Docosahexaenoic acid,22:6n-3: its roles in the structure and function of the brain

Kokoteksti

(1)UEF//eRepository DSpace Rinnakkaistallenteet. https://erepo.uef.fi Terveystieteiden tiedekunta. 2019. Docosahexaenoic acid,22:6n-3: its roles in the structure and function of the brain Mallick, Rahul Elsevier BV Tieteelliset aikakauslehtiartikkelit © ISDN CC BY-NC-ND https://creativecommons.org/licenses/by-nc-nd/4.0/ http://dx.doi.org/10.1016/j.ijdevneu.2019.10.004 https://erepo.uef.fi/handle/123456789/7832 Downloaded from University of Eastern Finland's eRepository.

(2) Journal Pre-proof Docosahexaenoic acid,22:6n-3: its roles in the structure and function of the brain Rahul Mallick, Sanjay Basak, Asim K. Duttaroy. PII:. S0736-5748(19)30214-X. DOI:. https://doi.org/10.1016/j.ijdevneu.2019.10.004. Reference:. DN 2396. To appear in:. International Journal of Developmental Neuroscience. Received Date:. 22 August 2019. Revised Date:. 10 October 2019. Accepted Date:. 11 October 2019. Please cite this article as: Mallick R, Basak S, Duttaroy AK, Docosahexaenoic acid,22:6n-3: its roles in the structure and function of the brain, International Journal of Developmental Neuroscience (2019), doi: https://doi.org/10.1016/j.ijdevneu.2019.10.004. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier..

(3) Docosahexaenoic acid,22:6n-3: its roles in the structure and function of the brain Rahul Mallick1, Sanjay Basak2 & Asim K. Duttaroy3# a.k.duttaroy@medisin.uio.no 1. Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for. Molecular Sciences, University of Eastern Finland, Finland ICMR-National Institute of Nutrition, Hyderabad, India. 3. Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine,. -p. #. ro. University of Oslo, Norway. of. 2. Corresponding Author: Professor Asim K. Duttaroy, Faculty of Medicine,. re. University of Oslo, POB 1046 Blindern, N-0316 Oslo, Norway, Tel: +47 22 85 15 47,. Highlights. Docosahexaenoic acid,22:6n-3 (DHA) is important for brain growth and. ur na. . lP. Fax: +47 22 85 13 41. development. Dietary intake of DHA is recommended throughout the life cycle. . DHA and its metabolites are involved in the brain structure and function. . DHA deficiency is observed in brain disorders. Jo. . . Clinical trials of DHA supplementation improve brain function. 1.

(4) Abstract: Docosahexaenoic acid,22:6n-3 (DHA) and its metabolites are vital for the structure and functional brain development of the fetus and infants, and also for maintenance of healthy brain function of adults. DHA is thought to be an essential nutrient required throughout the life cycle for the maintenance of overall brain health. The mode of actions of DHA and its derivatives at both cellular and molecular levels in the brain are emerging. DHA is the major prevalent fatty acid in the brain membrane.. of. The brain maintains its fatty acid levels mainly via the uptake of plasma free fatty acids. Therefore, circulating plasma DHA is significantly related to cognitive abilities during. ro. ageing and is inversely associated with cognitive decline. The signaling pathways of DHA and its metabolites are involved in neurogenesis, antinociceptive effects, anti. -p. apoptotic effect, synaptic plasticity, Ca2+ homeostasis in brain diseases, and the functioning of nigrostriatal activities. Mechanisms of action of DHA metabolites on. re. various processes in the brain are not yet well known. Epidemiological studies support a link between low habitual intake of DHA and a higher risk of brain disorders. A diet. lP. characterized by higher intakes of foods containing high in n 3 fatty acids, and/or lower intake of n 6 fatty acids was strongly associated with a lower Alzheimer's Disease and other brain disorders. Supplementation of DHA improves some behaviors. ur na. associated with attention deficit hyperactivity disorder, bipolar disorder, schizophrenia, and impulsive behavior, as well as cognition. Nevertheless, the outcomes of trials with DHA supplementation have been controversial. Many intervention studies with DHA have shown an apparent benefit in brain function. However, clinical trials are needed. Jo. for definitive conclusions. Dietary deficiency of n 3 fatty acids during fetal development in utero and the postnatal state has detrimental effects on cognitive abilities. Further research in humans is required to assess a variety of clinical outcomes, including quality of life and mental status, by supplementation of DHA.. Keywords:. Docosahexaenoic. acid,22:6n-3;. cognitive;. brain. development;. endocannabinoid system; marine oil; neurogenesis; resolvins; clinical trials; DHA uptake; FABPs; brain disorders 2.

(5) Abbreviations: AA : Arachidonic acid; AD: Alzheimers disease; ADHD: Attention deficit hyperactivity disorder; ALA: α-linolenic acid, 18:3n-3; APOE : Apolipoprotein E; B-FABP: Brainfatty acid-binding proteins; COX: Cyclooxygenase; CYP : Cytochrome P450; DHA:Docosahexaenoic acid,22:6n-3; EDPs: Epoxydocosapentaenoic acids; EPA: Eicosapentaenoic acid,20:5n-3; EFOX : Electrophilic oxo-derivatives; FABP : Fatty. of. acid-binding proteins; FAHFA : Fatty acid esters of hydroxy fatty acids; FADS2 : Delta 6 desaturase enzyme; GPRs : G-protein coupled receptors; H-FABP: Heart-fatty acidproteins;. HPA. :. Hypothalamus-Pituitary-Adrenal;. ro. binding. HDoHE:. -p. Hydroxydocosahexaenoic acids; HpDHA : DHA hydroperoxides; LCPUFA : Longchain polyunsaturated fatty acids; MaR1 : Maresin 1; NPD1 : Neuroprotectin D1;. re. LOX:Lipoxygenases; NO : Nitric oxide; PEMT : Phosphatidyl ethanolamine–N– methyltransferase; p-FABPpm: Placental plasma membrane fatty acid-binding. lP. protein; PPAR :Peroxisome proliferator-activated receptor; PPAR-α : Peroxisome proliferator-activated receptor α; PPAR-γ : Peroxisome proliferator-activated. ur na. receptor gamma; PUFAs:Polyunsaturated fatty acids; RXR : Retinoid X receptor:. Jo. Specialized pro-resolving mediators. 3.

(6) 1.Introduction: α-Linolenic acid,18;3n-3 (ALA) and linoleic acid, 18:2n-6 (LA) are the two essential fatty acids for human health. ALA is available in plant oils, e.g., walnut, edible seeds (hemp, chia), canola, kukui, flaxseed oil and hemp oil whereas its long-chain polyunsaturated fatty acids (LCPUFAs) eicosapentaenoic acid,20:5n-3 (EPA) and docosahexaenoic acid, 22:6n-3 (DHA) are obtained from marine fish and oils. In. of. healthy young adults, consumed ALA from the diet can be converted into EPA and DHA in little amount (Burdge and Wootton, 2002), but with age, the conversion. ro. capability is reduced (Bradbury, 2011). DHA is, therefore, a conditionally essential. -p. fatty acid for human health. DHA influences numerous processes in the body, e.g., signal transduction, membrane structure and function, cellular proliferation,. re. inflammation, angiogenesis and host of other processes affecting health and disease (Basak et al. , 2013, Bradbury, 2011, Quinn et al. , 2010b). DHA metabolites also play. lP. a significant role in different biological and cellular processes. Risk of inflammatory disorders, cognitive disorders, insufficient brain growth and development may occur. ur na. due to low intake of DHA and its precursor EPA (Quinn et al., 2010b). DHA is also recommended to treat cardiovascular disease (CVD) risk factors such as hypercholesterolemia, hypertriglyceridemia, and hypertension (Mori et al. , 2000a, Mori et al. , 2000b). Higher intake of DHA is usually recommended to prevent CVD.. Jo. EPA is mostly involved in cell signalling, whereas DHA is mainly used for cell membrane structure and function (Bradbury, 2011, Innis, 2008). However, recently several studies demonstrated the signalling pathways of DHA metabolites in the brain. A significant number of reviews are available on DHA and human brain (Bradbury, 2011, Brenna and Carlson, 2014, Salem and Eggersdorfer, 2015, Sun et al. , 2018). This. 4.

(7) review describes the roles of DHA and its metabolites in the structure and function of the human brain. 2. DHA uptake and metabolism in human DHA is mostly deposited in the brain and retina, whereas its distribution in other tissues such as heart, liver, skeletal muscle, adipose tissue, blood cell is low. The most significant n-3 fatty acid present in the brain is DHA, whereas EPA and ALA are. of. present in very small amounts. DHA constitutes over 90% of the n-3 PUFAs in the. brain and constitutes 10%–20% of its total lipids(Brenna and Carlson, 2014). DHA is. ro. especially found in the grey matter(Suzuki et al. , 1997). In a cellular context, DHA is. -p. esterified into the cell membrane phospholipids mostly in phosphatidylethanolamine and phosphatidylserine and other complex lipids (Calder, 2016). Following insertion. re. into the cell membrane, DHA interacts with cholesterol that influences the membrane phospholipid width by packing constraints and conformation of adjacent phospholipid. lP. acyl chains (Sherratt and Mason, 2018). Physical nature of DHA increases electron density in the phospholipid head group region within the cell membrane, which. ur na. attributes rapid conformational changes. Owing to the unique structure, DHA is capable of providing a wide range of cell membrane structure and functions. Thus, DHA affects different biophysical characteristics and physiological processes such as membrane fluidity, lipid raft function, neurotransmitter release, membrane receptors, gene. Jo. expression, signaling pathways, myelination, inflammation, and cell growth and differentiation (Duttaroy, 2016, O'Brien and Sampson, 1965, Sun et al., 2018, Suzuki et al., 1997). Depending on the maternal supply of ALA, EPA or DHA, DHA accumulates in the fetal brain during the last period of pregnancy. The brain’s frontal lobes are more responsive to DHA supply in adolescent and older adults for executive and higher-order cognitive activities (Goustard-Langelier et al. , 1999).. 5.

(8) EPA plays a dominant role in inhibiting delta-5-desaturase enzyme-mediated production of the arachidonic acid,20:4n-6(AA). Therefore, the AA derived proinflammatory eicosanoids (prostaglandins, thromboxanes, leukotrienes) are inhibited by EPA intake in the diet. Also, EPA competes with AA for phospholipase A2 enzyme. These are unique roles of EPA whereas DHA neither fits the catalytic site of delta-5desaturase enzyme nor competes with AA for phospholipase A2 enzyme due to its. of. massive spatial structure. Unlike DHA, EPA level is not high enough in the brain to contribute to neurological function. EPA is reported to be rapidly oxidized in the brain. ro. (Chen et al. , 2009).. -p. While EPA inhibits the delta-5-desaturase enzyme that directly inhibits AA, DHA inhibits another role-playing enzyme delta-6-desaturase enzyme that involves in. re. LA metabolism (Sato et al. , 2001). Due to more massive spatial structure, DHA sweeps out a higher volume of fluid in the membrane than EPA which increases in membrane. lP. fluidity for critical synaptic vesicles and the retina to transmit signals from the surface of the membrane to the interior of the nerve cells. DHA may also involve in the breakup. ur na. of lipid rafts in membranes due to its continuous sweeping motion (Chapkin et al. , 2008). As a result, cancer cells cannot survive, and inflammatory cytokines struggle to initiate signaling responses (Li et al. , 2005). The spatial characteristics of DHA cause an increase in the LDL particle sizes comparatively, which reduces the entry of LDL. Jo. particles into arterial muscle cells to develop atherosclerosis lesions (Mori et al., 2000a).. 3. Dietary and metabolic sources of DHA and its worldwide consumption DHA and EPA are present together ubiquitously in marine mammals and plant plankton, whereas all terrestrial plants contain ALA. DHA and EPA are present in marine sources as triacylglycerols and phospholipids. Usually, 100 grams of cooked. 6.

(9) salmon fish contains 500-1500 mg DHA. Caviar, anchovies, mackerel, and herring are the other high sources of DHA (Agriculture, 2005). Beef, lamb, pork, and chicken contain around 0.02 gm of DHA per 100 gm of meat (Calder, 2016). Although DHA is mainly obtained from marine fish sources, nowadays, DHA is commercially manufactured from microalgal sources such as Crypthecodinium cohnii and Schizochytrium (Ulven and Holven, 2015). The metabolic biosynthesis of DHA via a. of. series of elongation, desaturation, and beta-oxidation reactions from EPA is known as “Sprecher’s Shunt” (Burdge et al. , 2002, Burdge and Wootton, 2002). Maternal DHA. ro. supplementation can contribute to brain and visual development and function of the. -p. fetus and the infant. Maternal breast milk also contains DHA around 0.32% of total fatty acid (Calder, 2016). N-3 LC-PUFA dietary supplements are widely available,. re. usually in the triacylglycerol, non-esterified fatty acid, and ethyl ester forms. The fish oil supplements are reported not only have n-3 LCPUFA contents well below those. lP. claimed by labels but are also considerably oxidized(Albert et al. , 2015); however, the associated health implications of consuming oxidized LCPUFAs are unclear(Myhrstad. ur na. et al. , 2016). The human body converts ALA to EPA and DHA via desaturases and elongases. pathways. ALA and LA compete for the same desaturase and elongase in order to form their respective LCPUFA metabolites (Chilton et al. , 2014, Duttaroy, 2009). Low. Jo. levels of vitamin B6, magnesium, zinc and ageing reduce the delta 6 desaturase activity. The activity of delta-6-desaturase is also blocked by trans fats, present in hydrogenated. oils, fast foods, and many packaged foods. The delta 6 desaturase activity is decreased in chronic alcoholism and in diabetes. Delta 5 desaturase is inhibited by deficiencies of vitamin C, niacin and zinc. Higher intakes of LA can dominate these enzymes, especially the delta 6 desaturase enzyme (FADS2); thus biosynthesis of EPA and DHA. 7.

(10) from ALA is reduced. So, consumption of the higher amount of ALA can increase DHA level to some extent; however, this may not increase plasma DHA in humans sufficiently (Neff et al. , 2010, Plourde and Cunnane, 2008). Figure-1 shows the conversion of dietary ALA to EPA and DHA. In order to increase the DHA level in the body, dietary supplementation of DHA is the most preferred strategy (Cunnane et al. , 2013). The synthesis of DHA from ALA by elevating levels of enzymes such as FADS2. of. and elongase 2 by curcumin is promising. Interestingly, curcumin also enhances DHA absorption (Wu et al. , 2015). Curcumin is widely consumed as a cooking spice in. ro. Indian sub-continent; therefore, the low intake of DHA in this population may be. -p. compensated by the curcumin intake. Another nutraceutical, quercetin enhanced the anti-inflammatory effects of DHA on LPS-stimulated inflammatory response in. re. microglial cells (Sun et al. , 2019). These studies indicate that the certain phytochemicals may enhance the synthesis, bioavailability and functionalities of DHA;. lP. however, further work is required to promote the role of these phytochemicals in DHA mediated human health effects.. ur na. Retro-conversion of DHA to EPA occurs in the peroxisomes via β-oxidation to remove the double bond at position 4. Retro-conversion of DHA is more common in non-neural cells than neural cells (Park et al. , 2016). However, recently it was shown that increased plasma level of EPA in human following DHA supplementation did not. Jo. occur via retro-conversion rather a result of slowed metabolism and/or accumulation of plasma EPA(Metherel et al. , 2019).. During the last 30 years or so, the increasing. incidence of several metabolic diseases are thought to be due to the results of high dietary intake of n-6 fatty acid containing foods and oils compared with n-3 fatty acids, thus increased the ratio of n-6:n-3 fatty acids (20:1) intake to a much higher level than the recommended ratio for optimal health benefits (Simopoulos, 2016).. 8.

(11) DHA intake among developed countries varies a lot. DHA intake is the highest among the people in Iceland (793.4 mg/day). Even in the USA, daily DHA intake is around 3.5 times lower than that of Iceland. Among the Scandinavian countries, Danish people consume the highest level of DHA (232.3 mg/day). The highest and lowest DHA consumption levels in developing countries by the people of Maldives (1409.3 mg/day) and Ethiopia (7.01 mg/day) respectively. Estimated dietary intake indicate that the. of. people from India consume only 52.1 mg DHA/day, while people from Bangladesh consume 167 mg DHA/day through diet. Pakistanis (24 mg/day) and Nepalese (23.2. ro. mg/day) consume the lowest level of DHA among all South-Asian countries (Forsyth. -p. et al. , 2016). Overall, the daily intake of DHA as a per cent of daily total energy intake (% energy) from food sources is highest in Japan (0.152%) followed by China. re. (0.090%), USA and Canada (0.055%). The people from Oceania and Europe continents consume 0.052% DHA of total energy intake. However, these data had several. lP. limitations including the fact that the data did not directly measure food consumption but instead reflected the food supply in a certain country and might not accurately. ur na. reflect the real intake of DHA. DHA consumption is lowest in low-income countries (Forsyth et al., 2016). The countries having access to coastal areas consume a greater amount of seafood, and therefore, dietary intake of DHA in these countries is quite higher than other countries comparatively. N-3 PUFA intake of 0.5-2.0% of total. Jo. energy is recommended for adults. Dietary intakes of 0.1-0.18% DHA of total energy for infants above six months old and 10-12 mg of DHA/Kg body weight for infants aged up to six months are recommended (WHO and FAO, 2008). Pregnant or breastfeeding mothers are advised to consume 200 mg of DHA, or 300–900 mg of combined EPA and DHA per person per day. Vegetarians and vegans can take microalgae supplements that contain DHA (Davis and Kris-Etherton, 2003, Yurko-. 9.

(12) Mauro et al. , 2010). The European Food Safety Authority (EFSA) recommended a maximum dose of 5g/day of EPA+DHA as safe(EFSAReport). 4. DHA and its impact on the structure and function of the brain As a crucial structural membrane component of the brain, DHA is present in the cerebral cortex, synaptic membrane regions, retinal mitochondria, and photoreceptors. Brain and retina tissues contain around 40% and 60% DHA of total PUFAs,. of. respectively. DHA is present in high amounts in retinal photoreceptors and is therefore essential for visual function(Liu et al. , 2011). Animal studies and human observational. ro. studies have suggested that there is an inverse relationship between dietary intake of n-. 3 LCPUFAs and the risk of developing age related macular degeneration. The data. -p. from intervention trials have been mixed, although the delayed progression of an. re. intermediate type of age related macular degeneration was reported earlier (Huang et al. , 2008). The later studies did not find any positive effect on the age-related macular. lP. after supplementation with n-3 LCPUFAs (Souied et al. , 2015, Wu et al. , 2017). The X-linked retinitis pigmentosa was shown to be improved with DHA supplementation (Hoffman et al. , 2004). The recent clinical trial did not observe such improvement for. ur na. X-linked retinitis pigmentosa(Hoffman et al. , 2014). However, some positive effects, such as the reduced elevation in final dark-adapted thresholds and slowed loss of the visual field sensitivity, were observed(Hoffman et al. , 2015). Neuronal cell membranes contain approximately 50% DHA (Calder,. Jo. 2016, Singh, 2005). DHA contributes around 15% of the total fatty acid composition in. the adult prefrontal cortex. DHA is important for hippocampal and cortical neurogenesis, neuronal migration, and outgrowth (Calderon and Kim, 2004, Cao et al. , 2005, Kawakita et al. , 2006). DHA suppresses cell death by promoting cell-cycle exit in neuro-progenitor cells (Insua et al. , 2003, Kawakita et al., 2006). Along with other fatty acids, DHA has a significant role in monoaminergic and cholinergic systems. 10.

(13) during brain development (Aïd et al. , 2003, Chalon, 2006, Innis, 1991). Prenatal DHA supply has a long term effect on serotonergic and dopaminergic neurotransmission (Anderson et al. , 2005, Chalon, 2006) indicating the importance of DHA as a nutrient in early brain development. DHA influences gene expression, neurotransmission, and oxidative stress (Innis, 2018). DHA is an essential factor for neurogenesis, phospholipid synthesis, and turnover (Coti Bertrand et al. , 2006, Kawakita et al., 2006,. of. Salem et al. , 2001). The brain is atrophied in different neurodegenerative diseases. Brain atrophy is. ro. also associated with age and cognitive degradation. Various studies showed that DHA could improve learning and memory, along with neuronal loss reduction (Weiser et al.. -p. , 2016). DHA accumulates during intrauterine fetal brain growth and maintains its levels lifelong (Carver et al. , 2001). DHA accumulation in the fetal brain is highest. re. during the third trimester of pregnancy. DHA incorporation into brain membrane in. lP. early life solely depends on its supply via the placenta, breastfeeding, and endogenous LCPUFAs production(Duttaroy, 2016, Innis, 2008, Lauritzen et al. , 2016). DHA has a significant role in both brain and retinal development (Authority, 2011, Lauritzen et al.,. ur na. 2016). Since the brain has a critical developmental window in utero as well as during the postnatal life, therefore, any perturbations such as nutritional and environmental or postnatal nutrition would significantly affect brain development. During critical periods of development, any perturbation leads to profound and potentially irreversible defects. Jo. of brain maturation. A significant linear relationship between maternal DHA level and umbilical cord plasma phospholipid contents are observed (Calder, 2016). Optimal placental growth and development are crucial for the effective exchange of nutrients and waste products between the mother and the fetus(Basak et al., 2013). The growing fetus mostly depends on the placental supply of maternal DHA due to its limited DHA synthetic capacity (Duttaroy, 2000). Aberrant placental development with a deranged. 11.

(14) vasculature may influence fetal development and survival(Duttaroy, 2016). Recent studies suggested that DHA has a role in early placentation processes along with the brain and retinal development during the last trimester of pregnancy(Basak et al., 2013, Duttaroy, 2000, Johnsen et al. , 2011). Preferential transfer of maternal DHA to the fetus during the last trimester of pregnancy was suggested to be performed by the highaffinity placental plasma membrane fatty acid-binding protein (p-FABPpm)(Duttaroy,. of. 2009). Intracellular DHA is transported by FABPs (please see details on FABP in the. ro. next section). DHA is the ligand for peroxisome proliferator-activated receptor gamma. (PPAR-γ), which is expressed in the embryonic mouse brain and neural stem cells. The. -p. critical early brain development regulator, PPAR-γ heterodimerizes with the retinoid X. re. receptor (RXR) and regulates the transcription of target genes (Wada et al. , 2006). DHA is one of the key ligands for brain RXR (Lengqvist et al. , 2004). Along with. lP. retinoic acid receptor, RXR plays an important role in embryonic neurogenesis, neuronal plasticity, and catecholaminergic neuron differentiation. RXR is highly expressed in the hippocampus (Lengqvist et al., 2004, Rioux and Arnold, 2005). As a. ur na. free radical scavenger, DHA protects the developing brain from peroxidative damages of lipid and protein (Cao et al. , 2004, Green et al. , 2001, Okada et al. , 1996). 5. Fatty acid transport and metabolism in the human brain It is generally assumed that the transport of fatty acids to the tissues occurs in. Jo. the form of the non-esterified pool of fatty acids (FFAs) bound to serum albumin. The plasma FFAs is transferred across the cell via fatty acid membrane transporters (FAT, FABPpm. FATP) and cytoplasmic fatty acid-binding proteins (FABPs) (Duttaroy, 2009). Figure-2 summarises the putative roles of fatty acid-binding/transport proteins in the uptake of free fatty acids. Recent studies showed that the mammalian brain uniquely takes up DHA in the form of lysophosphatidylcholine (LPC-DHA)(Chan et 12.

(15) al. , 2018). LPC-DHA uptake is mediated by the major facilitator superfamily domaincontaining protein 2 (Mfsd2 or Mfsd2a) present at the blood-brain barrier(Nguyen et al. , 2014). Therefore it may be necessary to increase the plasma level of LPC-DHA for efficient enrichment of brain DHA in human, however further work is required for confirmation. An essential requirement common to both prenatal and postnatal brain development is the biosynthesis of a huge amount of membrane phospholipid, the. of. origin of which was believed to be exclusively derived from de novo biosynthesis. within cells of the brain, and acquisition of essential fatty acids from the periphery into. ro. the developing brain. A major function of DHA during brain development is to regulate. saturation(Huang et al. , 2017).. -p. SREBP-1 and SREBP-2 activity resulting in major changes in phospholipid FABP is thought to play a crucial role in the. re. cytoplasmic fatty acid transfer and thus help fatty acids affect gene expression and synthesis of other metabolites. There are two types of FABPs available in the brain: (1). lP. B-FABP, which is found in ventricular germinal and glial cells in the embryonic brain and in the astrocytes of developing and adult brains and (2) H-FABP, which is only. ur na. available in adult brains (Owada et al. , 2006, Veerkamp and Zimmerman, 2001). DHA has a preference for binding with B-FABP that may be necessary for early neurogenesis or neuronal migration (Owada et al., 2006). Fatty acid metabolism is one of the vital steps for energy requirement in the. Jo. brain. Brain gets 20% of total energy from β-oxidation of fatty acid in mitochondria of astrocytes. In the pre-oxidation step, fatty acids are initially converted to fatty acyl-CoA by acyl-CoA synthases. Besides mitochondria, peroxisome also plays a significant role in fatty acid metabolism. Peroxisome proliferator-activated receptor α (PPAR-α) stimulates the expression of catabolic enzymes, such as the CPT family, and acyl-CoA dehydrogenases in low energy status (Tracey et al. , 2018). Through the β-oxidation,. 13.

(16) very long and branched-chain fatty acids are oxidized to shorten them. Also, αoxidation clears a single carbon from fatty acids that are incapable of typical βoxidation in peroxisome (Tracey et al., 2018). The peroxisomal β-oxidation is unable to breakdown the full fatty acids, while mitochondria degrade the fatty acids completely via the tricarboxylic acid pathway (Tracey et al., 2018).. However, for energy. production, utilization of fatty acids is increased significantly during fasting or extreme. of. exertion which may damage the brain due to reactive oxygen species, specifically in the form of superoxide (Tracey et al., 2018).. ro. Another important pathway for the utilization of fatty acids in brain astrocytes. -p. is the ketogenesis pathway. Ketone bodies may form from fatty acid-derived acetylCoA in the hypoglycemic condition. In suitable condition, these ketone bodies are lysed. re. again into acetyl-CoA, which again enter into the tricarboxylic acid cycle (Tracey et al., 2018).. lP. 6. Roles of DHA and its metabolites in brain function. As an integral component of cell membrane phospholipid, DHA contributes to. ur na. maintaining membrane fluidity and lipid raft assembly and other membrane functions. DHA influences electrical, chemical, hormonal, or antigenic signals of the cells. One study demonstrated that higher signal transduction mediated by two DHA molecules than no or one DHA molecule along with other highly unsaturated fatty acids in the. Jo. phospholipid bilayer (Calder, 2016). DHA acts via cell membrane surface and intracellular receptors. DHA promotes membrane-associated G-protein-coupled receptor (GPR)120 mediated gene activation to promote anti-inflammatory conditions (Oh et al. , 2014). DHA also activates PPARs and upregulates PPAR targeted genes to increase insulin sensitivity, reduce plasma triglyceride level and inflammation (Calder, 2016). Dietary intervention plays a significant role to maintain healthy brain function,. 14.

(17) which prevents stress, depression, and brain degenerative disorders (McEwen, 2010, Sun et al., 2018). The beneficial effects of DHA are mediated by the fatty acid itself (PPAR ligand) as well as by its bioactive metabolites. DHA and its metabolites have a wide range of actions at different levels and sites (Diep et al. , 2000, Zúñiga et al. , 2011). The DHA metabolites have a wide range of actions at different levels and sites. Table-1 summarizes various functions of DHA metabolites. Bioactive DHA-. of. derived specialized pro-resolving mediators (SPMs), DHA epoxides, electrophilic oxoderivatives (EFOX) of DHA, neuroprostanes, ethanolamines, acylglycerols,. ro. docosahexaenoyl amides of amino acids or neurotransmitters, and branched DHA. -p. esters of hydroxy fatty acids are the metabolic end products of DHA (Anderson and Taylor, 2012, Robertson et al. , 2013). Also, epoxydocosapentaenoic acids (EDPs) and. re. 22-hydroxydocosahexaenoic acids (22-HDoHEs) are the metabolized from DHA (Kuda, 2017, Westphal et al. , 2011). 5-, 12- and 15-lipoxygenases (LOX), COX-2 and. lP. cytochrome P450 (CYP) are the responsible enzymes for DHA metabolism. Table - 2 summarizes the enzymes responsible for DHA metabolism. As most exigent by-. ur na. products of DHA, resolvins are formed by either LOX15 or CYP or aspirin-treated COX-2 stimulation (Figure- 3) (Duvall and Levy, 2016, Sun et al., 2018). Although the LOX15 treated formed resolvins are homologous to CYP, or aspirin-treated formed resolvins (Duvall and Levy, 2016). As the potential inflammation resolution mediators,. Jo. resolvins act through a different GPR (Duvall and Levy, 2016, Serhan, 2014). The neuroprotectors, resolvin D1, and aspirin-triggered resolvin D1 improve. brain functions and impair neuronal death by downregulating NF-kB, TLR4, CD200, and IL6R (Bisicchia et al. , 2018, Recchiuti et al. , 2010). They induce remote functional recovery after brain damage (Bisicchia et al., 2018). Resolvin D2 and aspirin-triggered resolvin D2 protect from cerebral ischemic injury through ERK1/2. 15.

(18) phosphorylation followed by stimulation of nNOS or eNOS to inhibit programmed neuronal cell death and increase zonula occludens-1 for the maintenance of blood-brain barrier integrity (Zuo et al. , 2018). Resolvin D3, resolvin D5, aspirin-triggered resolvin D3, and aspirin-triggered resolvin D5 halt neuroinflammatory process (Dalli et al. , 2013, Hong et al. , 2005). However, the functions of other resolvins are still not known. Table 3 shows the DHA-derived resolvins and their receptors with functions.. of. Macrophage derived anti-inflammatory pro-resolving mediator; maresins are biosynthesized from DHA in response to inflammation, healing, and regeneration. ro. process (Ariel and Serhan, 2012, Stables et al. , 2011, Zhang and Spite, 2012). Maresin. -p. 1(MaR1) is the leading subtype of maresins. Along with the reduction of LTB4 production, MaR1 stimulates macrophagic phagocytosis and efferocytosis at the. re. inflammatory site (Serhan et al. , 2015b, Serhan et al. , 2012, Serhan et al. , 2008). MaR1 regulates stem cell differentiation to accelerate tissue repair along with an. lP. analgesic role via TRPV1-mediated responses blockage (Serhan et al., 2012, Yanes et al. , 2010). MaR1 plays a role in the improvement of neurocognitive functions by. ur na. regulating macrophage infiltration, NF-κB signaling, oxidative stress, and after cytokine release Maresin 1 attenuates neuroinflammation in a mouse model of perioperative neurocognitive disorders (Yang et al. , 2019). Also, MaR1 has shown significant improvement of locomotive function in a post-spinal cord injury model. Jo. (Francos-Quijorna et al. , 2017).. Neuroprotectin D1(NPD1) is one of the DHA derived SPMs, improve brain cell. survival, and repair in ageing and neurodegenerative diseases (Bazan et al. , 2011). Like MaR1, NPD1 also possesses anti-inflammatory and neuroprotective activity (Balas and Durand, 2016). However, NPD1 has anti-apoptotic activity, which makes it unique from MaR1 (Ariel et al. , 2005, Serhan et al., 2015b). In response to neuroinflammation,. 16.

(19) NPD1 is produced from endogenous DHA in retina and brain (Bazan, 2005, Calandria et al. , 2009). Besides antiviral protection, NPD1 helps in neurocognitive functions (García-Sastre, 2013, Morita et al. , 2013, Zhao et al. , 2011). NDP1 can repress inflammation, oxidative stress, and cell apoptosis induced by Ab 42 and promote neuronal survival. NDP1 may prevent Alzheimer's disease progression through upregulating PPARγ, amyloid precursor protein-α, and downregulating β-amyloid. of. precursor protein. Thus, the amyloid-β peptide is reduced in neuronal tissue (Zhao et al., 2011).. ro. Anti-inflammatory signaling properties of EFOX and neuroprostanes are. -p. beneficial for different neuroinflammatory disorders in association with Parkinson’s disease, and Alzheimer’s disease (Dyall, 2015, Gladine et al. , 2014, Groeger et al. , On the other hand, docosahexaenoyl ethanolamide improves energy. re. 2010).. homoeostasis in association with mood, pain modulation, anti-inflammation, hunger,. lP. and glucose uptake in the brain through the endocannabinoid system (De Petrocellis et al. , 1999, Kim et al. , 2014, Piazza et al. , 2007, Soderstrom, 2004, Valenti et al. , 2005,. ur na. Watanabe et al. , 2003).. DHA glyceryl ester controls food intake and neuroinflammation in the brain in. the same fashion as docosahexaenoyl ethanolamide by using the endocannabinoid system (D'Addario et al. , 2014, Masoodi et al. , 2015). As an integral part of brain. Jo. structure, the endocannabinoid system has a significant role in memory, cognition, and pain perception (Wagner and Alger, 1996, Wilson and Nicoll, 2002). DHA conjugates reduce neuroinflammation and cause neurogenesis by acting on cannabinoid receptors (Calder, 2013, Lu and MacKie, 2016). Stress-induced hormone production via hypothalamus-pituitary-adrenal (HPA) axis pathways can be regulated and modulated by nutritional approaches (Lupien et al.. 17.

(20) , 2009, Ranabir and Reetu, 2011). The lipid is an integrated part of the brain, so fatty acid status should have a relationship with stress (Laugero et al. , 2011, O'Brien and Sampson, 1965). Adequate dietary DHA supplementation lowers HPA activation, corticosterone peak, and stress-induced weight loss (Chen and Su, 2013, Hennebelle et al. , 2012). Not only to alleviate short-term stress, but DHA also has a significant role in brain development, which prevents anxiety and stress in later life (Robertson et al.,. of. 2013, Song et al. , 2008). Although, due to some conflicting precedents for association. with PUFA supplementation and cognitive development, it has become more critical to. ro. determine optimum DHA doses for effective neurodevelopment at different ages. -p. (Qawasmi et al. , 2012, Simmer et al. , 2011, Smithers et al. , 2008). Stress stimulated TNF-alfa, and IFN-γ production, lipopolysaccharide (LPS) stimulated IL-6 production. re. are reduced by a significantly higher level of DHA supplementation (Kiecolt-Glaser et al. , 2011, Lucas et al. , 2009, Maes et al. , 2000, Robertson et al., 2013).. lP. Though stress and anxiety have a close relationship with depression, DHA is suggested to be an important nutrient for preventing and treating depression (Murray. ur na. and Lopez, 1996, Robertson et al., 2013). DHA has shown some beneficial effects in the treatment of various psychiatric disorders, e.g., schizophrenia, unipolar and bipolar mood disorders, anxiety disorders, obsessive-compulsive disorder, ADHD, autism, aggression, hostility and impulsivity, borderline personality disorder, substance abuse. Jo. and anorexia nervosa (Bozzatello et al. , 2016, Sun et al., 2018). During the last decades several trials using n-3 LCPUFAs in mental diseases were performed. However, the findings of most of the trials are controversial and inconclusive(Pusceddu et al. , 2016, Sun et al., 2018). There is evidence that consumption of n-3 fatty acids containing fishes reduce depression (Hibbeln, 1998). However, the studies have shown that EPA is more potent. 18.

(21) to treat depression than DHA (Bourre, 2005, Marangell et al. , 2003, Peet and Horrobin, 2002). Lower pro-inflammatory plasma IL-6 level and higher EPA/AA ratio have been observed in PUFA treated depressed patients (Lin and Su, 2007). Higher consumption of marine fish improves cognitive function (Van Gelder et al. , 2007). DHA has a significant role in the reduction of dementia risk (Schaefer et al. , 2006). Neuroinflammation can be dampened by DHA supplementation in the. of. pathogenesis of Alzheimer’s disease (Kinney et al. , 2018, Trépanier et al. , 2016). DHA derived anti-inflammatory eicosanoids, neuroprotectins prevent Alzheimer's disease. ro. pathogenesis (Lukiw et al. , 2005). DHA regulates Alzheimer's disease-related. -p. processes such as cholesterol and apolipoprotein E (APOE) along with lipid raft assembly alteration and cell signalling regulation (Boudrault et al. , 2009, Hashimoto. re. et al. , 2005). Neuronal protection against cytotoxicity, inhibition of nitrogen oxide production, calcium influx, activation of antioxidant enzymes (glutathione peroxidase. lP. and glutathione reductase) and reduction of apoptosis are the significant molecular functions of DHA (Seidl et al. , 2014). The second most prevalent neurodegenerative. ur na. disease, Parkinson’s disease is suggested to be prevented by the neuroprotective role of DHA (Seidl et al., 2014). Attention deficit hyperactivity disorder (ADHD) is another common neurodevelopmental disorder among school-aged children that leads to severe problems in social behavior. Studies showed evidence for the successful treatment of a. Jo. mild form of ADHD symptoms with DHA supplementation (Kiliaan and Königs, 2016). Several reviews on DHA supplementation in ADHD were published in recent years(Ramalho et al. , 2018, Sun et al., 2018). Despite the heterogeneity of the studies, DHA may contribute to improvements in the capacity of reading, learning , nonverbal cognitive development, perceptive visual capacity and executive function of. 19.

(22) ADHD children. Future in depth large-scale, well-designed randomized clinical trials are required to achieve evidence for clinical recommendations. Bipolar disorder of the brain is characterized by periods of depression and mania. DHA improves depressive symptoms of bipolar disorder by increasing N-acetylaspartate levels in the brain, but it has no significant effects on the protection of mania (Bozzatello et al., 2016). Intelligence quotient in children and cognitive function in the. of. ageing brain are improved by DHA supplementation (Lauritzen et al., 2016, Weiser et al., 2016). Sun et al. (Sun et al., 2018)recently reviewed the mechanistic relationships. ro. of brain DHA with different mental disorders, including autism. Interestingly the. -p. studies have been reported that EPA in association with DHA improves outcome in cognitive function than DHA alone. DHA can be divided into two different types based. re. on their properties in brain function: lipid-bound DHA in membrane bilayer and unesterified DHA (Innis, 2018). Lipid-bound DHA influences lipid rafting, signal. lP. transduction, and neurotransmission (Chalon, 2006, Grossfield et al. , 2006, Stillwell et al. , 2005). On the other hand, regulation of gene expression and ion channel activities. ur na. are related to unesterified DHA properties (Bazan, 2006, Kitajka et al. , 2002, Vreugdenhil et al. , 2002). DHA also inhibits cell migration, growth arrest and apoptosis of brain tumor cells via activation of PPAR-γ in the nucleus (Mita et al. , 2010).. Jo. 7. DHA deficiency and human brain function As an integral component of brain structure, fatty acids play a significant role. in healthy brain function. Different diseases/disorders, e.g., Alzheimer's disease, Parkinson’s disease, Huntington’s disease, schizophrenia, mood disorders, are linked due to altered membrane fatty acid composition and their signalling in disease progression (Bazinet and Layé, 2014, Shamim et al. , 2018). The encephalopathy “Reye. 20.

(23) syndrome” is causally associated with altered fatty acid oxidation (Orlowski, 1999). A rare congenital peroxisome biogenesis disorder called by "Zellweger syndrome," is linked with abnormal fatty acid accumulation that impairs brain development (Crane, 2014). DHA deficiency is linked with depressive disorder, bipolar disorder (McNamara, 2010, McNamara et al. , 2007). The studies on pregnant women showed that DHA deficiency might lead to poor. of. language skill among children (Mulder et al. , 2014). Even autistic spectrum disorder or ADHD among teenagers is related to DHA deficiency (Bos et al. , 2015, Parellada. ro. et al. , 2017). Due to DHA deficiency, neurocognitive functional insufficiency in young. -p. adults or loneliness related memory problems in middle age has been observed (Bauer et al. , 2014, Jaremka et al. , 2014). DHA deficiency in the third trimester significantly. re. affects brain development(Smith and Rouse, 2017).. 8. Clinical trials of DHA supplementation and brain function. lP. N-3 LCPUFAs supplementation is recommended worldwide for feto-maternal and maternal-childhood growth and development,. and cognitive function of the. ur na. child(Carlson et al. , 2013, Julvez et al. , 2016, Koletzko et al. , 2007, Parra-Cabrera et al. , 2011). DHA supplementation improved pregnancy outcome, gestation, reduction in early preterm and very low birth weight, childhood visual and psychomotor development (Carlson et al., 2013, Shulkin et al. , 2018). Several clinical studies were reported on n-3 LCPUFAs and mental disorders.. Jo. Some of these clinical trials and their health outcomes are presented in Table - 4. Most of the clinical studies did not show any significant effects of DHA supplementation(Sun et al., 2018). Differences in methodologies, the sample size, dietary habit, selection criteria, age, choice and dosage of LCPUFAs (EPA, or DHA, or a combination of EPA+DHA) and the duration of the intervention are mostl possibly responsible for inconclusive results(Sun et al., 2018). 21.

(24) 9. Conclusions The optimal structure and function of the brain are critical for quality of life, productivity and individual growth. DHA and its metabolites influence the brain’s development, structure and functions, signaling pathways, receptor function, and enzyme activities. All these functionalities are critical for optimum brain physiology throughout the lifespan. In order to achieve these functionalities, sustained supply of. of. DHA is required well before conception, during the gestation period, adolescence,. adulthood and adult life. Therefore, maintaining optimal levels of DHA in the brain are. ro. likely to be required throughout the lifespan by obtaining preformed DHA via dietary. -p. or supplementation. Several studies suggest that the consumption of DHA leads to many inherent positive physiological and behavioral effects, however further clinical. re. trials are required to assess different clinical outcomes, including mental health status. Conflicts of Interest:. lP. and quality of life.. ur na. The authors declare no conflict of interest.. Acknowledgements. This study was supported in part by the Thune Holst Foundation, Oslo, Norway References:. Jo. Agriculture UDo. EPA and DHA Content of Fish Species. Appendix G2. 2005. Aïd S, Vancassel S, Poumès-Ballihaut C, Chalon S, Guesnet P, Lavialle M. Effect of a diet-induced n-3 PUFA depletion on cholinergic parameters in the rat hippocampus. Journal of Lipid Research. 2003;44:1545-51. Albert BB, Derraik JG, Cameron-Smith D, Hofman PL, Tumanov S, Villas-Boas SG, et al. Fish oil supplements in New Zealand are highly oxidised and do not meet label content of n-3 PUFA. Sci Rep. 2015;5:7928. Anderson E, Taylor D. Stressing the heart of the matter: re-thinking the mechanisms underlying therapeutic effects of n-3 polyunsaturated fatty acids. F1000 Medicine Reports. 2012;4:13. Anderson GJ, Neuringer M, Lin DS, Connor WS. Can prenatal N-3 fatty acid deficiency be completely reversed after birth? Effects on retinal and brain biochemistry and visual function in rhesus monkeys. Pediatric Research. 2005;58:865-72. 22.

(25) Jo. ur na. lP. re. -p. ro. of. Ariel A, Li PL, Wang W, Tang WX, Fredman G, Hong S, et al. The docosatriene protectin D1 is produced by T H 2 skewing promotes human T cell via lipid raft clustering. Journal of Biological Chemistry. 2005;280:43079-86. Ariel A, Serhan CN. New lives given by cell death: Macrophage differentiation following their encounter with apoptotic leukocytes during the resolution of inflammation. Frontiers in Immunology2012. p. 4. Authority EFS. Scientific Opinion on the substantiation of health claims related to docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA). EFSA Journal. 2011;8:10. Balas L, Durand T. Dihydroxylated E,E,Z-docosatrienes. An overview of their synthesis and biological significance. Progress in Lipid Research. 2016;61:1-18. Basak S, Das MK, Duttaroy AK. Fatty acid-induced angiogenesis in first trimester placental trophoblast cells: possible roles of cellular fatty acid-binding proteins. Life Sci. 2013;93:755-62. Bauer I, Hughes M, Rowsell R, Cockerell R, Pipingas A, Crewther S, et al. Omega-3 supplementation improves cognition and modifies brain activation in young adults. Human Psychopharmacology. 2014;29:133-44. Bazan NG. Neuroprotectin D1 (NPD1): a DHA-derived mediator that protects brain and retina against cell injury-induced oxidative stress. Brain pathology (Zurich, Switzerland). 2005;15:15267-78. Bazan NG. Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors. Trends in Neurosciences2006. p. 263-71. Bazan NG, Molina MF, Gordon WC. Docosahexaenoic Acid Signalolipidomics in Nutrition: Significance in Aging, Neuroinflammation, Macular Degeneration, Alzheimer's, and Other Neurodegenerative Diseases. Annual Review of Nutrition. 2011;31:321-51. Bazinet RP, Layé S. Polyunsaturated fatty acids and their metabolites in brain function and disease. Nature Reviews Neuroscience2014. p. 771-85. Bisicchia E, Sasso V, Catanzaro G, Leuti A, Besharat ZM, Chiacchiarini M, et al. Resolvin D1 Halts Remote Neuroinflammation and Improves Functional Recovery after Focal Brain Damage Via ALX/FPR2 Receptor-Regulated MicroRNAs. Molecular Neurobiology. 2018;55:6894-905. Bos DJ, Oranje B, Veerhoek ES, Van Diepen RM, Weusten JMH, Demmelmair H, et al. Reduced Symptoms of Inattention after Dietary Omega-3 Fatty Acid Supplementation in Boys with and without Attention Deficit/Hyperactivity Disorder. Neuropsychopharmacology. 2015;40:2298-306. Boudrault C, Bazinet RP, Ma DWL. Experimental models and mechanisms underlying the protective effects of n-3 polyunsaturated fatty acids in Alzheimer's disease. Journal of Nutritional Biochemistry2009. p. 1-10. Bourre JM. Dietary omega-3 Fatty acids and psychiatry: mood, behaviour, stress, depression, dementia and aging. The journal of nutrition, health & aging. 2005;9. Bozzatello P, Brignolo E, De Grandi E, Bellino S. Supplementation with Omega-3 Fatty Acids in Psychiatric Disorders: A Review of Literature Data. Journal of Clinical Medicine. 2016;5:8. Bradbury J. Docosahexaenoic acid (DHA): An ancient nutrient for the modern human brain. Nutrients. 2011;3:529-54. Brenna JT, Carlson SE. Docosahexaenoic acid and human brain development: Evidence that adietary supply is needed for optimal development. Journal of Human Evolution. 2014;77:99-106.. 23.

(26) Jo. ur na. lP. re. -p. ro. of. Burdge GC, Jones AE, Wootton SA. Eicosapentaenoic and docosapentaenoic acids are the principal products of α-linolenic acid metabolism in young men. British Journal of Nutrition. 2002;88:355-63. Burdge GC, Wootton SA. Conversion of α-linolenic acid to eicosapentaenoic, docosapentaenoic and docosahexaenoic acids in young women. British Journal of Nutrition. 2002;88:411-20. Calandria JM, Marcheselli VL, Mukherjee PK, Uddin J, Winkler JW, Petasis NA, et al. Selective survival rescue in 15-lipoxygenase-1-deficient retinal pigment epithelial cells by the novel docosahexaenoic acid-derived mediator, neuroprotectin D1. Journal of Biological Chemistry. 2009;284:17877-82. Calder PC. Omega-3 polyunsaturated fatty acids and inflammatory processes: Nutrition or pharmacology? British Journal of Clinical Pharmacology. 2013;75:645-62. Calder PC. The DHA content of a cell membrane can have a significant influence on cellular behaviour and responsiveness to signals. Annals of Nutrition and Metabolism. 2016;69:8-21. Calderon F, Kim HY. Docosahexaenoic acid promotes neurite growth in hippocampal neurons. Journal of Neurochemistry. 2004;90:979-88. Cao D, Xue R, Xu J, Liu Z. Effects of docosahexaenoic acid on the survival and neurite outgrowth of rat cortical neurons in primary cultures. Journal of Nutritional Biochemistry. 2005;16:538-46. Cao DH, Xu JF, Xue RH, Zheng WF, Liu ZL. Protective effect of chronic ethyl docosahexaenoate administration on brain injury in ischemic gerbils. Pharmacology Biochemistry and Behavior. 2004;79:651-9. Carlson SE, Colombo J, Gajewski BJ, Gustafson KM, Mundy D, Yeast J, et al. DHA supplementation and pregnancy outcomes. Am J Clin Nutr. 2013;97:808-15. Carver JD, Benford VJ, Han B, Cantor AB. The relationship between age and the fatty acid composition of cerebral cortex and erythrocytes in human subjects. Brain Research Bulletin. 2001;56:79-85. Chalon S. Omega-3 fatty acids and monoamine neurotransmission. Prostaglandins Leukotrienes and Essential Fatty Acids. 2006;75:259-69. Chan JP, Wong BH, Chin CF, Galam DLA, Foo JC, Wong LC, et al. The lysolipid transporter Mfsd2a regulates lipogenesis in the developing brain. PLoS Biol. 2018;16:e2006443. Chapkin RS, Mcmurray DN, Davidson LA, Patil BS, Fan YY, Lupton JR. Bioactive dietary long-chain fatty acids: Emerging mechanisms of action. British Journal of Nutrition2008. p. 1152-7. Chen CT, Liu Z, Ouellet M, Calon F, Bazinet RP. Rapid β-oxidation of eicosapentaenoic acid in mouse brain: An in situ study. Prostaglandins Leukotrienes and Essential Fatty Acids. 2009;80:157-63. Chen HF, Su HM. Exposure to a maternal n-3 fatty acid-deficient diet during brain development provokes excessive hypothalamic-pituitary-adrenal axis responses to stress and behavioral indices of depression and anxiety in male rat offspring later in life. Journal of Nutritional Biochemistry. 2013;24:70-80. Chilton FH, Murphy RC, Wilson BA, Sergeant S, Ainsworth H, Seeds MC, et al. Dietgene interactions and PUFA metabolism: A potential contributor to health disparities and human diseases. Nutrients2014. p. 1993-2022. Coti Bertrand P, O'Kusky JR, Innis SM. Maternal dietary (n-3) fatty acid deficiency alters neurogenesis in the embryonic rat brain. The Journal of nutrition. 2006;136:15705.. 24.

(27) Jo. ur na. lP. re. -p. ro. of. Crane DI. Revisiting the neuropathogenesis of Zellweger syndrome. Neurochem Int. 2014;69:1-8. Cunnane SC, Chouinard-Watkins R, Castellano CA, Barberger-Gateau P. Docosahexaenoic acid homeostasis, brain aging and Alzheimer's disease: Can we reconcile the evidence? Prostaglandins Leukotrienes and Essential Fatty Acids. 2013;88:61-70. D'Addario C, Micioni Di Bonaventura MV, Pucci M, Romano A, Gaetani S, Ciccocioppo R, et al. Endocannabinoid signaling and food addiction. Neuroscience and Biobehavioral Reviews2014. p. 203-24. Dalli J, Winkler JW, Colas RA, Arnardottir H, Cheng CYC, Chiang N, et al. Resolvin D3 and aspirin-triggered resolvin D3 are potent immunoresolvents. Chemistry and Biology. 2013;20:188-201. Davis BC, Kris-Etherton PM. Achieving optimal essential fatty acid status in vegetarians: Current knowledge and practical implications. American Journal of Clinical Nutrition2003. De Petrocellis L, Melck D, Bisogno T, Milone A, Di Marzo V. Finding of the endocannabinoid signalling system in Hydra, a very primitive organism: Possible role in the feeding response. Neuroscience. 1999;92:377-87. Diep QN, Touyz RM, Schiffrin EL. Docosahexaenoic acid, a peroxisome proliferatoractivated receptor-α ligand, induces apoptosis in vascular smooth muscle cells by stimulation of p38: Mitogen-activated protein kinase. Hypertension. 2000;36:851-5. Duttaroy AK. Transport mechanisms for long-chain polyunsaturated fatty acids in the human placenta. American Journal of Clinical Nutrition2000. Duttaroy AK. Transport of fatty acids across the human placenta: a review. Prog Lipid Res. 2009;48:52-61. Duttaroy AK. Docosahexaenoic acid supports feto-placental growth andprotects cardiovascular and cognitive function: A mini review. Eur J Lipid Sci Technol. 2016;118:1439-49. Duvall MG, Levy BD. DHA- and EPA-derived resolvins, protectins, and maresins in airway inflammation. European Journal of Pharmacology. 2016;785:144-55. Dyall SC. Long-chain omega-3 fatty acids and the brain: A review of the independent and shared effects of EPA, DPA and DHA. Frontiers in Aging Neuroscience2015. p. 52. EFSAReport. EFSA Panel on Dietetic Products NaA. Scientific opinion on the tolerable upper intake level of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). EFSA Journal.10:2815. Farooqui A. n-3 Fatty Acid-Derived Lipid Mediators in the Brain: New Weapons Against Oxidative Stress and Inflammation. Current Medicinal Chemistry. 2012;19:532-43. Forsyth S, Gautier S, Salem N. Global estimates of dietary intake of docosahexaenoic acid and arachidonic acid in developing and developed countries. Annals of Nutrition and Metabolism. 2016;68:258-67. Francos-Quijorna I, Santos-Nogueira E, Gronert K, Sullivan AB, Kopp MA, Brommer B, et al. Maresin 1 Promotes Inflammatory Resolution, Neuroprotection, and Functional Neurological Recovery After Spinal Cord Injury. The Journal of Neuroscience. 2017;37:11731-43. García-Sastre A. XLessons from lipids in the fight against influenza. Cell2013. p. 223. Gladine C, Laurie J-C, Giulia C, Dominique B, Corinne C, Nathalie H, et al. Neuroprostanes, produced by free-radical mediated peroxidation of DHA, inhibit the 25.

(28) Jo. ur na. lP. re. -p. ro. of. inflammatory response of human macrophages. Free Radical Biology and Medicine. 2014;75:S15-S25. Goustard-Langelier B, Guesnet P, Durand G, Antoine JM, Alessandri JM. n-3 and n-6 Fatty acid enrichment by dietary fish oil and phospholipid sources in brain cortical areas and nonneural tissues of formula-fed piglets. Lipids. 1999;34:5-16. Green P, Glozman S, Weiner L, Yavin E. Enhanced free radical scavenging and decreased lipid peroxidation in the rat fetal brain after treatment with ethyl docosahexaenoate. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. 2001;1532:203-12. Groeger AL, Cipollina C, Cole MP, Woodcock SR, Bonacci G, Rudolph TK, et al. Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acids. Nature Chemical Biology. 2010;6:433-41. Grossfield A, Feller SE, Pitman MC. A role for direct interactions in the modulation of rhodopsin by -3 polyunsaturated lipids. Proceedings of the National Academy of Sciences. 2006;103:4888-93. Hashimoto M, Hossain S, Agdul H, Shido O. Docosahexaenoic acid-induced amelioration on impairment of memory learning in amyloid β-infused rats relates to the decreases of amyloid β and cholesterol levels in detergent-insoluble membrane fractions. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. 2005;1738:91-8. Hennebelle M, Balasse L, Latour A, Champeil-Potokar G, Denis S, Lavialle M, et al. Influence of omega-3 fatty acid status on the way rats adapt to chronic restraint stress. PLoS ONE. 2012;7:e42142. Hibbeln JR. Fish consumption and major depression [9]. Lancet1998. p. 1213. Hoffman DR, Hughbanks-Wheaton DK, Pearson NS, Fish GE, Spencer R, Takacs A, et al. Four-year placebo-controlled trial of docosahexaenoic acid in X-linked retinitis pigmentosa (DHAX trial): a randomized clinical trial. JAMA Ophthalmol. 2014;132:866-73. Hoffman DR, Hughbanks-Wheaton DK, Spencer R, Fish GE, Pearson NS, Wang YZ, et al. Docosahexaenoic Acid Slows Visual Field Progression in X-Linked Retinitis Pigmentosa: Ancillary Outcomes of the DHAX Trial. Invest Ophthalmol Vis Sci. 2015;56:6646-53. Hong S, Tjonahen E, Morgan EL, Lu Y, Serhan CN, Rowley AF. Rainbow trout (Oncorhynchus mykiss) brain cells biosynthesize novel docosahexaenoic acid-derived resolvins and protectins - Mediator lipidomic analysis. Prostaglandins and Other Lipid Mediators. 2005;78:107-16. Huang LH, Chung HY, Su HM. Docosahexaenoic acid reduces sterol regulatory element binding protein-1 and fatty acid synthase expression and inhibits cell proliferation by inhibiting pAkt signaling in a human breast cancer MCF-7 cell line. BMC Cancer. 2017;17:890. Innis SM. Essential fatty acids in growth and development. Progress in Lipid Research1991. p. 39-103. Innis SM. Dietary omega 3 fatty acids and the developing brain. Brain Research2008. p. 35-43. Innis SM. Dietary (n-3) Fatty Acids and Brain Development. The Journal of Nutrition. 2018;137:855-9. Insua MF, Garelli A, Rotstein NP, German OL, Arias A, Politi LE. Cell cycle regulation in retinal progenitors by glia-derived neurotrophic factor and docosahexaenoic acid. Investigative Ophthalmology and Visual Science. 2003;44:2235-44.. 26.

(29) Jo. ur na. lP. re. -p. ro. of. Jaremka LM, Derry HM, Bornstein R, Prakash RS, Peng J, Belury MA, et al. Omega3 supplementation and loneliness-related memory problems: Secondary analyses of a randomized controlled trial. Psychosomatic Medicine. 2014;76:650-8. Johnsen GM, Basak S, Weedon-Fekjaer MS, Staff AC, Duttaroy AK. Docosahexaenoic acid stimulates tube formation in first trimester trophoblast cells, HTR8/SVneo. Placenta. 2011;32:626-32. Judge MP, Harel O, Lammi-Keefe CJ. Maternal consumption of a docosahexaenoic acid-containing functional food during pregnancy: benefit for infant performance on problem-solving but not on recognition memory tasks at age 9 mo. Am J Clin Nutr. 2007;85:1572-7. Julvez J, Mendez M, Fernandez-Barres S, Romaguera D, Vioque J, Llop S, et al. Maternal Consumption of Seafood in Pregnancy and Child Neuropsychological Development: A Longitudinal Study Based on a Population With High Consumption Levels. Am J Epidemiol. 2016;183:169-82. Kawakita E, Hashimoto M, Shido O. Docosahexaenoic acid promotes neurogenesis in vitro and in vivo. Neuroscience. 2006;139:991-7. Kiecolt-Glaser JK, Belury MA, Andridge R, Malarkey WB, Glaser R. Omega-3 supplementation lowers inflammation and anxiety in medical students: A randomized controlled trial. Brain, Behavior, and Immunity. 2011;25:1725-34. Kiliaan A, Königs A. Critical appraisal of omega-3 fatty acids in attentiondeficit/hyperactivity disorder treatment. Neuropsychiatric Disease and Treatment. 2016;Volume 12:1869-82. Kim J, Carlson ME, Watkins BA. Docosahexaenoyl ethanolamide improves glucose uptake and alters endocannabinoid system gene expression in proliferating and differentiating C2C12 myoblasts. Frontiers in Physiology. 2014;5. Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement (N Y). 2018;4:575-90. Kitajka K, Puskas LG, Zvara A, Hackler L, Barcelo-Coblijn G, Yeo YK, et al. The role of n-3 polyunsaturated fatty acids in brain: Modulation of rat brain gene expression by dietary n-3 fatty acids. Proceedings of the National Academy of Sciences. 2002;99:2619-24. Klein CP, Sperotto NDM, Maciel IS, Leite CE, Souza AH, Campos MM. Effects of Dseries resolvins on behavioral and neurochemical changes in a fibromyalgia-like model in mice. Neuropharmacology. 2014;86:57-66. Koletzko B, Cetin I, Brenna JT, Perinatal Lipid Intake Working G, Child Health F, Diabetic Pregnancy Study G, et al. Dietary fat intakes for pregnant and lactating women. Br J Nutr. 2007;98:873-7. Kuda O. Bioactive metabolites of docosahexaenoic acid. Biochimie2017. p. 12-20. Laugero KD, Smilowitz JT, German JB, Jarcho MR, Mendoza SP, Bales KL. Plasma omega 3 polyunsaturated fatty acid status and monounsaturated fatty acids are altered by chronic social stress and predict endocrine responses to acute stress in titi monkeys. Prostaglandins Leukotrienes and Essential Fatty Acids. 2011;84:71-8. Lauritzen L, Brambilla P, Mazzocchi A, Harsløf LBS, Ciappolino V, Agostoni C. DHA effects in brain development and function. Nutrients2016. p. 6. Lengqvist J, Mata de Urquiza A, Bergman A-C, Willson TM, Sjövall J, Perlmann T, et al. Polyunsaturated Fatty Acids Including Docosahexaenoic and Arachidonic Acid Bind to the Retinoid X Receptor α Ligand-binding Domain. Molecular & Cellular Proteomics. 2004;3:692-703.. 27.

(30) Jo. ur na. lP. re. -p. ro. of. Li Q, Wang M, Tan L, Wang C, Ma J, Li N, et al. Docosahexaenoic acid changes lipid composition and interleukin-2 receptor signaling in membrane rafts. Journal of Lipid Research. 2005;46:1904-13. Lim JY, Park C-K, Hwang SW. Biological Roles of Resolvins and Related Substances in the Resolution of Pain. BioMed Research International. 2015;2015. Lima-Garcia JF, Dutra RC, Da Silva KABS, Motta EM, Campos MM, Calixto JB. The precursor of resolvin D series and aspirin-triggered resolvin D1 display antihyperalgesic properties in adjuvant-induced arthritis in rats. British Journal of Pharmacology. 2011;164:278-93. Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. Journal of Clinical Psychiatry. 2007;68:1056-61. Liu A, Lin Y, Terry R, Nelson K, Bernstein PS. Role of long-chain and very-long-chain polyunsaturated fatty acids in macular degenerations and dystrophies. Clin Lipidol. 2011;6:593-613. Lu HC, MacKie K. An introduction to the endogenous cannabinoid system. Biological Psychiatry2016. p. 516-25. Lucas M, Dewailly É, Blanchet C, Gingras S, Holub BJ. Plasma omega-3 and psychological distress among Nunavik Inuit (Canada). Psychiatry Research. 2009;167:266-78. Lukiw WJ, Cui JG, Marcheselli VL, Bodker M, Botkjaer A, Gotlinger K, et al. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. Journal of Clinical Investigation. 2005;115:2774-83. Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nature Reviews Neuroscience2009. p. 434-45. Maes M, Christophe A, Bosmans E, Lin A, Neels H. In humans, serum polyunsaturated fatty acid levels predict the response of proinflammatory cytokines to psychologic stress. Biological Psychiatry. 2000;47:910-20. Makrides M, Gibson RA, McPhee AJ, Collins CT, Davis PG, Doyle LW, et al. Neurodevelopmental outcomes of preterm infants fed high-dose docosahexaenoic acid: a randomized controlled trial. JAMA. 2009;301:175-82. Marangell LB, Martinez JM, Zboyan HA, Kertz B, Kim HFS, Puryear LJ. A doubleblind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. American Journal of Psychiatry. 2003;160:996-8. Masoodi M, Kuda O, Rossmeisl M, Flachs P, Kopecky J. Lipid signaling in adipose tissue: Connecting inflammation & metabolism. Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids2015. p. 503-18. McEwen BS. Stress, sex, and neural adaptation to a changing environment: Mechanisms of neuronal remodeling. Annals of the New York Academy of Sciences. 2010;1204:E38-E59. McNamara RK. DHA Deficiency and Prefrontal Cortex Neuropathology in Recurrent Affective Disorders. The Journal of Nutrition. 2010;140:864-8. McNamara RK, Hahn CG, Jandacek R, Rider T, Tso P, Stanford KE, et al. Selective Deficits in the Omega-3 Fatty Acid Docosahexaenoic Acid in the Postmortem Orbitofrontal Cortex of Patients with Major Depressive Disorder. Biological Psychiatry. 2007;62:17-24. Metherel AH, Irfan M, Klingel SL, Mutch DM, Bazinet RP. Compound-specific isotope analysis reveals no retroconversion of DHA to EPA but substantial conversion of EPA to DHA following supplementation : a randomized control trial. American Journal of Clinical Nutrition. 2019:1-9. 28.

(31) Jo. ur na. lP. re. -p. ro. of. Mita R, Beaulieu MJ, Field C, Godbout R. Brain Fatty Acid-binding Protein and ω3/ω-6 Fatty Acids. Journal of Biological Chemistry. 2010;285:37005-15. Mori TA, Burke V, Puddey IB, Watts GF, O'Neal DN, Best JD, et al. Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hypedipidemic men. American Journal of Clinical Nutrition. 2000a;71:1085-94. Mori TA, Watts GF, Burke V, Hilme E, Puddey IB, Beilin LJ. Differential effects of eicosapentaenoic acid and docosahexaenoic acid on vascular reactivity of the forearm microcirculation in hyperlipidemic, overweight men. Circulation. 2000b;102:1264-71. Morita M, Kuba K, Ichikawa A, Nakayama M, Katahira J, Iwamoto R, et al. The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza. Cell. 2013;153:112-25. Mulder KA, King DJ, Innis SM. Omega-3 fatty acid deficiency in infants before birth identified using a randomized trial of maternal DHA supplementation in pregnancy. PLoS ONE. 2014;9:e83764. Murray CJL, Lopez A. A comprehensive assessment of mortality and disability from disease, injures and risk factors in 1990 and projected to 2020. The Global Burden of Disease1996. Myhrstad MC, Ottestad I, Gunther CC, Ryeng E, Holden M, Nilsson A, et al. The PBMC transcriptome profile after intake of oxidized versus high-quality fish oil: an explorative study in healthy subjects. Genes Nutr. 2016;11:16. Neff LM, Culiner J, Cunningham Rundles S, Seidman C, Meehan D, Maturi J, et al. Algal Docosahexaenoic Acid Affects Plasma Lipoprotein Particle Size Distribution in Overweight and Obese Adults. The Journal of Nutrition. 2010;141:207-13. Nguyen LN, Ma D, Shui G, Wong P, Cazenave-Gassiot A, Zhang X, et al. Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature. 2014;509:503-6. O'Brien JS, Sampson EL. Lipid composition of the normal human brain: gray matter, white matter, and myelin. Journal of lipid research. 1965;6:545-51. Oh DY, Walenta E, Akiyama TE, Lagakos WS, Lackey D, Pessentheiner AR, et al. A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice. Nature Medicine. 2014;20:942-7. Okada M, Amamoto T, Tomonaga M, Kawachi A, Yazawa K, Mine K, et al. The chronic administration of docosahexaenoic acid reduces the spatial cognitive deficit following transient forebrain ischemia in rats. Neuroscience. 1996;71:17-25. Orlowski JP. Whatever happened to Reye's syndrome? Did it ever really exist? Critical Care Medicine. 1999;27:1582-7. Owada Y, Abdelwahab SA, Kitanaka N, Sakagami H, Takano H, Sugitani Y, et al. Altered emotional behavioral responses in mice lacking brain-type fatty acid-binding protein gene. European Journal of Neuroscience. 2006;24:175-87. Parellada M, Llorente C, Calvo R, Gutierrez S, Lázaro L, Graell M, et al. Randomized trial of omega-3 for autism spectrum disorders: Effect on cell membrane composition and behavior. European Neuropsychopharmacology. 2017;27:1319-30. Park HG, Lawrence P, Engel MG, Kothapalli K, Brenna JT. Metabolic fate of docosahexaenoic acid (DHA; 22:6n-3) in human cells: direct retroconversion of DHA to eicosapentaenoic acid (20:5n-3) dominates over elongation to tetracosahexaenoic acid (24:6n-3). FEBS Letters2016. p. 3188-94. Parra-Cabrera S, Stein AD, Wang M, Martorell R, Rivera J, Ramakrishnan U. Dietary intakes of polyunsaturated fatty acids among pregnant Mexican women. Matern Child Nutr. 2011;7:140-7. 29.

(32) Jo. ur na. lP. re. -p. ro. of. Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Archives of General Psychiatry. 2002;59:913-9. Piazza PV, Lafontan M, Girard J. Integrated physiology and pathophysiology of CB1mediated effects of the endocannabinoid system. Diabetes and Metabolism2007. p. 97107. Plourde M, Cunnane SC. Erratum: Extremely limited synthesis of long-chain polyunsaturates in adults: implications for their dietary essentiality and use as supplements. Applied Physiology, Nutrition, and Metabolism. 2008;32:619-34. Pusceddu MM, Kelly P, Stanton C, Cryan JF, Dinan TG. N-3 Polyunsaturated Fatty Acids through the Lifespan: Implication for Psychopathology. Int J Neuropsychopharmacol. 2016;19. Qawasmi A, Landeros-Weisenberger A, Leckman JF, Bloch MH. Meta-analysis of Long-Chain Polyunsaturated Fatty Acid Supplementation of Formula and Infant Cognition. PEDIATRICS. 2012;129:1141-9. Qu Q, Xuan W, Fan GH. Roles of resolvins in the resolution of acute inflammation. Cell Biology International2015. p. 3-22. Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, Van Dyck C, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 2010a;304:1903-11. Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, Van Dyck C, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: A randomized trial. JAMA - Journal of the American Medical Association. 2010b;304:1903-11. Ramalho R, Pereira AC, Vicente F, Pereira P. Docosahexaenoic acid supplementation for children with attention deficit hyperactivity disorder: A comprehensive review of the evidence. Clin Nutr ESPEN. 2018;25:1-7. Ranabir S, Reetu K. Stress and hormones. Indian Journal of Endocrinology and Metabolism. 2011;15:18-22. Recchiuti A, Krishnamoorthy S, Fredman G, Chiang N, Serhan CN. MicroRNAs in resolution of acute inflammation: identification of novel resolvin D1-miRNA circuits. The FASEB Journal. 2010;25:544-60. Rioux L, Arnold SE. The expression of retinoic acid receptor alpha is increased in the granule cells of the dentate gyrus in schizophrenia. Psychiatry Research. 2005;133:1321. Robertson R, Guihéneuf F, Stengel DB, Fitzgerald G, Ross P, Stanton C. AlgaeDerived Polyunsaturated Fatty Acids : Implications for Human Health. Polyunsaturated fatty acids sources, antioxidant properties and health Benefits2013. Salem N, Eggersdorfer M. Is the world supply of omega-3 fatty acids adequate for optimal human nutrition? Current Opinion in Clinical Nutrition and Metabolic Care. 2015;18:147-54. Salem N, Litman B, Kim HY, Gawrisch K. Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids. 2001;36:945-59. Sato M, Adan Y, Shibata K, Shoji Y, Sato H, Imaizumi K. Cloning of rat delta 6desaturase and its regulation by dietary eicosapentaenoic or docosahexaenoic acid. World Rev Nutr Diet. 2001;88:196-9. Schaefer EJ, Bongard V, Beiser AS, Lamon-Fava S, Robins SJ, Au R, et al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and alzheimer disease: The framingham heart study. Archives of Neurology. 2006;63:1545-50.. 30.

(33) Jo. ur na. lP. re. -p. ro. of. Seidl SE, Santiago JA, Bilyk H, Potashkin JA. The emerging role of nutrition in Parkinson's disease. Frontiers in Aging Neuroscience2014. Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature2014. p. 92-101. Serhan CN, Chiang N, Dalli J, Levy BD. Lipid mediators in the resolution of inflammation. Cold Spring Harbor Perspectives in Biology. 2015a;7:a016311. Serhan CN, Dalli J, Colas RA, Winkler JW, Chiang N. Protectins and maresins: New pro-resolving families of mediators in acute inflammation and resolution bioactive metabolome. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids2015b. p. 397-413. Serhan CN, Dalli J, Karamnov S, Choi A, Park C-K, Xu Z-Z, et al. Macrophage proresolving mediator maresin 1 stimulates tissue regeneration and controls pain. The FASEB Journal. 2012;26:1755-65. Serhan CN, Yang R, Martinod K, Kasuga K, Pillai PS, Porter TF, et al. Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions. The Journal of Experimental Medicine. 2008;206:15-23. Shamim A, Mahmood T, Ahsan F, Kumar A, Bagga P. Lipids: An insight into the neurodegenerative disorders. Clinical Nutrition Experimental2018. p. 1-19. Sherratt SCR, Mason RP. Eicosapentaenoic acid and docosahexaenoic acid have distinct membrane locations and lipid interactions as determined by X-ray diffraction. Chemistry and Physics of Lipids. 2018;212:73-9. Shinohara M, Serhan CN. Novel Endogenous Proresolving Molecules:Essential Fatty Acid-Derived and Gaseous Mediators in the Resolution of Inflammation. Journal of Atherosclerosis and Thrombosis. 2016;23:655-64. Shulkin M, Pimpin L, Bellinger D, Kranz S, Fawzi W, Duggan C, et al. N-3 fatty acid supplementation in mothers, preterm infants, and term infants and childhood psychomotor and visual development: A systematic review and meta-analysis. Journal of Nutrition. 2018;149:409-18. Simmer K, Patole SK, Rao SC. Long-chain polyunsaturated fatty acid supplementation in infants born at term. The Cochrane database of systematic reviews. 2011;4:CD000376. Simopoulos AP. An increase in the Omega-6/Omega-3 fatty acid ratio increases the risk for obesity. Nutrients. 2016;8:1-17. Singh M. Essential fatty acids, DHA and human brain. Indian J Pediatr. 2005;72:23942. Smith SL, Rouse CA. Docosahexaenoic acid and the preterm infant. Maternal Health, Neonatology and Perinatology. 2017;3:22. Smithers LG, Gibson RA, McPhee A, Makrides M. Effect of long-chain polyunsaturated fatty acid supplementation of preterm infants on disease risk and neurodevelopment: A systematic review of randomized controlled trials. American Journal of Clinical Nutrition. 2008;87:912-20. Soderstrom K. Endocannabinoids Link Feeding State and Auditory Perception-Related Gene Expression. Journal of Neuroscience. 2004;24:10013-24. Song C, Manku MS, Horrobin DF. Long-Chain Polyunsaturated Fatty Acids Modulate Interleukin-1β–Induced Changes in Behavior, Monoaminergic Neurotransmitters, and Brain Inflammation in Rats. The Journal of Nutrition. 2008;138:954-63. Souied EH, Aslam T, Garcia-Layana A, Holz FG, Leys A, Silva R, et al. Omega-3 Fatty Acids and Age-Related Macular Degeneration. Ophthalmic Res. 2015;55:62-9. Spite M, Clària J, Serhan CN. Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases. Cell Metabolism2014. p. 21-36. 31.