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Ertunc ME, Konduri S, Ma Z, Pinto AFM, Donaldson CJ, Momper J, Siegel D, Saghatelian A. Acute inflammation upregulates FAHFAs in adipose tissue and in co-cultured adipocytes. J Biol Chem 2024:107972. [PMID: 39510180 DOI: 10.1016/j.jbc.2024.107972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 10/21/2024] [Accepted: 10/30/2024] [Indexed: 11/15/2024] Open
Abstract
Since the discovery of fatty acid hydroxy fatty acids (FAHFAs), significant progress has been made in understanding their regulation, biochemistry, and physiological activities. Here, we contribute to this understanding by revealing that inflammation induces the production of fatty acid hydroxy stearic acids (FAHSAs) and fatty acid hydroxyoctadecadienoic acids (FAHODEs) in white adipose tissue depots and in adipocytes co-cultured with macrophages. In LPS-induced co-culture systems, we confirm that adipose triglyceride lipase (ATGL) is required for inflammation-induced FAHFA generation and demonstrate that inflammation is necessary for producing hydroxy fatty acids. Chemically synthesized FAHODEs show anti-inflammatory activities in vivo, but only at supraphysiological concentrations. While endogenous FAHFAs are unlikely to be anti-inflammatory due to their low concentrations, conversion of pro-inflammatory hydroxy fatty acids into FAHFAs may modulate inflammation. We test this concept by showing the pro-inflammatory lipids-hydroxyeicosatetraenoic acids (HETEs) and leukotriene B4 (LTB4)-are converted into FAHFAs in cell culture, and that two LTB4-derived FAHFAs have are modestly anti- not pro-inflammatory. Further research is needed to establish whether these increased FAFHA levels have a role in inflammation or are simply markers of inflammation, but the discovery of significant increases in FAHFA upon acute inflammation advances our knowledge of FAHFAs.
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Affiliation(s)
- Meric Erikci Ertunc
- Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA.
| | - Srihari Konduri
- The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA
| | - Zhichen Ma
- The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA
| | - Antonio F M Pinto
- Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA
| | - Cynthia J Donaldson
- Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA
| | - Jeremiah Momper
- The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA
| | - Dionicio Siegel
- The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA.
| | - Alan Saghatelian
- Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA.
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Wenderoth T, Feldotto M, Hernandez J, Schäffer J, Leisengang S, Pflieger FJ, Bredehöft J, Mayer K, Kang JX, Bier J, Grimminger F, Paßlack N, Rummel C. Effects of Omega-3 Polyunsaturated Fatty Acids on the Formation of Adipokines, Cytokines, and Oxylipins in Retroperitoneal Adipose Tissue of Mice. Int J Mol Sci 2024; 25:9904. [PMID: 39337391 PMCID: PMC11432517 DOI: 10.3390/ijms25189904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/04/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
Oxylipins and specialized pro-resolving lipid mediators (SPMs) derived from polyunsaturated fatty acids (PUFAs) are mediators that coordinate an active process of inflammation resolution. While these mediators have potential as circulating biomarkers for several disease states with inflammatory components, the source of plasma oxylipins/SPMs remains a matter of debate but may involve white adipose tissue (WAT). Here, we aimed to investigate to what extent high or low omega (n)-3 PUFA enrichment affects the production of cytokines and adipokines (RT-PCR), as well as oxylipins/SPMs (liquid chromatography-tandem mass spectrometry) in the WAT of mice during lipopolysaccharide (LPS)-induced systemic inflammation (intraperitoneal injection, 2.5 mg/kg, 24 h). For this purpose, n-3 PUFA genetically enriched mice (FAT-1), which endogenously synthesize n-3 PUFAs, were compared to wild-type mice (WT) and combined with n-3 PUFA-sufficient or deficient diets. LPS-induced systemic inflammation resulted in the decreased expression of most adipokines and interleukin-6 in WAT, whereas the n-3-sufficient diet increased them compared to the deficient diet. The n-6 PUFA arachidonic acid was decreased in WAT of FAT-1 mice, while n-3 derived PUFAs (eicosapentaenoic acid, docosahexaenoic acid) and their metabolites (oxylipins/SPMs) were increased in WAT by genetic and nutritional n-3 enrichment. Several oxylipins/SPMs were increased by LPS treatment in WAT compared to PBS-treated controls in genetically n-3 enriched FAT-1 mice. Overall, we show that WAT may significantly contribute to circulating oxylipin production. Moreover, n-3-sufficient or n-3-deficient diets alter adipokine production. The precise interplay between cytokines, adipokines, and oxylipins remains to be further investigated.
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Affiliation(s)
- Tatjana Wenderoth
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University, 35392 Giessen, Germany; (T.W.); (M.F.); (J.H.); (J.S.); (S.L.); (F.J.P.); (J.B.)
| | - Martin Feldotto
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University, 35392 Giessen, Germany; (T.W.); (M.F.); (J.H.); (J.S.); (S.L.); (F.J.P.); (J.B.)
| | - Jessica Hernandez
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University, 35392 Giessen, Germany; (T.W.); (M.F.); (J.H.); (J.S.); (S.L.); (F.J.P.); (J.B.)
| | - Julia Schäffer
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University, 35392 Giessen, Germany; (T.W.); (M.F.); (J.H.); (J.S.); (S.L.); (F.J.P.); (J.B.)
| | - Stephan Leisengang
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University, 35392 Giessen, Germany; (T.W.); (M.F.); (J.H.); (J.S.); (S.L.); (F.J.P.); (J.B.)
- Center for Mind Brain and Behavior (CMMB), Universities Giessen and Marburg, 34032 Marburg, Germany
- Translational Neuroscience Network Giessen (TNNG), Justus Liebig University, 35392 Giessen, Germany
| | - Fabian Johannes Pflieger
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University, 35392 Giessen, Germany; (T.W.); (M.F.); (J.H.); (J.S.); (S.L.); (F.J.P.); (J.B.)
| | - Janne Bredehöft
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University, 35392 Giessen, Germany; (T.W.); (M.F.); (J.H.); (J.S.); (S.L.); (F.J.P.); (J.B.)
| | - Konstantin Mayer
- Department of Internal Medicine, Justus Liebig University, 35392 Giessen, Germany;
| | - Jing X. Kang
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical, Charlestown, MA 02129, USA;
| | - Jens Bier
- Cardio-Pulmonary Institute, Justus Liebig University, 35392 Giessen, Germany; (J.B.); (F.G.)
- Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), 35392 Giessen, Germany
| | - Friedrich Grimminger
- Cardio-Pulmonary Institute, Justus Liebig University, 35392 Giessen, Germany; (J.B.); (F.G.)
- Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), 35392 Giessen, Germany
| | - Nadine Paßlack
- Small Animal Clinic, Internal Medicine and Department of Veterinary Clinical Sciences, Justus Liebig University, 35392 Giessen, Germany;
| | - Christoph Rummel
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University, 35392 Giessen, Germany; (T.W.); (M.F.); (J.H.); (J.S.); (S.L.); (F.J.P.); (J.B.)
- Center for Mind Brain and Behavior (CMMB), Universities Giessen and Marburg, 34032 Marburg, Germany
- Translational Neuroscience Network Giessen (TNNG), Justus Liebig University, 35392 Giessen, Germany
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Li S, Jing M, Mohamed N, Rey-Dubois C, Zhao S, Aukema HM, House JD. The Effect of Increasing Concentrations of Omega-3 Fatty Acids from either Flaxseed Oil or Preformed Docosahexaenoic Acid on Fatty Acid Composition, Plasma Oxylipin, and Immune Response of Laying Hens. J Nutr 2023; 153:2105-2116. [PMID: 37187351 DOI: 10.1016/j.tjnut.2023.05.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 04/28/2023] [Accepted: 05/11/2023] [Indexed: 05/17/2023] Open
Abstract
BACKGROUND There is a lack of nutrition guidelines for the feeding of omega-3 polyunsaturated fatty acids (PUFA) to laying hens. Knowledge as to whether the type and concentrations of α-linolenic acid (ALA) and/or docosahexaenoic acid (DHA) in the diet can make a difference to the birds' immune responses when subjected to a lipopolysaccharide (LPS) challenge is limited. OBJECTIVES The study was designed to determine the potential nutritional and health benefits to laying hens when receiving dietary omega-3 PUFA from either ALA or DHA. METHODS A total of 80 Lohmann LSL-Classic (white egg layer, 20 wk old) were randomly assigned to 1 of 8 treatment diets (10 hens/treatment), provided 0.2%, 0.4%, 0.6%, or 0.8% of total dietary omega-3 PUFA, provided as either ALA-rich flaxseed oil or DHA-enriched algal biomass. After an 8-wk feeding period, the birds were challenged with Escherichia coli-derived LPS (8 mg/kg; i.v. injection), with terminal sample collection 4 h after challenge. Egg yolk, plasma, liver, and spleen samples were collected for subsequent analyses. RESULTS Increasing dietary omega-3 supplementation yielded predictable responses in egg yolk, plasma, and liver fatty acid concentrations. Dietary intake of ALA contributed mainly to ALA-derived oxylipins. Meanwhile, eicosapentaenoic acid- and DHA-derived oxylipins were primarily influenced by DHA dietary intake. LPS increased the concentrations of almost all the omega-6 PUFA-, ALA-, and DHA-derived oxylipins in plasma and decreased hepatic mRNA expression of COX-2 and 5-LOX (P < 0.001) involved in the biosynthesis of oxylipins. LPS also increased mRNA expression of proinflammatory cytokine IFN-γ and receptor TLR-4 (P < 0.001) in the spleen. CONCLUSIONS These results revealed that dietary intake of ALA and DHA had unique impacts on fatty acid deposition and their derived oxylipins and inflammatory responses under the administration of LPS in laying hens.
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Affiliation(s)
- Shengnan Li
- Department of Animal Science, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Mingyan Jing
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Neijat Mohamed
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Cameron Rey-Dubois
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Shusheng Zhao
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Harold M Aukema
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Research Centre, Winnipeg, Manitoba, Canada
| | - James D House
- Department of Animal Science, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Research Centre, Winnipeg, Manitoba, Canada; Richardson Centre for Food Technology and Research, University of Manitoba, Winnipeg, Manitoba, Canada.
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Witkamp RF, de Bus I, Albada B, Balvers MGJ. Analysis of Omega-3 Fatty Acid-Derived N-Acylethanolamines in Biological Matrices. Methods Mol Biol 2023; 2576:49-66. [PMID: 36152177 DOI: 10.1007/978-1-0716-2728-0_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
The adequate quantification of endocannabinoids and related N-acylethanolamines can be complex due to their low endogenous levels, structural diversity, and metabolism. Therefore, advanced analytical approaches, involving LC-MS, are required to quantify these molecules in plasma, tissues, and other matrices. It has been shown that endocannabinoid congeners synthesized from n-3 poly-unsaturated fatty acids (n-3 PUFAs), such as docosahexaenoylethanolamide (DHEA) and eicosapentaenoylethanolamide (EPEA), have interesting immunomodulatory and tumor-inhibiting properties. Recent work has shown that DHEA and EPEA can be further enzymatically metabolized by cyclo-oxygenase 2 (COX-2), forming oxygenated metabolites. Here, an LC-MS-based method for the quantification of the n-3 PUFA-derived endocannabinoid congeners DHEA and EPEA is described, which is also suited to measure a wider spectrum of endocannabinoids. The chapter contains a step-by-step protocol for the analysis of (n-3) endocannabinoids in plasma, including sample collection and solid phase extraction, LC-MS analysis, and data processing. In addition, protocol modifications are provided to allow quantification of n-3 PUFA-derived endocannabinoids and their COX-2 metabolites in tissues and cell culture media. Finally, conditions that alter endocannabinoid concentrations are briefly discussed.
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Affiliation(s)
- Renger F Witkamp
- Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
| | - Ian de Bus
- Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
- Laboratory of Organic Chemistry, Wageningen University, Wageningen, The Netherlands
| | - Bauke Albada
- Laboratory of Organic Chemistry, Wageningen University, Wageningen, The Netherlands
| | - Michiel G J Balvers
- Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands.
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Park Y, Watkins BA. Dietary PUFAs and Exercise Dynamic Actions on Endocannabinoids in Brain: Consequences for Neural Plasticity and Neuroinflammation. Adv Nutr 2022; 13:1989-2001. [PMID: 35675221 PMCID: PMC9526838 DOI: 10.1093/advances/nmac064] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 10/15/2021] [Accepted: 06/02/2022] [Indexed: 01/28/2023] Open
Abstract
The brain and peripheral nervous system provide oversight to muscle physiology and metabolism. Muscle is the largest organ in the body and critical for glucose sensitivity, prevention of diabetes, and control of obesity. The central nervous system produces endocannabinoids (eCBs) that play a role in brain neurobiology, such as inflammation and pain. Interestingly, studies in humans and rodents show that a moderate duration of exercise increases eCBs in the brain and blood and influences cannabinoid receptors. Cannabinoid actions in the nervous system have advanced our understanding of pain, well-being, and disease. Nutrition is an important aspect of brain and eCB physiology because eCBs are biosynthesized from PUFAs. The primary eCB metabolites are derived from arachidonic acid, a 20:4n-6 (ω-6) PUFA, and the n-3 (ω-3) PUFAs, EPA and DHA. The eCBs bind to cannabinoid receptors CB1 and CB2 to exert a wide range of activities, such as stimulating appetite, influencing energy metabolism, supporting the immune system, and facilitating neuroplasticity. A diet containing different essential n-6 and n-3 PUFAs will dominate the formation of specific eCBs, and subsequently their actions as ligands for CB1 and CB2. The eCBs also function as substrates for cyclooxygenase enzymes, including potential substrates for the oxylipins (OxLs), which can be proinflammatory. Together, the eCBs and OxLs act as modulators of neuroinflammation. Thus, dietary PUFAs have implications for exercise responses via synthesis of eCBs and their effects on neuroinflammation. Neurotrophins also participate in interactions between diet and the eCBs, specifically brain-derived neurotrophic factor (BDNF). BDNF supports neuroplasticity in cooperation with the endocannabinoid system (ECS). This review will describe the role of PUFAs in eCB biosynthesis, discuss the ECS and OxLs in neuroinflammation, highlight the evidence for exercise effects on eCBs, and describe eCB and BDNF actions on neuroplasticity.
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de Bus I, van Krimpen S, Hooiveld GJ, Boekschoten MV, Poland M, Witkamp RF, Albada B, Balvers MGJ. Immunomodulating effects of 13- and 16-hydroxylated docosahexaenoyl ethanolamide in LPS stimulated RAW264.7 macrophages. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1866:158908. [PMID: 33610761 DOI: 10.1016/j.bbalip.2021.158908] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 01/23/2021] [Accepted: 02/15/2021] [Indexed: 12/12/2022]
Abstract
Docosahexaenoyl ethanolamide (DHEA), the ethanolamine conjugate of the n-3 long chain polyunsaturated fatty acid docosahexaenoic acid, is endogenously present in the human circulation and in tissues. Its immunomodulating properties have been (partly) attributed to an interaction with the cyclooxygenase-2 (COX-2) enzyme. Recently, we discovered that COX-2 converts DHEA into two oxygenated metabolites, 13- and 16-hydroxylated-DHEA (13- and 16-HDHEA, respectively). It remained unclear whether these oxygenated metabolites also display immunomodulating properties like their parent DHEA. In the current study we investigated the immunomodulating properties of 13- and 16-HDHEA in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The compounds reduced production of tumor necrosis factor alpha (TNFα), interleukin (IL)-1β and IL-1Ra, but did not affect nitric oxide (NO) and IL-6 release. Transcriptome analysis showed that the compounds inhibited the LPS-mediated induction of pro-inflammatory genes (InhbA, Ifit1) and suggested potential inhibition of regulators such as toll-like receptor 4 (TLR4), MyD88, and interferon regulatory factor 3 (IRF3), whereas anti-inflammatory genes (SerpinB2) and potential regulators IL-10, sirtuin 1 (Sirt-1), fluticasone propionate were induced. Additionally, transcriptome analysis of 13-HDHEA suggests a potential anti-angiogenic role. In contrast to the known oxylipin-lowering effects of DHEA, liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analyses revealed that 13- and 16-HDHEA did not affect oxylipin formation. Overall, the anti-inflammatory effects of 13-HDHEA and 16-HDHEA are less pronounced compared to their parent molecule DHEA. Therefore, we propose that COX-2 metabolism of DHEA acts as a regulatory mechanism to limit the anti-inflammatory properties of DHEA.
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Affiliation(s)
- Ian de Bus
- Division of Human Nutrition and Health, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands; Laboratory of Organic Chemistry, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands
| | - Sandra van Krimpen
- Division of Human Nutrition and Health, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands
| | - Guido J Hooiveld
- Division of Human Nutrition and Health, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands
| | - Mark V Boekschoten
- Division of Human Nutrition and Health, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands
| | - Mieke Poland
- Division of Human Nutrition and Health, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands
| | - Renger F Witkamp
- Division of Human Nutrition and Health, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands
| | - Bauke Albada
- Laboratory of Organic Chemistry, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands.
| | - Michiel G J Balvers
- Division of Human Nutrition and Health, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands.
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Endocannabinoid System and Its Regulation by Polyunsaturated Fatty Acids and Full Spectrum Hemp Oils. Int J Mol Sci 2021; 22:ijms22115479. [PMID: 34067450 PMCID: PMC8196941 DOI: 10.3390/ijms22115479] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/13/2021] [Accepted: 05/14/2021] [Indexed: 12/17/2022] Open
Abstract
The endocannabinoid system (ECS) consists of endogenous cannabinoids, their receptors, and metabolic enzymes that play a critical homeostatic role in modulating polyunsaturated omega fatty acid (PUFA) signaling to maintain a balanced inflammatory and redox state. Whole food-based diets and dietary interventions linked to PUFAs of animal (fish, calamari, krill) or plant (hemp, flax, walnut, algae) origin, as well as full-spectrum hemp oils, are increasingly used to support the ECS tone, promote healthy metabolism, improve risk factors associated with cardiovascular disorders, encourage brain health and emotional well-being, and ameliorate inflammation. While hemp cannabinoids of THC and CBD groups show distinct but complementary actions through a variety of cannabinoid (CB1 and CB2), adenosine (A2A), and vanilloid (TRPV1) receptors, they also modulate PUFA metabolism within a wide variety of specialized lipid mediators that promote or resolve inflammation and oxidative stress. Clinical evidence reviewed in this study links PUFAs and cannabinoids to changes in ECS tone, immune function, metabolic and oxidative stress adaptation, and overall maintenance of a well-balanced systemic function of the body. Understanding how the body coordinates signals from the exogenous and endogenous ECS modulators is critical for discerning the underlying molecular mechanisms of the ECS tone in healthy and disease states. Nutritional and lifestyle interventions represent promising approaches to address chronic metabolic and inflammatory disorders that may overlap in the population at risk. Further investigation and validation of dietary interventions that modulate the ECS are required in order to devise clinically successful second-generation management strategies.
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Activity of sEH and Oxidant Status during Systemic Bovine Coliform Mastitis. Antioxidants (Basel) 2021; 10:antiox10050812. [PMID: 34065244 PMCID: PMC8161397 DOI: 10.3390/antiox10050812] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/14/2021] [Accepted: 05/15/2021] [Indexed: 12/31/2022] Open
Abstract
Bovine coliform mastitis presents treatment challenges because of systemic inflammation and oxidative stress. Soluble epoxide hydrolase (sEH) is a promising therapeutic target in conditions characterized by inflammation and oxidative stress but has not been evaluated in cattle. We compared sEH activity and oxidant status in healthy Holstein dairy cows to those with systemic coliform mastitis (n = 5/group) using complementary approaches. First, the activity of sEH on [3H]-trans-diphenyl-propene oxide (tDPPO) was assessed ex vivo using tissue homogenates (mammary, liver, and kidney). Second, the concentrations of sEH substrates and metabolites in plasma, milk, and urine were determined as an index of in vivo sEH activity. Oxidant status was assessed in serum and milk. Data were analyzed by non-parametric methods. Metabolism of tDPPO was greater in mammary tissues from cows with coliform mastitis compared to controls. In contrast, ratios of sEH substrates and metabolites predicted lower sEH activity in cows with coliform mastitis than controls. Milk oxidant status showed greater prooxidant levels in coliform mastitis cows. Cows with coliform mastitis exhibit increased sEH activity in mammary tissue; at the same time, milk oxidant status is increased. Future studies should characterize sEH activity and oxidant status patterns and explore therapies targeting sEH during coliform mastitis.
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Dasilva G, Lois S, Méndez L, Miralles-Pérez B, Romeu M, Ramos-Romero S, Torres JL, Medina I. Fish Oil Improves Pathway-Oriented Profiling of Lipid Mediators for Maintaining Metabolic Homeostasis in Adipose Tissue of Prediabetic Rats. Front Immunol 2021; 12:608875. [PMID: 33968013 PMCID: PMC8097180 DOI: 10.3389/fimmu.2021.608875] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 03/31/2021] [Indexed: 12/12/2022] Open
Abstract
Adipose tissue is now recognized as an active organ with an important homeostatic function in glucose and lipid metabolism and the development of insulin resistance. The present research investigates the role of lipid mediators and lipid profiling for controlling inflammation and the metabolic normal function of white adipose tissue from rats suffering from diet-induced prediabetes. Additionally, the contribution to the adipose lipidome induced by the consumption of marine ω-3 PUFAs as potential regulators of inflammation is addressed. For that, the effects on the inflammatory response triggered by high-fat high-sucrose (HFHS) diets were studied in male Sprague-Dawley rats. Using SPE-LC-MS/MS-based metabolo-lipidomics, a range of eicosanoids, docosanoids and specialized pro-resolving mediators (SPMs) were measured in white adipose tissue. The inflammatory response occurring in prediabetic adipose tissue was associated with the decomposition of ARA epoxides to ARA-dihydroxides, the reduction of oxo-derivatives and the formation of prostaglandins (PGs). In an attempt to control the inflammatory response initiated, LOX and non-enzymatic oxidation shifted toward the production of the less pro-inflammatory EPA and DHA metabolites rather than the high pro-inflammatory ARA hydroxides. Additionally, the change in LOX activity induced the production of intermediate hydroxides precursors of SPMs as protectins (PDs), resolvins (Rvs) and maresins (MaRs). This compensatory mechanism to achieve the restoration of tissue homeostasis was significantly strengthened through supplementation with fish oils. Increasing proportions of ω-3 PUFAs in adipose tissue significantly stimulated the formation of DHA-epoxides by cytochrome P450, the production of non-enzymatic EPA-metabolites and prompted the activity of 12LOX. Finally, protectin PDX was significantly reduced in the adipose tissue of prediabetic rats and highly enhanced through ω-3 PUFAs supplementation. Taken together, these actively coordinated modifications constitute key mechanisms to restore adipose tissue homeostasis with an important role of lipid mediators. This compensatory mechanism is reinforced through the supplementation of the diet with fish oils with high and balanced contents of EPA and DHA. The study highlights new insides on the targets for effective treatment of incipient diet-induced diabetes and the mechanism underlying the potential anti-inflammatory action of marine lipids.
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Affiliation(s)
- Gabriel Dasilva
- Food Science Department, Instituto de Investigaciones Marinas (IIM-CSIC), Vigo, Spain
| | - Salomé Lois
- Food Science Department, Instituto de Investigaciones Marinas (IIM-CSIC), Vigo, Spain
| | - Lucía Méndez
- Food Science Department, Instituto de Investigaciones Marinas (IIM-CSIC), Vigo, Spain
| | - Bernat Miralles-Pérez
- Unitat de Farmacologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Spain
| | - Marta Romeu
- Unitat de Farmacologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Spain
| | - Sara Ramos-Romero
- Biological Chemistry Department, Instituto de Química Avanzada de Catalunya (IQAC-CSIC), Barcelona, Spain
| | - Josep L Torres
- Biological Chemistry Department, Instituto de Química Avanzada de Catalunya (IQAC-CSIC), Barcelona, Spain
| | - Isabel Medina
- Food Science Department, Instituto de Investigaciones Marinas (IIM-CSIC), Vigo, Spain
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Fish Hydrolysate Supplementation Containing n-3 Long Chain Polyunsaturated Fatty Acids and Peptides Prevents LPS-Induced Neuroinflammation. Nutrients 2021; 13:nu13030824. [PMID: 33801489 PMCID: PMC7998148 DOI: 10.3390/nu13030824] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/18/2021] [Accepted: 02/26/2021] [Indexed: 12/11/2022] Open
Abstract
Neuroinflammation constitutes a normal part of the brain immune response orchestrated by microglial cells. However, a sustained and uncontrolled production of proinflammatory factors together with microglial activation contribute to the onset of a chronic low-grade inflammation, leading to neuronal damage and cognitive as well as behavioral impairments. Hence, limiting brain inflammatory response and improving the resolution of inflammation could be particularly of interest to prevent these alterations. Dietary n-3 long chain polyunsaturated fatty acids (LC-PUFAs) and low molecular weight peptides are good candidates because of their immunomodulatory and proresolutive properties. These compounds are present in a fish hydrolysate derived from marine-derived byproducts. In this study, we compared the effect of an 18-day supplementation with this fish hydrolysate to a supplementation with docosahexaenoic acid (DHA) on lipopolysaccharide (LPS)-induced inflammation in mice. In response to peripherally injected LPS, the fish hydrolysate supplementation decreased the hippocampal mRNA expression of the proinflammatory cytokines IL-6 (p < 0.001), IL-1β (p = 0.0008) and TNF-α (p < 0.0001), whereas the DHA supplementation reduced only the expression of IL-6 (p = 0.004). This decline in proinflammatory cytokine expressions was associated with an increase in the protein expression of IκB (p = 0.014 and p = 0.0054 as compared to the DHA supplementation and control groups, respectively) and to a modulation of microglial activation markers in the hippocampus. The beneficial effects of the fish hydrolysate could be due in part to the switch of the hippocampal oxylipin profile towards a more anti-inflammatory profile as compared to the DHA supplementation. Thus, the valorization of fish byproducts seems very attractive to prevent and counteract neuroinflammation.
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11
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Endocannabinoids and aging-Inflammation, neuroplasticity, mood and pain. VITAMINS AND HORMONES 2021; 115:129-172. [PMID: 33706946 DOI: 10.1016/bs.vh.2020.12.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Aging is associated with changes in hormones, slowing of metabolism, diminished physiological processes, chronic inflammation and high exposure to oxidative stress factors, generally described as the biological cost of living. Lifestyle interventions of diet and exercise can improve the quality of life during aging and lower diet-related chronic disease. The endocannabinoid system (ECS) has important effects on systemic metabolism and physiological systems, including the central and peripheral nervous systems. Exercise can reduce the loss of muscle mass and improve strength, and increase the levels of endocannabinoids (eCB) in brain and blood. Although the ECS exerts controls on multiple systems throughout life it affords benefits to natural aging. The eCB are synthesized from polyunsaturated fatty acids (PUFA) and the primary ones are produced from arachidonic acid (n-6 PUFA) and others from the n-3 PUFA, namely eicosapentaenoic and docosahexaenoic acids. The eCB ligands bind to their receptors, CB1 and CB2, with effects on appetite stimulation, metabolism, immune functions, and brain physiology and neuroplasticity. Dietary families of PUFA are a primary factor that can influence the types and levels of eCB and as a consequence, the downstream actions when the ligands bind to their receptors. Furthermore, the association of eCB with the synthesis of oxylipins (OxL) is a connection between the physiological actions of eCB and the lipid derived immunological OxL mediators of inflammation. OxL are ubiquitous and influence neuroinflammation and inflammatory processes. The emerging actions of eCB on neuroplasticity, well-being and pain are important to aging. Herein, we present information about the ECS and its components, how exercise and diet affects specific eCB, their role in neuroplasticity, neuroinflammation, pain, mood, and relationship to OxL. Poor nutrition status and low nutrient intakes observed with many elderly are reasons to examine the role of dietary PUFA actions on the ECS to improve health.
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12
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Reinicke M, Dorow J, Bischof K, Leyh J, Bechmann I, Ceglarek U. Tissue pretreatment for LC-MS/MS analysis of PUFA and eicosanoid distribution in mouse brain and liver. Anal Bioanal Chem 2020; 412:2211-2223. [PMID: 31865417 PMCID: PMC7118053 DOI: 10.1007/s00216-019-02170-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 09/16/2019] [Accepted: 09/24/2019] [Indexed: 12/20/2022]
Abstract
Polyunsaturated fatty acids (PUFAs) and eicosanoids are important mediators of inflammation. The functional role of eicosanoids in metabolic-syndrome-related diseases has been extensively studied. However, their role in neuroinflammation and the development of neurodegenerative diseases is still unclear. The aim of this study was the development of a sample pretreatment protocol for the simultaneous analysis of PUFAs and eicosanoids in mouse liver and brain. Liver and brain samples of male wild-type C57BL/6J mice (11-122 mg) were used to investigate conditions for tissue rinsing, homogenization, extraction, and storage. A targeted liquid chromatography-negative electrospray ionization tandem mass spectrometry method was applied to quantify 7 PUFAs and 94 eicosanoids. The final pretreatment protocol consisted of a 5-min homogenization step by sonication in 650 μL n-hexane/2-propanol (60:40 v/v) containing 2,6-di-tert-butyl-4-methylphenol at 50 μg/mL. Homogenates representing 1 mg tissue were extracted in a single step with n-hexane/2-propanol (60:40 v/v) containing 0.1% formic acid. Autoxidation was prevented by addition of 2,6-di-tert-butyl-4-methylphenol at 50 μg/mL and keeping the samples at 4 °C during sample preparation. Extracts were dried under nitrogen and reconstituted in liquid chromatography eluent before analysis. Recovery was determined to range from 45% to 149% for both liver and brain tissue. Within-run and between-run variability ranged between 7% and 18% for PUFAs and between 1% and 24% for eicosanoids. In liver, 7 PUFAs and 15 eicosanoids were quantified; in brain, 6 PUFAs and 21 eicosanoids had significant differences within the brain substructures. In conclusion, a robust and reproducible sample preparation protocol for the multiplexed analysis of PUFAs and eicosanoids by liquid chromatography-tandem mass spectrometry in liver and discrete brain substructures was developed.
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Affiliation(s)
- Madlen Reinicke
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig University, Liebigstr. 27, 04103, Leipzig, Germany.
| | - Juliane Dorow
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig University, Liebigstr. 27, 04103, Leipzig, Germany
| | - Karoline Bischof
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig University, Liebigstr. 27, 04103, Leipzig, Germany
| | - Judith Leyh
- Institute of Anatomy, Leipzig University, Liebigstr. 13, 04103, Leipzig, Germany
| | - Ingo Bechmann
- Institute of Anatomy, Leipzig University, Liebigstr. 13, 04103, Leipzig, Germany
| | - Uta Ceglarek
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig University, Liebigstr. 27, 04103, Leipzig, Germany
- LIFE - Leipzig Research Center for Civilization Diseases, Leipzig University, Philipp-Rosenthal-Str. 27, 04103, Leipzig, Germany
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13
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Yang B, Lin L, Bazinet RP, Chien YC, Chang JPC, Satyanarayanan SK, Su H, Su KP. Clinical Efficacy and Biological Regulations of ω-3 PUFA-Derived Endocannabinoids in Major Depressive Disorder. PSYCHOTHERAPY AND PSYCHOSOMATICS 2020; 88:215-224. [PMID: 31269506 DOI: 10.1159/000501158] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 05/24/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND Endocannabinoids (ECs) are one type of bioactive endogenous neuroinflammatory mediator derived from polyunsaturated fatty acids (PUFAs), which may regulate the emotional processes. Here, we assessed the effect of ω-3 PUFAs on EC levels, which may be the novel targets for the ω-3 PUFAs' antidepressive effects. METHODS We conducted a 12-week double-blind, nonplacebo, randomized controlled trial. Eighty-eight major depressive disorder (MDD) participants were randomly assigned to receive eicosapentaenoic acid (EPA, 3.0 g/day), docosahexaenoic acid (DHA, 1.4 g/day), or a combination of EPA (1.5 g/d) and DHA (0.7 g/day). Eighty-five participants completed the trial, and their clinical remission and plasma PUFA-derived EC levels (pmol/mL) were measured. RESULTS The cumulative rates of clinical remission were significantly higher in the EPA and EPA + DHA groups than the DHA group (51.85 and 53.84 vs. 34.37%; p =0.027 and p =0.024, respectively). EPA and EPA + DHA treatments increased the eicosapentaenoylethanolamide (EPEA) levels compared to DHA treatment (0.33 ± 0.18 and 0.35 ± 0.24 vs. 0.08 ± 0.12; p =0.002 and p =0.001, respectively), while EPA + DHA treatment increased the docosahexaenoylethanolamide levels more than EPA treatment (1.34 ± 2.09 vs. 0.01 ± 1.79; p =0.006). Plasma EPEA levels were positively correlated with rates of clinical remission (hazard ratio: 1.60, 95% confidence interval: 1.08-2.39). CONCLUSIONS Treatments enriched with EPA increased plasma EPEA levels, which was positively associated with clinical remission. This finding may suggest that levels of plasma EPEA play a potential novel endogenous therapeutic target in MDD.
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Affiliation(s)
- Bo Yang
- Institute of Lipids Medicine and School of Public Health, Wenzhou Medical University, Wenzhou, China.,Department of Psychiatry and Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan
| | - Lin Lin
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Richard P Bazinet
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Yu-Chuan Chien
- Department of Psychiatry and Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan
| | - Jane Pei-Chen Chang
- Department of Psychiatry and Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan
| | - Senthil Kumaran Satyanarayanan
- Department of Psychiatry and Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan.,State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Huanxing Su
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Kuan-Pin Su
- Institute of Lipids Medicine and School of Public Health, Wenzhou Medical University, Wenzhou, China, .,Department of Psychiatry and Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan, .,College of Medicine, China Medical University, Taichung, Taiwan,
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14
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Mavangira V, Brown J, Gandy JC, Sordillo LM. 20-hydroxyeicosatetraenoic acid alters endothelial cell barrier integrity independent of oxidative stress and cell death. Prostaglandins Other Lipid Mediat 2020; 149:106425. [PMID: 32032703 DOI: 10.1016/j.prostaglandins.2020.106425] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 01/13/2020] [Accepted: 01/31/2020] [Indexed: 12/18/2022]
Abstract
Unregulated inflammation during bovine mastitis is characterized by severe mammary tissue damage with systemic involvement. Vascular dysfunction underlies tissue pathology because of concurrent oxidative stress mediated by several inflammatory mediators. We recently demonstrated increased production of 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P450-derived (CYP) oxylipid that correlated with oxidative stress during severe bovine coliform mastitis. The hypothesis for this study was that 20-HETE-induced oxidative stress disrupts barrier function of endothelial cells. Primary endothelial cells from the bovine aorta were utilized to investigate the effects of 20-HETE on barrier integrity in an in-vitro model of oxidative stress. The effects of various antioxidants on modulating the 20-HETE barrier integrity effects also were investigated. Our results showed that 20-HETE decreased endothelial barrier integrity, which was associated with increased reactive metabolite production and decreased total glutathione. The antioxidant, vitamin E, partially delayed the loss of endothelial resistance upon exposure to 20-HETE but did not prevent complete loss of barrier integrity. The decrease in barrier resistance due to 20-HETE was neither associated with oxidative stress as assessed by oxidative protein or lipid damage nor endothelial cell apoptosis; however, selenium supplementation conferred resistance to loss of barrier integrity suggesting a role for shifts in redox status. Specific mechanisms by which 20-HETE alters vascular barrier integrity require further investigation to identify targets for therapy during inflammatory conditions with enhanced CYP450 activity.
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Affiliation(s)
- Vengai Mavangira
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing 48824 United States
| | - Jennifer Brown
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing 48824 United States
| | - Jeffery C Gandy
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing 48824 United States
| | - Lorraine M Sordillo
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing 48824 United States.
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15
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Gladine C, Ostermann AI, Newman JW, Schebb NH. MS-based targeted metabolomics of eicosanoids and other oxylipins: Analytical and inter-individual variabilities. Free Radic Biol Med 2019; 144:72-89. [PMID: 31085232 DOI: 10.1016/j.freeradbiomed.2019.05.012] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/19/2019] [Accepted: 05/10/2019] [Indexed: 02/07/2023]
Abstract
Oxylipins, including the well-known eicosanoids, are potent lipid mediators involved in numerous physiological and pathological processes. Therefore, their quantitative profiling has gained a lot of attention during the last years notably in the active field of health biomarker discovery. Oxylipins include hundreds of structurally and stereochemically distinct lipid species which today are most commonly analyzed by (ultra) high performance liquid chromatography-mass spectrometry based ((U)HPLC-MS) methods. To maximize the utility of oxylipin profiling in clinical research, it is crucial to understand and assess the factors contributing to the analytical and biological variability of oxylipin profiles in humans. In this review, these factors and their impacts are summarized and discussed, providing a framework for recommendations expected to enhance the interlaboratory comparability and biological interpretation of oxylipin profiling in clinical research.
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Affiliation(s)
- Cécile Gladine
- Université Clermont Auvergne, INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, Clermont-Ferrand, France.
| | - Annika I Ostermann
- Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, Gaußstraße 20, University of Wuppertal, 42119, Wuppertal, Germany
| | - John W Newman
- United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA, USA; University of California Davis, Department of Nutrition, Davis, CA, USA
| | - Nils Helge Schebb
- Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, Gaußstraße 20, University of Wuppertal, 42119, Wuppertal, Germany
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16
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Dasilva G, Medina I. Lipidomic methodologies for biomarkers of chronic inflammation in nutritional research: ω-3 and ω-6 lipid mediators. Free Radic Biol Med 2019; 144:90-109. [PMID: 30902758 DOI: 10.1016/j.freeradbiomed.2019.03.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 02/20/2019] [Accepted: 03/13/2019] [Indexed: 02/06/2023]
Abstract
The evolutionary history of hominins has been characterized by significant dietary changes, which include the introduction of meat eating, cooking, and the changes associated with plant and animal domestication. The Western pattern diet has been linked with the onset of chronic inflammation, and serious health problems including obesity, metabolic syndrome, and cardiovascular diseases. Diets enriched with ω-3 marine PUFAs have revealed additional improvements in health status associated to a reduction of proinflammatory ω-3 and ω-6 lipid mediators. Lipid mediators are produced from enzymatic and non-enzymatic oxidation of PUFAs. Interest in better understanding the occurrence of these metabolites has increased exponentially as a result of the growing evidence of their role on inflammatory processes, control of the immune system, cell signaling, onset of metabolic diseases, or even cancer. The scope of this review has been to highlight the recent findings on: a) the formation of lipid mediators and their role in different inflammatory and metabolic conditions, b) the direct use of lipid mediators as antiinflammatory drugs or the potential of new drugs as a new therapeutic option for the synthesis of antiinflammatory or resolving lipid mediators and c) the impact of nutritional interventions to modulate lipid mediators synthesis towards antiinflammatory conditions. In a second part, we have summarized methodological approaches (Lipidomics) for the accurate analysis of lipid mediators. Although several techniques have been used, most authors preferred the combination of SPE with LC-MS. Advantages and disadvantages of each method are herein addressed, as well as the main LC-MS difficulties and challenges for the establishment of new biomarkers and standardization of experimental designs, and finally to deepen the study of mechanisms involved on the inflammatory response.
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Affiliation(s)
- Gabriel Dasilva
- Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Científicas (IIM-CSIC), c/Eduardo Cabello 6, 36208, Vigo, Spain.
| | - Isabel Medina
- Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Científicas (IIM-CSIC), c/Eduardo Cabello 6, 36208, Vigo, Spain
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17
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Tunctan B, Senol SP, Temiz-Resitoglu M, Guden DS, Sahan-Firat S, Falck JR, Malik KU. Eicosanoids derived from cytochrome P450 pathway of arachidonic acid and inflammatory shock. Prostaglandins Other Lipid Mediat 2019; 145:106377. [PMID: 31586592 DOI: 10.1016/j.prostaglandins.2019.106377] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2019] [Revised: 09/06/2019] [Accepted: 09/18/2019] [Indexed: 12/14/2022]
Abstract
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock, the most common form of vasodilatory shock, is a subset of sepsis in which circulatory and cellular/metabolic abnormalities are severe enough to increase mortality. Inflammatory shock constitutes the hallmark of sepsis, but also a final common pathway of any form of severe long-term tissue hypoperfusion. The pathogenesis of inflammatory shock seems to be due to circulating substances released by pathogens (e.g., bacterial endotoxins) and host immuno-inflammatory responses (e.g., changes in the production of histamine, bradykinin, serotonin, nitric oxide [NO], reactive nitrogen and oxygen species, and arachidonic acid [AA]-derived eicosanoids mainly through NO synthase, cyclooxygenase, and cytochrome P450 [CYP] pathways, and proinflammatory cytokine formation). Therefore, refractory hypotension to vasoconstrictors with end-organ hypoperfusion is a life threatening feature of inflammatory shock. This review summarizes the current knowledge regarding the role of eicosanoids derived from CYP pathway of AA in animal models of inflammatory shock syndromes with an emphasis on septic shock in addition to potential therapeutic strategies targeting specific CYP isoforms responsible for proinflammatory/anti-inflammatory mediator production.
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Affiliation(s)
- Bahar Tunctan
- Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey.
| | - Sefika Pinar Senol
- Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey
| | | | - Demet Sinem Guden
- Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey
| | - Seyhan Sahan-Firat
- Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey
| | - John R Falck
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Kafait U Malik
- Department of Pharmacology, College of Medicine, University of Tennessee, Center for Health Sciences, Memphis, TN, USA
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18
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de Bus I, Witkamp R, Zuilhof H, Albada B, Balvers M. The role of n-3 PUFA-derived fatty acid derivatives and their oxygenated metabolites in the modulation of inflammation. Prostaglandins Other Lipid Mediat 2019; 144:106351. [PMID: 31260750 DOI: 10.1016/j.prostaglandins.2019.106351] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 06/27/2019] [Indexed: 12/14/2022]
Abstract
Notwithstanding the ongoing debate on their full potential in health and disease, there is general consensus that n-3 PUFAs play important physiological roles. Increasing dietary n-3 PUFA intake results in increased DHA and EPA content in cell membranes as well as an increase in n-3 derived oxylipin and -endocannabinoid concentrations, like fatty acid amides and glycerol-esters. These shifts are believed to (partly) explain the pharmacological and anti-inflammatory effects of n-3 PUFAs. Recent studies discovered that n-3 PUFA-derived endocannabinoids can be further metabolized by the oxidative enzymes CYP-450, LOX and COX, similar to the n-6 derived endocannabinoids. Interestingly, these oxidized n-3 PUFA derived endocannabinoids of eicosapentaenoyl ethanolamide (EPEA) and docosahexaenoyl ethanolamide (DHEA) have higher anti-inflammatory and anti-proliferative potential than their precursors. In this review, an overview of recently discovered n-3 PUFA derived endocannabinoids and their metabolites is provided. In addition, the use of chemical probes will be presented as a promising technique to study the n-3 PUFA and n-3 PUFA metabolism within the field of lipid biochemistry.
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Affiliation(s)
- Ian de Bus
- Nutrition and Pharmacology Group, Division of Human Nutrition, Wageningen University & Research, Stippeneng 4, 6708 WE, Wageningen, the Netherlands; Laboratory of Organic Chemistry, Wageningen University & Research, Stippeneng 4, 6708 WE, Wageningen, the Netherlands
| | - Renger Witkamp
- Nutrition and Pharmacology Group, Division of Human Nutrition, Wageningen University & Research, Stippeneng 4, 6708 WE, Wageningen, the Netherlands
| | - Han Zuilhof
- Laboratory of Organic Chemistry, Wageningen University & Research, Stippeneng 4, 6708 WE, Wageningen, the Netherlands; School of Pharmaceutical Sciences and Technology, Tianjin University, 92 Weijin Road, Tianjin, PR China; Department of Chemical and Materials Engineering, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Bauke Albada
- Laboratory of Organic Chemistry, Wageningen University & Research, Stippeneng 4, 6708 WE, Wageningen, the Netherlands.
| | - Michiel Balvers
- Nutrition and Pharmacology Group, Division of Human Nutrition, Wageningen University & Research, Stippeneng 4, 6708 WE, Wageningen, the Netherlands.
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Non-Targeted LC-MS/MS Assay for Screening Over 100 Lipid Mediators from ARA, EPA, and DHA in Biological Samples Based on Mass Spectral Fragmentations. Molecules 2019; 24:molecules24122276. [PMID: 31248084 PMCID: PMC6630234 DOI: 10.3390/molecules24122276] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 06/13/2019] [Accepted: 06/17/2019] [Indexed: 12/15/2022] Open
Abstract
A non-targeted strategy to simultaneously screen for over 100 lipid mediators from ω-6 ARA and ω-3 EPA and DHA fatty acids is presented. The method based on an extensive study of fragmentation patterns obtained by SPE-LC-MS/MS analysis-provided fingerprints to comprehensively elucidate and identify lipid mediators in biological samples. Many of these metabolites are associated to metabolic disorders, inflammatory, immune and oxidative stress. The methodology consisted of a three-step procedure. (1) SPE extraction of compounds from plasma and adipose tissue was followed by LC-MS/MS analysis operating in full scan mode. The methodology was validated for a group of 65 metabolites using standards. SPE recoveries ranged from 29–134% and matrix effect from 10–580%. LOD and LOQ ranged from 0.01 to 1765 ng/mL and 0.03 to 5884 ng/mL respectively, similarly than current analytical strategies based on MRM mode. (2) An extensive study of the mass spectra of a wide range of compounds was done to stablish a specific fragmentation pattern. Interestingly, illustrative fragmentations and new specific transitions to identify EPA and DHA lipid mediators have been innovatively established. (3) After analysis, 30 lipid mediators were tentatively identified in plasma and 35 in adipose tissue of rats according to the pre stablished fragmentation patterns. The hypothetical identification of compounds was validated by using reference standards. Around 85–90% of proposed identifications were correctly assigned and only 4 and 3 identifications failed in adipose tissue and plasma, respectively. The method allowed the identification of these metabolites without losing information by the use of predefined ions list. Therefore, the use of full scan mode together with the study of fragmentation patterns provided a novel and stronger analytical tool to study the complete profile of lipid mediators in biological samples than the analysis through MRM based methods. Importantly, no analytical standards were required at this qualitative screening stage and the performance and sensitivity of the assay were very similar to that of a MRM method.
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20
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Yu J, He JQ, Chen DY, Pan QL, Yang JF, Cao HC, Li LJ. Dynamic changes of key metabolites during liver fibrosis in rats. World J Gastroenterol 2019; 25:941-954. [PMID: 30833800 PMCID: PMC6397726 DOI: 10.3748/wjg.v25.i8.941] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 01/10/2019] [Accepted: 01/28/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Fibrosis is the single most important predictor of significant morbidity and mortality in patients with chronic liver disease. Established non-invasive tests for monitoring fibrosis are lacking, and new biomarkers of liver fibrosis and function are needed.
AIM To depict the process of liver fibrosis and look for novel biomarkers for diagnosis and monitoring fibrosis progression.
METHODS CCl4 was used to establish the rat liver fibrosis model. Liver fibrosis process was measured by liver chemical tests, liver histopathology, and Masson’s trichrome staining. The expression levels of two fibrotic markers including α-smooth muscle actin and transforming growth factor β1 were assessed using immunohistochemistry and real-time polymerase chain reaction. Dynamic changes in metabolic profiles and biomarker concentrations in rat serum during liver fibrosis progression were investigated using ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. The discriminatory capability of potential biomarkers was evaluated by receiver operating characteristic (ROC) curve analysis.
RESULTS To investigate the dynamic changes of metabolites during the process of liver fibrosis, sera from control and fibrosis model rats based on pathological results were analyzed at five different time points. We investigated the association of liver fibrosis with 21 metabolites including hydroxyethyl glycine, L-threonine, indoleacrylic acid, β-muricholic acid (β-MCA), cervonoyl ethanolamide (CEA), phosphatidylcholines, and lysophosphatidylcholines. Two metabolites, CEA and β-MCA, differed significantly in the fibrosis model rats compared to controls (P < 0.05) and showed prognostic value for fibrosis. ROC curve analyses performed to calculate the area under the curve (AUC) revealed that CEA and β-MCA differed significantly in the fibrosis group compared to controls with AUC values exceeding 0.8, and can clearly differentiate early stage from late stage fibrosis or cirrhosis.
CONCLUSION This study identified two novel biomarkers of fibrosis, CEA and β-MCA, which were effective for diagnosing fibrosis in an animal model.
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Affiliation(s)
- Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Jian-Qin He
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - De-Ying Chen
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Qiao-Ling Pan
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Jin-Feng Yang
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Hong-Cui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Lan-Juan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
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21
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Colson C, Ghandour RA, Dufies O, Rekima S, Loubat A, Munro P, Boyer L, Pisani DF. Diet Supplementation in ω3 Polyunsaturated Fatty Acid Favors an Anti-Inflammatory Basal Environment in Mouse Adipose Tissue. Nutrients 2019; 11:nu11020438. [PMID: 30791540 PMCID: PMC6412622 DOI: 10.3390/nu11020438] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/12/2019] [Accepted: 02/15/2019] [Indexed: 12/17/2022] Open
Abstract
Oxylipins are metabolized from dietary ω3 and ω6 polyunsaturated fatty acids and are involved in an inflammatory response. Adipose tissue inflammatory background is a key factor of metabolic disorders and it is accepted that dietary fatty acids, in terms of quality and quantity, modulate oxylipin synthesis in this tissue. Moreover, it has been reported that diet supplementation in ω3 polyunsaturated fatty acids resolves some inflammatory situations. Thus, it is crucial to assess the influence of dietary polyunsaturated fatty acids on oxylipin synthesis and their impact on adipose tissue inflammation. To this end, mice fed an ω6- or ω3-enriched standard diet (ω6/ω3 ratio of 30 and 3.75, respectively) were analyzed for inflammatory phenotype and adipose tissue oxylipin content. Diet enrichment with an ω3 polyunsaturated fatty acid induced an increase in the oxylipins derived from ω6 linoleic acid, ω3 eicosapentaenoic, and ω3 docosahexaenoic acids in brown and white adipose tissues. Among these, the level of pro-resolving mediator intermediates, as well as anti-inflammatory metabolites, were augmented. Concomitantly, expressions of M2 macrophage markers were increased without affecting inflammatory cytokine contents. In vitro, these metabolites did not activate macrophages but participated in macrophage polarization by inflammatory stimuli. In conclusion, we demonstrated that an ω3-enriched diet, in non-obesogenic non-inflammatory conditions, induced synthesis of oxylipins which were involved in an anti-inflammatory response as well as enhancement of the M2 macrophage molecular signature, without affecting inflammatory cytokine secretion.
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Affiliation(s)
- Cecilia Colson
- Université Côte d'Azur, CNRS, Inserm, iBV, 06107 Nice, France.
| | | | - Océane Dufies
- Université Côte d'Azur, Inserm, C3M, 06107 Nice, France.
| | - Samah Rekima
- Université Côte d'Azur, CNRS, Inserm, iBV, 06107 Nice, France.
| | - Agnès Loubat
- Université Côte d'Azur, CNRS, Inserm, iBV, 06107 Nice, France.
| | - Patrick Munro
- Université Côte d'Azur, Inserm, C3M, 06107 Nice, France.
| | - Laurent Boyer
- Université Côte d'Azur, Inserm, C3M, 06107 Nice, France.
| | - Didier F Pisani
- Université Côte d'Azur, CNRS, Inserm, iBV, 06107 Nice, France.
- Didier Pisani, Laboratoire de PhysioMédecine Moléculaire-LP2M, Univ. Nice Sophia Antipolis, 28 Avenue de Valombrose, 06107 Nice CEDEX 2, France.
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22
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Rey C, Delpech JC, Madore C, Nadjar A, Greenhalgh AD, Amadieu C, Aubert A, Pallet V, Vaysse C, Layé S, Joffre C. Dietary n-3 long chain PUFA supplementation promotes a pro-resolving oxylipin profile in the brain. Brain Behav Immun 2019; 76:17-27. [PMID: 30086401 DOI: 10.1016/j.bbi.2018.07.025] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 07/27/2018] [Accepted: 07/30/2018] [Indexed: 11/26/2022] Open
Abstract
The brain is highly enriched in long chain polyunsaturated fatty acids (LC-PUFAs) that display immunomodulatory properties in the brain. At the periphery, the modulation of inflammation by LC-PUFAs occurs through lipid mediators called oxylipins which have anti-inflammatory and pro-resolving activities when derived from n-3 LC-PUFAs and pro-inflammatory activities when derived from n-6 LC-PUFAs. However, whether a diet rich in LC-PUFAs modulates oxylipins and neuroinflammation in the brain has been poorly investigated. In this study, the effect of a dietary n-3 LC-PUFA supplementation on oxylipin profile and neuroinflammation in the brain was analyzed. Mice were given diets deficient or supplemented in n-3 LC-PUFAs for a 2-month period starting at post-natal day 21, followed by a peripheral administration of lipopolysaccharide (LPS) at adulthood. We first showed that dietary n-3 LC-PUFA supplementation induced n-3 LC-PUFA enrichment in the hippocampus and subsequently an increase in n-3 PUFA-derived oxylipins and a decrease in n-6 PUFA-derived oxylipins. In response to LPS, n-3 LC-PUFA deficient mice presented a pro-inflammatory oxylipin profile whereas n-3 LC-PUFA supplemented mice displayed an anti-inflammatory oxylipin profile in the hippocampus. Accordingly, the expression of cyclooxygenase-2 and 5-lipoxygenase, the enzymes implicated in pro- and anti-inflammatory oxylipin synthesis, was induced by LPS in both diets. In addition, LPS-induced pro-inflammatory cytokine increase was reduced by dietary n-3 LC-PUFA supplementation. These results indicate that brain n-3 LC-PUFAs increase by dietary means and promote the synthesis of anti-inflammatory derived bioactive oxylipins. As neuroinflammation plays a key role in all brain injuries and many neurodegenerative disorders, the present data suggest that dietary habits may be an important regulator of brain cytokine production in these contexts.
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Affiliation(s)
- C Rey
- INRA, Nutrition et Neurobiologie Intégrée, UMR 1286, 33076 Bordeaux, France; ITERG, Institut des corps gras, 33600 Pessac, France
| | - J C Delpech
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
| | - C Madore
- Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - A Nadjar
- INRA, Nutrition et Neurobiologie Intégrée, UMR 1286, 33076 Bordeaux, France; Université de Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France
| | - A D Greenhalgh
- INRA, Nutrition et Neurobiologie Intégrée, UMR 1286, 33076 Bordeaux, France; Université de Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France
| | - C Amadieu
- INRA, Nutrition et Neurobiologie Intégrée, UMR 1286, 33076 Bordeaux, France; Université de Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France
| | - A Aubert
- INRA, Nutrition et Neurobiologie Intégrée, UMR 1286, 33076 Bordeaux, France; Université de Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France
| | - V Pallet
- INRA, Nutrition et Neurobiologie Intégrée, UMR 1286, 33076 Bordeaux, France; Université de Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France
| | - C Vaysse
- ITERG, Institut des corps gras, 33600 Pessac, France
| | - S Layé
- INRA, Nutrition et Neurobiologie Intégrée, UMR 1286, 33076 Bordeaux, France; Université de Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France
| | - C Joffre
- INRA, Nutrition et Neurobiologie Intégrée, UMR 1286, 33076 Bordeaux, France; Université de Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France.
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23
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Cayer LGJ, Mendonça AM, Pauls SD, Winter T, Leng S, Taylor CG, Zahradka P, Aukema HM. Adipose tissue oxylipin profiles vary by anatomical site and are altered by dietary linoleic acid in rats. Prostaglandins Leukot Essent Fatty Acids 2019; 141:24-32. [PMID: 30661602 DOI: 10.1016/j.plefa.2018.12.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 12/22/2018] [Accepted: 12/23/2018] [Indexed: 12/16/2022]
Abstract
Dietary PUFA and their effects on adipose tissue have been well studied, but oxylipins, the oxygenated metabolites of PUFA, have been sparsely studied in adipose tissue. To determine the oxylipin profile and to examine their potential importance in various adipose sites, female and male rats were provided control, high linoleic acid (LA), or high LA and high α-linolenic acid (LA + ALA) diets for six weeks. Analysis of gonadal (GAT), mesenteric (MAT), perirenal (PAT), and subcutaneous adipose tissues (SAT) revealed higher numbers of oxylipins in MAT and SAT, primarily due to 20-22 carbon cytochrome P450 oxylipins, as well as metabolites of cyclooxygenase derived oxylipins. LA oxylipins made up 75-96% of the total oxylipin mass and largely determined the total relative amounts between depots (GAT > MAT > PAT > SAT). However, when the two most abundant LA oxylipins (TriHOMEs) were excluded, MAT had the highest mass of oxylipins and exhibited the most sex differences. These differences existed despite comparable PUFA composition between depots. Dietary LA increased oxylipins derived from n-6 PUFA, and the addition of ALA generally returned n-6 PUFA oxylipins to levels similar to control and elevated some n-3 oxylipins. These data on oxylipin profiles in adipose depots from different anatomical sites and the effects of diet and sex provide fundamental knowledge that will aid future studies investigating the physiological effects of adipose tissue.
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Affiliation(s)
- Lucien G J Cayer
- Department of Food and Human Nutritional Sciences, University of Manitoba, Canada; Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg, Canada
| | - Anne M Mendonça
- Department of Food and Human Nutritional Sciences, University of Manitoba, Canada; School of Medicine, Federal University of Uberlândia, Brazil
| | - Samantha D Pauls
- Department of Food and Human Nutritional Sciences, University of Manitoba, Canada; Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg, Canada
| | - Tanja Winter
- Department of Food and Human Nutritional Sciences, University of Manitoba, Canada; Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg, Canada
| | - Shan Leng
- Department of Food and Human Nutritional Sciences, University of Manitoba, Canada
| | - Carla G Taylor
- Department of Food and Human Nutritional Sciences, University of Manitoba, Canada; Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg, Canada; Department of Physiology and Pathophysiology, University of Manitoba, Canada
| | - Peter Zahradka
- Department of Food and Human Nutritional Sciences, University of Manitoba, Canada; Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg, Canada; Department of Physiology and Pathophysiology, University of Manitoba, Canada
| | - Harold M Aukema
- Department of Food and Human Nutritional Sciences, University of Manitoba, Canada; Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg, Canada.
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Mendonça AM, Cayer LGJ, Pauls SD, Winter T, Leng S, Taylor CG, Zahradka P, Aukema HM. Distinct effects of dietary ALA, EPA and DHA on rat adipose oxylipins vary by depot location and sex. Prostaglandins Leukot Essent Fatty Acids 2018; 129:13-24. [PMID: 29482766 DOI: 10.1016/j.plefa.2017.12.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 12/20/2017] [Accepted: 12/22/2017] [Indexed: 12/22/2022]
Abstract
Dietary EPA and DHA given together alter oxylipins in adipose tissue. To compare the separate effects of individual dietary n-3 PUFA on oxylipins in different adipose depots (gonadal, mesenteric, perirenal, subcutaneous) in males and females, rats were provided diets containing higher levels of α-linolenic acid (ALA), EPA or DHA. Each n-3 PUFA enhanced its respective oxylipins the most, while effects on other n-3 oxylipins varied. For example: in perirenal and subcutaneous depots, more DHA oxylipins were higher with dietary ALA than with EPA; dietary EPA uniquely decreased 14-hydroxy-docosahexaenoic acid, in contrast to increasing many other DHA oxylipins. The n-3 PUFAs also reduced oxylipins from n-6 PUFAs in order of effectiveness: DHA > EPA > ALA. Diet by sex interactions in all depots except the perirenal depot resulted in higher oxylipins in males given DHA, and higher oxylipins in females given the other diets. Diet and sex effects on oxylipins did not necessarily reflect effects on either their tissue phospholipid or neutral lipid PUFA precursors. These varying diet and sex effects on oxylipins in the different adipose sites indicate that they may have distinct effects on adipose function.
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Affiliation(s)
- Anne M Mendonça
- School of Medicine, Federal University of Uberlândia, Brazil; Department of Food and Human Nutritional Sciences, University of Manitoba, Canada
| | - Lucien G J Cayer
- Department of Food and Human Nutritional Sciences, University of Manitoba, Canada
| | - Samantha D Pauls
- Department of Food and Human Nutritional Sciences, University of Manitoba, Canada
| | - Tanja Winter
- Department of Food and Human Nutritional Sciences, University of Manitoba, Canada
| | - Shan Leng
- Department of Food and Human Nutritional Sciences, University of Manitoba, Canada
| | - Carla G Taylor
- Department of Food and Human Nutritional Sciences, University of Manitoba, Canada; Canadian Centre for Research in Agri-Food Research in Health and Medicine, Winnipeg, Canada; Department of Physiology and Pathophysiology, University of Manitoba, Canada
| | - Peter Zahradka
- Department of Food and Human Nutritional Sciences, University of Manitoba, Canada; Canadian Centre for Research in Agri-Food Research in Health and Medicine, Winnipeg, Canada; Department of Physiology and Pathophysiology, University of Manitoba, Canada
| | - Harold M Aukema
- Department of Food and Human Nutritional Sciences, University of Manitoba, Canada; Canadian Centre for Research in Agri-Food Research in Health and Medicine, Winnipeg, Canada.
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25
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Tan X, Du X, Jiang Y, Botchway BOA, Hu Z, Fang M. Inhibition of Autophagy in Microglia Alters Depressive-Like Behavior via BDNF Pathway in Postpartum Depression. Front Psychiatry 2018; 9:434. [PMID: 30349488 PMCID: PMC6186788 DOI: 10.3389/fpsyt.2018.00434] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Accepted: 08/23/2018] [Indexed: 01/12/2023] Open
Abstract
Postpartum depression (PPD) is associated with mood disorders and elevated inflammation. Studies have evidenced the activation/inhibition of autophagy and excessive activation of microglia to have a close relationship with depression. C57 and microglia-specific autophagy-deficient mice (Cx3Cr1Cre/+ATG5loxp/loxp) were employed to establish the chronic unpredicted mild stress depression mice model from embryonic day 7 (E7) to embryonic day 16 (E16). Fluoxetine was administered for 3 weeks (commencing from 1 week after birth). Behavioral tests (open field, forced swimming, and sucrose preference tests) were implemented. Western blot and immunofluorescence staining were employed to assess the brain-derived neurotrophic factor (BDNF) expression level, autophagy-associated proteins, and inflammatory factors. Depressive behavior was reversed following fluoxetine treatment; this was evidenced via open field, sucrose preference, and forced swimming tests. Both BDNF and autophagy-associated proteins (ATG5, Beclin-1, and LC3II) were upregulated following fluoxetine treatment. Inflammatory factors including nuclear factor kappa B and inducible nitric oxide synthase were reduced while anti-inflammatory factor interleukin-10 (IL-10) was increased after fluoxetine treatment. Microglia-specific autophagy-deficient mice (Cx3Cr1Cre/+ATG5loxp/loxp) showed a curtailed autophagy level, higher inflammatory level, and reduced BDNF expression when compared with C57 mice. Autophagy inhibition in microglia contributes to inflammation, which further instigates PPD. Fluoxetine might mediate its antidepressant effect in PPD through the autophagic pathway while upregulating BDNF expression. In view of this, regulating BDNF in microglia is a potential novel therapy target for PPD.
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Affiliation(s)
- Xiaoning Tan
- Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoxue Du
- Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuting Jiang
- Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, China
| | - Benson O A Botchway
- Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhiying Hu
- Department of Obstetrics and Gynecology, Hangzhou Red Cross Hospital, Hangzhou, China
| | - Marong Fang
- Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, China
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Abstract
The adequate quantification of endocannabinoids can be complex due to their low endogenous levels and structural diversity. Therefore, advanced analytical approaches, such as LC-MS, are used to measure endocannabinoids in plasma, tissues, and other matrices. Recent work has shown that endocannabinoids that are synthesized from n-3 fatty acids, such as docosahexaenoylethanolamide (DHEA) and eicosapentaenoylethanolamide (EPEA), have anti-inflammatory and anti-tumorigenic properties and stimulate synapse formation in neurites. Here, an LC-MS based method for the quantification of n-3 endocannabinoids DHEA and EPEA which is also suited to measure a wider spectrum of endocannabinoids is described. The chapter contains a step-by-step protocol for the analysis of n-3 endocannabinoids in plasma, including sample collection and solid phase extraction, LC-MS analysis, and data processing. Modifications to the protocol that allow quantifying n-3 endocannabinoids in tissues and cell culture media will also be discussed. Finally, conditions that alter endocannabinoid concentrations are briefly discussed.
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Contreras GA, Strieder-Barboza C, de Souza J, Gandy J, Mavangira V, Lock AL, Sordillo LM. Periparturient lipolysis and oxylipid biosynthesis in bovine adipose tissues. PLoS One 2017; 12:e0188621. [PMID: 29206843 PMCID: PMC5716552 DOI: 10.1371/journal.pone.0188621] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 11/10/2017] [Indexed: 12/20/2022] Open
Abstract
The periparturient period of dairy cows is characterized by intense lipolysis in adipose tissues (AT), which induces the release of free fatty acids (FFA) into circulation. Among FFA, polyunsaturated fatty acids are susceptible to oxidation and can modulate inflammatory responses during lipolysis within AT. Linoleic and arachidonic acid oxidized products (oxylipids) such as hydroxy-octadecadienoic acids (HODE) and hydroxy-eicosatetraenoic acids (HETE), were recently identified as products of lipolysis that could modulate AT inflammation during lipolysis. However, the effect of lipolysis intensity during the transition from gestation to lactation on fatty acid substrate availability and subsequent AT oxylipid biosynthesis is currently unknown. We hypothesized that in periparturient dairy cows, alterations in AT and plasma fatty acids and oxylipid profiles coincide with changes in lipolysis intensity and stage of lactation. Blood and subcutaneous AT samples were collected from periparturient cows at -27±7 (G1) and -10±5 (G2) d prepartum and at 8±3 d postpartum (PP). Targeted lipidomic analysis was performed on plasma and AT using HPLC-MS/MS. We report that FFA concentrations increased as parturition approached and were highest at PP. Cows exhibiting high lipolysis rate at PP (FFA>1.0 mEq/L) had higher body condition scores at G1 compared to cows with low lipolysis rate (FFA<1.0 mEq/L). Concentrations of plasma linoleic and arachidonic acids were increased at PP. In AT, 13-HODE, and 5-, 11- and 15-HETE were increased at PP compared to G1 and G2. Concentrations of beta hydroxybutyrate were positively correlated with those of 13-HODE and 15-HETE in AT. Plasma concentrations of 5- and 20-HETE were increased at PP. These data demonstrate that prepartum adiposity predisposes cows to intense lipolysis post-partum and may exacerbate AT inflammation because of increased production of pro-inflammatory oxylipids including 5- and 15-HETE and 13-HODE. These results support a role for certain linoleic and arachidonic acid-derived oxylipids as positive and negative modulators of AT inflammation during periparturient lipolysis.
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Affiliation(s)
- G. Andres Contreras
- Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, United States of America
| | - Clarissa Strieder-Barboza
- Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, United States of America
| | - Jonas de Souza
- Department of Animal Science, Michigan State University, East Lansing, MI, United States of America
| | - Jeff Gandy
- Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, United States of America
| | - Vengai Mavangira
- Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, United States of America
| | - Adam L. Lock
- Department of Animal Science, Michigan State University, East Lansing, MI, United States of America
| | - Lorraine M. Sordillo
- Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, United States of America
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28
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Carta G, Murru E, Banni S, Manca C. Palmitic Acid: Physiological Role, Metabolism and Nutritional Implications. Front Physiol 2017; 8:902. [PMID: 29167646 PMCID: PMC5682332 DOI: 10.3389/fphys.2017.00902] [Citation(s) in RCA: 406] [Impact Index Per Article: 50.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2017] [Accepted: 10/24/2017] [Indexed: 12/19/2022] Open
Abstract
Palmitic acid (PA) has been for long time negatively depicted for its putative detrimental health effects, shadowing its multiple crucial physiological activities. PA is the most common saturated fatty acid accounting for 20–30% of total fatty acids in the human body and can be provided in the diet or synthesized endogenously via de novo lipogenesis (DNL). PA tissue content seems to be controlled around a well-defined concentration, and changes in its intake do not influence significantly its tissue concentration because the exogenous source is counterbalanced by PA endogenous biosynthesis. Particular physiopathological conditions and nutritional factors may strongly induce DNL, resulting in increased tissue content of PA and disrupted homeostatic control of its tissue concentration. The tight homeostatic control of PA tissue concentration is likely related to its fundamental physiological role to guarantee membrane physical properties but also to consent protein palmitoylation, palmitoylethanolamide (PEA) biosynthesis, and in the lung an efficient surfactant activity. In order to maintain membrane phospholipids (PL) balance may be crucial an optimal intake of PA in a certain ratio with unsaturated fatty acids, especially PUFAs of both n-6 and n-3 families. However, in presence of other factors such as positive energy balance, excessive intake of carbohydrates (in particular mono and disaccharides), and a sedentary lifestyle, the mechanisms to maintain a steady state of PA concentration may be disrupted leading to an over accumulation of tissue PA resulting in dyslipidemia, hyperglycemia, increased ectopic fat accumulation and increased inflammatory tone via toll-like receptor 4. It is therefore likely that the controversial data on the association of dietary PA with detrimental health effects, may be related to an excessive imbalance of dietary PA/PUFA ratio which, in certain physiopathological conditions, and in presence of an enhanced DNL, may further accelerate these deleterious effects.
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Affiliation(s)
- Gianfranca Carta
- Dipartimento Scienze Biomediche, Università degli studi di Cagliari, Cagliari, Italy
| | - Elisabetta Murru
- Dipartimento Scienze Biomediche, Università degli studi di Cagliari, Cagliari, Italy
| | - Sebastiano Banni
- Dipartimento Scienze Biomediche, Università degli studi di Cagliari, Cagliari, Italy
| | - Claudia Manca
- Dipartimento Scienze Biomediche, Università degli studi di Cagliari, Cagliari, Italy
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29
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Dasilva G, Pazos M, García-Egido E, Gallardo JM, Ramos-Romero S, Torres JL, Romeu M, Nogués MR, Medina I. A lipidomic study on the regulation of inflammation and oxidative stress targeted by marine ω-3 PUFA and polyphenols in high-fat high-sucrose diets. J Nutr Biochem 2017; 43:53-67. [PMID: 28260647 DOI: 10.1016/j.jnutbio.2017.02.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 01/19/2017] [Accepted: 02/08/2017] [Indexed: 01/14/2023]
Abstract
The ability of polyphenols to ameliorate potential oxidative damage of ω-3 PUFAs when they are consumed together and then, to enhance their potentially individual effects on metabolic health is discussed through the modulation of fatty acids profiling and the production of lipid mediators. For that, the effects of the combined consumption of fish oils and grape seed procyanidins on the inflammatory response and redox unbalance triggered by high-fat high-sucrose (HFHS) diets were studied in an animal model of Wistar rats. A standard diet was used as control. Results suggested that fish oils produced a replacement of ω-6 by ω-3 PUFAs in membranes and tissues, and consequently they improved inflammatory and oxidative stress parameters: favored the activity of 12/15-lipoxygenases on ω-3 PUFAs, enhanced glutathione peroxidases activity, modulated proinflammatory lipid mediators synthesis through the cyclooxygenase (COX) pathways and down-regulated the synthesis de novo of ARA leaded by Δ5 desaturase. Although polyphenols exerted an antioxidative and antiinflammatory effect in the standard diet, they were less effective to reduce inflammation in the HFHS dietary model. Contrary to the effect observed in the standard diet, polyphenols up-regulated COX pathways toward ω-6 proinflammatory eicosanoids as PGE2 and 11-HETE and decreased the detoxification of ω-3 hydroperoxides in the HFHS diet. As a result, additive effects between fish oils and polyphenols were found in the standard diet in terms of reducing inflammation and oxidative stress. However, in the HFHS diets, fish oils seem to be the one responsible for the positive effects found in the combined group.
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Affiliation(s)
- Gabriel Dasilva
- Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Científicas (IIM-CSIC), E-36208 Vigo, Galicia, Spain; Department of Analytical Chemistry, Nutrition and Bromatology and Research Institute for Food Analysis (I.I.A.A.), University of Santiago de Compostela, E-15782 Santiago de Compostela, Galicia, Spain.
| | - Manuel Pazos
- Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Científicas (IIM-CSIC), E-36208 Vigo, Galicia, Spain
| | - Eduardo García-Egido
- Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Científicas (IIM-CSIC), E-36208 Vigo, Galicia, Spain
| | - José M Gallardo
- Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Científicas (IIM-CSIC), E-36208 Vigo, Galicia, Spain
| | - Sara Ramos-Romero
- Instituto de Química Avanzada de Catalunya (IQAC-CSIC), Jordi Girona 18-26, E-08034 Barcelona, Spain
| | - Josep Lluís Torres
- Instituto de Química Avanzada de Catalunya (IQAC-CSIC), Jordi Girona 18-26, E-08034 Barcelona, Spain
| | - Marta Romeu
- Unidad de Farmacología, Facultad de Medicina, Universidad Rovira i Virgili, Sant Llorenç 21, E-43201 Reus, Spain
| | - María-Rosa Nogués
- Unidad de Farmacología, Facultad de Medicina, Universidad Rovira i Virgili, Sant Llorenç 21, E-43201 Reus, Spain
| | - Isabel Medina
- Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Científicas (IIM-CSIC), E-36208 Vigo, Galicia, Spain
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Poland M, Ten Klooster JP, Wang Z, Pieters R, Boekschoten M, Witkamp R, Meijerink J. Docosahexaenoyl serotonin, an endogenously formed n-3 fatty acid-serotonin conjugate has anti-inflammatory properties by attenuating IL-23-IL-17 signaling in macrophages. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1861:2020-2028. [PMID: 27663185 DOI: 10.1016/j.bbalip.2016.09.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 08/24/2016] [Accepted: 09/16/2016] [Indexed: 01/01/2023]
Abstract
Conjugates of fatty acids and amines, including endocannabinoids, are known to play important roles as endogenous signaling molecules. Among these, the ethanolamine conjugate of the n-3 poly unsaturated long chain fatty acid (PUFA) docosahexaenoic acid (22:6n-3) (DHA) was shown to possess strong anti-inflammatory properties. Previously, we identified the serotonin conjugate of DHA, docosahexaenoyl serotonin (DHA-5-HT), in intestinal tissues and showed that its levels are markedly influenced by intake of n-3 PUFAs. However, its biological roles remain to be elucidated. Here, we show that DHA-5-HT possesses potent anti-inflammatory properties by attenuating the IL-23-IL-17 signaling cascade in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Transcriptome analysis revealed that DHA-5-HT down-regulates LPS-induced genes, particularly those involved in generating a CD4+ Th17 response. Hence, levels of PGE2, IL-6, IL-1β, and IL-23, all pivotal macrophage-produced mediators driving the activation of pathogenic Th17 cells in a concerted way, were found to be significantly suppressed by concentrations as low as 100-500nM DHA-5-HT. Furthermore, DHA-5-HT inhibited the ability of RAW264.7 cells to migrate and downregulated chemokines like MCP-1, CCL-20, and gene-expression of CCL-22 and of several metalloproteinases. Gene set enrichment analysis (GSEA) suggested negative overlap with gene sets linked to inflammatory bowel disease (IBD) and positive overlap with gene sets related to the Nrf2 pathway. The specific formation of DHA-5-HT in the gut, combined with increasing data underlining the importance of the IL-23-IL-17 signaling pathway in the etiology of many chronic inflammatory diseases merits further investigation into its potential as therapeutic compound in e.g. IBD or intestinal tumorigenesis.
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Affiliation(s)
- Mieke Poland
- Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands.
| | - Jean Paul Ten Klooster
- Institute for Life Sciences & Chemistry, Utrecht University of Applied Sciences, Utrecht, The Netherlands.
| | - Zheng Wang
- Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands.
| | - Raymond Pieters
- Institute for Life Sciences & Chemistry, Utrecht University of Applied Sciences, Utrecht, The Netherlands.
| | - Mark Boekschoten
- Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands.
| | - Renger Witkamp
- Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands.
| | - Jocelijn Meijerink
- Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands.
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Bessonneau V, Zhan Y, De Lannoy IA, Saldivia V, Pawliszyn J. In vivo solid-phase microextraction liquid chromatography–tandem mass spectrometry for monitoring blood eicosanoids time profile after lipopolysaccharide-induced inflammation in Sprague-Dawley rats. J Chromatogr A 2015; 1424:134-8. [DOI: 10.1016/j.chroma.2015.10.067] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 10/20/2015] [Accepted: 10/22/2015] [Indexed: 01/03/2023]
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Mavangira V, Gandy JC, Zhang C, Ryman VE, Daniel Jones A, Sordillo LM. Polyunsaturated fatty acids influence differential biosynthesis of oxylipids and other lipid mediators during bovine coliform mastitis. J Dairy Sci 2015; 98:6202-15. [DOI: 10.3168/jds.2015-9570] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Accepted: 05/27/2015] [Indexed: 01/12/2023]
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Ryman V, Pighetti G, Lippolis J, Gandy J, Applegate C, Sordillo L. Quantification of bovine oxylipids during intramammary Streptococcus uberis infection. Prostaglandins Other Lipid Mediat 2015; 121:207-17. [DOI: 10.1016/j.prostaglandins.2015.09.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 09/09/2015] [Accepted: 09/24/2015] [Indexed: 12/19/2022]
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Fatty acids, endocannabinoids and inflammation. Eur J Pharmacol 2015; 785:96-107. [PMID: 26325095 DOI: 10.1016/j.ejphar.2015.08.051] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 07/01/2015] [Accepted: 08/26/2015] [Indexed: 01/08/2023]
Abstract
From their phylogenetic and pharmacological classification it might be inferred that cannabinoid receptors and their endogenous ligands constitute a rather specialised and biologically distinct signalling system. However, the opposite is true and accumulating data underline how much the endocannabinoid system is intertwined with other lipid and non-lipid signalling systems. Endocannabinoids per se have many structural congeners, and these molecules exist in dynamic equilibria with different other lipid-derived mediators, including eicosanoids and prostamides. With multiple crossroads and shared targets, this creates a versatile system involved in fine-tuning different physiological and metabolic processes, including inflammation. A key feature of this 'expanded' endocannabinoid system, or 'endocannabinoidome', is its subtle orchestration based on interactions between a relatively small number of receptors and multiple ligands with different but partly overlapping activities. Following an update on the role of the 'endocannabinoidome' in inflammatory processes, this review continues with possible targets for intervention at the level of receptors or enzymes involved in formation or breakdown of endocannabinoids and their congeners. Although its pleiotropic character poses scientific challenges, the 'expanded' endocannabinoid system offers several opportunities for prevention and therapy of chronic diseases. In this respect, successes are more likely to come from 'multiple-target' than from 'single-target' strategies.
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Secci G, Parisi G, Dasilva G, Medina I. Stress during slaughter increases lipid metabolites and decreases oxidative stability of farmed rainbow trout (Oncorhynchus mykiss) during frozen storage. Food Chem 2015. [PMID: 26212934 DOI: 10.1016/j.foodchem.2015.05.051] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The consequences of slaughter on the formation of lipid metabolites and oxidative stability of fish muscle during long term frozen storage (-10 °C) were evaluated using farmed rainbow trout killed by asphyxia in air or percussion. The level of major adenine nucleotides and their related compounds was determined in order to check the stress level during slaughter. Plasma lipid metabolites were studied through the determination of eicosanoids and docosanoids such as prostaglandins, leukotrienes, thromboxanes, isoprostanes, resolvins, hydroxides, hydroperoxides, coming from eicosapentaenoic (EPA), arachidonic (ARA), and docosahexaenoic (DHA) acids. In addition, lipid oxidative stability of fillets was monitored. Results revealed that stress during slaughter can greatly influence oxidative stress and oxidative stability of rainbow trout fillets. In fact, asphyxia, which was the most stressful, induced a higher production of some lipid mediators such as hydroperoxides and EPA-derived prostaglandins, such as 12-HpHEPE/15-HpHEPE and PGD3/PGE3. As a consequence, fillets derived from asphyxiated fish were less stable in terms of oxidative stability and showed lower shelf-life.
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Affiliation(s)
- G Secci
- Department of Agri-Food Production and Environmental Sciences, Section of Animal Sciences, University of Firenze, via delle Cascine 5, 50144 Firenze, Italy
| | - G Parisi
- Department of Agri-Food Production and Environmental Sciences, Section of Animal Sciences, University of Firenze, via delle Cascine 5, 50144 Firenze, Italy.
| | - G Dasilva
- Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Científicas (IIM-CSIC), Eduardo Cabello 6, E-36208 Vigo, Spain
| | - I Medina
- Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Científicas (IIM-CSIC), Eduardo Cabello 6, E-36208 Vigo, Spain
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Patsenker E, Sachse P, Chicca A, Gachet MS, Schneider V, Mattsson J, Lanz C, Worni M, de Gottardi A, Semmo M, Hampe J, Schafmayer C, Brenneisen R, Gertsch J, Stickel F, Semmo N. Elevated levels of endocannabinoids in chronic hepatitis C may modulate cellular immune response and hepatic stellate cell activation. Int J Mol Sci 2015; 16:7057-76. [PMID: 25826533 PMCID: PMC4425004 DOI: 10.3390/ijms16047057] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 03/06/2015] [Accepted: 03/23/2015] [Indexed: 12/17/2022] Open
Abstract
The endocannabinoid (EC) system is implicated in many chronic liver diseases, including hepatitis C viral (HCV) infection. Cannabis consumption is associated with fibrosis progression in patients with chronic hepatitis C (CHC), however, the role of ECs in the development of CHC has never been explored. To study this question, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) were quantified in samples of HCV patients and healthy controls by gas and liquid chromatography mass spectrometry. Fatty acid amide hydrolase (FAAH) and monoaclyglycerol lipase (MAGL) activity was assessed by [3H]AEA and [3H]2-AG hydrolysis, respectively. Gene expression and cytokine release were assayed by TaqMan PCR and ELISpot, respectively. AEA and 2-AG levels were increased in plasma of HCV patients, but not in liver tissues. Hepatic FAAH and MAGL activity was not changed. In peripheral blood mononuclear cells (PBMC), ECs inhibited IFN-γ, TNF-α, and IL-2 secretion. Inhibition of IL-2 by endogenous AEA was stronger in PBMC from HCV patients. In hepatocytes, 2-AG induced the expression of IL-6, -17A, -32 and COX-2, and enhanced activation of hepatic stellate cells (HSC) co-cultivated with PBMC from subjects with CHC. In conclusion, ECs are increased in plasma of patients with CHC and might reveal immunosuppressive and profibrogenic effects.
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Affiliation(s)
- Eleonora Patsenker
- Department of Clinical Research, University of Bern, Bern 3010, Switzerland.
| | - Philip Sachse
- Department of Clinical Research, University of Bern, Bern 3010, Switzerland.
| | - Andrea Chicca
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern 3012, Switzerland.
| | - María Salomé Gachet
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern 3012, Switzerland.
| | - Vreni Schneider
- Department of Clinical Research, University of Bern, Bern 3010, Switzerland.
| | - Johan Mattsson
- Department of Clinical Research, Laboratory of Phytopharmacology, Bioanalytics and Pharmacokinetics, University of Bern, Bern 3010, Switzerland.
| | - Christian Lanz
- Department of Clinical Research, Laboratory of Phytopharmacology, Bioanalytics and Pharmacokinetics, University of Bern, Bern 3010, Switzerland.
| | - Mathias Worni
- Department of Visceral Surgery and Medicine, Inselspital, University of Bern, Bern 3010, Switzerland.
| | - Andrea de Gottardi
- Department of Visceral Surgery and Medicine, Inselspital, University of Bern, Bern 3010, Switzerland.
| | - Mariam Semmo
- Department of Nephrology, Inselspital, University of Bern, Bern 3010, Switzerland.
| | - Jochen Hampe
- Department of Medicine II, Division of Gastroenterology, University of Dresden, Dresden 01307, Germany.
| | - Clemens Schafmayer
- Department of Visceral Surgery, University of Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany.
| | - Rudolf Brenneisen
- Department of Clinical Research, Laboratory of Phytopharmacology, Bioanalytics and Pharmacokinetics, University of Bern, Bern 3010, Switzerland.
| | - Jürg Gertsch
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern 3012, Switzerland.
| | - Felix Stickel
- Department of Clinical Research, University of Bern, Bern 3010, Switzerland.
| | - Nasser Semmo
- Department of Clinical Research, University of Bern, Bern 3010, Switzerland.
- Department of Visceral Surgery and Medicine, Inselspital, University of Bern, Bern 3010, Switzerland.
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Sayd A, Antón M, Alén F, Caso JR, Pavón J, Leza JC, Rodríguez de Fonseca F, García-Bueno B, Orio L. Systemic administration of oleoylethanolamide protects from neuroinflammation and anhedonia induced by LPS in rats. Int J Neuropsychopharmacol 2015; 18:pyu111. [PMID: 25548106 PMCID: PMC4438549 DOI: 10.1093/ijnp/pyu111] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 12/15/2014] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The acylethanolamides oleoylethanolamide and palmitoylethanolamide are endogenous lipid mediators with proposed neuroprotectant properties in central nervous system (CNS) pathologies. The precise mechanisms remain partly unknown, but growing evidence suggests an antiinflammatory/antioxidant profile. METHODS We tested whether oleoylethanolamide/palmitoylethanolamide (10 mg/kg, i.p.) attenuate neuroinflammation and acute phase responses (hypothalamus-pituitary-adrenal (HPA) stress axis stress axis activation, thermoregulation, and anhedonia) induced by lipopolysaccharide (0.5 mg/kg, i.p.) in rats. RESULTS Lipopolysaccharide increased mRNA levels of the proinflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6, nuclear transcription factor-κB activity, and the expression of its inhibitory protein IκBα in cytoplasm, the inducible isoforms of nitric oxide synthase and cyclooxygenase-2, microsomal prostaglandin E2 synthase mRNA, and proinflammatory prostaglandin E2 content in frontal cortex 150 minutes after administration. As a result, the markers of nitrosative/oxidative stress nitrites (NO2(-)) and malondialdehyde were increased. Pretreatment with oleoylethanolamide/ palmitoylethanolamide reduced plasma tumor necrosis factor-α levels after lipopolysaccharide, but only oleoylethanolamide significantly reduced brain tumor necrosis factor-α mRNA. Oleoylethanolamide and palmitoylethanolamide prevented lipopolysaccharide-induced nuclear transcription factor-κB (NF-κB)/IκBα upregulation in nuclear and cytosolic extracts, respectively, the expression of inducible isoforms of nitric oxide synthase, cyclooxygenase-2, and microsomal prostaglandin E2 synthase and the levels of prostaglandin E2. Additionally, both acylethanolamides reduced lipopolysaccharide-induced oxidative/nitrosative stress. Neither oleoylethanolamide nor palmitoylethanolamide modified plasma corticosterone levels after lipopolysaccharide, but both acylethanolamides reduced the expression of hypothalamic markers of thermoregulation interleukin-1β, cyclooxygenase-2, and prostaglandin E2, and potentiated the hypothermic response after lipopolysaccharide. Interestingly, only oleoylethanolamide disrupted lipopolysaccharide-induced anhedonia in a saccharine preference test. CONCLUSIONS Results indicate that oleoylethanolamide and palmitoylethanolamide have antiinflammatory/neuroprotective properties and suggest a role for these acylethanolamides as modulators of CNS pathologies with a neuroinflammatory component.
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Affiliation(s)
| | | | | | | | | | | | | | - Borja García-Bueno
- Department of Psychobiology, Faculty of Psychology, Complutense University, Complutense University of Madrid (UCM), Madrid, Spain (Ms Antón, and Drs Alén, Rodríguez de Fonseca and Orio); Department of Pharmacology, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)), Madrid, Spain (Ms Sayd, and Drs Leza and García-Bueno); Department of Psychiatry, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain (Dr Caso); UGC Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga-Universidad de Málaga, and Red de Trastornos Adictivos, Málaga, Spain (Drs Pavón and Rodríguez de Fonseca).
| | - Laura Orio
- Department of Psychobiology, Faculty of Psychology, Complutense University, Complutense University of Madrid (UCM), Madrid, Spain (Ms Antón, and Drs Alén, Rodríguez de Fonseca and Orio); Department of Pharmacology, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)), Madrid, Spain (Ms Sayd, and Drs Leza and García-Bueno); Department of Psychiatry, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain (Dr Caso); UGC Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga-Universidad de Málaga, and Red de Trastornos Adictivos, Málaga, Spain (Drs Pavón and Rodríguez de Fonseca).
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Meijerink J, Balvers M, Witkamp R. N-Acyl amines of docosahexaenoic acid and other n-3 polyunsatured fatty acids - from fishy endocannabinoids to potential leads. Br J Pharmacol 2014; 169:772-83. [PMID: 23088259 DOI: 10.1111/bph.12030] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Revised: 09/15/2012] [Accepted: 10/15/2012] [Indexed: 02/06/2023] Open
Abstract
N-3 Long-chain polyunsaturated fatty acids (n-3 LC-PUFAs), in particular α-linolenic acid (18:3n-3), eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) are receiving much attention because of their presumed beneficial health effects. To explain these, a variety of mechanisms have been proposed, but their interactions with the endocannabinoid system have received relatively little attention so far. However, it has already been shown some time ago that consumption of n-3 LC-PUFAs not only affects the synthesis of prototypic endocannabinoids like anandamide but also stimulates the formation of specific n-3 LC-PUFA-derived conjugates with ethanolamine, dopamine, serotonin or other amines. Some of these fatty amides show overlapping biological activities with those of typical endocannabinoids, whereas others possess distinct and sometimes largely unknown receptor affinities and other properties. The ethanolamine and dopamine conjugates of DHA have been the most investigated thus far. These mediators may provide promising new leads to the field of inflammatory and neurological disorders and for other pharmacological applications, including their use as carrier molecules for neurotransmitters to target the brain. Furthermore, combinations of n-3 LC-PUFA-derived fatty acid amides, their precursors and FAAH inhibitors offer possibilities to optimise their effects in health and disease.
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Affiliation(s)
- Jocelijn Meijerink
- Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
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Meijerink J, Poland M, Balvers MGJ, Plastina P, Lute C, Dwarkasing J, van Norren K, Witkamp RF. Inhibition of COX-2-mediated eicosanoid production plays a major role in the anti-inflammatory effects of the endocannabinoid N-docosahexaenoylethanolamine (DHEA) in macrophages. Br J Pharmacol 2014; 172:24-37. [PMID: 24780080 DOI: 10.1111/bph.12747] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 04/03/2014] [Accepted: 04/11/2014] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND AND PURPOSE N-docosahexaenoylethanolamine (DHEA) is the ethanolamine conjugate of the long-chain polyunsaturated n-3 fatty acid docosahexaenoic (DHA; 22: 6n-3). Its concentration in animal tissues and human plasma increases when diets rich in fish or krill oil are consumed. DHEA displays anti-inflammatory properties in vitro and was found to be released during an inflammatory response in mice. Here, we further examine possible targets involved in the immune-modulating effects of DHEA. EXPERIMENTAL APPROACH Antagonists for cannabinoid (CB)1 and CB2 receptors and PPARγ were used to explore effects of DHEA on NO release by LPS-stimulated RAW264.7 cells. The possible involvement of CB2 receptors was studied by comparing effects in LPS-stimulated peritoneal macrophages obtained from CB2 (-/-) and CB2 (+/+) mice. Effects on NF-κB activation were determined using a reporter cell line. To study DHEA effects on COX-2 and lipoxygenase activity, 21 different eicosanoids produced by LPS-stimulated RAW264.7 cells were quantified by LC-MS/MS. Finally, effects on mRNA expression profiles were analysed using gene arrays followed by Ingenuity(®) Pathways Analysis. KEY RESULTS CB1 and CB2 receptors or PPARs were not involved in the effects of DHEA on NO release. NF-κB and IFN-β, key elements of the myeloid differentiation primary response protein D88 (MyD88)-dependent and MyD88-independent pathways were not decreased. By contrast, DHEA significantly reduced levels of several COX-2-derived eicosanoids. Gene expression analysis provided support for an effect on COX-2-mediated pathways. CONCLUSIONS AND IMPLICATIONS Our findings suggest that the anti-inflammatory effects of DHEA in macrophages predominantly take place via inhibition of eicosanoids produced through COX-2. LINKED ARTICLES This article is part of a themed section on Cannabinoids 2013 published in volume 171 issue 6. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.2014.171.issue-6/issuetoc.
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Affiliation(s)
- Jocelijn Meijerink
- Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
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Abstract
PURPOSE OF REVIEW The purpose of this review is to illustrate the expanding view of the endocannabinoid system (ECS) in relation to its roles in inflammation. RECENT FINDINGS According to the formal classification, the ECS consists of two cannabinoid receptors, their endogenous fatty acid-derived ligands, and a number of enzymes involved in their synthesis and breakdown. However, many endogenous congeners of classical endocannabinoids have now been discovered, together with a set of receptors structurally or functionally related to the cannabinoid receptors. Endocannabinoids per se behave 'promiscuously' with regard to their receptor interactions. It is increasingly recognized how tightly this expanded ECS is intertwined with key processes involved in inflammation. A continuous dynamic exchange of substrates and metabolites exists between ECS and eicosanoid pathways. Endocannabinoids can also be oxygenated by cyclooxygenase and other enzymes to biologically active 'hybrid' structures. Diet is among the main factors determining synthesis and release of endocannabinoids and related mediators. SUMMARY The complexity of what may be called the 'endocannabinoidome' requires approaches that take into account its dynamics and interconnections with other regulatory systems. This endocannabinoidome continues to offer possibilities for prevention and intervention, but multiple target approaches will probably provide the only keys to success.
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Affiliation(s)
- Renger Witkamp
- Wageningen University, Division of Human Nutrition, Wageningen, the Netherlands
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Li M, Yang L, Bai Y, Liu H. Analytical Methods in Lipidomics and Their Applications. Anal Chem 2013; 86:161-75. [DOI: 10.1021/ac403554h] [Citation(s) in RCA: 145] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Min Li
- Beijing National Laboratory for Molecular Sciences, Key
Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry
of Education, Institute of Analytical Chemistry, College of Chemistry
and Molecular Engineering, Peking University, Beijing 100871, China
| | - Li Yang
- Beijing National Laboratory for Molecular Sciences, Key
Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry
of Education, Institute of Analytical Chemistry, College of Chemistry
and Molecular Engineering, Peking University, Beijing 100871, China
| | - Yu Bai
- Beijing National Laboratory for Molecular Sciences, Key
Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry
of Education, Institute of Analytical Chemistry, College of Chemistry
and Molecular Engineering, Peking University, Beijing 100871, China
| | - Huwei Liu
- Beijing National Laboratory for Molecular Sciences, Key
Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry
of Education, Institute of Analytical Chemistry, College of Chemistry
and Molecular Engineering, Peking University, Beijing 100871, China
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Bastiaansen-Jenniskens YM, Wei W, Feijt C, Waarsing JH, Verhaar JAN, Zuurmond AM, Hanemaaijer R, Stoop R, van Osch GJVM. Stimulation of fibrotic processes by the infrapatellar fat pad in cultured synoviocytes from patients with osteoarthritis: a possible role for prostaglandin f2α. ACTA ACUST UNITED AC 2013; 65:2070-80. [PMID: 23666869 DOI: 10.1002/art.37996] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Accepted: 04/24/2013] [Indexed: 01/04/2023]
Abstract
OBJECTIVE Stiffening of the joint is a feature of knee osteoarthritis (OA) that can be caused by fibrosis of the synovium. The infrapatellar fat pad (IPFP) present in the knee joint produces immune-modulatory and angiogenic factors. The goal of the present study was to investigate whether the IPFP can influence fibrotic processes in synovial fibroblasts, and to determine the role of transforming growth factor β (TGFβ) and prostaglandin F2α (PGF2α ) in these processes. METHODS Batches of fat-conditioned medium (FCM) were made by culturing pieces of IPFP obtained from the knees of 13 patients with OA. Human OA fibroblast-like synoviocytes (FLS) (from passage 3) were cultured in FCM with or without inhibitors of TGFβ/activin receptor-like kinase 5 or PGF2α for 4 days. The FLS were analyzed for production of collagen and expression of the gene for procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2; encoding lysyl hydroxylase 2b, an enzyme involved in collagen crosslinking) as well as the genes encoding α-smooth muscle actin and type I collagen α1 chain. In parallel, proliferation and migration of the synoviocytes were analyzed. RESULTS Collagen production and PLOD2 gene expression by the FLS were increased 1.8-fold (P < 0.05) and 6.0-fold (P < 0.01), respectively, in the presence of FCM, relative to control cultures without FCM. Moreover, the migration and proliferation of synoviocytes were stimulated by FCM. Collagen production was positively associated with PGF2α levels in the FCM (R = 0.89, P < 0.05), and inhibition of PGF2α levels reduced the extent of FCM-induced collagen production and PLOD2 expression. Inhibition of TGFβ signaling had no effect on the profibrotic changes. CONCLUSION These results indicate that the IPFP can contribute to the development of synovial fibrosis in the knee joint by increasing collagen production, PLOD2 expression, cell proliferation, and cell migration. In addition, whereas the findings showed that TGFβ is not involved, the more recently discovered profibrotic factor PGF2α appears to be partially involved in the regulation of profibrotic changes.
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Markworth JF, Vella L, Lingard BS, Tull DL, Rupasinghe TW, Sinclair AJ, Maddipati KR, Cameron-Smith D. Human inflammatory and resolving lipid mediator responses to resistance exercise and ibuprofen treatment. Am J Physiol Regul Integr Comp Physiol 2013; 305:R1281-96. [PMID: 24089379 DOI: 10.1152/ajpregu.00128.2013] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Classical proinflammatory eicosanoids, and more recently discovered lipid mediators with anti-inflammatory and proresolving bioactivity, exert a complex role in the initiation, control, and resolution of inflammation. Using a targeted lipidomics approach, we investigated circulating lipid mediator responses to resistance exercise and treatment with the NSAID ibuprofen. Human subjects undertook a single bout of unaccustomed resistance exercise (80% of one repetition maximum) following oral ingestion of ibuprofen (400 mg) or placebo control. Venous blood was collected during early recovery (0-3 h and 24 h postexercise), and serum lipid mediator composition was analyzed by LC-MS-based targeted lipidomics. Postexercise recovery was characterized by elevated levels of cyclooxygenase (COX)-1 and 2-derived prostanoids (TXB2, PGE2, PGD2, PGF2α, and PGI2), lipooxygenase (5-LOX, 12-LOX, and 15-LOX)-derived hydroxyeicosatetraenoic acids (HETEs), and leukotrienes (e.g., LTB4), and epoxygenase (CYP)-derived epoxy/dihydroxy eicosatrienoic acids (EpETrEs/DiHETrEs). Additionally, we detected elevated levels of bioactive lipid mediators with anti-inflammatory and proresolving properties, including arachidonic acid-derived lipoxins (LXA4 and LXB4), and the EPA (E-series) and DHA (D-series)-derived resolvins (RvD1 and RvE1), and protectins (PD1 isomer 10S, 17S-diHDoHE). Ibuprofen treatment blocked exercise-induced increases in COX-1 and COX-2-derived prostanoids but also resulted in off-target reductions in leukotriene biosynthesis, and a diminished proresolving lipid mediator response. CYP pathway product metabolism was also altered by ibuprofen treatment, as indicated by elevated postexercise serum 5,6-DiHETrE and 8,9-DiHETrE only in those receiving ibuprofen. These findings characterize the blood inflammatory lipid mediator response to unaccustomed resistance exercise in humans and show that acute proinflammatory signals are mechanistically linked to the induction of a biological active inflammatory resolution program, regulated by proresolving lipid mediators during postexercise recovery.
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Affiliation(s)
- James F Markworth
- School of Exercise and Nutrition Science, Deakin University, Melbourne, Victoria, Australia
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Rago B, Fu C. Development of a high-throughput ultra performance liquid chromatography–mass spectrometry assay to profile 18 eicosanoids as exploratory biomarkers for atherosclerotic diseases. J Chromatogr B Analyt Technol Biomed Life Sci 2013; 936:25-32. [DOI: 10.1016/j.jchromb.2013.08.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Revised: 07/23/2013] [Accepted: 08/01/2013] [Indexed: 12/22/2022]
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Balgoma D, Checa A, Sar DG, Snowden S, Wheelock CE. Quantitative metabolic profiling of lipid mediators. Mol Nutr Food Res 2013; 57:1359-77. [PMID: 23828856 DOI: 10.1002/mnfr.201200840] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 05/07/2013] [Accepted: 05/08/2013] [Indexed: 12/25/2022]
Abstract
Lipids are heterogeneous biological molecules that possess multiple physiological roles including cell structure, homeostasis, and restoration of tissue functionality during and after inflammation. Lipid metabolism constitutes a network of pathways that are related at multiple biosynthetic hubs. Disregulation of lipid metabolism can lead to pathophysiological effects and multiple lipid mediators have been described to be involved in physiological processes, (e.g. inflammation). Accordingly, a thorough description of these pathways may shed light on putative relations in multiple complex diseases, including chronic obstructive pulmonary disease, asthma, Alzheimer's disease, multiple sclerosis, obesity, and cancer. Due to the structural complexity of lipids and the low abundance of many lipid mediators, mass spectrometry is the most commonly employed method for analysis. However, multiple challenges remain in the efforts to analyze every lipid subfamily. In this review, the biological role of sphingolipids, glycerolipids, oxylipins (e.g. eicosanoids), endocannabinoids, and N-acylethanolamines in relation to health and disease and the state-of-the-art analyses are summarized. The characterization and understanding of these pathways will increase our ability to examine for interrelations among lipid pathways and improve the knowledge of biological mechanisms in health and disease.
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Affiliation(s)
- David Balgoma
- Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, Stockholm, Sweden
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Liquid chromatography–tandem mass spectrometry analysis of free and esterified fatty acid N-acyl ethanolamines in plasma and blood cells. Anal Biochem 2013. [DOI: 10.1016/j.ab.2012.11.008] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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