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1、PUFAArachidonicAcid(AA)SourceAnimalPlantHuman40%50%ofbrainandnervePUFA40%50%ofbrainandnervePUFAplasm400mg/Lmilkfrommother0.4%MicroorganismHyphochytrimyceteHytridiomycetesOomycetesMortierella AAistheprecursorsofEicosanoids:Prostaglandinsandleukotrienesarelocallyacting,hormone-likelipidsderivedfromdie
2、tarilyessentialunsaturatedfattyacidsthatareimportantdrugtargetslActionsofprostaglandinsinclude:inflammatory,pain/fever,bloodclotting(viacontrolofplatelet-endothelialcellinteractions),intestinal,renal,uterineeffectslActionsofleukotrienesinclude:mainlyhypersensitivityandallergicreactionsSynthesisofEic
3、osanoidsR=HorCHR=HorCH3 3IncellmembraneIncellmembraneHydrolysisofHydrolysisofsnsn-2esterbond-2esterbondbyphospholipaseAbyphospholipaseA2 2(PLA(PLA2 2)orC)orCArachidonateesterificationesterificationMembrane phospholipidsMembrane phospholipidsArachidonic acidArachidonic acid Prostaglandins Prostagland
4、ins and thromboxanesand thromboxanes(C Cyclic/ring product)yclic/ring product)Phospholipase APhospholipase A2 2 (PLA(PLA2 2)LeukotrienesLeukotrienes(L Linear product)inear product)Arachidonic acidArachidonic acidC Cyclooxygenayclooxygenasese(COX)(COX)L Lipooxygenaipooxygenasese(LOX)(LOX)Liberationof
5、arachidonicacidanditsmetabolismtoLiberationofarachidonicacidanditsmetabolismtoprostaglandins/thromboxanesortoleukotrienesprostaglandins/thromboxanesortoleukotrienesSynthesisofProstaglandinCyclicCyclicendoperoxideendoperoxideHydroperoxideHydroperoxideProstaglandinProstaglandinendoperoxideendoperoxide
6、synthetasesynthetase(COX-1)(COX-1)COX-2COX-2HydroperoxidaseHydroperoxidaseProstaglandinendoperoxidesynthetase(alsocalledcyclooxygenase)Prostaglandinendoperoxidesynthetase(alsocalledcyclooxygenase)possessesbothcyclooxygenaseandhydroperoxidaseactivitypossessesbothcyclooxygenaseandhydroperoxidaseactivi
7、tyTwoformsofcyclooxygenase:COX-1-constitutivelyexpressedTwoformsofcyclooxygenase:COX-1-constitutivelyexpressedCOX-2-inducibleCOX-2-induciblePGHPGH2 2PGGPGG2 2PGH2central intermediate(Head of pathway)PGI2platelet disaggregation(Inhibits aggregation);vasodilation stomach acid secretionProstacyclinSynt
8、haseendothelialcellsThromboxaneSynthaseTXA2platelet aggregation(Together)vasoconstrictionplateletsPGF2 labor induction(Fetus)PGE2 wake(Eye opener),pain,fever,inflammation,renal arteriolar dilationIsomerase(many cells)ReductasePGD2Sleep(Drowsy)Isomerase(CNS,mast&fat cells)15-deoxy-12,14-PGJ2induce fa
9、t cell differentiation(Jumbo)fat cellsConversion of PGH2 to prostaglandins and thromboxane of the“2-series”TXB2inactiveNon-EnzymaticLeukotrieneBiosynthesisArachidonicacidArachidonicacid5-Hydroperoxyeicosa-5-Hydroperoxyeicosa-6,8,11,14-tetraenoicacid6,8,11,14-tetraenoicacid(5-HPETE)(5-HPETE)5-Lipoxyg
10、enase5-LipoxygenaseLeukotrieneALeukotrieneA44(LTA(LTA4 4)5-Lipoxygenase5-LipoxygenaseGlutathioneGlutathioneLTCLTC4 4synthasesynthaseLeukotrieneCLeukotrieneC44(LTC(LTC4 4)LeukotrieneELeukotrieneE44(LTE(LTE4 4)-Glu-Glu-Gly-GlyLTALTAHydrolaseHydrolaseLeukotrieneBLeukotrieneB44(LTB(LTB4 4)Leukotrienesar
11、eLeukotrienesareimportantmediatorsimportantmediatorsofinflammationofinflammationCysteinylleukotrienesCysteinylleukotrienesLeukotrieneBiosynthesis(Contd)ArachidonicacidArachidonicacid12-Lipoxygenase12-Lipoxygenase12-Hydroperoxyeicosa-12-Hydroperoxyeicosa-5,8,10,14-tetraenoicacid5,8,10,14-tetraenoicac
12、id(12-HPETE)(12-HPETE)12-Hydroxyeicosa-12-Hydroxyeicosa-5,8,10,14-tetraenoicacid5,8,10,14-tetraenoicacid(12-HETE)(12-HETE)Aspirin,Indomethacin,Ibuprofen esterificationMembrane phospholipidsDietary linoleic acidArachidonic acidmetabolism Cell Activation Events:mechanical trauma,cytokines growth facto
13、rsAnti-inflammatory glucocorticoids Prostaglandins and thromboxanes(Cyclic/ring product)Phospholipase A2(PLA2)Leukotrienes(Linear product)Arachidonic acidCyclooxygenase(COX)Lipooxygenase(LOX)ZyfloLiberation of arachidonic acid and its metabolism to prostaglandins/thromboxanes or to leukotrienes Leuk
14、otriene ReceptorAccolatelAnti-inflammatoryglucocorticoidsinhibitphospholipaseA2and,therefore,preventbothprostaglandinandleukotrieneformationlNonsteroidalanti-inflammatorydrugs(NSAIDs)inhibitcyclooxygenase(COX),andthuspreventonlyprostaglandin/thromboxanesynthesislZyfloinhibitslipoxygenasetoprecludeon
15、lyleukotrienesynthesis;Accolateisaselectiveleukotrienereceptorantagonist(blocker)Cyclooxygenase(COX)InhibitorsNonsteroidalantiinflammatorydrugs:Nonsteroidalantiinflammatorydrugs:AcetylsalicylicacidAcetylsalicylicacid(aspirin)(aspirin)Ser-530Ser-530IrreversibleinhibitionofCOXbyacetylationIrreversible
16、inhibitionofCOXbyacetylationoftheactivesiteoftheactivesiteActionsofAspirin:ActionsofAspirin:Antiinflammatory(COX-2inhibition)Antiinflammatory(COX-2inhibition)GIinjury(COX-1inhibition)GIinjury(COX-1inhibition)COX-2SelectiveInhibitorsRofecoxib(Vioxx)Rofecoxib(Vioxx)Celecoxib(Celebrex)Celecoxib(Celebre
17、x)GlucocorticoidsblockCOX-2expressionGlucocorticoidsblockCOX-2expressionLeukotrieneBiosynthesisInhibitionZileuton(Zyflo)Zileuton(Zyflo)Aninhibitorof5-lipoxygenaseAninhibitorof5-lipoxygenaseUsedinthetreatmentofasthmaUsedinthetreatmentofasthmaFunctionofProstaglandins TXA2plateletsTXA2plateletsaggregat
18、ionaggregationvasoconstrictionvasoconstriction PGI2endothelialcellsPGI2endothelialcellsplateletdisaggregationplateletdisaggregationvasodilationvasodilationgastricmucosagastricmucosadecreasedstomachaciddecreasedstomachacid PGE2manycellsPGE2manycellswakingwakingpainpaininflammationinflammationfeverfev
19、errenalarteriolardilationrenalarteriolardilationFunctionofProstaglandinsPGD2mastcells,fatcellssleepprecursortoPGJ2PGF2laborinducingPGJ2fatcellsfromPGD2inducesfatcelldifferentiationBiologicalactivitiesofleukotrienesLTBLTB4 4-potentchemoattractent-potentchemoattractent-mediatorofhyperalgesia-mediatoro
20、fhyperalgesia-growthfactorforkeratinocytes-growthfactorforkeratinocytesLTCLTC4 4-constrictslungsmoothmuscle-constrictslungsmoothmuscle-promotescapillaryleakage-promotescapillaryleakage1000Xhistamine1000XhistamineLTDLTD4 4-constrictssmoothmuscle-constrictssmoothmuscle-lungairwayhyperactivity-lungairw
21、ayhyperactivity-vasoconstriction-vasoconstrictionLTELTE4 4-1000 xlesspotentthanLTD4-1000 xlesspotentthanLTD4(exceptinasthmatics)(exceptinasthmatics)FunctionofAASecondsignalImprovecAMP,cGMPImmunityHETEs,HPETEs,LTinhibitimmunecellLTB4,LTD4,LTE4inhibitimmunityCardiovascularDiseaseLiverandGallbladderInf
22、lammationNerveCellDivisionApplicationNannie,Pregnant,Baby FAO/WHO baby recipe milk powder AA 60mg/kg DHA 40mg/kgApplicationImproverememberandeyesightAdjustbloodTGandSugarPreventCVDAnti-tumorCometicOtherAnimal experiment resultsControlControlAA-oilAA-oilBloodsugarBloodsugarBloodlipidBloodlipidTotalch
23、olesterolTotalcholesterolHDLHDLCHOCHOLDLLDLCHOCHOVLDLVLDLCHOCHOapoAapoAapoBapoB139.4139.463.263.278.378.310.510.536.736.731.131.13.053.057.987.98109.6109.623.623.661.261.218.818.827.727.714.814.83.233.233.743.74AA的产业化技术路线工业化生产工业化生产菌体菌体提油提油菌体胶囊菌体胶囊干菌体干菌体油胶囊油胶囊功能保健品功能保健品纯化油纯化油食食品品添添加加剂剂高高级级饲饲料料前前列列腺腺素
24、素科科 研研新新 药药-FAZhangDequan-3PUFA18:2Linoleicacid(LA)18:2Linoleicacid(LA)18:3-Linolenicacid(GLA)18:3-Linolenicacid(GLA)20:3Dihomo-linolenic20:3Dihomo-linolenicacidacid20:4Arachidonicacid(AA)20:4Arachidonicacid(AA)22:4Adrenicacid22:4Adrenicacid18:3-Linolenicacid(LNA)18:3-Linolenicacid(LNA)20:5Eicosapen
25、taenoicacid20:5Eicosapentaenoicacid(EPA)(EPA)22:5Docosapentaenoic22:5Docosapentaenoicacid(DPA)acid(DPA)22:6Docosahexaenoicacid22:6Docosahexaenoicacid(DHA)(DHA)-6PUFAKINDS-6and-3synthesize-6LAGLAAA-6eicosanoids-3LNAEPADHA-3eicosanoidsEicosanoidssynthesisAAPGH2Theeicosanoidsandtheirbiosyntheticorigins
26、.A)Synthesisfrom-6precursorsLA(6)PGI2,PGE2,PGD2,PGF2TXA2,TXB2LTsA.The eicosanoids and their biosynthetic origins.B)Synthesis from -3 precursors SERIES 5Leukotrienes:LOX COX SERIES 3Prostanoids:PGD3 PGE3 PGF3PGI3(strong activity)TXA3(weak activity)B.-Linolenic Acid(3 essential fatty acid)for membrane
27、 integrity in phospholipidsDiet-3 fatty acidsEicosapentaenoic Acid EPA(3)for membrane integrity in phospholipidsplant sourcesDocosahexaenoic Acid DHA(3)in breast milk;required forinfant brain developmentCOOHCOOHcold water fish-FAalsoleadstoproductionofPGI3andTXA3PGI3productionisfavored,anditalsohasm
28、uchgreaterintrinsicactivity(thanitsTXA3counter-hormone)tofavorvasodilationandplateletdisaggregationwithareducedriskofthrombosis(bloodclotting).Thisexplainswhy-3dietaryfattyacidspreventvasculardiseaseandheartattacksControl of platelet aggregation.Suppression of platelet aggregation by drug or dietary
29、 intervention PGI2TXA2Normal PhysiologyLow dose aspirin interventionKnocks down platelet TXA2PGI2TXA2favors plateletdisaggregationPlateletSmooth Muscle CellEndothelial CellBlood Vessel Wall TXA2PGI2PGI3TXA3Dietary-3 fatty acid intervention(cold water fish)PGI3 activity TXA3favors plateletdisaggregat
30、ion-6promoteTXA2synthesizing-3promoteTXA3synthesizingFUNCTIONAnticancerCVD-6promotePGE2synthesizing-3inhibitPGE2synthesizing-3inhibitplateletaggregationandbloodinhibitplateletaggregationandbloodtoclotbypromotingformationTXA3,PGI3toclotbypromotingformationTXA3,PGI3modifydyslipidemiaEPA/DHAmodifydysli
31、pidemiaEPA/DHA inhibitVLDLinhibitVLDLandapoB,bylowertriacylglycerolsandandapoB,bylowertriacylglycerolsandCholesterol,increaseinHDL2-CCholesterol,increaseinHDL2-Cimprovearterialfunction,inhibitmonocytesimprovearterialfunction,inhibitmonocytesmigratinonintoplaque,andcytkine,PDGFmigratinonintoplaque,an
32、dcytkine,PDGFanditsmRNAproduction,relaxbloodanditsmRNAproduction,relaxbloodvesselsandreduceBPbystimulatevesselsandreduceBPbystimulateendothelialproductionofNOendothelialproductionofNOantiarrhythmiasbyalteringcellmembraneantiarrhythmiasbyalteringcellmembranefattyacidscompositionandfattyacidscompositi
33、onandelectrophysiologicalfunction,reduceelectrophysiologicalfunction,reducevulnerabilitytoventricularfibrillation,andvulnerabilitytoventricularfibrillation,andlessriskofcardiacarrest&suddendeathlessriskofcardiacarrest&suddendeathanti-inflammationbyreducingproductionofanti-inflammationbyreducingprodu
34、ctionofTXB2,PGE2TXB2,PGE2-6-6 DecreasedChol&DecreasedChol&LDLCLDLC SmallreductionHDLSmallreductionHDL SmallreductionTGsSmallreductionTGs LowerserumLowerserumcholesterolcholesterol IncreasedIncreasedthromboxaneA2thromboxaneA2 IncreasedprostacylinIncreasedprostacylin1212 ControlofControlofinflammation
35、inflammation PlateletaggregationPlateletaggregation Vasoconstriction/dilatVasoconstriction/dilationion Membranestructure-Membranestructure-fluidity,receptors,fluidity,receptors,enzymesandenzymesandchannelschannels-3-3 DecreasedChol&TGDecreasedChol&TG LittleeffectonLDLLittleeffectonLDL Decreasedthrom
36、boxaneA2DecreasedthromboxaneA2 Increasedprostacylin12Increasedprostacylin12 AntithromboticeffectAntithromboticeffect ReduceplateletaggregationReduceplateletaggregation PreventingcardiacarrestPreventingcardiacarrest DecreasingriskofbreastDecreasingriskofbreastandcoloncancerandcoloncancer Bothomega3an
37、d6FABothomega3and6FAimprovebloodpressure,improvebloodpressure,Omega3FAhasagreaterOmega3FAhasagreatereffectthanomega6FAeffectthanomega6FA LNAStructure-LinolenicALA18:3cis9,12,15-LinolenicGLA18:3cis6,9,12ALAGLAEPADihomo-GLADHAAAALAPerillaoil45%50%oil，ALA60%Linseedoil35%oil，ALA50%GLAEveningPrimroseEven
38、ingPrimrose23%30%oil,GLA8%10%23%30%oil,GLA8%10%CONJUGATEDLINOLEICACIDCLASTRUCTUREtrans10,cis12CLAtrans10,cis12CLAcis9,trans11CLAcis9,trans11CLAlinoleicacidlinoleicacidHISTORY1951.Nichols1951.NicholssynthesizesynthesizeCLA.CLA.1966,.Keplerdiscoverthat9c,11t-CLAisthemediators1966,.Keplerdiscoverthat9c
39、,11t-CLAisthemediatorsofhydrogenationoflinoleicinruminant.ofhydrogenationoflinoleicinruminant.1978,MichaelParizadicoverCLAcananticancer.1978,MichaelParizadicoverCLAcananticancer.1985,Pariza,CLAinhibitmouseskincancer.1985,Pariza,CLAinhibitmouseskincancer.19911991，Haetal,CLAinhibitBPinducedtumor.Haeta
40、l,CLAinhibitBPinducedtumor.1994,Ip,CLAinhibitmouse1994,Ip,CLAinhibitmousegalactophoregalactophorecancer.cancer.1990s,theevidenceofCLAanti-tumor.1990s,theevidenceofCLAanti-tumor.1997,Pariza,CLAdecreasefatmass,increaseLBM.1997,Pariza,CLAdecreasefatmass,increaseLBM.1999,Japan,builtCLAplant1999,Japan,bu
41、iltCLAplant，CLAcapsuleofCLAcapsuleofdecreasingfatcomeintomarketinUSA.decreasingfatcomeintomarketinUSA.2002,China,CLA“TenthfivePlan”.2002,China,CLA“TenthfivePlan”.2003,CLAproductwillcomeintomarket2003,CLAproductwillcomeintomarketBodyCompositionIncreasedleanbodymassIncreasedleanbodymass(LBMLBM)andandd
42、ecreasedfatmassdecreasedfatmass(FM)(FM)提高肉毒碱棕榈酰转移酶（一种脂肪提高肉毒碱棕榈酰转移酶（一种脂肪提高肉毒碱棕榈酰转移酶（一种脂肪提高肉毒碱棕榈酰转移酶（一种脂肪-氧化的限速酶）氧化的限速酶）氧化的限速酶）氧化的限速酶）提高荷尔蒙敏感酶（负责脂肪水解释放至血液中的酶）提高荷尔蒙敏感酶（负责脂肪水解释放至血液中的酶）提高荷尔蒙敏感酶（负责脂肪水解释放至血液中的酶）提高荷尔蒙敏感酶（负责脂肪水解释放至血液中的酶）inhibitinhibit脂蛋白脂肪酶脂蛋白脂肪酶脂蛋白脂肪酶脂蛋白脂肪酶（促进脂肪吸收）（促进脂肪吸收）（促进脂肪吸收）（促进脂肪吸收）In
43、crease3T3-L1Increase3T3-L1脂肪细胞中的脂肪水解速度脂肪细胞中的脂肪水解速度脂肪细胞中的脂肪水解速度脂肪细胞中的脂肪水解速度 BodyCompositionExample2000,Blankson,1.7-6.8gCLA/dFMdecreasedobviouslyLBMdecreasedobviously2001,Riserus,et.al,4.2gCLA/dFMdecreasedobviously2001,Smedman,etal.4.2gCLA/dFMdecreasedobviouslyBodyComposition2001,Mougios,2001,Mougios
44、,3g/dCLA,90d3g/dCLA,90d20%lessFM20%lessFM5%moreLBM5%moreLBM 2001,Smedman,etal,2001,Smedman,etal,MicedietscontainingMicedietscontaining0.5%CLA0.5%CLA60%lessFM60%lessFM10%moreLBM10%moreLBM2002,Riserus,etal.2002,Riserus,etal.3.4gCLA/d3.4gCLA/dFMdecreasedobviouslyFMdecreasedobviouslyBodyComposition2003,
45、Susie,etal.60 subjects 5 groups 12 capsules/day Placebo=olive oil TreatmentGroups CLA Doses g/d:1.7 3.4 5.1 6.8BodyCompositionChangesfromWeeks0to12ChangesfromWeeks0to12 1.71.73.43.45.15.16.86.899 Weight,Weight,kgkg-0.4-0.4-0.4-0.4-0.1-0.1-0.8-0.8+1.4+1.4BFM,BFM,kgkg-1.2*-1.2*-1.7*-1.7*-0.4-0.4-1.3*-
46、1.3*+1.5+1.5LBM,LBM,kgkg 0.90.91.31.30.50.50.9*0.9*-0.05-0.05*Significantchangesfromplacebo(pSignificantchangesfromplacebo(p 0.05)0.05)*Significantchangeswithingroups(*Significantchangeswithingroups(0.05)0.05)Daily Dosage of CLA Placebo g/dg/dBodyComposition2003,Susie,etal.2003,Susie,etal.6men,3gCLA
47、/day,6weeks6men,3gCLA/day,6weeksCLAPossibleMechanismBloodstreamBloodstreamMuscleMuscleTriglycerideTriglycerideFFAFFAAdipocytesAdipocytesLPLStep 1:CLA decreases the activity of adipocyte LPL Step 2:CLA increases theactivity of Hormone Sensitive Lipase within the adipocyte increasing lipolysisCLA-Pote
48、ntialMechanismBloodstreamBloodstreamMuscleMuscleFFAFFATGTGB-OxidB-OxidCOCO2 2EnergyEnergyHSLHSLTGTGTGTGPreventCancer动物实验证明：CLA对胃癌、皮肤癌、前列腺癌有明显的抑制作用。细胞培养实验也证明，CLA能抑制人乳腺癌、肠癌、肺癌、黑色素癌、白血病、间皮瘤、皮胶质细胞癌、卵巢癌、结肠癌、前列腺癌和肝癌等细胞株的生长和增殖。实验同时也发现，植物油中普遍存在的亚油酸对癌细胞的增殖具有促进作用。PreventCancerCLAisapotentanticancerDirectinflu
49、enceDecreasefatImprovecachexiaPreventCancerPreventCancerIncreaseof55mg/dofCLAreducetheriskofbreastcancer“IfmargarinewasreplacedbybutterintheAmericandietitwouldincreaseCLAintakebyapproximately54mg/day.”PreventCVDCLA能够降低LDL与HDL的比例能够抑制由花生四烯酸或胶原质引起的血小板聚集，阻止脂肪和血小板在粥样病变的动脉壁上的沉积，从而抗血栓。PreventCVDRabbitswere
50、fed0.5gCLAperdayLowercirculatingLDLLowercirculatingLDLLowertriglycerideconcentrationsLowertriglycerideconcentrationsLessatherosclerosisLessatherosclerosisCLAImpactonTCCLA:ImpactonHDLcCLA:ImpactonLDLCLA:ImpactonTGPreventdiabetesCLAcanadjustanddecreasebloodglucose,preventdiabetes.PreventdiabetesPlasma