPA and marked increase of n-3 docosapentaenoic acid and a minor increase of docosahexaenoic acid in parallel with several hundred percent increase of the activity index of elongase ELOVL2 transforming C20-22 fatty acids. The highest LA supply was unexpectantly associated with the highest transformation of the n-3 fatty acids. Similar fatty acid patterns in two contrasting hibernating species indicates a link to the hibernation phenotype and requires further studies in relation to consciousness and metabolism.
Topics: Animals; alpha-Linolenic Acid; Eicosapentaenoic Acid; Fatty Acids; Fatty Acids, Omega-3; Linoleic Acid; Myoxidae; Phospholipids; Ursidae; Hibernation
PubMed: 37294822
DOI: 10.1371/journal.pone.0285782 -
Journal of the American Heart... Jun 2023Background Previous randomized control trials showed mixed results concerning the effect of omega-3 fatty acids (n-3 FAs) on atrial fibrillation (AF). The associations...
Background Previous randomized control trials showed mixed results concerning the effect of omega-3 fatty acids (n-3 FAs) on atrial fibrillation (AF). The associations of n-3 FA blood levels with heart rhythm in patients with established AF are unknown. The goal of this study was to assess the associations of total and individual n-3 FA blood levels with AF type (paroxysmal versus nonparoxysmal), heart rate (HR), and HR variability in patients with AF. Methods and Results Total n-3 FAs, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, and alpha-linolenic acid blood levels were determined in 1969 patients with known AF from the SWISS-AF (Swiss Atrial Fibrillation cohort). Individual and total n-3 FAs were correlated with type of AF, HR, and HR variability using standard logistic and linear regression, adjusted for potential confounders. Only a mild association with nonparoxysmal AF was found with total n-3 FA (odds ratio [OR], 0.97 [95% CI, 0.89-1.05]) and docosahexaenoic acid (OR, 0.93 [95% CI, 0.82-1.06]), whereas other individual n-3 FAs showed no association with nonparoxysmal AF. Higher total n-3 FAs (estimate 0.99 [95% CI, 0.98-1.00]) and higher docosahexaenoic acid (0.99 [95% CI, 0.97-1.00]) tended to be associated with slower HR in multivariate analysis. Docosapentaenoic acid was associated with a lower HR variability triangular index (0.94 [95% CI, 0.89-0.99]). Conclusions We found no strong evidence for an association of n-3 FA blood levels with AF type, but higher total n-3 FA levels and docosahexaenoic acid might correlate with lower HR, and docosapentaenoic acid with a lower HR variability triangular index.
Topics: Humans; Atrial Fibrillation; Docosahexaenoic Acids; Follow-Up Studies; Fatty Acids, Omega-3; Eicosapentaenoic Acid; Heart Rate
PubMed: 37259986
DOI: 10.1161/JAHA.122.027646 -
Journal of Animal Science and... Sep 2022Transgenerational effects of certain nutrients such as essential fatty acids are gaining increased attention in the field of human medicine and animal sciences as a new... (Review)
Review
Transgenerational effects of certain nutrients such as essential fatty acids are gaining increased attention in the field of human medicine and animal sciences as a new tool to improve health and animal performance during perinatal life. Omega-3 (n-3) and omega-6 (n-6) fatty acids are denoted by the position of the first double bond from methyl end of the hydrocarbon chain. Alpha-linolenic acid (18:3 n-3) and linoleic acid (18:2 n-6) are essential n-3 and n-6 fatty acids and cannot be synthesized by the vertebrates including chickens. Alpha-linolenic acid and linoleic acid are the parent fatty acids of long chain (> 20-22C) n-3 and n-6 polyunsaturated fatty acids (PUFA) such as eicosapentaenoic acid (20:5 n-3, EPA), docosapentaenoic acid (22:5 n-3/or 22:5 n-6, DPA), docosahexaenoic acid (22:6 n-3, DHA) and arachidonic acid (20:4 n-6). As components of cell membrane phospholipids, PUFA serves as precursors of eicosanoids, act as ligands for membrane receptors and transcription factors that regulate gene expression and are pivotal for normal chick growth and development. Considering the role of egg lipids as the sole source of essential fatty acids to the hatchling, dietary deficiencies or inadequate in ovo supply may have repercussions in tissue PUFA incorporation, lipid metabolism, chick growth and development during pre and early post-hatch period. This review focus on studies showing how maternal dietary n-3 or n-6 fatty acids can lead to remodeling of long chain n-3 and n-6 PUFA in the hatching egg and progeny chick tissue phospholipid molecular species and its impact on chick growth and PUFA metabolism during early life.
PubMed: 36117183
DOI: 10.1186/s40104-022-00757-5 -
Arthritis Research & Therapy May 2015Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of the joints and bones. Omega-3 (ω3) fatty acid supplementation has been associated with a...
Eicosapentaenoic acid and docosapentaenoic acid monoglycerides are more potent than docosahexaenoic acid monoglyceride to resolve inflammation in a rheumatoid arthritis model.
INTRODUCTION
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of the joints and bones. Omega-3 (ω3) fatty acid supplementation has been associated with a decreased production of inflammatory cytokines and eicosanoids involved in RA pathogenesis. The aim of this study was to determine the therapeutic potential of ω3 monoglyceride (MAG-ω3) compounds in an in vivo rat model of RA induced by Complete Freund's Adjuvant (CFA).
METHOD
CFA rats were untreated or treated per os with three specific compounds, namely, MAG-docosahexaenoic acid (MAG-DHA), MAG-eicosapentaenoic acid (MAG-EPA) and MAG-docosapentaenoic acid (MAG-DPA). Morphological and histological analyses, as well as pro-inflammatory marker levels were determined following MAG-ω3 treatments.
RESULTS
Morphological and histological analyses revealed that MAG-EPA and MAG-DPA exhibited strong activity in reducing the progression and severity of arthritic disease in CFA rats. Following MAG-EPA and MAG-DPA treatments, plasma levels of the pro-inflammatory cytokines; interleukin 17A (IL-17A), IL-1β, IL-6 and tumor necrosis factor α (TNFα) were markedly lower when compared to CFA-untreated rats. Results also revealed a decreased activation of p38 mitogen-activated protein kinases (p38 MAPK) and nuclear factor-kappa B (NFκB) pathways correlated with a reduced expression of TNFα, cyclooxygenase-2 (COX-2), matrix metalloproteinase-2 (MMP-2) and MMP-9 in paw homogenates derived from MAG-EPA and MAG-DPA-treated rats. Of interest, the combined treatment of MAG-EPA and vitamin E displayed an antagonistic effect on anti-inflammatory properties of MAG-EPA in CFA rats.
CONCLUSION
Altogether, the present data suggest that MAG-EPA, without vitamin E, represents a new potential therapeutic strategy for resolving inflammation in arthritis.
Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Blotting, Western; Cyclooxygenase 2; Docosahexaenoic Acids; Eicosapentaenoic Acid; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Unsaturated; Female; Inflammation; Interleukin-17; Interleukin-1beta; Interleukin-6; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Monoglycerides; NF-kappa B; Rats, Inbred Lew; Severity of Illness Index; Tumor Necrosis Factor-alpha; p38 Mitogen-Activated Protein Kinases
PubMed: 26022389
DOI: 10.1186/s13075-015-0653-y -
Lipids in Health and Disease Apr 2007Docosahexaenoic acid (22:6n-3, DHA) and n-6 docosapentaenoic acid (22:5n-6, DPAn-6) are highly unsaturated fatty acids (HUFA, > or = 20 carbons, > or = 3 double bonds)... (Comparative Study)
Comparative Study
BACKGROUND
Docosahexaenoic acid (22:6n-3, DHA) and n-6 docosapentaenoic acid (22:5n-6, DPAn-6) are highly unsaturated fatty acids (HUFA, > or = 20 carbons, > or = 3 double bonds) that differ by a single carbon-carbon double bond at the Delta19 position. Membrane 22:6n-3 may support skeletal muscle function through optimal ion pump activity of sarcoplasmic reticulum and electron transport in the mitochondria. Typically n-3 fatty acid deficient feeding trials utilize linoleic acid (18:2n-6, LA) as a comparison group, possibly introducing a lower level of HUFA in addition to n-3 fatty acid deficiency. The use of 22:5n-6 as a dietary control is ideal for determining specific requirements for 22:6n-3 in various physiological processes. The incorporation of dietary 22:5n-6 into rat skeletal muscles has not been demonstrated previously. A one generation, artificial rearing model was utilized to supply 22:6n-3 and/or 22:5n-6 to rats from d2 after birth to adulthood. An n-3 fatty acid deficient, artificial milk with 18:2n-6 was supplemented with 22:6n-3 and/or 22:5n-6 resulting in four artificially reared (AR) dietary groups; AR-LA, AR-DHA, AR-DPAn-6, AR-DHA+DPAn-6. A dam reared group (DAM) was included as an additional control. Animals were sacrificed at 15 wks and soleus, white gastrocnemius and red gastrocnemius muscles were collected for fatty acid analyses.
RESULTS
In all muscles of the DAM group, the concentration of 22:5n-6 was significantly lower than 22:6n-3 concentrations. While 22:5n-6 was elevated in the AR-LA group and the AR-DPAn-6 group, 20:4n-6 tended to be higher in the AR-LA muscles and not in the AR-DPAn-6 muscles. The AR-DHA+DPAn-6 had a slight, but non-significant increase in 22:5n-6 content. In the red gastrocnemius of the AR-DPAn-6 group, 22:5n-6 levels (8.1 +/- 2.8 wt. %) did not reciprocally replace the 22:6n-3 levels observed in AR-DHA reared rats (12.2 +/- 2.3 wt. %) suggesting a specific preference/requirement for 22:6n-3 in red gastrocnemius.
CONCLUSION
Dietary 22:5n-6 is incorporated into skeletal muscles and appears to largely compete with 22:6n-3 for incorporation into lipids. In contrast, 18:2n-6 feeding tends to result in elevations of 20:4n-6 and restrained increases of 22:5n-6. As such, 22:5n-6 dietary comparison groups may be useful in elucidating specific requirements for 22:6n-3 to support optimal health and disease prevention.
Topics: Animals; Animals, Suckling; Dietary Supplements; Docosahexaenoic Acids; Electron Transport; Fatty Acids, Unsaturated; Female; Lipid Metabolism; Male; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Muscle, Skeletal; Pregnancy; Random Allocation; Rats; Rats, Long-Evans; Sarcoplasmic Reticulum
PubMed: 17459159
DOI: 10.1186/1476-511X-6-13 -
Frontiers in Immunology 2020Neuroinflammation plays a crucial role in the development and progression of Alzheimer's disease (AD), in which activated microglia are found to be associated with...
The Novel Omega-6 Fatty Acid Docosapentaenoic Acid Positively Modulates Brain Innate Immune Response for Resolving Neuroinflammation at Early and Late Stages of Humanized APOE-Based Alzheimer's Disease Models.
Neuroinflammation plays a crucial role in the development and progression of Alzheimer's disease (AD), in which activated microglia are found to be associated with neurodegeneration. However, there is limited evidence showing how neuroinflammation and activated microglia are directly linked to neurodegeneration . Besides, there are currently no effective anti-inflammatory drugs for AD. In this study, we report on an effective anti-inflammatory lipid, linoleic acid (LA) metabolite docosapentaenoic acid (DPAn-6) treatment of aged humanized EFAD mice with advanced AD pathology. We also report the associations of neuroinflammatory and/or activated microglial markers with neurodegeneration . First, we found that dietary LA reduced proinflammatory cytokines of IL1-β, IL-6, as well as mRNA expression of COX2 toward resolving neuroinflammation with an increase of IL-10 in adult AD models E3FAD and E4FAD mice. Brain fatty acid assays showed a five to six-fold increase in DPAn-6 by dietary LA, especially more in E4FAD mice, when compared to standard diet. Thus, we tested DPAn-6 in aged E4FAD mice. After DPAn-6 was administered to the E4FAD mice by oral gavage for three weeks, we found that DPAn-6 reduced microgliosis and mRNA expressions of inflammatory, microglial, and caspase markers. Further, DPAn-6 increased mRNA expressions of ADCYAP1, VGF, and neuronal pentraxin 2 in parallel, all of which were inversely correlated with inflammatory and microglial markers. Finally, both LA and DPAn-6 directly reduced mRNA expression of COX2 in amyloid-beta42 oligomer-challenged BV2 microglial cells. Together, these data indicated that DPAn-6 modulated neuroinflammatory responses toward resolution and improvement of neurodegeneration in the late stages of AD models.
Topics: Alzheimer Disease; Animals; Apolipoproteins E; Brain; Cytokines; Disease Models, Animal; Disease Susceptibility; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Immunity, Innate; Immunohistochemistry; Inflammation Mediators; Mice; Mice, Transgenic; Microglia; Neurodegenerative Diseases
PubMed: 33178186
DOI: 10.3389/fimmu.2020.558036 -
Acta Biomaterialia Mar 2022Polyunsaturated fatty acids (PUFAs) play an important role in the establishment and the maintenance of the skin barrier function. However, the impact of their derived...
Polyunsaturated fatty acids (PUFAs) play an important role in the establishment and the maintenance of the skin barrier function. However, the impact of their derived lipid mediators remains unclear. Skin substitutes were engineered according to the self-assembly method with a culture medium supplemented with 10 μM of both α-linolenic acid (ALA) and linoleic acid (LA). The supplementation with ALA and LA decreased testosterone absorption through a tissue-engineered reconstructed skin model, thus indicating an improved skin barrier function following supplementation. The exogenously provided fatty acids were incorporated into the phospholipid and triglyceride fractions of the skin substitutes. Indeed, the dual supplementation increased the levels of eicosapentaenoic acid (EPA) (15-fold), docosapentaenoic acid (DPA) (3-fold), and LA (1.5-fold) in the epidermal phospholipids while it increased the levels of ALA (>20-fold), DPA (3-fold) and LA (1.5-fold) in the epidermal triglycerides. The bioactive lipid mediator profile of the skin substitutes, including prostaglandins, hydroxy-fatty acids, N-acylethanolamines and monoacylglycerols, was next analyzed using liquid chromatography-tandem mass spectrometry. The lipid supplementation further modulated bioactive lipid mediator levels of the reconstructed skin substitutes, leading to a lipid mediator profile more representative of the one found in normal human skin. These findings show that an optimized supply of PUFAs via culture media is essential for the establishment of improved barrier function in vitro. STATEMENT OF SIGNIFICANCE: Supplementation of the culture medium with 10 μM of both α-linolenic acid (ALA) and linoleic acid (LA) improved the skin barrier function of a tissue-engineered skin model. The exogenously provided fatty acids were incorporated into the phospholipid and triglyceride fractions of the skin substitutes and further modulated bioactive lipid mediator levels, including prostaglandins, hydroxy-fatty acids, N-acylethanolamines and monoacylglycerols. These findings highlight the important role of ALA and LA in skin homeostasis and show that an optimized supply of polyunsaturated fatty acids via culture media is essential for the establishment of improved barrier function in vitro.
Topics: Eicosapentaenoic Acid; Humans; Linoleic Acid; Lipidomics; Skin; alpha-Linolenic Acid
PubMed: 34808417
DOI: 10.1016/j.actbio.2021.11.021 -
Journal of Oleo Science Dec 2016Docosapentaenoic acids (DPAs) are long chain polyunsaturated fatty acids that exist as two major structural isomers: n-3 DPA and n-6 DPA. n-3 DPA is found in seal meat,...
Docosapentaenoic acids (DPAs) are long chain polyunsaturated fatty acids that exist as two major structural isomers: n-3 DPA and n-6 DPA. n-3 DPA is found in seal meat, salmon and abalone, and n-6 DPA is found in several marine microbial oil. We investigated the bioconversion of n-3 and n-6 DPAs in three different human cell lines, Caco-2, HepG2, and THP-1. n-3 DPA was converted to docosahexaenoic acid only in HepG2 cells. In contrast, retro-conversion to eicosapentaenoic acid (EPA) was observed in all three cell lines. n-6 DPA was also retro-converted to arachidonic acid (AA) in Caco-2 and HepG2 cells. EPA and AA were particularly elevated in Caco-2 cells, compared to HepG2 cells. Further, the retro-conversion of n-3 DPA led to a greater increase of EPA in the phospholipid fraction than in the neutral lipid fraction.
Topics: Arachidonic Acid; Caco-2 Cells; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Unsaturated; Hep G2 Cells; Humans; Tumor Cells, Cultured
PubMed: 27829615
DOI: 10.5650/jos.ess16128