Review ArticleFactors Influencing the Eicosanoids Synthesis In Vivo
JarosBaw Szefel12 WiesBaw Janusz Kruszewski12 and Ewa Sobczak1
1Department of Propaedeutic Oncology Faculty of Health Sciences Medical University of GdanskPowstania Styczniowego 9b 81-519 Gdynia Poland2Department of Surgical Oncology Gdynia Oncology Center PCKrsquos Maritime Hospital in GdyniaPowstania Styczniowego 1 81-519 Gdynia Poland
Correspondence should be addressed to Jarosław Szefel jaszefelmppl
Received 19 November 2014 Accepted 24 February 2015
Academic Editor Beverly Muhlhausler
Copyright copy 2015 Jarosław Szefel et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited
External factors activate a sequence of reactions involving the reception transduction and transmission of signals to effectorcells There are two main phases of the bodyrsquos reaction to harmful factors the first aims to neutralize the harmful factor whilein the second the inflammatory process is reduced in size and resolved Secondary messengers such as eicosanoids are activein both phases The discovery of lipoxins and epi-lipoxins demonstrated that not all arachidonic acid (AA) derivatives haveproinflammatory activity It was also revealed that metabolites of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)such as resolvins protectins and maresins also take part in the resolution of inflammation Knowledge of the above properties hasstimulated several clinical trials on the influence of EPA and DHA supplementation on various diseases However the equivocalresults of those trials prevent the formulation of guidelines on EPA and DHA supplementation Prescription drugs are among thesubstances with the strongest influence on the profile and quantity of the synthesized eicosanoids The lack of knowledge abouttheir influence on the conversion of EPA and DHA into eicosanoids may lead to erroneous conclusions from clinical trials
1 Stages of Eicosanoid Synthesis
Because the human body lacks the set of enzymes neededto synthesize the polyunsaturated fatty acids (PUFAs) and120572-linolenic (ALA) and linoleic acids (LA) diet is their onlysource The rate of (PUFAs) conversion into AA DHA andEPA is slow due to the low activity of the Δ6 desaturase Thatis why only 02ndash2 of the dietary ALA is converted into EPAand DHA while the rest undergoes 120573-oxidation [1] The sim-plest way to bypass this step towards eicosanoid synthesis isto increase the dietary intake of DHA and EPA Cells also usePUFAs to de novo synthesize glycerophospholipids via theKennedy pathway or via lysophospholipids remodeling in theLands cycle [1 2] Glycerophospholipids are part of the cellmembranes and influence their properties and functionsThenext step in eicosanoid synthesis is catalyzed by the phospho-lipase A
2(PLA2) with calcium ions and ATP as cofactors and
involves the hydrolysis at the sn-2 position of glycerophos-pholipidsTheproducts of this reaction are free fatty acids andlysophospholipids The AA DHA and EPA released by thisreaction are converted into biologically active eicosanoids
by the 5- 12- and 15-lipoxygenase (LOX) cyclooxygenase(COX) -1 and -2 and other enzymes (Figure 1)
Each step of the described reactions in Figure 1 is suscep-tible to the activity of drugs and other factors that influencethe profile and quantity of the synthesized eicosanoids Thevast body of knowledge about the drug interactions withmetabolic pathways is beyond the scope of daily medicalpractice however it should be taken into account whenplanning clinical trials The daily clinical experience withcommonmedication such as nonsteroidal anti-inflammatorydrugs (NSAIDs) or the corticosteroids and 5-LOX inhibitorsdemonstrates the scope of changes inmedical practice causedby drugs For that reason the precise determination of patientexclusion criteria is just as important in clinical trial designas the criteria of inclusion It should be noted that whenanalyzing the influence of DHA and EPA supplementationon the inflammatory markers we will obtain very differentresults among patients who are prescribed medication forasthma coronary artery disease and diabetes and those whoare taking no medications
Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 690692 6 pageshttpdxdoiorg1011552015690692
2 BioMed Research International
Diet
PUFA
n-3n-6
LA ALA
Δ6 desaturation
Δ6 desaturation
Elongation
Elongation
Δ5 desaturation
AA EPA
DHA
Landrsquos cycle orKennedy pathway
Phospholipids
Phospholipase A2
AA EPA DHA + lysophospholipidsCOX-1 -25- 12- and 15-LOXCYP
Eicosanoids
Figure 1 Simplified diagram of eicosanoid synthesis The 120572-linolenic and linoleic acids are substrates for the synthesis ofAA EPA and DHA which are added at the sn-2 position tolysophospholipids (via the Lands cycle) or to glycerophospholipids(via the Kennedy pathway) The AAs EPAs and DHAs that werereleased from glycerophospholipids by the PLA(2) are substrates forCOX LOX cytochrome (CYP) and other enzymes involved in theeicosanoid synthesis
2 Absorption of LCPUFAs in theGastrointestinal Tract
Triglycerides (TGs) are emulsified in the stomach and duo-denum by the bile and pancreatic juices and then hydrolyzedby the pancreatic lipase into free fatty acids (FFAs) andmonoacylglycerolsThe FFAs absorption ratio decreases pro-portionally to the increasing FFA carbon chain length andhydrophobicity whereas the ratio increases proportionallyto the increasing desaturation [3] A small part of short-chain fatty acids (SCFAs) diffuse via the intestinal mucosalmembrane via the flip-flop mechanism [4] The rest ofSCFAs and all of long-chain FAs (LCFAs) are bound to thelipid raft proteins found in the cell membrane domains andtransmitted through the intestinal wall [5]The FAs absorbedby the enterocytes bind to caveolin-1 and accumulate in thecytoplasmic lipid droplets
Before exiting the enterocytes the PUFAs are boundinto TGs at the sn-2 position [6] Chylomicrons resultingfrom the bonding of TG with cholesterol phospholipids andapolipoproteins enter the portal circulation Several proteinsare known to transport FA across cell membranes and theirdistribution is specific to the tissue type and function Forexample the fatty acid translocase (FAT)CD 36 has thehighest expression in muscle tissue whereas the enterocytesof the small intestine have the highest activity of fatty acidtransport protein 4 (FATP4) which specifically binds PUFAs[7 8]
A reduction of PUFA absorption from the intestinallumen is observed in diseases involving the damage to theintestinal mucosa or the reduction of pancreatic lipase andbile acid secretion such as inflammatory bowel diseasespancreatitis liver diseases intestinal fistulas and extensiveresections of the small intestine At this moment it is difficultto assess the degree to which the above-mentioned diseasesinfluence the PUFA absorption and eicosanoid synthesis
3 The Influence of PUFA Supply Route on theRate of LCPUFA and Eicosanoid Synthesis
Themain PUFAs substrates for this process are the dietary 120572-linolenic and linoleic acids Their absorption rate is largelydependent on supply route and physical structure Thusthe PUFA n-3n-6 concentration ratio in cell membranessignificantly increases after just 48 hours after intravenousadministration whereas after oral administration the con-centration increases more slowly due to extra time neededfor its absorption in the gastrointestinal tract The profile ofsynthesized eicosanoids in tissues generally results from theΔ6 desaturasersquos greater affinity for 120572-linolenic acid than forlinoleic acid [9 10] Currently the typical Western diet hasn-6n-3 ratio of 15 1 instead of the recommended 3 1 [11]Raatz et al demonstrated that the n-3 PUFAs absorbtion inthe form of lipid emulsion intravenously is faster than oralfish oil capsules [12] FA emulsification and absorption areimpaired in pancreatic insufficiency inflammatory bowel dis-eases postgastrectomy states intestinal fistulas and extensivebowel resections [13 14]
4 Transcellular Biosynthesis of Eicosanoids
Although eicosanoids can theoretically be synthesized in onecell it is observed that in vivo this process occurs sequentiallyin different cell types for example blood endothelial andconnective tissue cells [15 16] The intermediate from LCP-UFA (eg PGH
2or leukotriene A
4) from a single donor cell
is transported to an acceptor cell which synthesizes the finalproduct [17 18] To this date it has not been explained whythis process occursmdashafter all each cell contains a full set ofenzymes needed to complete the synthesis It is even moresurprising because the lipophilicity of these products makestheir transport across membranes more difficult [19 20]
Besides the change in cell number another factor affect-ing the eicosanoid synthesis is the maturity of cells In statesof intense catabolism severe infection and sepsis and in
BioMed Research International 3
neoplastic disease the bone marrow releases myeloid-derivedsuppressor cells (MDSCs) The MDSCs can be subdividedinto two major groups immature granulocytes MDSC (G-MDSC) andmonocytesMDSC (M-MDSC) released from thebone marrow into the peripheral bloodstream In order tosuppress immune function theG-MDSCs primarily use reac-tive oxygen species (ROS) whereas the M-MDSCs use nitricoxide synthase (iNOS) and arginase [21ndash24] The intensityofMDSC-induced immunosuppression dynamically changeswith the patientrsquos stateThe activity ofMDSC leads to argininestarvation lowering of the proliferation rate and loss ofthe T-cell-receptor- (TCR-) associated CD3 120577 chain [25 26]Besides the arginine starvation in tissues immunosuppres-sion may be triggered by glutamine deficiency A deficiencyof these amino acids can be expected in undernourished orseptic patients as well as during intense catabolic states forexample after large surgical procedures or posttrauma [27]The assessment of PUFA supplementationrsquos influence on theinflammatory reactionmay be complicated by the immaturityof the immune system cells or amino acid deficiency [28 29]
5 Factors Inhibiting the Δ6Desaturase Activity
Δ6 desaturase catalyzes the conversion of LA and ALA intoAA EPA and DHA Several studies on animal models madein the 90s of the last century mainly on rats demonstratedthat this conversion is greater in females [30 31] anddecreasesdue to age [32ndash34] metabolic syndrome diabetes [35 36]and deficiencies of folic acid zinc [37 38] and vitamins B
6
B12[39 40] and A [41] In addition Δ6 desaturase activity is
decreased by alcohol [42] The above-mentioned factors maysignificantly alter the results of clinical trials on the role ofeicosanoids in the inflammatory reaction
6 Factors Modifying the Activity ofPhospholipase A2 (PLA2)
A very important step in eicosanoid synthesis is the hydrol-ysis of the membrane glycerophospholipids at the n-2 posi-tion by PLA2 into free PUFAs and lysophospholipids Theefficiency of this reaction determines the rate of eicosanoidsynthesis Many factors such as thrombin angiotensin II andinterleukin-2 influence the activity of PLA2 [43ndash45] It isdecreased in neoplasms associatedwith the human epidermalgrowth factor (HER2) overexpression as well as under theinfluence of angiotensin II receptor inhibitors used in thetreatment of arterial hypertension and thrombin inhibitorscommonly used in the treatment and prevention of thevenous thromboembolic disease [46ndash48] Glucocorticoidsincrease the synthesis of lipocortin and annexin stronginhibitors of PLA2 activity leading to the inhibition ofeicosanoid synthesis [49ndash52]
The glycerophospholipid deacylationreacylation cycleknown as the Lands cycle is responsible for the continu-ous change of cell membrane composition and properties[53] After the PLA
2-catalyzed deacylation of phospholipids
the lysophospholipid acyltransferases (LPAATs) catalyze the
reacylation of lysophospholipids [54 55] The efficiency ofreacylation of lysophospholipids is influenced primarily bythe availability of active PUFA (PUFA-CoA) and the freeL-carnitine concentration which by binding a significantamount of PUFA limits the rate of this step of eicosanoidsynthesis [56 57]
7 Factors Influencing COX Activity
NSAIDs inhibit eicosanoid synthesis by acting on COX-1 and -2 Aspirin differs from the other NSAIDs due toits ability to irreversibly acetylate COX-2 and switch thisenzyme to instead generate 15R-HETE a substrate for the 5-LOX This results in the synthesis of 15-epi-lipoxin A
4 also
known as aspirin-triggered lipoxin (ATL) [58] Celecoxib androfecoxib inhibit the activity of acetylated COX-2 and thesynthesis of the anti-inflammatory 15(R)-epi-LXA4 thereforecombining them with aspirin significantly increases the riskof gastric mucosa damage [59] These adverse interactionshave not been observed after the administration of celecoxiband rofecoxib with the new acetylsalicylic acid derivativeNCX 4016 [60] The acetylated COX-2 converts EPA into18(R)-hydroxyeicosapentaenoic acid (18R-HEPE) which isthen converted by 5-LOX into resolvin (Rv) E
1and RvE
2
RvE1exerts its anti-inflammatory activity after binding with
the ChemR23 and leukotriene BLT1receptors [61 62] The
synthesis of D-series Rvmay take place via two pathwaysThefirst of them is dependent on the aspirin-acetylated COX-2and uses DHA as a substrate for 17(R)-hydroxy-DHA whichlater is converted by LOX to 17(R)-RvD1 to D4 known as theaspirin-triggered RvD-series (AT-RvDs) [63 64] whereas thesecond pathway is independent of aspirin and yields resolvinssimilar to those from the first pathway
Although statins use a slightly different mechanism thanaspirin to modify COX-2 activity both drugs produce 15(R)HETE which is converted by the 5-LOX to 15(R)-epi-LXA4[65 66] Clinical studies of the DHArsquos and EPArsquos effect on theinflammatory reaction need to consider the fact that aspirinNSAIDs and statins all significantly change the eicosanoidprofile (Equation (1)) [67]
Aspirin- (ASA-) induced acetylation of cyclooxygenase-2(COX-2) alters enzymersquos specificity as follows
AA COX2+ASA997888997888997888997888997888997888997888997888rarr 15R-HETE 5-LOX997888997888997888997888997888rarr 15-epi- LXA4
+ 15-epi- LXB4
AA COX2+ASA+NSAIDs997888997888997888997888997888997888997888997888997888997888997888997888997888997888997888rarr 0
DHA COX2+ASA997888997888997888997888997888997888997888997888rarr AT-PD1 + AT-RvD (1ndash4)
Aspirin- (ASA-) induced acetylation of cyclooxygenase-2(COX-2) alters the enzyme specificity changing the outcome
4 BioMed Research International
of the catalytic reaction with fatty acids leading to the so-called ldquoaspirin-triggered (AT)rdquo products instead Arachi-donic acid (AA) gets converted into 15R hydroxyeicosate-traenoic acid (15R-HETE) which in the presence of 5-LOXtransforms further into 15-epi-lipoxins (15-epiLX) known asATLXA4 and ATLXB4 Docosahexaenoic acid (DHA) pro-duces aspirin-triggered resolvins and protectin D ATRvD1to ATRvD4 and ATPD while reaction with eicosapentaenoicacid (EPA) results in resolvins E ATRvE1 and ATRvE2However certain NSAIDs can block these reactions
8 Factors Influencing the 5- 12- and15-LOX Activity
Leukotrienes (LTs) generated by 5-LOX play a key rolein the pathogenesis of asthma allergic rhinitis and otherdiseases [68] Inhibitors of this enzyme and the cysteinylleukotriene receptor antagonists (eg zafirlukast mon-telukast pabilukast and pranlukast) are successfully usedto prevent the exacerbations of those diseases The 5-LOXinhibitors are not useful in the treatment of asthmatic attacksbecause the inhibition of LT synthesis also inhibits thetranscellular synthesis of the proresolving substances suchas resolvins protectins and maresins [69] Pergola et aldemonstrated that the low levels of testosterone in womenare the reason for their nearly double higher level of 5-LOXproducts than in men [70 71] This observation explainswhy the treatment and asthma symptoms control are moredifficult in women than in men
9 Conclusions
Laboratory research on PUFAs metabolism is devoid of theconfounding factors that exist in clinical practice age sexsocial conditions coexisting diseases and current medica-tion All of the above factors change the course of numerouschemical reactions and metabolic pathways We suggest thatone of the reasons for the inconsistencies between the resultsof laboratory and clinical researchmight be imprecise patientinclusion and exclusion criteria In this paper we presentedinformation that is infrequently described in medical litera-ture some of the factors modulating the eicosanoid synthesisand the resultant inflammatory reaction We hope that thisinformation will help reduce the flaws at the study designstage of clinical trials regarding the PUFA supplementation
Conflict of Interests
The authors declare that they have no competing interests
Authorsrsquo Contribution
Each author has participated sufficiently intellectually orpractically in the work to take public responsibility for thecontent of the paper
References
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[2] K DHa B A Clarke andW J Brown ldquoRegulation of theGolgicomplex by phospholipid remodeling enzymesrdquo Biochimica etBiophysica Acta vol 1821 no 8 pp 1078ndash1088 2012
[3] R L McKimmie L Easter and R B Weinberg ldquoAcyl chainlength saturation and hydrophobicity modulate the efficiencyof dietary fatty acid absorption in adult humansrdquoTheAmericanJournal of PhysiologymdashGastrointestinal and Liver Physiologyvol 305 no 9 pp G620ndashG627 2013
[4] A N Carley and A M Kleinfeld ldquoFlip-flop is the rate-limiting step for transport of free fatty acids across lipid vesiclemembranesrdquo Biochemistry vol 48 no 43 pp 10437ndash104452009
[5] S Siddiqi A Sheth F Patel M Barnes and C M MansbachII ldquoIntestinal caveolin-1 is important for dietary fatty acidabsorptionrdquo Biochimica et Biophysica Acta vol 1831 no 8 pp1311ndash1321 2013
[6] HMu andC-EHoslashy ldquoThedigestion of dietary triacylglycerolsrdquoProgress in Lipid Research vol 43 no 2 pp 105ndash133 2004
[7] J Shim C L Moulson E P Newberry et al ldquoFatty acidtransport protein 4 is dispensable for intestinal lipid absorptionin micerdquo Journal of Lipid Research vol 50 no 3 pp 491ndash5002009
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[10] R A Gibson B Muhlhausler and M Makrides ldquoConversionof linoleic acid and alpha-linolenic acid to long-chain polyun-saturated fatty acids (LCPUFAs) with a focus on pregnancylactation and the first 2 years of liferdquo Maternal and ChildNutrition vol 7 supplement 2 pp 17ndash26 2011
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[12] S K Raatz J B Redmon N Wimmergren J V Donadio andD M Bibus ldquoEnhanced absorption of n-3 fatty acids fromemulsified compared with encapsulated fish oilrdquo Journal of theAmerican Dietetic Association vol 109 no 6 pp 1076ndash10812009
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[15] S Moncada A G Herman E A Higgs and J R VaneldquoDifferential formation of prostacyclin (PGX or PGI2) by layersof the arterial wall An explanation for the anti-thromboticproperties of vascular endotheliumrdquo Thrombosis Research vol11 no 3 pp 323ndash344 1977
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[18] J Nowak and G A FitzGerald ldquoRedirection of prostaglandinendoperoxide metabolism at the platelet-vascular interface inmanrdquo Journal of Clinical Investigation vol 83 no 2 pp 380ndash385 1989
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[20] N Maugeri V Evangelista A Celardo et al ldquoPolymor-phonuclear leukocyte-platelet interaction role of P-selectin inthromboxane B2 and leukotriene C4 cooperative synthesisrdquoThrombosis and Haemostasis vol 72 no 3 pp 450ndash456 1994
[21] E Peranzoni S Zilio I Marigo et al ldquoMyeloid-derivedsuppressor cell heterogeneity and subset definitionrdquo CurrentOpinion in Immunology vol 22 no 2 pp 238ndash244 2010
[22] E Ribechini V Greifenberg S Sandwick andM B Lutz ldquoSub-sets expansion and activation of myeloid-derived suppressorcellsrdquoMedical Microbiology and Immunology vol 199 no 3 pp273ndash281 2010
[23] P Raber A C Ochoa and P C Rodrıguez ldquoMetabolismof L-arginine by myeloid-derived suppressor cells in cancermechanisms of T cell suppression and therapeutic perspectivesrdquoImmunological Investigations vol 41 no 6-7 pp 614ndash634 2012
[24] P J Popovic H J Zeh III and J B Ochoa ldquoArginine andimmunityrdquo Journal of Nutrition vol 137 supplement 2 no 6pp 1681Sndash1686S 2007
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[26] P C Rodriguez A H Zea J DeSalvo et al ldquoL-arginineconsumption bymacrophagesmodulates the expression of CD3zeta chain in T lymphocytesrdquo Journal of Immunology vol 171no 3 pp 1232ndash1239 2003
[27] S S Yarandi V M Zhao G Hebbar and T R Ziegler ldquoAminoacid composition in parenteral nutrition what is the evidencerdquoCurrent Opinion in Clinical Nutrition and Metabolic Care vol14 no 1 pp 75ndash82 2011
[28] P Yaqoob and P C Calder ldquoCytokine production by humanperipheral blood mononuclear cells differential sensitivity toglutamine availabilityrdquo Cytokine vol 10 no 10 pp 790ndash7941998
[29] CMurphy and P Newsholme ldquoMacrophage-mediated lysis of abeta-cell line tumour necrosis factor-alpha release from bacil-lus Calmette-Guerin (BCG)-activated murine macrophagesand interleukin-8 release from human monocytes are depen-dent on extracellular glutamine concentration and glutaminemetabolismrdquo Clinical Science vol 96 no 1 pp 89ndash97 1999
[30] S Sfar F Laporte H Braham A Jawed S Amor and AKerkeni ldquoInfluence of dietary habits age and gender on plasmafatty acids levels in a population of healthy Tunisian subjectsrdquoExperimental Gerontology vol 45 no 9 pp 719ndash725 2010
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on stearoyl-CoA desaturase and its influence on the acylcomposition of phospholipid in rat liver Comparison withclofibric acid and tiadenolrdquo Biochemical Journal vol 263 no3 pp 897ndash904 1989
[32] D F Horrobin ldquoLoss of delta-6-desaturase activity as a keyfactor in agingrdquoMedical Hypotheses vol 7 no 9 pp 1211ndash12201981
[33] S Hrelia A Bordoni M Celadon E Turchetto P L Biagiand C A Rossi ldquoAge-related changes in linoleate and 120572-linolenate desaturation by rat liver microsomesrdquo Biochemicaland Biophysical Research Communications vol 163 no 1 pp348ndash355 1989
[34] S Hrelia M Celadon C A Rossi P L Biagi and A BordonildquoDelta-6-desaturation of linoleic and 120572-linolenic acids in agedrats a kinetic analysisrdquo Biochemistry International vol 22 no4 pp 659ndash667 1990
[35] D E Barre ldquoThe role of consumption of alpha-linolenic eicos-apentaenoic and docosahexaenoic acids in human metabolicsyndrome and type 2 diabetesmdasha mini-reviewrdquo Journal of OleoScience vol 56 no 7 pp 319ndash325 2007
[36] J Kroger and M B Schulze ldquoRecent insights into the relationof Δ5 desaturase and Δ6 desaturase activity to the developmentof type 2 diabetesrdquo Current Opinion in Lipidology vol 23 no 1pp 4ndash10 2012
[37] K Eder and M Kirchgessner ldquoActivities of liver microsomalfatty acid desaturases in zinc-deficient rats force-fed diets with acoconut oilsafflower oil mixture of linseed oilrdquo Biological TraceElement Research vol 48 no 3 pp 215ndash229 1995
[38] K Eder and M Kirchgessner ldquoZinc deficiency and the desatu-ration of linoleic acid in rats force-fed fat-free dietsrdquo BiologicalTrace Element Research vol 54 no 2 pp 173ndash181 1996
[39] A Bordoni S Hrelia A Lorenzini et al ldquoDual influence ofaging and vitamin B6 deficiency on delta-6-desaturation ofessential fatty acids in rat liver microsomesrdquo ProstaglandinsLeukotrienes and Essential Fatty Acids vol 58 no 6 pp 417ndash420 1998
[40] H Tsuge N Hotta and T Hayakawa ldquoEffects of vitamin B-6 on (n-3) polyunsaturated fatty acid metabolismrdquo Journal ofNutrition vol 130 no 25 supplement pp 333Sndash334S 2000
[41] R Zolfaghari C J Cifelli M D Banta and A C Ross ldquoFattyacid Δ5-Desaturase mRNA is regulated by dietary vitamin Aand exogenous retinoic acid in liver of adult ratsrdquo Archives ofBiochemistry and Biophysics vol 391 no 1 pp 8ndash15 2001
[42] U N Das ldquoFetal alcohol syndrome and essential fatty acidsrdquoPLoS Medicine vol 3 no 5 article e247 2006
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induced platelet activation mechanismsrdquo The InternationalJournal of Biochemistry amp Cell Biology vol 30 no 10 pp 1107ndash1122 1998
[44] S A-V Leyen M F Romero M C Khosla and J G DouglasldquoModulation of phospholipase A2 activity and sodium trans-port by angiotensin-(1-7)rdquo Kidney International vol 44 no 5pp 932ndash936 1993
[45] R T Abraham M M McKinney C Forray G D Shipley andB S Handwerger ldquoStimulation of arachidonic acid release andeicosanoid biosynthesis in an interleukin 2-dependent T celllinerdquo Journal of Immunopharmacology vol 8 no 2 pp 165ndash2041986
[46] F Caiazza B J Harvey and W Thomas ldquoCytosolic phos-pholipase A2 activation correlates with HER2 overexpressionand mediates estrogen-dependent breast cancer cell growthrdquoMolecular Endocrinology vol 24 no 5 pp 953ndash968 2010
6 BioMed Research International
[47] L Oleksowicz Y Liu R B Bracken et al ldquoSecretory phospholi-pase A2-IIa is a target gene of the HERHER2-elicited pathwayand a potential plasma biomarker for poor prognosis of prostatecancerrdquo Prostate vol 72 no 10 pp 1140ndash1149 2012
[48] M Hernandez R Martin M D Garcia-Cubillas P Maeso-Hernandez and M L Nieto ldquoSecreted PLA2 induces pro-liferation in astrocytoma through the EGF receptor anotherinflammation-cancer linkrdquo Neuro-Oncology vol 12 no 10 pp1014ndash1023 2010
[49] F F Davidson E A Dennis M Powell and J R Glenney JrldquoInhibition of phospholipase A2 by lsquolipocortinsrsquo and calpactinsAn effect of binding to substrate phospholipidsrdquo Journal ofBiological Chemistry vol 262 no 4 pp 1698ndash1705 1987
[50] Y Li H Yamada Y Kita et al ldquoRoles of ERK and cPLA2in
the angiotensin II-mediated biphasic regulation of Na+-HCOminus3
transportrdquo Journal of the American Society of Nephrology vol 19no 2 pp 252ndash259 2008
[51] M Holinstat O Boutaud P L Apopa et al ldquoProtease-activatedreceptor signaling in platelets activates cytosolic phospholipaseA2120572differently for cyclooxygenase-1 and 12-lipoxygenase catal-
[52] R M Kramer E F Roberts J V Manetta P A Hyslopand J A Jakubowski ldquoThrombin-induced phosphorylationand activation of Ca2+-sensitive cytosolic phospholipase A2 inhuman plateletsrdquo Journal of Biological Chemistry vol 268 no35 pp 26796ndash26804 1993
[53] W E M Lands ldquoStories about acyl chainsrdquo Biochimica etBiophysica ActamdashMolecular and Cell Biology of Lipids vol 1483no 1 pp 1ndash14 2000
[54] H Shindou and T Shimizu ldquoAcyl-CoAlysophospholipid acyl-transferasesrdquo Journal of Biological Chemistry vol 284 no 1 pp1ndash5 2009
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[56] A Arduini V Tyurin Y Tyuruna et al ldquoAcyl-trafficking inmembrane phospholipid fatty acid turnover the transfer of fattyacid from the acyl-L-carnitine pool tomembrane phospholipidsin intact human erythrocytesrdquo Biochemical and BiophysicalResearch Communications vol 187 no 1 pp 353ndash358 1992
[57] A Arduini G Mancinelli and R R Ramsay ldquoPalmitoyl-L-carnitine a metabolic intermediate of the fatty acid incor-poration pathway in erythrocyte membrane phospholipidsrdquoBiochemical and Biophysical Research Communications vol 173no 1 pp 212ndash217 1990
[58] C N Serhan ldquoLipoxins and aspirin-triggered 15-epi-lipoxinbiosynthesis an update and role in anti-inflammation and pro-resolutionrdquo Prostaglandins and Other Lipid Mediators vol 68-69 pp 433ndash455 2002
[59] S Fiorucci O M De Lima Jr A Mencarelli et alldquoCyclooxygenase-2-derived lipoxin A4 increases gastricresistance to aspirin-induced damagerdquo Gastroenterology vol123 no 5 pp 1598ndash1606 2002
[60] J L Wallace S R Zamuner W McKnight et al ldquoAspirin butnot NO-releasing aspirin (NCX-4016) interacts with selectiveCOX-2 inhibitors to aggravate gastric damage and inflam-mationrdquo American Journal of PhysiologymdashGastrointestinal andLiver Physiology vol 286 no 1 pp G76ndashG81 2004
[61] M Arita T Ohira Y P Sun S Elangovan N Chiang and C NSerhan ldquoResolvin E1 selectively interacts with leukotriene B4
receptor BLT1 and ChemR23 to regulate inflammationrdquo Journalof Immunology vol 178 no 6 pp 3912ndash3917 2007
[62] S F Oh P S Pillai A Recchiuti R Yang and C N SerhanldquoPro-resolving actions and stereoselective biosynthesis of 18SE-series resolvins in human leukocytes and murine inflamma-tionrdquo Journal of Clinical Investigation vol 121 no 2 pp 569ndash5812011
[63] Y-P Sun S F Oh J Uddin et al ldquoResolvin D1 and itsaspirin-triggered 17R epimer stereochemical assignments anti-inflammatory properties and enzymatic inactivationrdquo Journalof Biological Chemistry vol 282 no 13 pp 9323ndash9334 2007
[64] S Hong K Gronert P R Devchand R-L Moussignac andC N Serhan ldquoNovel docosatrienes and 17S-resolvins generatedfrom docosahexaenoic acid in murine brain human bloodand glial cells Autacoids in anti-inflammationrdquo The Journal ofBiological Chemistry vol 278 no 17 pp 14677ndash14687 2003
[65] H R OrsquoNeal T Koyama E A S Koehler et al ldquoPrehospitalstatin and aspirin use and the prevalence of severe sepsis andacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 39 no 6 pp 1343ndash1350 2011
[66] M Spite and C N Serhan ldquoNovel lipid mediators promoteresolution of acute inflammation impact of aspirin and statinsrdquoCirculation Research vol 107 no 10 pp 1170ndash1184 2010
[67] J N Fullerton A J OrsquoBrien and DW Gilroy ldquoLipid mediatorsin immune dysfunction after severe inflammationrdquo Trends inImmunology vol 35 no 1 pp 12ndash21 2014
[68] T Hammarberg P Provost B Persson and O RadmarkldquoThe N-terminal domain of 5-lipoxygenase binds calcium andmediates calcium stimulation of enzyme activityrdquoThe Journal ofBiological Chemistry vol 275 no 49 pp 38787ndash38793 2000
[69] C N Serhan S Krishnamoorthy A Recchiuti and N ChiangldquoNovel anti-inflammatorymdashpro-resolving mediators and theirreceptorsrdquo Current Topics in Medicinal Chemistry vol 11 no 6pp 629ndash647 2011
[70] C Pergola A Rogge G Dodt et al ldquoTestosterone suppressesphospholipase D causing sex differences in leukotriene biosyn-thesis in human monocytesrdquoThe FASEB Journal vol 25 no 10pp 3377ndash3387 2011
[71] C Pergola G Dodt A Rossi et al ldquoERK-mediated regulationof leukotriene biosynthesis by androgens a molecular basis forgender differences in inflammation and asthmardquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 105 no 50 pp 19881ndash19886 2008
AA EPA DHA + lysophospholipidsCOX-1 -25- 12- and 15-LOXCYP
Eicosanoids
Figure 1 Simplified diagram of eicosanoid synthesis The 120572-linolenic and linoleic acids are substrates for the synthesis ofAA EPA and DHA which are added at the sn-2 position tolysophospholipids (via the Lands cycle) or to glycerophospholipids(via the Kennedy pathway) The AAs EPAs and DHAs that werereleased from glycerophospholipids by the PLA(2) are substrates forCOX LOX cytochrome (CYP) and other enzymes involved in theeicosanoid synthesis
2 Absorption of LCPUFAs in theGastrointestinal Tract
Triglycerides (TGs) are emulsified in the stomach and duo-denum by the bile and pancreatic juices and then hydrolyzedby the pancreatic lipase into free fatty acids (FFAs) andmonoacylglycerolsThe FFAs absorption ratio decreases pro-portionally to the increasing FFA carbon chain length andhydrophobicity whereas the ratio increases proportionallyto the increasing desaturation [3] A small part of short-chain fatty acids (SCFAs) diffuse via the intestinal mucosalmembrane via the flip-flop mechanism [4] The rest ofSCFAs and all of long-chain FAs (LCFAs) are bound to thelipid raft proteins found in the cell membrane domains andtransmitted through the intestinal wall [5]The FAs absorbedby the enterocytes bind to caveolin-1 and accumulate in thecytoplasmic lipid droplets
Before exiting the enterocytes the PUFAs are boundinto TGs at the sn-2 position [6] Chylomicrons resultingfrom the bonding of TG with cholesterol phospholipids andapolipoproteins enter the portal circulation Several proteinsare known to transport FA across cell membranes and theirdistribution is specific to the tissue type and function Forexample the fatty acid translocase (FAT)CD 36 has thehighest expression in muscle tissue whereas the enterocytesof the small intestine have the highest activity of fatty acidtransport protein 4 (FATP4) which specifically binds PUFAs[7 8]
A reduction of PUFA absorption from the intestinallumen is observed in diseases involving the damage to theintestinal mucosa or the reduction of pancreatic lipase andbile acid secretion such as inflammatory bowel diseasespancreatitis liver diseases intestinal fistulas and extensiveresections of the small intestine At this moment it is difficultto assess the degree to which the above-mentioned diseasesinfluence the PUFA absorption and eicosanoid synthesis
3 The Influence of PUFA Supply Route on theRate of LCPUFA and Eicosanoid Synthesis
Themain PUFAs substrates for this process are the dietary 120572-linolenic and linoleic acids Their absorption rate is largelydependent on supply route and physical structure Thusthe PUFA n-3n-6 concentration ratio in cell membranessignificantly increases after just 48 hours after intravenousadministration whereas after oral administration the con-centration increases more slowly due to extra time neededfor its absorption in the gastrointestinal tract The profile ofsynthesized eicosanoids in tissues generally results from theΔ6 desaturasersquos greater affinity for 120572-linolenic acid than forlinoleic acid [9 10] Currently the typical Western diet hasn-6n-3 ratio of 15 1 instead of the recommended 3 1 [11]Raatz et al demonstrated that the n-3 PUFAs absorbtion inthe form of lipid emulsion intravenously is faster than oralfish oil capsules [12] FA emulsification and absorption areimpaired in pancreatic insufficiency inflammatory bowel dis-eases postgastrectomy states intestinal fistulas and extensivebowel resections [13 14]
4 Transcellular Biosynthesis of Eicosanoids
Although eicosanoids can theoretically be synthesized in onecell it is observed that in vivo this process occurs sequentiallyin different cell types for example blood endothelial andconnective tissue cells [15 16] The intermediate from LCP-UFA (eg PGH
2or leukotriene A
4) from a single donor cell
is transported to an acceptor cell which synthesizes the finalproduct [17 18] To this date it has not been explained whythis process occursmdashafter all each cell contains a full set ofenzymes needed to complete the synthesis It is even moresurprising because the lipophilicity of these products makestheir transport across membranes more difficult [19 20]
Besides the change in cell number another factor affect-ing the eicosanoid synthesis is the maturity of cells In statesof intense catabolism severe infection and sepsis and in
BioMed Research International 3
neoplastic disease the bone marrow releases myeloid-derivedsuppressor cells (MDSCs) The MDSCs can be subdividedinto two major groups immature granulocytes MDSC (G-MDSC) andmonocytesMDSC (M-MDSC) released from thebone marrow into the peripheral bloodstream In order tosuppress immune function theG-MDSCs primarily use reac-tive oxygen species (ROS) whereas the M-MDSCs use nitricoxide synthase (iNOS) and arginase [21ndash24] The intensityofMDSC-induced immunosuppression dynamically changeswith the patientrsquos stateThe activity ofMDSC leads to argininestarvation lowering of the proliferation rate and loss ofthe T-cell-receptor- (TCR-) associated CD3 120577 chain [25 26]Besides the arginine starvation in tissues immunosuppres-sion may be triggered by glutamine deficiency A deficiencyof these amino acids can be expected in undernourished orseptic patients as well as during intense catabolic states forexample after large surgical procedures or posttrauma [27]The assessment of PUFA supplementationrsquos influence on theinflammatory reactionmay be complicated by the immaturityof the immune system cells or amino acid deficiency [28 29]
5 Factors Inhibiting the Δ6Desaturase Activity
Δ6 desaturase catalyzes the conversion of LA and ALA intoAA EPA and DHA Several studies on animal models madein the 90s of the last century mainly on rats demonstratedthat this conversion is greater in females [30 31] anddecreasesdue to age [32ndash34] metabolic syndrome diabetes [35 36]and deficiencies of folic acid zinc [37 38] and vitamins B
6
B12[39 40] and A [41] In addition Δ6 desaturase activity is
decreased by alcohol [42] The above-mentioned factors maysignificantly alter the results of clinical trials on the role ofeicosanoids in the inflammatory reaction
6 Factors Modifying the Activity ofPhospholipase A2 (PLA2)
A very important step in eicosanoid synthesis is the hydrol-ysis of the membrane glycerophospholipids at the n-2 posi-tion by PLA2 into free PUFAs and lysophospholipids Theefficiency of this reaction determines the rate of eicosanoidsynthesis Many factors such as thrombin angiotensin II andinterleukin-2 influence the activity of PLA2 [43ndash45] It isdecreased in neoplasms associatedwith the human epidermalgrowth factor (HER2) overexpression as well as under theinfluence of angiotensin II receptor inhibitors used in thetreatment of arterial hypertension and thrombin inhibitorscommonly used in the treatment and prevention of thevenous thromboembolic disease [46ndash48] Glucocorticoidsincrease the synthesis of lipocortin and annexin stronginhibitors of PLA2 activity leading to the inhibition ofeicosanoid synthesis [49ndash52]
The glycerophospholipid deacylationreacylation cycleknown as the Lands cycle is responsible for the continu-ous change of cell membrane composition and properties[53] After the PLA
2-catalyzed deacylation of phospholipids
the lysophospholipid acyltransferases (LPAATs) catalyze the
reacylation of lysophospholipids [54 55] The efficiency ofreacylation of lysophospholipids is influenced primarily bythe availability of active PUFA (PUFA-CoA) and the freeL-carnitine concentration which by binding a significantamount of PUFA limits the rate of this step of eicosanoidsynthesis [56 57]
7 Factors Influencing COX Activity
NSAIDs inhibit eicosanoid synthesis by acting on COX-1 and -2 Aspirin differs from the other NSAIDs due toits ability to irreversibly acetylate COX-2 and switch thisenzyme to instead generate 15R-HETE a substrate for the 5-LOX This results in the synthesis of 15-epi-lipoxin A
4 also
known as aspirin-triggered lipoxin (ATL) [58] Celecoxib androfecoxib inhibit the activity of acetylated COX-2 and thesynthesis of the anti-inflammatory 15(R)-epi-LXA4 thereforecombining them with aspirin significantly increases the riskof gastric mucosa damage [59] These adverse interactionshave not been observed after the administration of celecoxiband rofecoxib with the new acetylsalicylic acid derivativeNCX 4016 [60] The acetylated COX-2 converts EPA into18(R)-hydroxyeicosapentaenoic acid (18R-HEPE) which isthen converted by 5-LOX into resolvin (Rv) E
1and RvE
2
RvE1exerts its anti-inflammatory activity after binding with
the ChemR23 and leukotriene BLT1receptors [61 62] The
synthesis of D-series Rvmay take place via two pathwaysThefirst of them is dependent on the aspirin-acetylated COX-2and uses DHA as a substrate for 17(R)-hydroxy-DHA whichlater is converted by LOX to 17(R)-RvD1 to D4 known as theaspirin-triggered RvD-series (AT-RvDs) [63 64] whereas thesecond pathway is independent of aspirin and yields resolvinssimilar to those from the first pathway
Although statins use a slightly different mechanism thanaspirin to modify COX-2 activity both drugs produce 15(R)HETE which is converted by the 5-LOX to 15(R)-epi-LXA4[65 66] Clinical studies of the DHArsquos and EPArsquos effect on theinflammatory reaction need to consider the fact that aspirinNSAIDs and statins all significantly change the eicosanoidprofile (Equation (1)) [67]
Aspirin- (ASA-) induced acetylation of cyclooxygenase-2(COX-2) alters enzymersquos specificity as follows
AA COX2+ASA997888997888997888997888997888997888997888997888rarr 15R-HETE 5-LOX997888997888997888997888997888rarr 15-epi- LXA4
+ 15-epi- LXB4
AA COX2+ASA+NSAIDs997888997888997888997888997888997888997888997888997888997888997888997888997888997888997888rarr 0
DHA COX2+ASA997888997888997888997888997888997888997888997888rarr AT-PD1 + AT-RvD (1ndash4)
Aspirin- (ASA-) induced acetylation of cyclooxygenase-2(COX-2) alters the enzyme specificity changing the outcome
4 BioMed Research International
of the catalytic reaction with fatty acids leading to the so-called ldquoaspirin-triggered (AT)rdquo products instead Arachi-donic acid (AA) gets converted into 15R hydroxyeicosate-traenoic acid (15R-HETE) which in the presence of 5-LOXtransforms further into 15-epi-lipoxins (15-epiLX) known asATLXA4 and ATLXB4 Docosahexaenoic acid (DHA) pro-duces aspirin-triggered resolvins and protectin D ATRvD1to ATRvD4 and ATPD while reaction with eicosapentaenoicacid (EPA) results in resolvins E ATRvE1 and ATRvE2However certain NSAIDs can block these reactions
8 Factors Influencing the 5- 12- and15-LOX Activity
Leukotrienes (LTs) generated by 5-LOX play a key rolein the pathogenesis of asthma allergic rhinitis and otherdiseases [68] Inhibitors of this enzyme and the cysteinylleukotriene receptor antagonists (eg zafirlukast mon-telukast pabilukast and pranlukast) are successfully usedto prevent the exacerbations of those diseases The 5-LOXinhibitors are not useful in the treatment of asthmatic attacksbecause the inhibition of LT synthesis also inhibits thetranscellular synthesis of the proresolving substances suchas resolvins protectins and maresins [69] Pergola et aldemonstrated that the low levels of testosterone in womenare the reason for their nearly double higher level of 5-LOXproducts than in men [70 71] This observation explainswhy the treatment and asthma symptoms control are moredifficult in women than in men
9 Conclusions
Laboratory research on PUFAs metabolism is devoid of theconfounding factors that exist in clinical practice age sexsocial conditions coexisting diseases and current medica-tion All of the above factors change the course of numerouschemical reactions and metabolic pathways We suggest thatone of the reasons for the inconsistencies between the resultsof laboratory and clinical researchmight be imprecise patientinclusion and exclusion criteria In this paper we presentedinformation that is infrequently described in medical litera-ture some of the factors modulating the eicosanoid synthesisand the resultant inflammatory reaction We hope that thisinformation will help reduce the flaws at the study designstage of clinical trials regarding the PUFA supplementation
Conflict of Interests
The authors declare that they have no competing interests
Authorsrsquo Contribution
Each author has participated sufficiently intellectually orpractically in the work to take public responsibility for thecontent of the paper
References
[1] F Gibellini and T K Smith ldquoThe Kennedy pathway-denovo synthesis of phosphatidylethanolamine and phosphatidyl-cholinerdquo IUBMB Life vol 62 no 6 pp 414ndash428 2010
[2] K DHa B A Clarke andW J Brown ldquoRegulation of theGolgicomplex by phospholipid remodeling enzymesrdquo Biochimica etBiophysica Acta vol 1821 no 8 pp 1078ndash1088 2012
[3] R L McKimmie L Easter and R B Weinberg ldquoAcyl chainlength saturation and hydrophobicity modulate the efficiencyof dietary fatty acid absorption in adult humansrdquoTheAmericanJournal of PhysiologymdashGastrointestinal and Liver Physiologyvol 305 no 9 pp G620ndashG627 2013
[4] A N Carley and A M Kleinfeld ldquoFlip-flop is the rate-limiting step for transport of free fatty acids across lipid vesiclemembranesrdquo Biochemistry vol 48 no 43 pp 10437ndash104452009
[5] S Siddiqi A Sheth F Patel M Barnes and C M MansbachII ldquoIntestinal caveolin-1 is important for dietary fatty acidabsorptionrdquo Biochimica et Biophysica Acta vol 1831 no 8 pp1311ndash1321 2013
[6] HMu andC-EHoslashy ldquoThedigestion of dietary triacylglycerolsrdquoProgress in Lipid Research vol 43 no 2 pp 105ndash133 2004
[7] J Shim C L Moulson E P Newberry et al ldquoFatty acidtransport protein 4 is dispensable for intestinal lipid absorptionin micerdquo Journal of Lipid Research vol 50 no 3 pp 491ndash5002009
[8] C Aguer M Foretz L Lantier et al ldquoIncreased FATCD36cycling and lipid accumulation inmyotubes derived from obesetype 2 diabetic patientsrdquo PLoS ONE vol 6 no 12 Article IDe28981 2011
[9] R Portolesi B C Powell and R A Gibson ldquoCompetitionbetween 245n-3 and ALA for Δ 6 desaturase may limit theaccumulation of DHA in HepG2 cell membranesrdquo Journal ofLipid Research vol 48 no 7 pp 1592ndash1598 2007
[10] R A Gibson B Muhlhausler and M Makrides ldquoConversionof linoleic acid and alpha-linolenic acid to long-chain polyun-saturated fatty acids (LCPUFAs) with a focus on pregnancylactation and the first 2 years of liferdquo Maternal and ChildNutrition vol 7 supplement 2 pp 17ndash26 2011
[11] A P Simopoulos ldquoOmega-3 fatty acids in health and diseaseand in growth and developmentrdquo The American Journal ofClinical Nutrition vol 54 no 3 pp 438ndash463 1991
[12] S K Raatz J B Redmon N Wimmergren J V Donadio andD M Bibus ldquoEnhanced absorption of n-3 fatty acids fromemulsified compared with encapsulated fish oilrdquo Journal of theAmerican Dietetic Association vol 109 no 6 pp 1076ndash10812009
[13] I Kalvaria and J E Clain ldquoDiabetic diarrhoea and steatorrhoeaA case report and review of the literaturerdquo South AfricanMedical Journal vol 55 no 14 pp 562ndash564 1979
[14] BWalther C Clementsson S Vallgren I Ihse and B AkessonldquoFat malabsorption in patients before and after total gastrec-tomy studied by the triolein breath testrdquo Scandinavian Journalof Gastroenterology vol 24 no 3 pp 309ndash314 1989
[15] S Moncada A G Herman E A Higgs and J R VaneldquoDifferential formation of prostacyclin (PGX or PGI2) by layersof the arterial wall An explanation for the anti-thromboticproperties of vascular endotheliumrdquo Thrombosis Research vol11 no 3 pp 323ndash344 1977
[16] A J Marcus B B Weksler and E A Jaffe ldquoEnzymaticconversion of prostaglandin endoperoxide H
2and arachidonic
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acid to prostacyclin by cultured human endothelial cellsrdquo TheJournal of Biological Chemistry vol 253 no 20 pp 7138ndash71411978
[17] S Bunting R Gryglewski S Moncada and J R Vane ldquoArterialwalls generate from prostaglandin endoperoxides a substance(prostaglandin X)which relaxes strips ofmesenteric and coeliacarteries and inhibits platelet aggregationrdquo Prostaglandins vol12 no 6 pp 897ndash913 1976
[18] J Nowak and G A FitzGerald ldquoRedirection of prostaglandinendoperoxide metabolism at the platelet-vascular interface inmanrdquo Journal of Clinical Investigation vol 83 no 2 pp 380ndash385 1989
[19] J E McGee and F A Fitzpatrick ldquoErythrocyte-neutrophilinteractions Formation of leukotriene B4 by transcellularbiosynthesisrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 83 no 5 pp 1349ndash1353 1986
[20] N Maugeri V Evangelista A Celardo et al ldquoPolymor-phonuclear leukocyte-platelet interaction role of P-selectin inthromboxane B2 and leukotriene C4 cooperative synthesisrdquoThrombosis and Haemostasis vol 72 no 3 pp 450ndash456 1994
[21] E Peranzoni S Zilio I Marigo et al ldquoMyeloid-derivedsuppressor cell heterogeneity and subset definitionrdquo CurrentOpinion in Immunology vol 22 no 2 pp 238ndash244 2010
[22] E Ribechini V Greifenberg S Sandwick andM B Lutz ldquoSub-sets expansion and activation of myeloid-derived suppressorcellsrdquoMedical Microbiology and Immunology vol 199 no 3 pp273ndash281 2010
[23] P Raber A C Ochoa and P C Rodrıguez ldquoMetabolismof L-arginine by myeloid-derived suppressor cells in cancermechanisms of T cell suppression and therapeutic perspectivesrdquoImmunological Investigations vol 41 no 6-7 pp 614ndash634 2012
[24] P J Popovic H J Zeh III and J B Ochoa ldquoArginine andimmunityrdquo Journal of Nutrition vol 137 supplement 2 no 6pp 1681Sndash1686S 2007
[25] M Munder H Schneider C Luckner et al ldquoSuppression of T-cell functions by human granulocyte arginaserdquo Blood vol 108no 5 pp 1627ndash1634 2006
[26] P C Rodriguez A H Zea J DeSalvo et al ldquoL-arginineconsumption bymacrophagesmodulates the expression of CD3zeta chain in T lymphocytesrdquo Journal of Immunology vol 171no 3 pp 1232ndash1239 2003
[27] S S Yarandi V M Zhao G Hebbar and T R Ziegler ldquoAminoacid composition in parenteral nutrition what is the evidencerdquoCurrent Opinion in Clinical Nutrition and Metabolic Care vol14 no 1 pp 75ndash82 2011
[28] P Yaqoob and P C Calder ldquoCytokine production by humanperipheral blood mononuclear cells differential sensitivity toglutamine availabilityrdquo Cytokine vol 10 no 10 pp 790ndash7941998
[29] CMurphy and P Newsholme ldquoMacrophage-mediated lysis of abeta-cell line tumour necrosis factor-alpha release from bacil-lus Calmette-Guerin (BCG)-activated murine macrophagesand interleukin-8 release from human monocytes are depen-dent on extracellular glutamine concentration and glutaminemetabolismrdquo Clinical Science vol 96 no 1 pp 89ndash97 1999
[30] S Sfar F Laporte H Braham A Jawed S Amor and AKerkeni ldquoInfluence of dietary habits age and gender on plasmafatty acids levels in a population of healthy Tunisian subjectsrdquoExperimental Gerontology vol 45 no 9 pp 719ndash725 2010
[31] Y Kawashimia N Uy-Yu and H Kozuka ldquoSex-related dif-ferences in the enhancing effects of perfluoro-octanoic acid
on stearoyl-CoA desaturase and its influence on the acylcomposition of phospholipid in rat liver Comparison withclofibric acid and tiadenolrdquo Biochemical Journal vol 263 no3 pp 897ndash904 1989
[32] D F Horrobin ldquoLoss of delta-6-desaturase activity as a keyfactor in agingrdquoMedical Hypotheses vol 7 no 9 pp 1211ndash12201981
[33] S Hrelia A Bordoni M Celadon E Turchetto P L Biagiand C A Rossi ldquoAge-related changes in linoleate and 120572-linolenate desaturation by rat liver microsomesrdquo Biochemicaland Biophysical Research Communications vol 163 no 1 pp348ndash355 1989
[34] S Hrelia M Celadon C A Rossi P L Biagi and A BordonildquoDelta-6-desaturation of linoleic and 120572-linolenic acids in agedrats a kinetic analysisrdquo Biochemistry International vol 22 no4 pp 659ndash667 1990
[35] D E Barre ldquoThe role of consumption of alpha-linolenic eicos-apentaenoic and docosahexaenoic acids in human metabolicsyndrome and type 2 diabetesmdasha mini-reviewrdquo Journal of OleoScience vol 56 no 7 pp 319ndash325 2007
[36] J Kroger and M B Schulze ldquoRecent insights into the relationof Δ5 desaturase and Δ6 desaturase activity to the developmentof type 2 diabetesrdquo Current Opinion in Lipidology vol 23 no 1pp 4ndash10 2012
[37] K Eder and M Kirchgessner ldquoActivities of liver microsomalfatty acid desaturases in zinc-deficient rats force-fed diets with acoconut oilsafflower oil mixture of linseed oilrdquo Biological TraceElement Research vol 48 no 3 pp 215ndash229 1995
[38] K Eder and M Kirchgessner ldquoZinc deficiency and the desatu-ration of linoleic acid in rats force-fed fat-free dietsrdquo BiologicalTrace Element Research vol 54 no 2 pp 173ndash181 1996
[39] A Bordoni S Hrelia A Lorenzini et al ldquoDual influence ofaging and vitamin B6 deficiency on delta-6-desaturation ofessential fatty acids in rat liver microsomesrdquo ProstaglandinsLeukotrienes and Essential Fatty Acids vol 58 no 6 pp 417ndash420 1998
[40] H Tsuge N Hotta and T Hayakawa ldquoEffects of vitamin B-6 on (n-3) polyunsaturated fatty acid metabolismrdquo Journal ofNutrition vol 130 no 25 supplement pp 333Sndash334S 2000
[41] R Zolfaghari C J Cifelli M D Banta and A C Ross ldquoFattyacid Δ5-Desaturase mRNA is regulated by dietary vitamin Aand exogenous retinoic acid in liver of adult ratsrdquo Archives ofBiochemistry and Biophysics vol 391 no 1 pp 8ndash15 2001
[42] U N Das ldquoFetal alcohol syndrome and essential fatty acidsrdquoPLoS Medicine vol 3 no 5 article e247 2006
[43] R N Puri ldquoPhospholipase A2 its role in ADP- and thrombin-
induced platelet activation mechanismsrdquo The InternationalJournal of Biochemistry amp Cell Biology vol 30 no 10 pp 1107ndash1122 1998
[44] S A-V Leyen M F Romero M C Khosla and J G DouglasldquoModulation of phospholipase A2 activity and sodium trans-port by angiotensin-(1-7)rdquo Kidney International vol 44 no 5pp 932ndash936 1993
[45] R T Abraham M M McKinney C Forray G D Shipley andB S Handwerger ldquoStimulation of arachidonic acid release andeicosanoid biosynthesis in an interleukin 2-dependent T celllinerdquo Journal of Immunopharmacology vol 8 no 2 pp 165ndash2041986
[46] F Caiazza B J Harvey and W Thomas ldquoCytosolic phos-pholipase A2 activation correlates with HER2 overexpressionand mediates estrogen-dependent breast cancer cell growthrdquoMolecular Endocrinology vol 24 no 5 pp 953ndash968 2010
6 BioMed Research International
[47] L Oleksowicz Y Liu R B Bracken et al ldquoSecretory phospholi-pase A2-IIa is a target gene of the HERHER2-elicited pathwayand a potential plasma biomarker for poor prognosis of prostatecancerrdquo Prostate vol 72 no 10 pp 1140ndash1149 2012
[48] M Hernandez R Martin M D Garcia-Cubillas P Maeso-Hernandez and M L Nieto ldquoSecreted PLA2 induces pro-liferation in astrocytoma through the EGF receptor anotherinflammation-cancer linkrdquo Neuro-Oncology vol 12 no 10 pp1014ndash1023 2010
[49] F F Davidson E A Dennis M Powell and J R Glenney JrldquoInhibition of phospholipase A2 by lsquolipocortinsrsquo and calpactinsAn effect of binding to substrate phospholipidsrdquo Journal ofBiological Chemistry vol 262 no 4 pp 1698ndash1705 1987
[50] Y Li H Yamada Y Kita et al ldquoRoles of ERK and cPLA2in
the angiotensin II-mediated biphasic regulation of Na+-HCOminus3
transportrdquo Journal of the American Society of Nephrology vol 19no 2 pp 252ndash259 2008
[51] M Holinstat O Boutaud P L Apopa et al ldquoProtease-activatedreceptor signaling in platelets activates cytosolic phospholipaseA2120572differently for cyclooxygenase-1 and 12-lipoxygenase catal-
[52] R M Kramer E F Roberts J V Manetta P A Hyslopand J A Jakubowski ldquoThrombin-induced phosphorylationand activation of Ca2+-sensitive cytosolic phospholipase A2 inhuman plateletsrdquo Journal of Biological Chemistry vol 268 no35 pp 26796ndash26804 1993
[53] W E M Lands ldquoStories about acyl chainsrdquo Biochimica etBiophysica ActamdashMolecular and Cell Biology of Lipids vol 1483no 1 pp 1ndash14 2000
[54] H Shindou and T Shimizu ldquoAcyl-CoAlysophospholipid acyl-transferasesrdquo Journal of Biological Chemistry vol 284 no 1 pp1ndash5 2009
[55] E Soupene and F A Kuypers ldquoMammalian long-chain acyl-CoA synthetasesrdquo Experimental Biology and Medicine vol 233no 5 pp 507ndash521 2008
[56] A Arduini V Tyurin Y Tyuruna et al ldquoAcyl-trafficking inmembrane phospholipid fatty acid turnover the transfer of fattyacid from the acyl-L-carnitine pool tomembrane phospholipidsin intact human erythrocytesrdquo Biochemical and BiophysicalResearch Communications vol 187 no 1 pp 353ndash358 1992
[57] A Arduini G Mancinelli and R R Ramsay ldquoPalmitoyl-L-carnitine a metabolic intermediate of the fatty acid incor-poration pathway in erythrocyte membrane phospholipidsrdquoBiochemical and Biophysical Research Communications vol 173no 1 pp 212ndash217 1990
[58] C N Serhan ldquoLipoxins and aspirin-triggered 15-epi-lipoxinbiosynthesis an update and role in anti-inflammation and pro-resolutionrdquo Prostaglandins and Other Lipid Mediators vol 68-69 pp 433ndash455 2002
[59] S Fiorucci O M De Lima Jr A Mencarelli et alldquoCyclooxygenase-2-derived lipoxin A4 increases gastricresistance to aspirin-induced damagerdquo Gastroenterology vol123 no 5 pp 1598ndash1606 2002
[60] J L Wallace S R Zamuner W McKnight et al ldquoAspirin butnot NO-releasing aspirin (NCX-4016) interacts with selectiveCOX-2 inhibitors to aggravate gastric damage and inflam-mationrdquo American Journal of PhysiologymdashGastrointestinal andLiver Physiology vol 286 no 1 pp G76ndashG81 2004
[61] M Arita T Ohira Y P Sun S Elangovan N Chiang and C NSerhan ldquoResolvin E1 selectively interacts with leukotriene B4
receptor BLT1 and ChemR23 to regulate inflammationrdquo Journalof Immunology vol 178 no 6 pp 3912ndash3917 2007
[62] S F Oh P S Pillai A Recchiuti R Yang and C N SerhanldquoPro-resolving actions and stereoselective biosynthesis of 18SE-series resolvins in human leukocytes and murine inflamma-tionrdquo Journal of Clinical Investigation vol 121 no 2 pp 569ndash5812011
[63] Y-P Sun S F Oh J Uddin et al ldquoResolvin D1 and itsaspirin-triggered 17R epimer stereochemical assignments anti-inflammatory properties and enzymatic inactivationrdquo Journalof Biological Chemistry vol 282 no 13 pp 9323ndash9334 2007
[64] S Hong K Gronert P R Devchand R-L Moussignac andC N Serhan ldquoNovel docosatrienes and 17S-resolvins generatedfrom docosahexaenoic acid in murine brain human bloodand glial cells Autacoids in anti-inflammationrdquo The Journal ofBiological Chemistry vol 278 no 17 pp 14677ndash14687 2003
[65] H R OrsquoNeal T Koyama E A S Koehler et al ldquoPrehospitalstatin and aspirin use and the prevalence of severe sepsis andacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 39 no 6 pp 1343ndash1350 2011
[66] M Spite and C N Serhan ldquoNovel lipid mediators promoteresolution of acute inflammation impact of aspirin and statinsrdquoCirculation Research vol 107 no 10 pp 1170ndash1184 2010
[67] J N Fullerton A J OrsquoBrien and DW Gilroy ldquoLipid mediatorsin immune dysfunction after severe inflammationrdquo Trends inImmunology vol 35 no 1 pp 12ndash21 2014
[68] T Hammarberg P Provost B Persson and O RadmarkldquoThe N-terminal domain of 5-lipoxygenase binds calcium andmediates calcium stimulation of enzyme activityrdquoThe Journal ofBiological Chemistry vol 275 no 49 pp 38787ndash38793 2000
[69] C N Serhan S Krishnamoorthy A Recchiuti and N ChiangldquoNovel anti-inflammatorymdashpro-resolving mediators and theirreceptorsrdquo Current Topics in Medicinal Chemistry vol 11 no 6pp 629ndash647 2011
[70] C Pergola A Rogge G Dodt et al ldquoTestosterone suppressesphospholipase D causing sex differences in leukotriene biosyn-thesis in human monocytesrdquoThe FASEB Journal vol 25 no 10pp 3377ndash3387 2011
[71] C Pergola G Dodt A Rossi et al ldquoERK-mediated regulationof leukotriene biosynthesis by androgens a molecular basis forgender differences in inflammation and asthmardquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 105 no 50 pp 19881ndash19886 2008
neoplastic disease the bone marrow releases myeloid-derivedsuppressor cells (MDSCs) The MDSCs can be subdividedinto two major groups immature granulocytes MDSC (G-MDSC) andmonocytesMDSC (M-MDSC) released from thebone marrow into the peripheral bloodstream In order tosuppress immune function theG-MDSCs primarily use reac-tive oxygen species (ROS) whereas the M-MDSCs use nitricoxide synthase (iNOS) and arginase [21ndash24] The intensityofMDSC-induced immunosuppression dynamically changeswith the patientrsquos stateThe activity ofMDSC leads to argininestarvation lowering of the proliferation rate and loss ofthe T-cell-receptor- (TCR-) associated CD3 120577 chain [25 26]Besides the arginine starvation in tissues immunosuppres-sion may be triggered by glutamine deficiency A deficiencyof these amino acids can be expected in undernourished orseptic patients as well as during intense catabolic states forexample after large surgical procedures or posttrauma [27]The assessment of PUFA supplementationrsquos influence on theinflammatory reactionmay be complicated by the immaturityof the immune system cells or amino acid deficiency [28 29]
5 Factors Inhibiting the Δ6Desaturase Activity
Δ6 desaturase catalyzes the conversion of LA and ALA intoAA EPA and DHA Several studies on animal models madein the 90s of the last century mainly on rats demonstratedthat this conversion is greater in females [30 31] anddecreasesdue to age [32ndash34] metabolic syndrome diabetes [35 36]and deficiencies of folic acid zinc [37 38] and vitamins B
6
B12[39 40] and A [41] In addition Δ6 desaturase activity is
decreased by alcohol [42] The above-mentioned factors maysignificantly alter the results of clinical trials on the role ofeicosanoids in the inflammatory reaction
6 Factors Modifying the Activity ofPhospholipase A2 (PLA2)
A very important step in eicosanoid synthesis is the hydrol-ysis of the membrane glycerophospholipids at the n-2 posi-tion by PLA2 into free PUFAs and lysophospholipids Theefficiency of this reaction determines the rate of eicosanoidsynthesis Many factors such as thrombin angiotensin II andinterleukin-2 influence the activity of PLA2 [43ndash45] It isdecreased in neoplasms associatedwith the human epidermalgrowth factor (HER2) overexpression as well as under theinfluence of angiotensin II receptor inhibitors used in thetreatment of arterial hypertension and thrombin inhibitorscommonly used in the treatment and prevention of thevenous thromboembolic disease [46ndash48] Glucocorticoidsincrease the synthesis of lipocortin and annexin stronginhibitors of PLA2 activity leading to the inhibition ofeicosanoid synthesis [49ndash52]
The glycerophospholipid deacylationreacylation cycleknown as the Lands cycle is responsible for the continu-ous change of cell membrane composition and properties[53] After the PLA
2-catalyzed deacylation of phospholipids
the lysophospholipid acyltransferases (LPAATs) catalyze the
reacylation of lysophospholipids [54 55] The efficiency ofreacylation of lysophospholipids is influenced primarily bythe availability of active PUFA (PUFA-CoA) and the freeL-carnitine concentration which by binding a significantamount of PUFA limits the rate of this step of eicosanoidsynthesis [56 57]
7 Factors Influencing COX Activity
NSAIDs inhibit eicosanoid synthesis by acting on COX-1 and -2 Aspirin differs from the other NSAIDs due toits ability to irreversibly acetylate COX-2 and switch thisenzyme to instead generate 15R-HETE a substrate for the 5-LOX This results in the synthesis of 15-epi-lipoxin A
4 also
known as aspirin-triggered lipoxin (ATL) [58] Celecoxib androfecoxib inhibit the activity of acetylated COX-2 and thesynthesis of the anti-inflammatory 15(R)-epi-LXA4 thereforecombining them with aspirin significantly increases the riskof gastric mucosa damage [59] These adverse interactionshave not been observed after the administration of celecoxiband rofecoxib with the new acetylsalicylic acid derivativeNCX 4016 [60] The acetylated COX-2 converts EPA into18(R)-hydroxyeicosapentaenoic acid (18R-HEPE) which isthen converted by 5-LOX into resolvin (Rv) E
1and RvE
2
RvE1exerts its anti-inflammatory activity after binding with
the ChemR23 and leukotriene BLT1receptors [61 62] The
synthesis of D-series Rvmay take place via two pathwaysThefirst of them is dependent on the aspirin-acetylated COX-2and uses DHA as a substrate for 17(R)-hydroxy-DHA whichlater is converted by LOX to 17(R)-RvD1 to D4 known as theaspirin-triggered RvD-series (AT-RvDs) [63 64] whereas thesecond pathway is independent of aspirin and yields resolvinssimilar to those from the first pathway
Although statins use a slightly different mechanism thanaspirin to modify COX-2 activity both drugs produce 15(R)HETE which is converted by the 5-LOX to 15(R)-epi-LXA4[65 66] Clinical studies of the DHArsquos and EPArsquos effect on theinflammatory reaction need to consider the fact that aspirinNSAIDs and statins all significantly change the eicosanoidprofile (Equation (1)) [67]
Aspirin- (ASA-) induced acetylation of cyclooxygenase-2(COX-2) alters enzymersquos specificity as follows
AA COX2+ASA997888997888997888997888997888997888997888997888rarr 15R-HETE 5-LOX997888997888997888997888997888rarr 15-epi- LXA4
+ 15-epi- LXB4
AA COX2+ASA+NSAIDs997888997888997888997888997888997888997888997888997888997888997888997888997888997888997888rarr 0
DHA COX2+ASA997888997888997888997888997888997888997888997888rarr AT-PD1 + AT-RvD (1ndash4)
Aspirin- (ASA-) induced acetylation of cyclooxygenase-2(COX-2) alters the enzyme specificity changing the outcome
4 BioMed Research International
of the catalytic reaction with fatty acids leading to the so-called ldquoaspirin-triggered (AT)rdquo products instead Arachi-donic acid (AA) gets converted into 15R hydroxyeicosate-traenoic acid (15R-HETE) which in the presence of 5-LOXtransforms further into 15-epi-lipoxins (15-epiLX) known asATLXA4 and ATLXB4 Docosahexaenoic acid (DHA) pro-duces aspirin-triggered resolvins and protectin D ATRvD1to ATRvD4 and ATPD while reaction with eicosapentaenoicacid (EPA) results in resolvins E ATRvE1 and ATRvE2However certain NSAIDs can block these reactions
8 Factors Influencing the 5- 12- and15-LOX Activity
Leukotrienes (LTs) generated by 5-LOX play a key rolein the pathogenesis of asthma allergic rhinitis and otherdiseases [68] Inhibitors of this enzyme and the cysteinylleukotriene receptor antagonists (eg zafirlukast mon-telukast pabilukast and pranlukast) are successfully usedto prevent the exacerbations of those diseases The 5-LOXinhibitors are not useful in the treatment of asthmatic attacksbecause the inhibition of LT synthesis also inhibits thetranscellular synthesis of the proresolving substances suchas resolvins protectins and maresins [69] Pergola et aldemonstrated that the low levels of testosterone in womenare the reason for their nearly double higher level of 5-LOXproducts than in men [70 71] This observation explainswhy the treatment and asthma symptoms control are moredifficult in women than in men
9 Conclusions
Laboratory research on PUFAs metabolism is devoid of theconfounding factors that exist in clinical practice age sexsocial conditions coexisting diseases and current medica-tion All of the above factors change the course of numerouschemical reactions and metabolic pathways We suggest thatone of the reasons for the inconsistencies between the resultsof laboratory and clinical researchmight be imprecise patientinclusion and exclusion criteria In this paper we presentedinformation that is infrequently described in medical litera-ture some of the factors modulating the eicosanoid synthesisand the resultant inflammatory reaction We hope that thisinformation will help reduce the flaws at the study designstage of clinical trials regarding the PUFA supplementation
Conflict of Interests
The authors declare that they have no competing interests
Authorsrsquo Contribution
Each author has participated sufficiently intellectually orpractically in the work to take public responsibility for thecontent of the paper
References
[1] F Gibellini and T K Smith ldquoThe Kennedy pathway-denovo synthesis of phosphatidylethanolamine and phosphatidyl-cholinerdquo IUBMB Life vol 62 no 6 pp 414ndash428 2010
[2] K DHa B A Clarke andW J Brown ldquoRegulation of theGolgicomplex by phospholipid remodeling enzymesrdquo Biochimica etBiophysica Acta vol 1821 no 8 pp 1078ndash1088 2012
[3] R L McKimmie L Easter and R B Weinberg ldquoAcyl chainlength saturation and hydrophobicity modulate the efficiencyof dietary fatty acid absorption in adult humansrdquoTheAmericanJournal of PhysiologymdashGastrointestinal and Liver Physiologyvol 305 no 9 pp G620ndashG627 2013
[4] A N Carley and A M Kleinfeld ldquoFlip-flop is the rate-limiting step for transport of free fatty acids across lipid vesiclemembranesrdquo Biochemistry vol 48 no 43 pp 10437ndash104452009
[5] S Siddiqi A Sheth F Patel M Barnes and C M MansbachII ldquoIntestinal caveolin-1 is important for dietary fatty acidabsorptionrdquo Biochimica et Biophysica Acta vol 1831 no 8 pp1311ndash1321 2013
[6] HMu andC-EHoslashy ldquoThedigestion of dietary triacylglycerolsrdquoProgress in Lipid Research vol 43 no 2 pp 105ndash133 2004
[7] J Shim C L Moulson E P Newberry et al ldquoFatty acidtransport protein 4 is dispensable for intestinal lipid absorptionin micerdquo Journal of Lipid Research vol 50 no 3 pp 491ndash5002009
[8] C Aguer M Foretz L Lantier et al ldquoIncreased FATCD36cycling and lipid accumulation inmyotubes derived from obesetype 2 diabetic patientsrdquo PLoS ONE vol 6 no 12 Article IDe28981 2011
[9] R Portolesi B C Powell and R A Gibson ldquoCompetitionbetween 245n-3 and ALA for Δ 6 desaturase may limit theaccumulation of DHA in HepG2 cell membranesrdquo Journal ofLipid Research vol 48 no 7 pp 1592ndash1598 2007
[10] R A Gibson B Muhlhausler and M Makrides ldquoConversionof linoleic acid and alpha-linolenic acid to long-chain polyun-saturated fatty acids (LCPUFAs) with a focus on pregnancylactation and the first 2 years of liferdquo Maternal and ChildNutrition vol 7 supplement 2 pp 17ndash26 2011
[11] A P Simopoulos ldquoOmega-3 fatty acids in health and diseaseand in growth and developmentrdquo The American Journal ofClinical Nutrition vol 54 no 3 pp 438ndash463 1991
[12] S K Raatz J B Redmon N Wimmergren J V Donadio andD M Bibus ldquoEnhanced absorption of n-3 fatty acids fromemulsified compared with encapsulated fish oilrdquo Journal of theAmerican Dietetic Association vol 109 no 6 pp 1076ndash10812009
[13] I Kalvaria and J E Clain ldquoDiabetic diarrhoea and steatorrhoeaA case report and review of the literaturerdquo South AfricanMedical Journal vol 55 no 14 pp 562ndash564 1979
[14] BWalther C Clementsson S Vallgren I Ihse and B AkessonldquoFat malabsorption in patients before and after total gastrec-tomy studied by the triolein breath testrdquo Scandinavian Journalof Gastroenterology vol 24 no 3 pp 309ndash314 1989
[15] S Moncada A G Herman E A Higgs and J R VaneldquoDifferential formation of prostacyclin (PGX or PGI2) by layersof the arterial wall An explanation for the anti-thromboticproperties of vascular endotheliumrdquo Thrombosis Research vol11 no 3 pp 323ndash344 1977
[16] A J Marcus B B Weksler and E A Jaffe ldquoEnzymaticconversion of prostaglandin endoperoxide H
2and arachidonic
BioMed Research International 5
acid to prostacyclin by cultured human endothelial cellsrdquo TheJournal of Biological Chemistry vol 253 no 20 pp 7138ndash71411978
[17] S Bunting R Gryglewski S Moncada and J R Vane ldquoArterialwalls generate from prostaglandin endoperoxides a substance(prostaglandin X)which relaxes strips ofmesenteric and coeliacarteries and inhibits platelet aggregationrdquo Prostaglandins vol12 no 6 pp 897ndash913 1976
[18] J Nowak and G A FitzGerald ldquoRedirection of prostaglandinendoperoxide metabolism at the platelet-vascular interface inmanrdquo Journal of Clinical Investigation vol 83 no 2 pp 380ndash385 1989
[19] J E McGee and F A Fitzpatrick ldquoErythrocyte-neutrophilinteractions Formation of leukotriene B4 by transcellularbiosynthesisrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 83 no 5 pp 1349ndash1353 1986
[20] N Maugeri V Evangelista A Celardo et al ldquoPolymor-phonuclear leukocyte-platelet interaction role of P-selectin inthromboxane B2 and leukotriene C4 cooperative synthesisrdquoThrombosis and Haemostasis vol 72 no 3 pp 450ndash456 1994
[21] E Peranzoni S Zilio I Marigo et al ldquoMyeloid-derivedsuppressor cell heterogeneity and subset definitionrdquo CurrentOpinion in Immunology vol 22 no 2 pp 238ndash244 2010
[22] E Ribechini V Greifenberg S Sandwick andM B Lutz ldquoSub-sets expansion and activation of myeloid-derived suppressorcellsrdquoMedical Microbiology and Immunology vol 199 no 3 pp273ndash281 2010
[23] P Raber A C Ochoa and P C Rodrıguez ldquoMetabolismof L-arginine by myeloid-derived suppressor cells in cancermechanisms of T cell suppression and therapeutic perspectivesrdquoImmunological Investigations vol 41 no 6-7 pp 614ndash634 2012
[24] P J Popovic H J Zeh III and J B Ochoa ldquoArginine andimmunityrdquo Journal of Nutrition vol 137 supplement 2 no 6pp 1681Sndash1686S 2007
[25] M Munder H Schneider C Luckner et al ldquoSuppression of T-cell functions by human granulocyte arginaserdquo Blood vol 108no 5 pp 1627ndash1634 2006
[26] P C Rodriguez A H Zea J DeSalvo et al ldquoL-arginineconsumption bymacrophagesmodulates the expression of CD3zeta chain in T lymphocytesrdquo Journal of Immunology vol 171no 3 pp 1232ndash1239 2003
[27] S S Yarandi V M Zhao G Hebbar and T R Ziegler ldquoAminoacid composition in parenteral nutrition what is the evidencerdquoCurrent Opinion in Clinical Nutrition and Metabolic Care vol14 no 1 pp 75ndash82 2011
[28] P Yaqoob and P C Calder ldquoCytokine production by humanperipheral blood mononuclear cells differential sensitivity toglutamine availabilityrdquo Cytokine vol 10 no 10 pp 790ndash7941998
[29] CMurphy and P Newsholme ldquoMacrophage-mediated lysis of abeta-cell line tumour necrosis factor-alpha release from bacil-lus Calmette-Guerin (BCG)-activated murine macrophagesand interleukin-8 release from human monocytes are depen-dent on extracellular glutamine concentration and glutaminemetabolismrdquo Clinical Science vol 96 no 1 pp 89ndash97 1999
[30] S Sfar F Laporte H Braham A Jawed S Amor and AKerkeni ldquoInfluence of dietary habits age and gender on plasmafatty acids levels in a population of healthy Tunisian subjectsrdquoExperimental Gerontology vol 45 no 9 pp 719ndash725 2010
[31] Y Kawashimia N Uy-Yu and H Kozuka ldquoSex-related dif-ferences in the enhancing effects of perfluoro-octanoic acid
on stearoyl-CoA desaturase and its influence on the acylcomposition of phospholipid in rat liver Comparison withclofibric acid and tiadenolrdquo Biochemical Journal vol 263 no3 pp 897ndash904 1989
[32] D F Horrobin ldquoLoss of delta-6-desaturase activity as a keyfactor in agingrdquoMedical Hypotheses vol 7 no 9 pp 1211ndash12201981
[33] S Hrelia A Bordoni M Celadon E Turchetto P L Biagiand C A Rossi ldquoAge-related changes in linoleate and 120572-linolenate desaturation by rat liver microsomesrdquo Biochemicaland Biophysical Research Communications vol 163 no 1 pp348ndash355 1989
[34] S Hrelia M Celadon C A Rossi P L Biagi and A BordonildquoDelta-6-desaturation of linoleic and 120572-linolenic acids in agedrats a kinetic analysisrdquo Biochemistry International vol 22 no4 pp 659ndash667 1990
[35] D E Barre ldquoThe role of consumption of alpha-linolenic eicos-apentaenoic and docosahexaenoic acids in human metabolicsyndrome and type 2 diabetesmdasha mini-reviewrdquo Journal of OleoScience vol 56 no 7 pp 319ndash325 2007
[36] J Kroger and M B Schulze ldquoRecent insights into the relationof Δ5 desaturase and Δ6 desaturase activity to the developmentof type 2 diabetesrdquo Current Opinion in Lipidology vol 23 no 1pp 4ndash10 2012
[37] K Eder and M Kirchgessner ldquoActivities of liver microsomalfatty acid desaturases in zinc-deficient rats force-fed diets with acoconut oilsafflower oil mixture of linseed oilrdquo Biological TraceElement Research vol 48 no 3 pp 215ndash229 1995
[38] K Eder and M Kirchgessner ldquoZinc deficiency and the desatu-ration of linoleic acid in rats force-fed fat-free dietsrdquo BiologicalTrace Element Research vol 54 no 2 pp 173ndash181 1996
[39] A Bordoni S Hrelia A Lorenzini et al ldquoDual influence ofaging and vitamin B6 deficiency on delta-6-desaturation ofessential fatty acids in rat liver microsomesrdquo ProstaglandinsLeukotrienes and Essential Fatty Acids vol 58 no 6 pp 417ndash420 1998
[40] H Tsuge N Hotta and T Hayakawa ldquoEffects of vitamin B-6 on (n-3) polyunsaturated fatty acid metabolismrdquo Journal ofNutrition vol 130 no 25 supplement pp 333Sndash334S 2000
[41] R Zolfaghari C J Cifelli M D Banta and A C Ross ldquoFattyacid Δ5-Desaturase mRNA is regulated by dietary vitamin Aand exogenous retinoic acid in liver of adult ratsrdquo Archives ofBiochemistry and Biophysics vol 391 no 1 pp 8ndash15 2001
[42] U N Das ldquoFetal alcohol syndrome and essential fatty acidsrdquoPLoS Medicine vol 3 no 5 article e247 2006
[43] R N Puri ldquoPhospholipase A2 its role in ADP- and thrombin-
induced platelet activation mechanismsrdquo The InternationalJournal of Biochemistry amp Cell Biology vol 30 no 10 pp 1107ndash1122 1998
[44] S A-V Leyen M F Romero M C Khosla and J G DouglasldquoModulation of phospholipase A2 activity and sodium trans-port by angiotensin-(1-7)rdquo Kidney International vol 44 no 5pp 932ndash936 1993
[45] R T Abraham M M McKinney C Forray G D Shipley andB S Handwerger ldquoStimulation of arachidonic acid release andeicosanoid biosynthesis in an interleukin 2-dependent T celllinerdquo Journal of Immunopharmacology vol 8 no 2 pp 165ndash2041986
[46] F Caiazza B J Harvey and W Thomas ldquoCytosolic phos-pholipase A2 activation correlates with HER2 overexpressionand mediates estrogen-dependent breast cancer cell growthrdquoMolecular Endocrinology vol 24 no 5 pp 953ndash968 2010
6 BioMed Research International
[47] L Oleksowicz Y Liu R B Bracken et al ldquoSecretory phospholi-pase A2-IIa is a target gene of the HERHER2-elicited pathwayand a potential plasma biomarker for poor prognosis of prostatecancerrdquo Prostate vol 72 no 10 pp 1140ndash1149 2012
[48] M Hernandez R Martin M D Garcia-Cubillas P Maeso-Hernandez and M L Nieto ldquoSecreted PLA2 induces pro-liferation in astrocytoma through the EGF receptor anotherinflammation-cancer linkrdquo Neuro-Oncology vol 12 no 10 pp1014ndash1023 2010
[49] F F Davidson E A Dennis M Powell and J R Glenney JrldquoInhibition of phospholipase A2 by lsquolipocortinsrsquo and calpactinsAn effect of binding to substrate phospholipidsrdquo Journal ofBiological Chemistry vol 262 no 4 pp 1698ndash1705 1987
[50] Y Li H Yamada Y Kita et al ldquoRoles of ERK and cPLA2in
the angiotensin II-mediated biphasic regulation of Na+-HCOminus3
transportrdquo Journal of the American Society of Nephrology vol 19no 2 pp 252ndash259 2008
[51] M Holinstat O Boutaud P L Apopa et al ldquoProtease-activatedreceptor signaling in platelets activates cytosolic phospholipaseA2120572differently for cyclooxygenase-1 and 12-lipoxygenase catal-
[52] R M Kramer E F Roberts J V Manetta P A Hyslopand J A Jakubowski ldquoThrombin-induced phosphorylationand activation of Ca2+-sensitive cytosolic phospholipase A2 inhuman plateletsrdquo Journal of Biological Chemistry vol 268 no35 pp 26796ndash26804 1993
[53] W E M Lands ldquoStories about acyl chainsrdquo Biochimica etBiophysica ActamdashMolecular and Cell Biology of Lipids vol 1483no 1 pp 1ndash14 2000
[54] H Shindou and T Shimizu ldquoAcyl-CoAlysophospholipid acyl-transferasesrdquo Journal of Biological Chemistry vol 284 no 1 pp1ndash5 2009
[55] E Soupene and F A Kuypers ldquoMammalian long-chain acyl-CoA synthetasesrdquo Experimental Biology and Medicine vol 233no 5 pp 507ndash521 2008
[56] A Arduini V Tyurin Y Tyuruna et al ldquoAcyl-trafficking inmembrane phospholipid fatty acid turnover the transfer of fattyacid from the acyl-L-carnitine pool tomembrane phospholipidsin intact human erythrocytesrdquo Biochemical and BiophysicalResearch Communications vol 187 no 1 pp 353ndash358 1992
[57] A Arduini G Mancinelli and R R Ramsay ldquoPalmitoyl-L-carnitine a metabolic intermediate of the fatty acid incor-poration pathway in erythrocyte membrane phospholipidsrdquoBiochemical and Biophysical Research Communications vol 173no 1 pp 212ndash217 1990
[58] C N Serhan ldquoLipoxins and aspirin-triggered 15-epi-lipoxinbiosynthesis an update and role in anti-inflammation and pro-resolutionrdquo Prostaglandins and Other Lipid Mediators vol 68-69 pp 433ndash455 2002
[59] S Fiorucci O M De Lima Jr A Mencarelli et alldquoCyclooxygenase-2-derived lipoxin A4 increases gastricresistance to aspirin-induced damagerdquo Gastroenterology vol123 no 5 pp 1598ndash1606 2002
[60] J L Wallace S R Zamuner W McKnight et al ldquoAspirin butnot NO-releasing aspirin (NCX-4016) interacts with selectiveCOX-2 inhibitors to aggravate gastric damage and inflam-mationrdquo American Journal of PhysiologymdashGastrointestinal andLiver Physiology vol 286 no 1 pp G76ndashG81 2004
[61] M Arita T Ohira Y P Sun S Elangovan N Chiang and C NSerhan ldquoResolvin E1 selectively interacts with leukotriene B4
receptor BLT1 and ChemR23 to regulate inflammationrdquo Journalof Immunology vol 178 no 6 pp 3912ndash3917 2007
[62] S F Oh P S Pillai A Recchiuti R Yang and C N SerhanldquoPro-resolving actions and stereoselective biosynthesis of 18SE-series resolvins in human leukocytes and murine inflamma-tionrdquo Journal of Clinical Investigation vol 121 no 2 pp 569ndash5812011
[63] Y-P Sun S F Oh J Uddin et al ldquoResolvin D1 and itsaspirin-triggered 17R epimer stereochemical assignments anti-inflammatory properties and enzymatic inactivationrdquo Journalof Biological Chemistry vol 282 no 13 pp 9323ndash9334 2007
[64] S Hong K Gronert P R Devchand R-L Moussignac andC N Serhan ldquoNovel docosatrienes and 17S-resolvins generatedfrom docosahexaenoic acid in murine brain human bloodand glial cells Autacoids in anti-inflammationrdquo The Journal ofBiological Chemistry vol 278 no 17 pp 14677ndash14687 2003
[65] H R OrsquoNeal T Koyama E A S Koehler et al ldquoPrehospitalstatin and aspirin use and the prevalence of severe sepsis andacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 39 no 6 pp 1343ndash1350 2011
[66] M Spite and C N Serhan ldquoNovel lipid mediators promoteresolution of acute inflammation impact of aspirin and statinsrdquoCirculation Research vol 107 no 10 pp 1170ndash1184 2010
[67] J N Fullerton A J OrsquoBrien and DW Gilroy ldquoLipid mediatorsin immune dysfunction after severe inflammationrdquo Trends inImmunology vol 35 no 1 pp 12ndash21 2014
[68] T Hammarberg P Provost B Persson and O RadmarkldquoThe N-terminal domain of 5-lipoxygenase binds calcium andmediates calcium stimulation of enzyme activityrdquoThe Journal ofBiological Chemistry vol 275 no 49 pp 38787ndash38793 2000
[69] C N Serhan S Krishnamoorthy A Recchiuti and N ChiangldquoNovel anti-inflammatorymdashpro-resolving mediators and theirreceptorsrdquo Current Topics in Medicinal Chemistry vol 11 no 6pp 629ndash647 2011
[70] C Pergola A Rogge G Dodt et al ldquoTestosterone suppressesphospholipase D causing sex differences in leukotriene biosyn-thesis in human monocytesrdquoThe FASEB Journal vol 25 no 10pp 3377ndash3387 2011
[71] C Pergola G Dodt A Rossi et al ldquoERK-mediated regulationof leukotriene biosynthesis by androgens a molecular basis forgender differences in inflammation and asthmardquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 105 no 50 pp 19881ndash19886 2008
of the catalytic reaction with fatty acids leading to the so-called ldquoaspirin-triggered (AT)rdquo products instead Arachi-donic acid (AA) gets converted into 15R hydroxyeicosate-traenoic acid (15R-HETE) which in the presence of 5-LOXtransforms further into 15-epi-lipoxins (15-epiLX) known asATLXA4 and ATLXB4 Docosahexaenoic acid (DHA) pro-duces aspirin-triggered resolvins and protectin D ATRvD1to ATRvD4 and ATPD while reaction with eicosapentaenoicacid (EPA) results in resolvins E ATRvE1 and ATRvE2However certain NSAIDs can block these reactions
8 Factors Influencing the 5- 12- and15-LOX Activity
Leukotrienes (LTs) generated by 5-LOX play a key rolein the pathogenesis of asthma allergic rhinitis and otherdiseases [68] Inhibitors of this enzyme and the cysteinylleukotriene receptor antagonists (eg zafirlukast mon-telukast pabilukast and pranlukast) are successfully usedto prevent the exacerbations of those diseases The 5-LOXinhibitors are not useful in the treatment of asthmatic attacksbecause the inhibition of LT synthesis also inhibits thetranscellular synthesis of the proresolving substances suchas resolvins protectins and maresins [69] Pergola et aldemonstrated that the low levels of testosterone in womenare the reason for their nearly double higher level of 5-LOXproducts than in men [70 71] This observation explainswhy the treatment and asthma symptoms control are moredifficult in women than in men
9 Conclusions
Laboratory research on PUFAs metabolism is devoid of theconfounding factors that exist in clinical practice age sexsocial conditions coexisting diseases and current medica-tion All of the above factors change the course of numerouschemical reactions and metabolic pathways We suggest thatone of the reasons for the inconsistencies between the resultsof laboratory and clinical researchmight be imprecise patientinclusion and exclusion criteria In this paper we presentedinformation that is infrequently described in medical litera-ture some of the factors modulating the eicosanoid synthesisand the resultant inflammatory reaction We hope that thisinformation will help reduce the flaws at the study designstage of clinical trials regarding the PUFA supplementation
Conflict of Interests
The authors declare that they have no competing interests
Authorsrsquo Contribution
Each author has participated sufficiently intellectually orpractically in the work to take public responsibility for thecontent of the paper
References
[1] F Gibellini and T K Smith ldquoThe Kennedy pathway-denovo synthesis of phosphatidylethanolamine and phosphatidyl-cholinerdquo IUBMB Life vol 62 no 6 pp 414ndash428 2010
[2] K DHa B A Clarke andW J Brown ldquoRegulation of theGolgicomplex by phospholipid remodeling enzymesrdquo Biochimica etBiophysica Acta vol 1821 no 8 pp 1078ndash1088 2012
[3] R L McKimmie L Easter and R B Weinberg ldquoAcyl chainlength saturation and hydrophobicity modulate the efficiencyof dietary fatty acid absorption in adult humansrdquoTheAmericanJournal of PhysiologymdashGastrointestinal and Liver Physiologyvol 305 no 9 pp G620ndashG627 2013
[4] A N Carley and A M Kleinfeld ldquoFlip-flop is the rate-limiting step for transport of free fatty acids across lipid vesiclemembranesrdquo Biochemistry vol 48 no 43 pp 10437ndash104452009
[5] S Siddiqi A Sheth F Patel M Barnes and C M MansbachII ldquoIntestinal caveolin-1 is important for dietary fatty acidabsorptionrdquo Biochimica et Biophysica Acta vol 1831 no 8 pp1311ndash1321 2013
[6] HMu andC-EHoslashy ldquoThedigestion of dietary triacylglycerolsrdquoProgress in Lipid Research vol 43 no 2 pp 105ndash133 2004
[7] J Shim C L Moulson E P Newberry et al ldquoFatty acidtransport protein 4 is dispensable for intestinal lipid absorptionin micerdquo Journal of Lipid Research vol 50 no 3 pp 491ndash5002009
[8] C Aguer M Foretz L Lantier et al ldquoIncreased FATCD36cycling and lipid accumulation inmyotubes derived from obesetype 2 diabetic patientsrdquo PLoS ONE vol 6 no 12 Article IDe28981 2011
[9] R Portolesi B C Powell and R A Gibson ldquoCompetitionbetween 245n-3 and ALA for Δ 6 desaturase may limit theaccumulation of DHA in HepG2 cell membranesrdquo Journal ofLipid Research vol 48 no 7 pp 1592ndash1598 2007
[10] R A Gibson B Muhlhausler and M Makrides ldquoConversionof linoleic acid and alpha-linolenic acid to long-chain polyun-saturated fatty acids (LCPUFAs) with a focus on pregnancylactation and the first 2 years of liferdquo Maternal and ChildNutrition vol 7 supplement 2 pp 17ndash26 2011
[11] A P Simopoulos ldquoOmega-3 fatty acids in health and diseaseand in growth and developmentrdquo The American Journal ofClinical Nutrition vol 54 no 3 pp 438ndash463 1991
[12] S K Raatz J B Redmon N Wimmergren J V Donadio andD M Bibus ldquoEnhanced absorption of n-3 fatty acids fromemulsified compared with encapsulated fish oilrdquo Journal of theAmerican Dietetic Association vol 109 no 6 pp 1076ndash10812009
[13] I Kalvaria and J E Clain ldquoDiabetic diarrhoea and steatorrhoeaA case report and review of the literaturerdquo South AfricanMedical Journal vol 55 no 14 pp 562ndash564 1979
[14] BWalther C Clementsson S Vallgren I Ihse and B AkessonldquoFat malabsorption in patients before and after total gastrec-tomy studied by the triolein breath testrdquo Scandinavian Journalof Gastroenterology vol 24 no 3 pp 309ndash314 1989
[15] S Moncada A G Herman E A Higgs and J R VaneldquoDifferential formation of prostacyclin (PGX or PGI2) by layersof the arterial wall An explanation for the anti-thromboticproperties of vascular endotheliumrdquo Thrombosis Research vol11 no 3 pp 323ndash344 1977
[16] A J Marcus B B Weksler and E A Jaffe ldquoEnzymaticconversion of prostaglandin endoperoxide H
2and arachidonic
BioMed Research International 5
acid to prostacyclin by cultured human endothelial cellsrdquo TheJournal of Biological Chemistry vol 253 no 20 pp 7138ndash71411978
[17] S Bunting R Gryglewski S Moncada and J R Vane ldquoArterialwalls generate from prostaglandin endoperoxides a substance(prostaglandin X)which relaxes strips ofmesenteric and coeliacarteries and inhibits platelet aggregationrdquo Prostaglandins vol12 no 6 pp 897ndash913 1976
[18] J Nowak and G A FitzGerald ldquoRedirection of prostaglandinendoperoxide metabolism at the platelet-vascular interface inmanrdquo Journal of Clinical Investigation vol 83 no 2 pp 380ndash385 1989
[19] J E McGee and F A Fitzpatrick ldquoErythrocyte-neutrophilinteractions Formation of leukotriene B4 by transcellularbiosynthesisrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 83 no 5 pp 1349ndash1353 1986
[20] N Maugeri V Evangelista A Celardo et al ldquoPolymor-phonuclear leukocyte-platelet interaction role of P-selectin inthromboxane B2 and leukotriene C4 cooperative synthesisrdquoThrombosis and Haemostasis vol 72 no 3 pp 450ndash456 1994
[21] E Peranzoni S Zilio I Marigo et al ldquoMyeloid-derivedsuppressor cell heterogeneity and subset definitionrdquo CurrentOpinion in Immunology vol 22 no 2 pp 238ndash244 2010
[22] E Ribechini V Greifenberg S Sandwick andM B Lutz ldquoSub-sets expansion and activation of myeloid-derived suppressorcellsrdquoMedical Microbiology and Immunology vol 199 no 3 pp273ndash281 2010
[23] P Raber A C Ochoa and P C Rodrıguez ldquoMetabolismof L-arginine by myeloid-derived suppressor cells in cancermechanisms of T cell suppression and therapeutic perspectivesrdquoImmunological Investigations vol 41 no 6-7 pp 614ndash634 2012
[24] P J Popovic H J Zeh III and J B Ochoa ldquoArginine andimmunityrdquo Journal of Nutrition vol 137 supplement 2 no 6pp 1681Sndash1686S 2007
[25] M Munder H Schneider C Luckner et al ldquoSuppression of T-cell functions by human granulocyte arginaserdquo Blood vol 108no 5 pp 1627ndash1634 2006
[26] P C Rodriguez A H Zea J DeSalvo et al ldquoL-arginineconsumption bymacrophagesmodulates the expression of CD3zeta chain in T lymphocytesrdquo Journal of Immunology vol 171no 3 pp 1232ndash1239 2003
[27] S S Yarandi V M Zhao G Hebbar and T R Ziegler ldquoAminoacid composition in parenteral nutrition what is the evidencerdquoCurrent Opinion in Clinical Nutrition and Metabolic Care vol14 no 1 pp 75ndash82 2011
[28] P Yaqoob and P C Calder ldquoCytokine production by humanperipheral blood mononuclear cells differential sensitivity toglutamine availabilityrdquo Cytokine vol 10 no 10 pp 790ndash7941998
[29] CMurphy and P Newsholme ldquoMacrophage-mediated lysis of abeta-cell line tumour necrosis factor-alpha release from bacil-lus Calmette-Guerin (BCG)-activated murine macrophagesand interleukin-8 release from human monocytes are depen-dent on extracellular glutamine concentration and glutaminemetabolismrdquo Clinical Science vol 96 no 1 pp 89ndash97 1999
[30] S Sfar F Laporte H Braham A Jawed S Amor and AKerkeni ldquoInfluence of dietary habits age and gender on plasmafatty acids levels in a population of healthy Tunisian subjectsrdquoExperimental Gerontology vol 45 no 9 pp 719ndash725 2010
[31] Y Kawashimia N Uy-Yu and H Kozuka ldquoSex-related dif-ferences in the enhancing effects of perfluoro-octanoic acid
on stearoyl-CoA desaturase and its influence on the acylcomposition of phospholipid in rat liver Comparison withclofibric acid and tiadenolrdquo Biochemical Journal vol 263 no3 pp 897ndash904 1989
[32] D F Horrobin ldquoLoss of delta-6-desaturase activity as a keyfactor in agingrdquoMedical Hypotheses vol 7 no 9 pp 1211ndash12201981
[33] S Hrelia A Bordoni M Celadon E Turchetto P L Biagiand C A Rossi ldquoAge-related changes in linoleate and 120572-linolenate desaturation by rat liver microsomesrdquo Biochemicaland Biophysical Research Communications vol 163 no 1 pp348ndash355 1989
[34] S Hrelia M Celadon C A Rossi P L Biagi and A BordonildquoDelta-6-desaturation of linoleic and 120572-linolenic acids in agedrats a kinetic analysisrdquo Biochemistry International vol 22 no4 pp 659ndash667 1990
[35] D E Barre ldquoThe role of consumption of alpha-linolenic eicos-apentaenoic and docosahexaenoic acids in human metabolicsyndrome and type 2 diabetesmdasha mini-reviewrdquo Journal of OleoScience vol 56 no 7 pp 319ndash325 2007
[36] J Kroger and M B Schulze ldquoRecent insights into the relationof Δ5 desaturase and Δ6 desaturase activity to the developmentof type 2 diabetesrdquo Current Opinion in Lipidology vol 23 no 1pp 4ndash10 2012
[37] K Eder and M Kirchgessner ldquoActivities of liver microsomalfatty acid desaturases in zinc-deficient rats force-fed diets with acoconut oilsafflower oil mixture of linseed oilrdquo Biological TraceElement Research vol 48 no 3 pp 215ndash229 1995
[38] K Eder and M Kirchgessner ldquoZinc deficiency and the desatu-ration of linoleic acid in rats force-fed fat-free dietsrdquo BiologicalTrace Element Research vol 54 no 2 pp 173ndash181 1996
[39] A Bordoni S Hrelia A Lorenzini et al ldquoDual influence ofaging and vitamin B6 deficiency on delta-6-desaturation ofessential fatty acids in rat liver microsomesrdquo ProstaglandinsLeukotrienes and Essential Fatty Acids vol 58 no 6 pp 417ndash420 1998
[40] H Tsuge N Hotta and T Hayakawa ldquoEffects of vitamin B-6 on (n-3) polyunsaturated fatty acid metabolismrdquo Journal ofNutrition vol 130 no 25 supplement pp 333Sndash334S 2000
[41] R Zolfaghari C J Cifelli M D Banta and A C Ross ldquoFattyacid Δ5-Desaturase mRNA is regulated by dietary vitamin Aand exogenous retinoic acid in liver of adult ratsrdquo Archives ofBiochemistry and Biophysics vol 391 no 1 pp 8ndash15 2001
[42] U N Das ldquoFetal alcohol syndrome and essential fatty acidsrdquoPLoS Medicine vol 3 no 5 article e247 2006
[43] R N Puri ldquoPhospholipase A2 its role in ADP- and thrombin-
induced platelet activation mechanismsrdquo The InternationalJournal of Biochemistry amp Cell Biology vol 30 no 10 pp 1107ndash1122 1998
[44] S A-V Leyen M F Romero M C Khosla and J G DouglasldquoModulation of phospholipase A2 activity and sodium trans-port by angiotensin-(1-7)rdquo Kidney International vol 44 no 5pp 932ndash936 1993
[45] R T Abraham M M McKinney C Forray G D Shipley andB S Handwerger ldquoStimulation of arachidonic acid release andeicosanoid biosynthesis in an interleukin 2-dependent T celllinerdquo Journal of Immunopharmacology vol 8 no 2 pp 165ndash2041986
[46] F Caiazza B J Harvey and W Thomas ldquoCytosolic phos-pholipase A2 activation correlates with HER2 overexpressionand mediates estrogen-dependent breast cancer cell growthrdquoMolecular Endocrinology vol 24 no 5 pp 953ndash968 2010
6 BioMed Research International
[47] L Oleksowicz Y Liu R B Bracken et al ldquoSecretory phospholi-pase A2-IIa is a target gene of the HERHER2-elicited pathwayand a potential plasma biomarker for poor prognosis of prostatecancerrdquo Prostate vol 72 no 10 pp 1140ndash1149 2012
[48] M Hernandez R Martin M D Garcia-Cubillas P Maeso-Hernandez and M L Nieto ldquoSecreted PLA2 induces pro-liferation in astrocytoma through the EGF receptor anotherinflammation-cancer linkrdquo Neuro-Oncology vol 12 no 10 pp1014ndash1023 2010
[49] F F Davidson E A Dennis M Powell and J R Glenney JrldquoInhibition of phospholipase A2 by lsquolipocortinsrsquo and calpactinsAn effect of binding to substrate phospholipidsrdquo Journal ofBiological Chemistry vol 262 no 4 pp 1698ndash1705 1987
[50] Y Li H Yamada Y Kita et al ldquoRoles of ERK and cPLA2in
the angiotensin II-mediated biphasic regulation of Na+-HCOminus3
transportrdquo Journal of the American Society of Nephrology vol 19no 2 pp 252ndash259 2008
[51] M Holinstat O Boutaud P L Apopa et al ldquoProtease-activatedreceptor signaling in platelets activates cytosolic phospholipaseA2120572differently for cyclooxygenase-1 and 12-lipoxygenase catal-
[52] R M Kramer E F Roberts J V Manetta P A Hyslopand J A Jakubowski ldquoThrombin-induced phosphorylationand activation of Ca2+-sensitive cytosolic phospholipase A2 inhuman plateletsrdquo Journal of Biological Chemistry vol 268 no35 pp 26796ndash26804 1993
[53] W E M Lands ldquoStories about acyl chainsrdquo Biochimica etBiophysica ActamdashMolecular and Cell Biology of Lipids vol 1483no 1 pp 1ndash14 2000
[54] H Shindou and T Shimizu ldquoAcyl-CoAlysophospholipid acyl-transferasesrdquo Journal of Biological Chemistry vol 284 no 1 pp1ndash5 2009
[55] E Soupene and F A Kuypers ldquoMammalian long-chain acyl-CoA synthetasesrdquo Experimental Biology and Medicine vol 233no 5 pp 507ndash521 2008
[56] A Arduini V Tyurin Y Tyuruna et al ldquoAcyl-trafficking inmembrane phospholipid fatty acid turnover the transfer of fattyacid from the acyl-L-carnitine pool tomembrane phospholipidsin intact human erythrocytesrdquo Biochemical and BiophysicalResearch Communications vol 187 no 1 pp 353ndash358 1992
[57] A Arduini G Mancinelli and R R Ramsay ldquoPalmitoyl-L-carnitine a metabolic intermediate of the fatty acid incor-poration pathway in erythrocyte membrane phospholipidsrdquoBiochemical and Biophysical Research Communications vol 173no 1 pp 212ndash217 1990
[58] C N Serhan ldquoLipoxins and aspirin-triggered 15-epi-lipoxinbiosynthesis an update and role in anti-inflammation and pro-resolutionrdquo Prostaglandins and Other Lipid Mediators vol 68-69 pp 433ndash455 2002
[59] S Fiorucci O M De Lima Jr A Mencarelli et alldquoCyclooxygenase-2-derived lipoxin A4 increases gastricresistance to aspirin-induced damagerdquo Gastroenterology vol123 no 5 pp 1598ndash1606 2002
[60] J L Wallace S R Zamuner W McKnight et al ldquoAspirin butnot NO-releasing aspirin (NCX-4016) interacts with selectiveCOX-2 inhibitors to aggravate gastric damage and inflam-mationrdquo American Journal of PhysiologymdashGastrointestinal andLiver Physiology vol 286 no 1 pp G76ndashG81 2004
[61] M Arita T Ohira Y P Sun S Elangovan N Chiang and C NSerhan ldquoResolvin E1 selectively interacts with leukotriene B4
receptor BLT1 and ChemR23 to regulate inflammationrdquo Journalof Immunology vol 178 no 6 pp 3912ndash3917 2007
[62] S F Oh P S Pillai A Recchiuti R Yang and C N SerhanldquoPro-resolving actions and stereoselective biosynthesis of 18SE-series resolvins in human leukocytes and murine inflamma-tionrdquo Journal of Clinical Investigation vol 121 no 2 pp 569ndash5812011
[63] Y-P Sun S F Oh J Uddin et al ldquoResolvin D1 and itsaspirin-triggered 17R epimer stereochemical assignments anti-inflammatory properties and enzymatic inactivationrdquo Journalof Biological Chemistry vol 282 no 13 pp 9323ndash9334 2007
[64] S Hong K Gronert P R Devchand R-L Moussignac andC N Serhan ldquoNovel docosatrienes and 17S-resolvins generatedfrom docosahexaenoic acid in murine brain human bloodand glial cells Autacoids in anti-inflammationrdquo The Journal ofBiological Chemistry vol 278 no 17 pp 14677ndash14687 2003
[65] H R OrsquoNeal T Koyama E A S Koehler et al ldquoPrehospitalstatin and aspirin use and the prevalence of severe sepsis andacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 39 no 6 pp 1343ndash1350 2011
[66] M Spite and C N Serhan ldquoNovel lipid mediators promoteresolution of acute inflammation impact of aspirin and statinsrdquoCirculation Research vol 107 no 10 pp 1170ndash1184 2010
[67] J N Fullerton A J OrsquoBrien and DW Gilroy ldquoLipid mediatorsin immune dysfunction after severe inflammationrdquo Trends inImmunology vol 35 no 1 pp 12ndash21 2014
[68] T Hammarberg P Provost B Persson and O RadmarkldquoThe N-terminal domain of 5-lipoxygenase binds calcium andmediates calcium stimulation of enzyme activityrdquoThe Journal ofBiological Chemistry vol 275 no 49 pp 38787ndash38793 2000
[69] C N Serhan S Krishnamoorthy A Recchiuti and N ChiangldquoNovel anti-inflammatorymdashpro-resolving mediators and theirreceptorsrdquo Current Topics in Medicinal Chemistry vol 11 no 6pp 629ndash647 2011
[70] C Pergola A Rogge G Dodt et al ldquoTestosterone suppressesphospholipase D causing sex differences in leukotriene biosyn-thesis in human monocytesrdquoThe FASEB Journal vol 25 no 10pp 3377ndash3387 2011
[71] C Pergola G Dodt A Rossi et al ldquoERK-mediated regulationof leukotriene biosynthesis by androgens a molecular basis forgender differences in inflammation and asthmardquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 105 no 50 pp 19881ndash19886 2008
acid to prostacyclin by cultured human endothelial cellsrdquo TheJournal of Biological Chemistry vol 253 no 20 pp 7138ndash71411978
[17] S Bunting R Gryglewski S Moncada and J R Vane ldquoArterialwalls generate from prostaglandin endoperoxides a substance(prostaglandin X)which relaxes strips ofmesenteric and coeliacarteries and inhibits platelet aggregationrdquo Prostaglandins vol12 no 6 pp 897ndash913 1976
[18] J Nowak and G A FitzGerald ldquoRedirection of prostaglandinendoperoxide metabolism at the platelet-vascular interface inmanrdquo Journal of Clinical Investigation vol 83 no 2 pp 380ndash385 1989
[19] J E McGee and F A Fitzpatrick ldquoErythrocyte-neutrophilinteractions Formation of leukotriene B4 by transcellularbiosynthesisrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 83 no 5 pp 1349ndash1353 1986
[20] N Maugeri V Evangelista A Celardo et al ldquoPolymor-phonuclear leukocyte-platelet interaction role of P-selectin inthromboxane B2 and leukotriene C4 cooperative synthesisrdquoThrombosis and Haemostasis vol 72 no 3 pp 450ndash456 1994
[21] E Peranzoni S Zilio I Marigo et al ldquoMyeloid-derivedsuppressor cell heterogeneity and subset definitionrdquo CurrentOpinion in Immunology vol 22 no 2 pp 238ndash244 2010
[22] E Ribechini V Greifenberg S Sandwick andM B Lutz ldquoSub-sets expansion and activation of myeloid-derived suppressorcellsrdquoMedical Microbiology and Immunology vol 199 no 3 pp273ndash281 2010
[23] P Raber A C Ochoa and P C Rodrıguez ldquoMetabolismof L-arginine by myeloid-derived suppressor cells in cancermechanisms of T cell suppression and therapeutic perspectivesrdquoImmunological Investigations vol 41 no 6-7 pp 614ndash634 2012
[24] P J Popovic H J Zeh III and J B Ochoa ldquoArginine andimmunityrdquo Journal of Nutrition vol 137 supplement 2 no 6pp 1681Sndash1686S 2007
[25] M Munder H Schneider C Luckner et al ldquoSuppression of T-cell functions by human granulocyte arginaserdquo Blood vol 108no 5 pp 1627ndash1634 2006
[26] P C Rodriguez A H Zea J DeSalvo et al ldquoL-arginineconsumption bymacrophagesmodulates the expression of CD3zeta chain in T lymphocytesrdquo Journal of Immunology vol 171no 3 pp 1232ndash1239 2003
[27] S S Yarandi V M Zhao G Hebbar and T R Ziegler ldquoAminoacid composition in parenteral nutrition what is the evidencerdquoCurrent Opinion in Clinical Nutrition and Metabolic Care vol14 no 1 pp 75ndash82 2011
[28] P Yaqoob and P C Calder ldquoCytokine production by humanperipheral blood mononuclear cells differential sensitivity toglutamine availabilityrdquo Cytokine vol 10 no 10 pp 790ndash7941998
[29] CMurphy and P Newsholme ldquoMacrophage-mediated lysis of abeta-cell line tumour necrosis factor-alpha release from bacil-lus Calmette-Guerin (BCG)-activated murine macrophagesand interleukin-8 release from human monocytes are depen-dent on extracellular glutamine concentration and glutaminemetabolismrdquo Clinical Science vol 96 no 1 pp 89ndash97 1999
[30] S Sfar F Laporte H Braham A Jawed S Amor and AKerkeni ldquoInfluence of dietary habits age and gender on plasmafatty acids levels in a population of healthy Tunisian subjectsrdquoExperimental Gerontology vol 45 no 9 pp 719ndash725 2010
[31] Y Kawashimia N Uy-Yu and H Kozuka ldquoSex-related dif-ferences in the enhancing effects of perfluoro-octanoic acid
on stearoyl-CoA desaturase and its influence on the acylcomposition of phospholipid in rat liver Comparison withclofibric acid and tiadenolrdquo Biochemical Journal vol 263 no3 pp 897ndash904 1989
[32] D F Horrobin ldquoLoss of delta-6-desaturase activity as a keyfactor in agingrdquoMedical Hypotheses vol 7 no 9 pp 1211ndash12201981
[33] S Hrelia A Bordoni M Celadon E Turchetto P L Biagiand C A Rossi ldquoAge-related changes in linoleate and 120572-linolenate desaturation by rat liver microsomesrdquo Biochemicaland Biophysical Research Communications vol 163 no 1 pp348ndash355 1989
[34] S Hrelia M Celadon C A Rossi P L Biagi and A BordonildquoDelta-6-desaturation of linoleic and 120572-linolenic acids in agedrats a kinetic analysisrdquo Biochemistry International vol 22 no4 pp 659ndash667 1990
[35] D E Barre ldquoThe role of consumption of alpha-linolenic eicos-apentaenoic and docosahexaenoic acids in human metabolicsyndrome and type 2 diabetesmdasha mini-reviewrdquo Journal of OleoScience vol 56 no 7 pp 319ndash325 2007
[36] J Kroger and M B Schulze ldquoRecent insights into the relationof Δ5 desaturase and Δ6 desaturase activity to the developmentof type 2 diabetesrdquo Current Opinion in Lipidology vol 23 no 1pp 4ndash10 2012
[37] K Eder and M Kirchgessner ldquoActivities of liver microsomalfatty acid desaturases in zinc-deficient rats force-fed diets with acoconut oilsafflower oil mixture of linseed oilrdquo Biological TraceElement Research vol 48 no 3 pp 215ndash229 1995
[38] K Eder and M Kirchgessner ldquoZinc deficiency and the desatu-ration of linoleic acid in rats force-fed fat-free dietsrdquo BiologicalTrace Element Research vol 54 no 2 pp 173ndash181 1996
[39] A Bordoni S Hrelia A Lorenzini et al ldquoDual influence ofaging and vitamin B6 deficiency on delta-6-desaturation ofessential fatty acids in rat liver microsomesrdquo ProstaglandinsLeukotrienes and Essential Fatty Acids vol 58 no 6 pp 417ndash420 1998
[40] H Tsuge N Hotta and T Hayakawa ldquoEffects of vitamin B-6 on (n-3) polyunsaturated fatty acid metabolismrdquo Journal ofNutrition vol 130 no 25 supplement pp 333Sndash334S 2000
[41] R Zolfaghari C J Cifelli M D Banta and A C Ross ldquoFattyacid Δ5-Desaturase mRNA is regulated by dietary vitamin Aand exogenous retinoic acid in liver of adult ratsrdquo Archives ofBiochemistry and Biophysics vol 391 no 1 pp 8ndash15 2001
[42] U N Das ldquoFetal alcohol syndrome and essential fatty acidsrdquoPLoS Medicine vol 3 no 5 article e247 2006
[43] R N Puri ldquoPhospholipase A2 its role in ADP- and thrombin-
induced platelet activation mechanismsrdquo The InternationalJournal of Biochemistry amp Cell Biology vol 30 no 10 pp 1107ndash1122 1998
[44] S A-V Leyen M F Romero M C Khosla and J G DouglasldquoModulation of phospholipase A2 activity and sodium trans-port by angiotensin-(1-7)rdquo Kidney International vol 44 no 5pp 932ndash936 1993
[45] R T Abraham M M McKinney C Forray G D Shipley andB S Handwerger ldquoStimulation of arachidonic acid release andeicosanoid biosynthesis in an interleukin 2-dependent T celllinerdquo Journal of Immunopharmacology vol 8 no 2 pp 165ndash2041986
[46] F Caiazza B J Harvey and W Thomas ldquoCytosolic phos-pholipase A2 activation correlates with HER2 overexpressionand mediates estrogen-dependent breast cancer cell growthrdquoMolecular Endocrinology vol 24 no 5 pp 953ndash968 2010
6 BioMed Research International
[47] L Oleksowicz Y Liu R B Bracken et al ldquoSecretory phospholi-pase A2-IIa is a target gene of the HERHER2-elicited pathwayand a potential plasma biomarker for poor prognosis of prostatecancerrdquo Prostate vol 72 no 10 pp 1140ndash1149 2012
[48] M Hernandez R Martin M D Garcia-Cubillas P Maeso-Hernandez and M L Nieto ldquoSecreted PLA2 induces pro-liferation in astrocytoma through the EGF receptor anotherinflammation-cancer linkrdquo Neuro-Oncology vol 12 no 10 pp1014ndash1023 2010
[49] F F Davidson E A Dennis M Powell and J R Glenney JrldquoInhibition of phospholipase A2 by lsquolipocortinsrsquo and calpactinsAn effect of binding to substrate phospholipidsrdquo Journal ofBiological Chemistry vol 262 no 4 pp 1698ndash1705 1987
[50] Y Li H Yamada Y Kita et al ldquoRoles of ERK and cPLA2in
the angiotensin II-mediated biphasic regulation of Na+-HCOminus3
transportrdquo Journal of the American Society of Nephrology vol 19no 2 pp 252ndash259 2008
[51] M Holinstat O Boutaud P L Apopa et al ldquoProtease-activatedreceptor signaling in platelets activates cytosolic phospholipaseA2120572differently for cyclooxygenase-1 and 12-lipoxygenase catal-
[52] R M Kramer E F Roberts J V Manetta P A Hyslopand J A Jakubowski ldquoThrombin-induced phosphorylationand activation of Ca2+-sensitive cytosolic phospholipase A2 inhuman plateletsrdquo Journal of Biological Chemistry vol 268 no35 pp 26796ndash26804 1993
[53] W E M Lands ldquoStories about acyl chainsrdquo Biochimica etBiophysica ActamdashMolecular and Cell Biology of Lipids vol 1483no 1 pp 1ndash14 2000
[54] H Shindou and T Shimizu ldquoAcyl-CoAlysophospholipid acyl-transferasesrdquo Journal of Biological Chemistry vol 284 no 1 pp1ndash5 2009
[55] E Soupene and F A Kuypers ldquoMammalian long-chain acyl-CoA synthetasesrdquo Experimental Biology and Medicine vol 233no 5 pp 507ndash521 2008
[56] A Arduini V Tyurin Y Tyuruna et al ldquoAcyl-trafficking inmembrane phospholipid fatty acid turnover the transfer of fattyacid from the acyl-L-carnitine pool tomembrane phospholipidsin intact human erythrocytesrdquo Biochemical and BiophysicalResearch Communications vol 187 no 1 pp 353ndash358 1992
[57] A Arduini G Mancinelli and R R Ramsay ldquoPalmitoyl-L-carnitine a metabolic intermediate of the fatty acid incor-poration pathway in erythrocyte membrane phospholipidsrdquoBiochemical and Biophysical Research Communications vol 173no 1 pp 212ndash217 1990
[58] C N Serhan ldquoLipoxins and aspirin-triggered 15-epi-lipoxinbiosynthesis an update and role in anti-inflammation and pro-resolutionrdquo Prostaglandins and Other Lipid Mediators vol 68-69 pp 433ndash455 2002
[59] S Fiorucci O M De Lima Jr A Mencarelli et alldquoCyclooxygenase-2-derived lipoxin A4 increases gastricresistance to aspirin-induced damagerdquo Gastroenterology vol123 no 5 pp 1598ndash1606 2002
[60] J L Wallace S R Zamuner W McKnight et al ldquoAspirin butnot NO-releasing aspirin (NCX-4016) interacts with selectiveCOX-2 inhibitors to aggravate gastric damage and inflam-mationrdquo American Journal of PhysiologymdashGastrointestinal andLiver Physiology vol 286 no 1 pp G76ndashG81 2004
[61] M Arita T Ohira Y P Sun S Elangovan N Chiang and C NSerhan ldquoResolvin E1 selectively interacts with leukotriene B4
receptor BLT1 and ChemR23 to regulate inflammationrdquo Journalof Immunology vol 178 no 6 pp 3912ndash3917 2007
[62] S F Oh P S Pillai A Recchiuti R Yang and C N SerhanldquoPro-resolving actions and stereoselective biosynthesis of 18SE-series resolvins in human leukocytes and murine inflamma-tionrdquo Journal of Clinical Investigation vol 121 no 2 pp 569ndash5812011
[63] Y-P Sun S F Oh J Uddin et al ldquoResolvin D1 and itsaspirin-triggered 17R epimer stereochemical assignments anti-inflammatory properties and enzymatic inactivationrdquo Journalof Biological Chemistry vol 282 no 13 pp 9323ndash9334 2007
[64] S Hong K Gronert P R Devchand R-L Moussignac andC N Serhan ldquoNovel docosatrienes and 17S-resolvins generatedfrom docosahexaenoic acid in murine brain human bloodand glial cells Autacoids in anti-inflammationrdquo The Journal ofBiological Chemistry vol 278 no 17 pp 14677ndash14687 2003
[65] H R OrsquoNeal T Koyama E A S Koehler et al ldquoPrehospitalstatin and aspirin use and the prevalence of severe sepsis andacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 39 no 6 pp 1343ndash1350 2011
[66] M Spite and C N Serhan ldquoNovel lipid mediators promoteresolution of acute inflammation impact of aspirin and statinsrdquoCirculation Research vol 107 no 10 pp 1170ndash1184 2010
[67] J N Fullerton A J OrsquoBrien and DW Gilroy ldquoLipid mediatorsin immune dysfunction after severe inflammationrdquo Trends inImmunology vol 35 no 1 pp 12ndash21 2014
[68] T Hammarberg P Provost B Persson and O RadmarkldquoThe N-terminal domain of 5-lipoxygenase binds calcium andmediates calcium stimulation of enzyme activityrdquoThe Journal ofBiological Chemistry vol 275 no 49 pp 38787ndash38793 2000
[69] C N Serhan S Krishnamoorthy A Recchiuti and N ChiangldquoNovel anti-inflammatorymdashpro-resolving mediators and theirreceptorsrdquo Current Topics in Medicinal Chemistry vol 11 no 6pp 629ndash647 2011
[70] C Pergola A Rogge G Dodt et al ldquoTestosterone suppressesphospholipase D causing sex differences in leukotriene biosyn-thesis in human monocytesrdquoThe FASEB Journal vol 25 no 10pp 3377ndash3387 2011
[71] C Pergola G Dodt A Rossi et al ldquoERK-mediated regulationof leukotriene biosynthesis by androgens a molecular basis forgender differences in inflammation and asthmardquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 105 no 50 pp 19881ndash19886 2008
[47] L Oleksowicz Y Liu R B Bracken et al ldquoSecretory phospholi-pase A2-IIa is a target gene of the HERHER2-elicited pathwayand a potential plasma biomarker for poor prognosis of prostatecancerrdquo Prostate vol 72 no 10 pp 1140ndash1149 2012
[48] M Hernandez R Martin M D Garcia-Cubillas P Maeso-Hernandez and M L Nieto ldquoSecreted PLA2 induces pro-liferation in astrocytoma through the EGF receptor anotherinflammation-cancer linkrdquo Neuro-Oncology vol 12 no 10 pp1014ndash1023 2010
[49] F F Davidson E A Dennis M Powell and J R Glenney JrldquoInhibition of phospholipase A2 by lsquolipocortinsrsquo and calpactinsAn effect of binding to substrate phospholipidsrdquo Journal ofBiological Chemistry vol 262 no 4 pp 1698ndash1705 1987
[50] Y Li H Yamada Y Kita et al ldquoRoles of ERK and cPLA2in
the angiotensin II-mediated biphasic regulation of Na+-HCOminus3
transportrdquo Journal of the American Society of Nephrology vol 19no 2 pp 252ndash259 2008
[51] M Holinstat O Boutaud P L Apopa et al ldquoProtease-activatedreceptor signaling in platelets activates cytosolic phospholipaseA2120572differently for cyclooxygenase-1 and 12-lipoxygenase catal-
[52] R M Kramer E F Roberts J V Manetta P A Hyslopand J A Jakubowski ldquoThrombin-induced phosphorylationand activation of Ca2+-sensitive cytosolic phospholipase A2 inhuman plateletsrdquo Journal of Biological Chemistry vol 268 no35 pp 26796ndash26804 1993
[53] W E M Lands ldquoStories about acyl chainsrdquo Biochimica etBiophysica ActamdashMolecular and Cell Biology of Lipids vol 1483no 1 pp 1ndash14 2000
[54] H Shindou and T Shimizu ldquoAcyl-CoAlysophospholipid acyl-transferasesrdquo Journal of Biological Chemistry vol 284 no 1 pp1ndash5 2009
[55] E Soupene and F A Kuypers ldquoMammalian long-chain acyl-CoA synthetasesrdquo Experimental Biology and Medicine vol 233no 5 pp 507ndash521 2008
[56] A Arduini V Tyurin Y Tyuruna et al ldquoAcyl-trafficking inmembrane phospholipid fatty acid turnover the transfer of fattyacid from the acyl-L-carnitine pool tomembrane phospholipidsin intact human erythrocytesrdquo Biochemical and BiophysicalResearch Communications vol 187 no 1 pp 353ndash358 1992
[57] A Arduini G Mancinelli and R R Ramsay ldquoPalmitoyl-L-carnitine a metabolic intermediate of the fatty acid incor-poration pathway in erythrocyte membrane phospholipidsrdquoBiochemical and Biophysical Research Communications vol 173no 1 pp 212ndash217 1990
[58] C N Serhan ldquoLipoxins and aspirin-triggered 15-epi-lipoxinbiosynthesis an update and role in anti-inflammation and pro-resolutionrdquo Prostaglandins and Other Lipid Mediators vol 68-69 pp 433ndash455 2002
[59] S Fiorucci O M De Lima Jr A Mencarelli et alldquoCyclooxygenase-2-derived lipoxin A4 increases gastricresistance to aspirin-induced damagerdquo Gastroenterology vol123 no 5 pp 1598ndash1606 2002
[60] J L Wallace S R Zamuner W McKnight et al ldquoAspirin butnot NO-releasing aspirin (NCX-4016) interacts with selectiveCOX-2 inhibitors to aggravate gastric damage and inflam-mationrdquo American Journal of PhysiologymdashGastrointestinal andLiver Physiology vol 286 no 1 pp G76ndashG81 2004
[61] M Arita T Ohira Y P Sun S Elangovan N Chiang and C NSerhan ldquoResolvin E1 selectively interacts with leukotriene B4
receptor BLT1 and ChemR23 to regulate inflammationrdquo Journalof Immunology vol 178 no 6 pp 3912ndash3917 2007
[62] S F Oh P S Pillai A Recchiuti R Yang and C N SerhanldquoPro-resolving actions and stereoselective biosynthesis of 18SE-series resolvins in human leukocytes and murine inflamma-tionrdquo Journal of Clinical Investigation vol 121 no 2 pp 569ndash5812011
[63] Y-P Sun S F Oh J Uddin et al ldquoResolvin D1 and itsaspirin-triggered 17R epimer stereochemical assignments anti-inflammatory properties and enzymatic inactivationrdquo Journalof Biological Chemistry vol 282 no 13 pp 9323ndash9334 2007
[64] S Hong K Gronert P R Devchand R-L Moussignac andC N Serhan ldquoNovel docosatrienes and 17S-resolvins generatedfrom docosahexaenoic acid in murine brain human bloodand glial cells Autacoids in anti-inflammationrdquo The Journal ofBiological Chemistry vol 278 no 17 pp 14677ndash14687 2003
[65] H R OrsquoNeal T Koyama E A S Koehler et al ldquoPrehospitalstatin and aspirin use and the prevalence of severe sepsis andacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 39 no 6 pp 1343ndash1350 2011
[66] M Spite and C N Serhan ldquoNovel lipid mediators promoteresolution of acute inflammation impact of aspirin and statinsrdquoCirculation Research vol 107 no 10 pp 1170ndash1184 2010
[67] J N Fullerton A J OrsquoBrien and DW Gilroy ldquoLipid mediatorsin immune dysfunction after severe inflammationrdquo Trends inImmunology vol 35 no 1 pp 12ndash21 2014
[68] T Hammarberg P Provost B Persson and O RadmarkldquoThe N-terminal domain of 5-lipoxygenase binds calcium andmediates calcium stimulation of enzyme activityrdquoThe Journal ofBiological Chemistry vol 275 no 49 pp 38787ndash38793 2000
[69] C N Serhan S Krishnamoorthy A Recchiuti and N ChiangldquoNovel anti-inflammatorymdashpro-resolving mediators and theirreceptorsrdquo Current Topics in Medicinal Chemistry vol 11 no 6pp 629ndash647 2011
[70] C Pergola A Rogge G Dodt et al ldquoTestosterone suppressesphospholipase D causing sex differences in leukotriene biosyn-thesis in human monocytesrdquoThe FASEB Journal vol 25 no 10pp 3377ndash3387 2011
[71] C Pergola G Dodt A Rossi et al ldquoERK-mediated regulationof leukotriene biosynthesis by androgens a molecular basis forgender differences in inflammation and asthmardquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 105 no 50 pp 19881ndash19886 2008
![Eicosanoids - Vinci-Biochem · 2017 1180 EAST ELLSWORTH ROAD · ANN ARBOR, MI 48108 · USA · [800] 364-9897 Eicosanoids The eicosanoid family of signaling molecules play important](https://static.documents.pub/doc/80x56/5f2c86e269400d690e589b1f/eicosanoids-vinci-biochem-2017-1180-east-ellsworth-road-ann-arbor-mi-48108-usa.jpg)
