“Cell Membrane Theory of Senescence” and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications

Lipids are an essential constituent of the cell membrane of which polyunsaturated fatty acids (PUFAs) are the most important component. Activation of phospholipase A2 (PLA2) induces the release of PUFAs from the cell membrane that form precursors to both pro- and ant-inflammatory bioactive lipids that participate in several cellular processes. PUFAs GLA (gamma-linolenic acid), DGLA (dihomo-GLA), AA (arachidonic acid), EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are derived from dietary linoleic acid (LA) and alpha-linolenic acid (ALA) by the action of desaturases whose activity declines with age. Consequently, aged cells are deficient in GLA, DGLA, AA, AA, EPA and DHA and their metabolites. LA, ALA, AA, EPA and DHA can also be obtained direct from diet and their deficiency (fatty acids) may indicate malnutrition and deficiency of several minerals, trace elements and vitamins some of which are also much needed co-factors for the normal activity of desaturases. In many instances (patients) the plasma and tissue levels of GLA, DGLA, AA, EPA and DHA are low (as seen in patients with hypertension, type 2 diabetes mellitus) but they do not have deficiency of other nutrients. Hence, it is reasonable to consider that the deficiency of GLA, DGLA, AA, EPA and DHA noted in these conditions are due to the decreased activity of desaturases and elongases. PUFAs stimulate SIRT1 through protein kinase A-dependent activation of SIRT1-PGC1α complex and thus, increase rates of fatty acid oxidation and prevent lipid dysregulation associated with aging. SIRT1 activation prevents aging. Of all the SIRTs, SIRT6 is critical for intermediary metabolism and genomic stability. SIRT6-deficient mice show shortened lifespan, defects in DNA repair and have a high incidence of cancer due to oncogene activation. SIRT6 overexpression lowers LDL and triglyceride level, improves glucose tolerance, and increases lifespan of mice in addition to its anti-inflammatory effects at the transcriptional level. PUFAs and their anti-inflammatory metabolites influence the activity of SIRT6 and other SIRTs and thus, bring about their actions on metabolism, inflammation, and genome maintenance. GLA, DGLA, AA, EPA and DHA and prostaglandin E2 (PGE2), lipoxin A4 (LXA4) (pro- and anti-inflammatory metabolites of AA respectively) activate/suppress various SIRTs (SIRt1 SIRT2, SIRT3, SIRT4, SIRT5, SIRT6), PPAR-γ, PARP, p53, SREBP1, intracellular cAMP content, PKA activity and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1-α). This implies that changes in the metabolism of bioactive lipids as a result of altered activities of desaturases, COX-2 and 5-, 12-, 15-LOX (cyclo-oxygenase and lipoxygenases respectively) may have a critical role in determining cell age and development of several aging associated diseases and genomic stability and gene and oncogene activation. Thus, methods designed to maintain homeostasis of bioactive lipids (GLA, DGLA, AA, EPA, DHA, PGE2, LXA4) may arrest aging process and associated metabolic abnormalities.

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α- Linolenic Acid Modulates Phagocytosis of Extracellular Tau and Induces Microglial Migration

10.21203/rs.3.rs-30891/v1 ◽

2020 ◽

Author(s):

Smita Eknath Desale ◽

Subashchandrabose Chinnathambi

Keyword(s):

Fatty Acids ◽

Cell Membrane ◽

Linolenic Acid ◽

Dietary Fatty Acids ◽

Omega 3 Fatty Acids ◽

Omega 3 ◽

Microtubule Organizing Center ◽

Intracellular Degradation ◽

Organizing Center ◽

Anti Inflammatory

Abstract Background The seeding effect of extracellular Tau species is an emerging aspect to study the Tauopathies in Alzheimer’s disease. Tau seeds enhance the propagation of disease along with its contribution to microglia-mediated inflammation. Omega-3 fatty acids are known to exert the anti-inflammatory property to microglia by modulating cell membrane compositions. The immunomodulatory function of omega-3 fatty acids exerts anti-inflammatory properties to microglia. Owing to the imparted anti-inflammatory nature enhance phagocytosis and increased migration property has been observed in microglia. The dietary omega-3 fatty acids are found to change the lipid composition of the cell membrane that predominated many signaling cascades and by modulating specific receptor response. Thus the omega-3 fatty acids influence microglial response in Tauopathy. Methods N9 microglia cells were exposed to extracellular full-length Tau monomer and aggregates along with ALA (α- Linolenic acid) to study the internalization of exposed Tau. The degradation of internalized Tau studied with the endosomal markers Rab5 and Rab7. The final degradation step in phagocytosis has been studied with LAMP-2A as lysosomal markers. The changes in the rate of migration of microglia were assessed by wound-scratch assay along with Microtubule organizing center (MTOC) reorientation were studied after exposure of Tau and ALA as the property of highly migratory microglia. Results The increased phagocytosis of extracellular Tau monomer and aggregates has been observed upon ALA exposure to microglia cells. The intracellular degradation of internalized Tau species was targeted by early and late endosomal markers Rab5 and Rab7. The increased levels of LAMP-2A and colocalization with internalized Tau indicated the degradation via lysosome. These results indicate the degradation of internalized Tau species in the presence of ALA instead of getting accumulated in the cell. The enhanced migratory ability of microglia in the presence of ALA induces the MTOC repolarization and reduces the nuclear-centrosomal axis polarity and favorable anterior positioning of MTOC. Conclusions Tau seeds greatly contribute to the spread of disease, one way to reduce the spreading is to reduce the presence of extracellular Tau seed. Microglia could be influenced to reduce extracellular Tau seed with dietary fatty acids. Our results suggest that dietary fatty acids ALA significantly enhances phagocytosis and intracellular degradation of internalized Tau. Enhanced migration supports the phagocytosis process. Our approach provides insights into the beneficial role of ALA as an anti-inflammatory dietary supplement to treat AD.

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Gamma-linolenic and pinolenic acids exert anti-inflammatory effects in cultured human endothelial cells through their elongation products

Proceedings of The Nutrition Society ◽

10.1017/s0029665120003146 ◽

2020 ◽

Vol 79 (OCE2) ◽

Author(s):

Ella Baker ◽

Elizabeth Miles ◽

Philip Calder

Keyword(s):

Fatty Acids ◽

Endothelial Cells ◽

Linolenic Acid ◽

Inflammatory Responses ◽

Cell Surface Expression ◽

Dependent Manner ◽

Epa And Dha ◽

Ea.Hy926 Cells ◽

Anti Inflammatory ◽

Pre Treatment

AbstractIt is recommended that humans consume fatty fish twice a week to increase dietary intake of eicosapentaenoic acid (EPA) and docosapentaenoic acid (DHA) to achieve long-term health benefits. However current stocks of fish are likely insufficient to meet the needs of humans. Plant-derived polyunsaturated fatty acids (PUFAs) gamma-linolenic acid (GLA) and pinolenic acid (PIN) may provide sustainable land-based sources of bioactive fatty acids.Anti-inflammatory effects of GLA and PIN were compared to EPA and DHA in cultured EA.hy926 cells. Cells were treated with PUFAs (10, 25 and 50 μM) for 48 hours prior to stimulation with tumour necrosis factor for 24 hours. Incorporation of PUFA was measured by gas chromatography; inflammatory responses were measured by ELISA and flow cytometry.All fatty acids were incorporated into EA.hy926 cells, after 48 hours, in a dose dependent manner (10 and 50 μM). Pre-treatment with GLA and PIN (50 μM) resulted in significant increases in their elongation products, dihomo-γ-linolenic acid (DGLA) (p < 0.0001) from GLA and eicosatrienoic (ETrA) (p < 0.0001) from PIN.Pre-treatment with GLA, PIN, EPA or DHA (50 μM) had differential effects depending on fatty acid and cytokine examined. Pre-treatment of EA.hy926 cells with both GLA and PIN resulted in a lower concentration of soluble ICAM-1 (p < 0.01); however EPA and DHA showed greater reduction (p < 0.0001). MCP-1 production was significantly lower after treatment with PIN (p < 0.05), again to a lesser extent than EPA and DHA (p < 0.0001). Pre-treatment with EPA and DHA (50 μM) resulted in lower cell surface expression of ICAM-1 (p < 0.001, p < 0.0001), an effect not observed with GLA or PIN.Anti-inflammatory effects of GLA and PIN were possibly due to their elongation products, and therefore silencing of elongase 5 (ELOVL5) was explored. ELOVL5 siRNA significantly inhibited the production of DGLA and ETrA in EA.hy926 cells pre-treated with GLA and PIN (50 μM). Furthermore significant decreases in sICAM-1 and MCP-1 were not seen after pre-treatment with GLA or PIN in ELOVL5 siRNA silenced EA.hy926 cells.Plant PUFAs (GLA and PIN) demonstrate anti-inflammatory effects in this model using endothelial cells, but are less potent than EPA or DHA. Anti-inflammatory effects of GLA and PIN may be due to their elongation metabolites; DGLA and ETrA.

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Bioactive Compounds in Edible Oils and Their Role in Oxidative Stress and Inflammation

Frontiers in Physiology ◽

10.3389/fphys.2021.659551 ◽

2021 ◽

Vol 12 ◽

Author(s):

Alessandra Mazzocchi ◽

Valentina De Cosmi ◽

Patrizia Risé ◽

Gregorio Paolo Milani ◽

Stefano Turolo ◽

...

Keyword(s):

Oxidative Stress ◽

Fatty Acids ◽

Chronic Diseases ◽

Bioactive Compounds ◽

Unsaturated Fatty Acids ◽

Edible Oils ◽

Fats And Oils ◽

Bioactive Lipids ◽

Edible Fats ◽

Anti Inflammatory

Diet and inflammatory response are recognized as strictly related, and interest in exploring the potential of edible fats and oils for health and chronic diseases is emerging worldwide. Polyunsaturated fatty acids (PUFAs) present in fish oil (FO), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may be partly converted into oxygenated bioactive lipids with anti-inflammatory and/or pro-resolving activities. Moreover, the co-presence of phenolic compounds and vitamins in edible oils may prevent the development of chronic diseases by their anti-inflammatory, antioxidant, neuroprotective, and immunomodulatory activities. Finally, a high content in mono-unsaturated fatty acids may improve the serum lipid profile and decrease the alterations caused by the oxidized low-density lipoproteins and free radicals. The present review aims to highlight the role of lipids and other bioactive compounds contained in edible oils on oxidative stress and inflammation, focusing on critical and controversial issues that recently emerged, and pointing to the opposing role often played by edible oils components and their oxidized metabolites.

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α- Linoleanic acid modulates phagocytosis of extracellular Tau and induces microglial migration by actin-remodeling

10.21203/rs.3.rs-22830/v1 ◽

2020 ◽

Author(s):

Smita Eknath Desale ◽

Subashchandrabose Chinnathambi

Keyword(s):

Fatty Acids ◽

Cell Membrane ◽

Dietary Fatty Acids ◽

Omega 3 Fatty Acids ◽

Omega 3 ◽

Actin Remodeling ◽

Membrane Ruffling ◽

Intracellular Degradation ◽

Anti Inflammatory

Abstract Background Seeding effect of extracellular Tau species is an emerging aspect to study the Tauopathies in Alzheimer’s disease. Tau seeds enhance the propagation of disease along with its contribution to microglia-mediated inflammation. Omega-3 fatty acids are known to exert the anti-inflammatory property to microglia by modulating cell membrane compositions. The immunomodulatory function of omega-3 fatty acids exerts anti-inflammatory property to microglia. Owing to the imparted anti-inflammatory nature enhance phagocytosis and increased migration property has been observed in microglia. The dietary omega-3 fatty acids are found to change the lipid composition of the cell membrane that predominated many signaling cascade and by modulating specific receptor response. Thus the omega-3 fatty acids influence microglial response in Tauopathy.Method N9 microglia cells were exposed to extracellular full-length Tau monomer and aggregates along with ALA (α- Linolenic acid) to study the internalization of exposed Tau. The degradation of internalized Tau studied with the endosomal markers Rab5 and Rab7. The final degradation step in phagocytosis has been studied with LAMP-2A as lysosomal markers. The changes in the rate of migration of microglia were assessed by wound-scratch assay along with Microtubule organizing center (MTOC) reorientation were studied after exposure of Tau and ALA as the property of highly migratory microglia. The role of actin in phagocytosis and migration was observed with the study of actin structures lamellipodia, filopodia, and membrane ruffling. The formation of extensive actin branching in lamellipodia and membrane ruffling was studied with the help of ARP2/3 complex for nucleating actin network.Results The increased phagocytosis of extracellular Tau monomer and aggregates has been observed upon ALA exposure to microglia cells. The intracellular degradation of internalized Tau species was targeted by early and late endosomal markers Rab5 and Rab7. The increase levels of LAMP-2A and colocalization with internalized Tau indicated the degradation via lysosome. These results indicate the degradation of internalized Tau species in the presence of ALA instead of getting accumulated in the cell. The enhanced migratory ability of microglia in the presence of ALA induces the MTOC repolarization and reduces the nuclear-centrosomal axis polarity and favorable anterior positioning of MTOC. The increased migration also complememnted with the enhance actin remodeling through lamellipodia, filopodia and membrane ruffles formation along with Iba-1 protein. The high desnity of ARP2/3 complex at the leading ends of migratory microglia confirmed the extensive branching of actin filaments on ALA exposure.Conclusions Tau seeds greatly contributes to the spread of disease, one way to reduce the spreading is to reduce the presence of extracellular Tau seed. Microglia could be influenced to reduce extracellular Tau seed with dietary fatty acids. Our results suggest that dietary fatty acids ALA significantly enhance phagocytosis and intracellular degradation of internalized Tau. The actin dynamics and enhanced migration supports the phagocytosis process. Our approach provides the insights of beneficial role of ALA as anti-inflammatory dietary supplement to treat AD.

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Dietary α-linolenic acid and health-related outcomes: a metabolic perspective

Nutrition Research Reviews ◽

10.1079/nrr2005113 ◽

2006 ◽

Vol 19 (1) ◽

pp. 26-52 ◽

Cited By ~ 181

Author(s):

Graham C Burdge ◽

Philip C Calder

Keyword(s):

Risk Factors ◽

Fatty Acids ◽

Linolenic Acid ◽

Inflammatory Markers ◽

De Novo ◽

Cvd Risk Factors ◽

Dietary Interventions ◽

Cvd Risk ◽

Beneficial Effects ◽

Epa And Dha

α-Linolenic acid (αLNA; 18: 3n-3) is essential in the human diet, probably because it is the substrate for the synthesis of longer-chain, more unsaturatedn-3 fatty acids, principally EPA (20: 5n-3) and DHA (22: 6n-3), which confer important biophysical properties on cell membranes and so are required for tissue function. The extent to which this molecular transformation occurs in man is controversial. The present paper reviews the recent literature on the metabolism of αLNA in man, including the use of dietary αLNA in β-oxidation, recycling of carbon by fatty acid synthesisde novoand conversion to longer-chain PUFA. Sex differences in αLNA metabolism and the possible biological consequences are discussed. Increased consumption of EPA and DHA in fish oil has a number of well-characterised beneficial effects on health. The present paper also reviews the efficacy of increased αLNA consumption in increasing the concentrations of EPA and DHA in blood and cell lipid pools, and the extent to which such dietary interventions might be protective against CVD and inflammation. Although the effects on CVD risk factors and inflammatory markers are variable, where beneficial effects have been reported these are weaker than have been achieved from increasing consumption of EPA+DHA or linoleic acid. Overall, the limited capacity for conversion to longer-chainn-3 fatty acids, and the lack of efficacy in ameliorating CVD risk factors and inflammatory markers in man suggests that increased consumption of αLNA may be of little benefit in altering EPA+DHA status or in improving health outcomes compared with other dietary interventions.

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Evening Primrose (Oenothera biennis) Biological Activity Dependent on Chemical Composition

Antioxidants ◽

10.3390/antiox7080108 ◽

2018 ◽

Vol 7 (8) ◽

pp. 108 ◽

Cited By ~ 20

Author(s):

Magdalena Timoszuk ◽

Katarzyna Bielawska ◽

Elżbieta Skrzydlewska

Keyword(s):

Fatty Acids ◽

Biological Activity ◽

Chemical Composition ◽

Linolenic Acid ◽

Biologically Active ◽

Oenothera Biennis ◽

Evening Primrose ◽

Beneficial Effects ◽

Anti Inflammatory ◽

Leukotriene A4

Evening primrose (Oenothera L.) is a plant belonging to the family Onagraceae, in which the most numerous species is Oenothera biennis. Some plants belonging to the genus Oenothera L. are characterized by biological activity. Therefore, studies were conducted to determine the dependence of biological activity on the chemical composition of various parts of the evening primrose, mainly leaves, stems, and seeds. Common components of all parts of the Oenothera biennis plants are fatty acids, phenolic acids, and flavonoids. In contrast, primrose seeds also contain proteins, carbohydrates, minerals, and vitamins. Therefore, it is believed that the most interesting sources of biologically active compounds are the seeds and, above all, evening primrose seed oil. This oil contains mainly aliphatic alcohols, fatty acids, sterols, and polyphenols. Evening primrose oil (EPO) is extremely high in linoleic acid (LA) (70–74%) and γ-linolenic acid (GLA) (8–10%), which may contribute to the proper functioning of human tissues because they are precursors of anti-inflammatory eicosanoids. EPO supplementation results in an increase in plasma levels of γ-linolenic acid and its metabolite dihomo-γ-linolenic acid (DGLA). This compound is oxidized by lipoxygenase (15-LOX) to 15-hydroxyeicosatrienoic acid (15-HETrE) or, under the influence of cyclooxygenase (COX), DGLA is metabolized to series 1 prostaglandins. These compounds have anti-inflammatory and anti-proliferative properties. Furthermore, 15-HETrE blocks the conversion of arachidonic acid (AA) to leukotriene A4 (LTA4) by direct inhibition of 5-LOX. In addition, γ-linolenic acid suppresses inflammation mediators such as interleukin 1β (IL-1β), interleukin 6 (IL-6), and cytokine - tumor necrosis factor α (TNF-α). The beneficial effects of EPO have been demonstrated in the case of atopic dermatitis, psoriasis, Sjögren’s syndrome, asthma, and anti-cancer therapy.

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Abstract 13690: Association of Serum Fatty Acids With Age at the Onset of Acute Ischemic Stroke in Patients Aged 50 Years or Older

Circulation ◽

10.1161/circ.142.suppl_3.13690 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Takahisa Mori ◽

Kazuhiro Yoshioka

Keyword(s):

Fatty Acids ◽

Regression Analysis ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Multiple Regression Analysis ◽

Multiple Regression ◽

Linolenic Acid ◽

Independent Factor ◽

Epa And Dha ◽

Serum Fatty Acids

Introduction: There are few reports about the association of concentrations and proportions of serum fatty acids with age at the onset of acute ischemic stroke (AIS) in elderly patients. Hypothesis: A higher level of saturated FA (SFA) and n-6 polyunsaturated FA (PUFA) cause a younger onset of AIS, and a higher level of n-3 PUFA causes an older onset of AIS. Methods: For the retrospective cross-sectional study, we included patients aged 50 years or older who: 1) were admitted to our institution between August 2016 and July 2019 within 24 hours of AIS onset, and 2) underwent an examination of serum fatty acids. We evaluated concentrations of palmitic acid (PA) and stearic acid (SA) as SFA, oleic acid (OlA) as n-9 PUFA, linoleic acid (LiA), dihomo-gamma-linolenic acid (DGLA), arachidonic acid (AA) as n-6 PUFA on admission. We evaluated the concentration of alpha-linolenic acid (AlA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) as n-3 PUFA on admission. We evaluated the proportion of PA, SA, OlA, LiA, DGLA, AA, AlA, EPA, and DHA on admission. Furthermore, we evaluated their correlations with age at the AIS onset. Results: Three hundred sixty-six patients met our inclusion criteria. Their median average age was 75 years. Age at the onset was negatively correlated with concentrations of PA, SA, OlA, LiA, DGLA, AA, and AlA. Age at the onset was negatively correlated with the proportion of SA, OlA, and DGLA and positively correlated with the proportion of EPA and DHA. Multiple regression analysis showed that DGLA was an independent factor for the younger onset of AIS. Multiple regression analysis showed that DHA proportion was an independent factor for the older onset and that proportions of SA and DGLA were independent factors for the younger onset of AIS. Conclusions: The higher proportion of SA (SFA) and higher concentration and proportion of DGLA (n-6 PUFA) were significantly correlated with the younger onset of AIS, and the higher proportion of DHA (n-3 PUFA) was significantly correlated with the older onset of AIS.

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Polarization of Macrophages in Human Adipose Tissue is Related to the Fatty Acid Spectrum in Membrane Phospholipids

Nutrients ◽

10.3390/nu12010008 ◽

2019 ◽

Vol 12 (1) ◽

pp. 8 ◽

Cited By ~ 5

Author(s):

Rudolf Poledne ◽

Hana Malinska ◽

Hana Kubatova ◽

Jiri Fronek ◽

Filip Thieme ◽

...

Keyword(s):

Fatty Acids ◽

Adipose Tissue ◽

Fatty Acid ◽

Cell Membrane ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Human Adipose Tissue ◽

Membrane Phospholipids ◽

Anti Inflammatory ◽

Inflammatory Macrophages

Residential macrophages in adipose tissue play a pivotal role in the development of inflammation not only within this tissue, but also affect the proinflammatory status of the whole body. Data on human adipose tissue inflammation and the role of macrophages are rather scarce. We previously documented that the proportion of proinflammatory macrophages in human adipose tissue correlates closely with non-HDL cholesterol concentrations. We hypothesized that this is due to the identical influence of diet on both parameters and decided to analyze the fatty acid spectrum in cell membrane phospholipids of the same individuals as a parameter of the diet consumed. Proinflammatory and anti-inflammatory macrophages were isolated from human adipose tissue (n = 43) and determined by flow cytometry as CD14+CD16+CD36high and CD14+CD16−CD163+, respectively. The spectrum of fatty acids in phospholipids in the cell membranes of specimens of the same adipose tissue was analyzed, and the proportion of proinflammatory macrophage increased with the proportions of palmitic and palmitoleic acids. Contrariwise, these macrophages decreased with increasing alpha-linolenic acid, total n-3 fatty acids, n-3/n-6 ratio, and eicosatetraenoic acid. A mirror picture was documented for the proportion of anti-inflammatory macrophages. The dietary score, obtained using a food frequency questionnaire, documented a positive relation to proinflammatory macrophages in individuals who consumed predominantly vegetable fat and fish, and individuals who consumed diets based on animal fat without fish and nut consumption. he present data support our hypothesis that macrophage polarization in human visceral adipose tissue is related to fatty acid metabolism, cell membrane composition, and diet consumed. It is suggested that fatty acid metabolism might participate also in inflammation and the risk of developing cardiovascular disease.

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Effects of RAMEA-complexed polyunsaturated fatty acids on the response of human dendritic cells to inflammatory signals

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.10.332 ◽

2014 ◽

Vol 10 ◽

pp. 3152-3160 ◽

Cited By ~ 7

Author(s):

Éva Rajnavölgyi ◽

Renáta Laczik ◽

Viktor Kun ◽

Lajos Szente ◽

Éva Fenyvesi

Keyword(s):

Fatty Acids ◽

Dendritic Cells ◽

Cell Membrane ◽

Membrane Structure ◽

Poly I:C ◽

Cell Surface Expression ◽

Inflammatory Reactions ◽

Inflammatory Signals ◽

Anti Inflammatory

The n−3 fatty acids are not produced by mammals, although they are essential for hormone synthesis and maintenance of cell membrane structure and integrity. They have recently been shown to inhibit inflammatory reactions and also emerged as potential treatment options for inflammatory diseases, such as rheumatoid arthritis, asthma and inflammatory bowel diseases. Dendritic cells (DC) play a central role in the regulation of both innate and adaptive immunity and upon inflammatory signals they produce various soluble factors among them cytokines and chemokines that act as inflammatory or regulatory mediators. In this study we monitored the effects of α-linoleic acid, eicosapentaenoic acid and docosahexaenoic acid solubilized in a dimethyl sulfoxide (DMSO)/ethanol 1:1 mixture or as complexed by randomly methylated α-cyclodextrin (RAMEA) on the inflammatory response of human monocyte-derived dendritic cells (moDC). The use of RAMEA for enhancing aqueous solubility of n−3 fatty acids has the unambiguous advantage over applying RAMEB (the β-cyclodextrin analog), since there is no interaction with cell membrane cholesterol. In vitro differentiated moDC were left untreated or were stimulated by bacterial lipopolysaccharide and polyinosinic:polycytidylic acid, mimicking bacterial and viral infections, respectively. The response of unstimulated and activated moDC to n−3 fatty acid treatment was tested by measuring the cell surface expression of CD1a used as a phenotypic and CD83 as an activation marker of inflammatory moDC differentiation and activation by using flow cytometry. Monocyte-derived DC activation was also monitored by the secretion level of the pro- and anti-inflammatory cytokines IL-1β, TNF-α, IL-6, IL-10 and IL-12, respectively. We found that RAMEA-complexed n−3 fatty acids reduced the expression of CD1a protein in both LPS and Poly(I:C) stimulated moDC significantly, but most efficiently by eicosapentaenic acid, while no significant change in the expression of CD83 protein was observed. The production of IL-6 by LPS-activated moDC was also reduced significantly when eicosapentaenic acid was added as a RAMEA complex as compared to its DMSO-solubilized form or to the other two n−3 fatty acids either complexed or not. Based on these results n−3 fatty acids solubilized by RAMEA provide with a new tool for optimizing the anti-inflammatory effects of n−3 fatty acids exerted on human moDC and mediated through the GP120 receptor without interfering with the cell membrane structure.

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Omega-3 fatty acids and inflammatory processes: from molecules to man

Biochemical Society Transactions ◽

10.1042/bst20160474 ◽

2017 ◽

Vol 45 (5) ◽

pp. 1105-1115 ◽

Cited By ~ 272

Author(s):

Philip C. Calder

Keyword(s):

Fatty Acids ◽

Transcription Factor ◽

Arachidonic Acid ◽

Fatty Acid ◽

Phospholipid Fatty Acid ◽

Phospholipid Fatty Acid Composition ◽

Omega 3 ◽

Epa And Dha ◽

Inflammatory Processes ◽

Anti Inflammatory

Inappropriate, excessive or uncontrolled inflammation contributes to a range of human diseases. Inflammation involves a multitude of cell types, chemical mediators and interactions. The present article will describe nutritional and metabolic aspects of omega-6 (n-6) and omega-3 (n-3) fatty acids and explain the roles of bioactive members of those fatty acid families in inflammatory processes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 fatty acids found in oily fish and fish oil supplements. These fatty acids are capable of partly inhibiting many aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte–endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid and production of pro-inflammatory cytokines. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid, and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of EPA and DHA include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor κB so reducing expression of inflammatory genes and activation of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor γ. Animal experiments demonstrate benefit from EPA and DHA in a range of models of inflammatory conditions. Human trials demonstrate benefit of oral n-3 fatty acids in rheumatoid arthritis and in stabilizing advanced atherosclerotic plaques. Intravenous n-3 fatty acids may have benefits in critically ill patients through reduced inflammation. The anti-inflammatory and inflammation resolving actions of EPA, DHA and their derivatives are of clinical relevance.

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