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Taurine:AMysteriousMolecule

withIntriguingPossibili8es

Downloadtheslidesfrom:

h2p://people.csail.mit.edu/seneff/

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Outline1. Introduction2. Some Biochemistry3. Some Observed Benefits of Taurine

The Skin The Heart The Pancreas The Brain The Blood

4. Mitochondrial Diseases5. Encephalitis6. Cancer7. Summary

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1. Introduction

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Haveyouthoughtabouttaurine?*

*AnnLauritzen,WiseTradiFonsWorkshop,WAP011,Dallas,TX

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WhatisTaurine?

Taurineisthemostcommonfreeaminoacidinthebody

Taurineisneverincorporatedintoanyprotein,andithardlyeverparFcipatesinanyreacFon

Yettaurineisfoundinhighconcen-traFonintheheart,brain,andliver

Whatisitdoingthere???

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SomeInteres8ngFactsaboutTaurine*

Importantinmanymarinespeciesforosmosis(asanosmolyte) Shallowwaterclamsandsnailshave

significantlymorethandeeperwaterspecies

Catsbecomeblindifraisedwithouttaurine

Braintaurinelevelsdeclinewithageinmammals;replacedwith

glutamate ArgumentusedtojusFfypresencein

energydrinks

*P.H.Yancey,JExperimentalBiology08,819-830,005.

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TaurinehasManyKnownRoles*

MaintainsosmoFcbalanceincells BileacidformaFon(digestfats) Rolesinmitochondria

HelpsthemmaintaintheirmembranepotenFal Suppressessuperoxidesynthesis(oxidaFondamage)

ClinicalobservaFons Maintainshealthyskin Protectsagainstdiabetesandheartdisease Protectsagainstheartarrhythmias Lowtaurineinbloodassociatedwithmanycancers

*Wesselingetal.,Hypertension.009,53,909-911

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Taurineisfoundonlyinanimal-basedfoods

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FoodSourcesofTaurine

Eggs,meat,fish,seafood,dairy

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FishOil+Taurine*

ExperimentondiabeFc/obesemice,threegroups ishoil ishoil+taurine Soybeanoil

Serumglucoselevelssignificantlylowerinmicefedfishoil(withorwithouttaurine) ishoil+taurinegrouphadenhancedGLUT4

distribuFoninplasmamembraneofmuscle

Fssue. GLUT4isthekeycatalystforglucoseuptakeinmuscles

*Mikamietal.,J.oodSci.01Jun,77(6),H114-0.

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AProvoca8veHypothesis

Taurineisverystable(manyclaimitisinert) Taurineisstoredinheartandbrainasbufferfor

sulfatesupplyduringextremeadversecondiFons EncephaliFsleadstosulfaterenewal!

Hypochlorite(bleach)[releasedbyimmunecellstofightinfecFon]

ever[enhancesenergyofreacFon] Seizures[induceelectriccurrentandprovidefree

electrons]

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TheImportanceofSulfate:SO4-2

Ihavetracedmostmoderndiseasestoadeficiencyinthesupplyofsulfate(Iwilltalk

muchmoreaboutthistomorrow)

TwocriFcalpoints:SulfaFonofcholesterolisessenFalforcholesterol

transportsulfatedeficiencyimpliescholesterol

deficiencySulfaFonisessenFalformanagingsugar:

insufficientsulfatesupplyleadstodiabetes

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2. Some Biochemistry

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Taurine!

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IsTaurineanAminoAcid?

Sulfonyl

Carboxylisreplaced

bySulfonyl

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TaurineSynthesisPathway*

*Wesselingetal.,

Hypertension.009,

53,909-911

PotentanFoxidant

Sourceofsulfate

EssenFalaminoacid

EssenFalto

proteinfolding

Ifyouhaveto

synthesizetaurine

fromprecursors,

theseotherrolesaresacrificed!

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BigHintsfromEarlyLiterature*

ArFclepublishedin1960 edcholesteroltomonkeys

Inducedatherosclerosis Ifsulfur-containingnutrients

areadded,atherosclerosisis

prevented

Taurineworkedaswellasothermoleculeslikecysteine,

methionine,andglutathione

*G.V.Mannetal.,Am.J.Clin.Nutr.8,491-497,1960.

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BreakingdownTaurinetogetSulfate

SuchareacFonmightbepossibleinthehuman,butitsnoteasy

AHint:hypochloriteisreleased

byneutrophilstofightinfecFonCitricAcidCycle

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AnotherUsefulReac8on

CH7NO3S+HONH4+CH3COO-+HS+O

taurine+waterammonia+acetate+hydrogensulfide+oxygen cysteine

N-acetylcysteine

VasorelaxaFon

Oxidizetothiosulfate&cholesterolsulfate

GenerateATP

NutriFonalsupplementfor

Tylenoloverdoseandtotreat

sulfatedeficiencyinauFsm

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3. Some Observed Benefits of Taurine

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TaurocholicAcid:inBileAcids

Makesbileacidsmorewatersoluble

taurine

cholesterol

AidsindigesFngfats

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The Skin

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SLS:aSkinIrritant*

Sodiumlaurylsulfate(SLS)isaddedtoshampoosmainlytomakethemfoamy

Surfactant(=surfaceacFveagent)

UsedinmanycommercialformulaFonsbecauseitisinexpensive,offersgreat

foaming,andcanbethickenedeasilywithsalt SLSisaskinirritant--inducesdry,scalyskindueto

itssurfactanteffects

*LeeandMaibach,ContactDermaFFs,1995,13,1-7

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Taurine,SLS,andtheSkin*

TaurineaccumulatesinoutermostkeraFnocytelayeroftheskinfollowingUVexposure SFmulatessynthesisofceramides,cholesterol,andfa2yacids

SLSinducesanincreaseinwaterlossthroughtheskin,inflammaFon,andproliferaFon

IncubaFonw/SLS+taurine DecreaseinIL-1andprostaglandinE(inflammatoryagents) StabilizaFonofmembraneintegrity ImprovementinkeraFnocyteviability

*B.Anderheggenetal.,JCosmetSci.006Jan-eb;57(1),1-10

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The Heart

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SuddenCardiacDeath*

Suddencardiacdeathistheleadingcauseofdeathinindustriallydevelopedcountries

Accountsfor300,000-500,000deathsperyearinU.S.

DuetoventricularfibrillaFon:life-threateningheartarrhythmia Manifestedbylowheartratevariability

Triggeredbyadrenalininresponsetostress

IntracellularpotassiumandcalciumdysregulaFoninsufficientmembranecholesterol?

*G.E.Billman,AmJPhysiolHeartCircPhysiol97:H1171-H1193,009

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Cardioprotec8veEffectsofTaurine*

TaurineisnormallyfoundinhighestconcentraFonintheheart AnFarrhythmiceffectsobservedexperimentally

incats,dogsandguineapigs.

AddiFonoftaurine Preventslossofpotassiumbymyocardium Reversesadverseeffectsofadrenalinanddigoxin EliminatesthepathologicalECGchangescausedby

strophanthininisolatedguineapighearts.

Myhypothesis:Istaurineasourceofsulfateforcholesterolsulfatesynthesis?

*GeorgyEby,TaurineRoleinCardiologyandCardiacArrhythmias

h2p://george-eby-research.com/html/taurine.html

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HighDietaryTaurineReducesApoptosis

(CellDeath)andAtherosclerosis* Highdietaryfishassociatedwithdecreased

cardiovasculardeathrate

Taurineishighlyconcentratedinfish Highdietarytaurinereducesriskofcoronary

heartdiseaseandinsulinresistance

Taurinedeficiencycanalsoleadtoobesity,ariskfactorforheartdisease

*A.Zullietal.,Hypertension,53,1017-10,009

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andAtherosclerosis:Experiment*

Rabbitsfedhighcholesteroldiet Examinedeffectoftaurine

supplementsonlemaincoronaryartery

ResultsReducedserumhomocysteinelevelsEndoplasmicReFculumstressreducedin

endothelialcellswhichprotectedthemfromapoptosis

ReducedatherosclerosisinarterywallReducedserumHDL

*A.Zullietal.,Hypertension,53,1017-10,009

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andAtherosclerosis*:MyInterpreta8on Taurinereactedwithhypochloritewhichalloweditto

bemetabolizedtosulfate

ProtectedLDLfromhypochloritetoxicity ReduceduptakeofLDLintoplaque

PlateletsuFlizednewlyavailablesulfatetoproducecholesterolsulfatefromcholesterolobtainedfromHDL

DepletedHDL

HomocysteinecouldbedivertedtocysteineandglutathioneinsteadofbeingheldinreserveasanalternaFvesourceofsulfate.

Serumhomocysteinelevelsdropped*A.Zullietal.,Hypertension,53,1017-10,009

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Recapitula8on Suddencardiacdeathisleadingcauseofdeathin

WesternnaFons

Taurineishighlyconcentratedintheheart Protectsfromsuddencardiacdeath

Lowdietarytaurineassociatedwithincreaseininsulinresistance,obesity,andheartdisease

Taurineprotectsrabbitsfromcholesterol-diet-inducedcardiovasculardisease

Ihypothesizethattheseeffectsareduetotaurine'sabilitytopromotecholesterolsulfatesynthesis

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The Pancreas

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TaurineandPancrea8cIsletCells*

Motherratsfedlow-proteindietduringgestaFon

andlactaFon

Offspringhadvulnerableisletsintheirpancreas(leadingtodiabetes)

ExcessproducFonoftoxicnitricoxide Increasedapoptosis(celldeath)

Supplementwithtaurineinprotein-deficientmothersalleviatestheseeffects

*KGoosseetal.,JournalofEndocrinology(009)00,177187

Thisshowshow

maternaldiet

canhavelong-

termeffectsonoffspring!

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Taurine,Fructose,andDiabetes*

*Nandhinietal.,SingaporeMedJ,46(),8-87,005

ructoseinducesdiabetesRatsfedcornstarchcompared

withratsfedfructose(60%ofdietarycalories)

ructoseinducedinsulinresistance(well-knownresponse)

Supplementwith%taurinesoluFonadlibitumprotectedratsfrominsulinresistance

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Taurine,Fructose,andDiabetes*

*Nandhinietal.,SingaporeMedJ,46(),8-87,005

CON=cornstarch

RU=fructose

TAU=taurine

TaurineCompletelyEliminatedtheSugarSpikeCausedbyructose

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The Brain

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TaurineinDevelopment*

HighestconcentraFonoccursindevelopingbrain

TaurineconcentraFonsfallduringdevelopment

Convertedtosulfate? Neonateshave3xlevelsofadults Trueforhumans,monkeys,mice,rabbits,rats,

andinsects

*R.J.Huxtable,PhysiologicalReviews7(1),101-163,Jan199

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TaurineisNeuroprotec8ve*

Taurinepreventsexcitotoxicityinducedbyglutamateinneurons

Mitochondrialelectrongradientiscalciumregulated

AcFvaFonbyglutamate Extracellularcalciuminflux MobilizaFonfrominternalstores(mitochondria) Associatedwithdecreaseinmitochondrialenergy

metabolism

Pretreatmentwithtaurinenormalizedcalciumhomeostasisandpreventedmitochondrialimpairment

*A.ElIdrissiandE.Trenkner,J.Neuroscience,19(1),9459-9468,1999.

mitochondrion

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The Blood

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TaurineProtectsPlateletsfromBloodClots*

*K.C.Hayesetal.,Am.J.Clin.Nutr.1989;49:111-6.

Taurineisespeciallyconcentratedinnervoussystemandplatelets Catsareoenafflictedwitha

taurine-deficiencycardiomyopathy

alongwitharterialthromboembolism- Bloodclotblocksflowtoheart

TaurinesuppressesreleaseofthromboxanebyplateletswhichtriggersbloodclotformaFon

- Studyconfirmedthisistrueforhumansaswell

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Sub-op8maltaurinestatusmaypromote

platelethyperaggregabilityinvegetarians*

Plasma taurine levels are lower, andurinary taurine excretion is substantiallylower, in vegetarians than in omnivores.

Platelets are rich in taurine, whichfunctions physiologically to dampen thecalcium influx evoked by aggregatingagonists thereby down-regulating platelet

aggregation.

*M..McCarty,MedicalHypotheses,63(3),46-433,004.

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Outline1. Introduction2. Some Biochemistry3. Some Observed Benefits of Taurine

The Skin The Heart The Pancreas The Brain The Blood

4. Mitochondrial Diseases5. Encephalitis6. Cancer7. Summary

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4. Mitochondrial Diseases

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MitochondrialDiseases*

MitochondriaconvertfoodintoATPforenergy MitochondrialstageIimpairment

associatedwithmanyneurological

andmusculardisorders

MitochondrialDiseases OencausedbymutaFons

inmitochondrialgenes

Symptomsincludepoorgrowth,lossofmusclecoordinaFon,muscleweakness,visualproblems,hearingproblems,learning

disabiliFes,heartdisease,liverdisease,kidneydisease,

gastrointesFnaldisorders,respiratorydisorders,neurological

problems,autonomicdysfuncFon,anddemenFa.

*romWikipedia

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Humanmitochondrialdiseases

causedbylackoftaurinemodifica8oninmitochondrialtRNAs*

*KirinoandSuzuki,RNABiology(),41-44,June005.

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DefectsfromGene8cMitochondrialDisorders*

*KirinoandSuzuki,RNABiology(),41-44,June005.

MutaFonspreventtaurinea2achmentstotRNAs

(1)ImpairUUGgenetranslaFon(taurine)

NADH-CoenzymeQreductaseimpaired MitochondrialComplexIdisrupted

()ImpairAAAandAAG(taurine+S)

DefectinwholemitochondrialtranslaFon QuesFon:DoestheaddiFonalSplayahighlysignificant

roleinenablinggenetranslaFon??

Generictaurinedeficiencymightleadto

similarmitochondrialimpairments

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Fever,Au8sm,andMitochondria*

oundaplausiblelinkbetweenmitochondria,fever,andtaurine

everimpactsauFsmSomeregressaerfever,someimproveSubsetwithmitochondrialdysfuncFonregress

AggressivetreatmentmayworsenoutcomeAcetaminophen(Tylenol)depletessulfateFeversuppressionpreventssulfateregenera4onfromtaurine?

*Shoffneretal.,JChildNeurol.009Sep

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FeverPlusMitochondrialDiseaseCould

BeRiskFactorsforAu8s8cRegression*

*h2p://blog.auFsmspeaks.org/010/03/11/fever-regression/

ChildrenwithASDand

mitochondrialdisease

60%with

regressionevents

70%withfever

orinfecFon

1/3with

vaccinaFon

Allchildrenwith

ASD(1in110

childrenborn)

14%ofthechildrenwith

bothauFsmand

mitochondrialdiseasesufferedregression

followingvaccinaFon

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5. Encephalitis

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AProvoca8veProposal:

Encephali8sisProtec8ve!

Taurineiskeptinreserveasabufferforsulfatesupply

EncephaliFsenablesconversionoftaurinetosulfate

ThisisanimportantposiFveoutcomeofencephaliFs

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WhatisEncephali8s?

EncephaliFsisanacuteinflammaFonofthebrain UsuallycausedbyinfecFon,mostoenbyavirus,but

someFmesbybacteria,afungus,oraparasite.

Symptoms Headache ever Confusion Sleepiness aFgue Seizuresandconvulsions Tremors Memoryproblems

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Figh8ngtheInfec8on:

NitricOxideandHypochlorite Neutrophilsfollowmicrobes

intobrain

A2ackmicrobeswithanFmicrobialagents:

- Nitricoxide- Hypochlorite

ExcessnitricoxideammoniacomplexreacFonintheastrocyte

reesuptaurinetoprotectfromhypochloritedamage

(bybecomingtaurinechloramine)

Neutrophil

Nitric

oxide

hypochlorite

Astrocyte

taurine chloramine

ammoniataurine

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TaurineChloramineisEnergized!

Althoughitisbelievedthattaurineisinert,taurinechloraminecanbemetabolizedto

sulfate!!(atleastbysomespecies)

Canhumansdothis??maybe!

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SomeMoreHelpfromAstrocytes

Astrocytesreleasebothtaurineandglutamateaerswellinginresponsetoammonia

exposure

GlutamateisanacFveneurotransmi2ercapableofinducingaHzresonance

phenomenon

ThiscouldbeakeysourceofseizuresSeizuresprovideelectriccurrent

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GlutamateCycling

Synapse

mitochondrion

Astrocyte

PresynapFcneuron

PostsynapFcneuron

GlutamateisanacFveneurotransmi2er ConversiontoglutaminerendersitinacFve

duringtransport

glutamate

glutamine

Ammonia

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GlutamateduringEncephali8s

Synapse

mitochondrion

ammonia

Astrocyte

PresynapFcneuron

PostsynapFcneuron

DuringencephaliFs,astrocyte

releasesammoniafromglutamineinmitochondria

andshipsoutglutamate

glutamate

glutamine

Ammonia

Glutamatecaninduceseizures

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WhyisAmmoniaNeededinthe

Mitochondrion? Toreplacetaurine! Astrocytereleasesbothtaurineandglutamate

intothemedium

Ammoniareplacestaurineasbufferingagentinmitochondria

HelpsthemmaintainbasicpHTHISREESUPTAURINE

TOPRODUCESULATE!!!

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GlutamateduringEncephali8s

Synapse

mitochondrion

ammonia

Astrocyte

PresynapFcneuron

PostsynapFcneuron

Ammoniareplacestaurinein

mitochondrionandfreesuptaurineforsomethingelse!

glutamate

glutamine

Ammonia

TAURINE!

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Hypochlorite+TaurineSalva8on!

Neutrophil

Nitric

oxide

hypochlorite

Astrocyte

taurine chloramine

ammoniataurine

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ARoleforMicrobes!*

Hypothesis:braininfecFonallowsbacteriatosupplysulfatetothebrain

UnderstresscondiFons,glutamateisreleasedbyastrocytesinthebrainandmetabolizedto-ketoglutarateintheneurons

(subsFtutesforglucosemetabolismtogenerateenergy) EcoliandmanyotherbacteriacanuFlizetheenzyme

-ketoglutaratedioxygenasetometabolizetaurine Inputsoxygen,-ketoglutarate,taurine Outputscarbondioxidesuccinate,sulfiteand

aminoacetaldehyde

ThisenzymeisinducedduringsulfatestarvaFon Sulfiteiseasilyoxidizedtosulfate

Microbesallowedtoflourishinthebraintosupplysulfate! *K.P.McCuskerandJ.P.Klinman*TetrahedronLe2ers50(009)611613

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Recapitula8on

EncephaliFsmaybeamechanismtorenewsulfatesupplytothebrain,bybreakingdown

taurine

Complexmechanisminvolvesglutamate,hypochlorite,nitricoxide,ammonia,etc.

everandseizuresalsoprovidecatalysis Bacteriamaybepermi2edintothebrainto

helpcarryoutthereacFon

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6. Cancer

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ProgressiveinhibiFonofapoptosis(celldeath)andinducFonofangiogenesis(bloodvessel

growth)contributetotumoriniFaFon,growth

andmetastasisinthepathogenesisofbreast

cancer

TaurinedisplaysanFneoplasFceffectsthroughDownregulaFonofangiogenesisEnhancementoftumorcellapoptosis

TaurineandBreastCancer*

*I.M.ElAgouzaetal.Angiogenesis14,31330,011

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85women50withdiagnosedbreastcancer10withbenigntumors5withfamilyhistory0controls

Serumtaurinesharplyreducedinwomenwithbreastcancer(p

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0

4

6

8

10

1

14

16

control highriskgroup cancerpaFents

VEG/TN

VEG/taurine

69-fold

increase


VEG

accelerates

growth

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TaurineInducesApoptosis*

Tumor

cell

Tumor

cell

Tumor

cell

Tumor

cellTN-

VEG

Proliferate

Die

Tumorcellsarerobustagainstexposuretotoxicagents;

theyproliferatewhileothernormalcellsdie

*A.Jacobietal,AnFcancerDru s16 9 ,917-91,005.

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TaurineInducesApoptosis*

Tumor

cell

Tumor

cell

Tumor

cell

Tumor

cellTN-

VEG

Proliferate

Die

Tumorcellsarerobustagainstexposuretotoxicagents;

theyproliferatewhileothernormalcellsdie

*A.Jacobietal,AnFcancerDru s16 9 ,917-91,005.

+Taurine

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LowSerumTaurineandCancer

Manydifferentcancershavebeenfoundtobeassociatedwithunusuallylowserumtaurinelevels

Breastcancer Ovariancancer Bladdercancer Lungcancer Uterinecancer Livercancer Coloncancer Gastro-intesFnalcancer Endometrialcancer

Hypothesis:cancerdepletestaurineby

converFngittosulfate

Tumorcellstypically

overproducesulfated

polysaccharides

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7. Summary

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FoodSourcesofTaurine

Eggs,meat,fish,seafood,dairy

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Summary

TaurineisafascinaFngandpoorlyunderstoodmolecule!

Weneedtoworryaboutdietarydeficiencies,especiallyvegetarians

TaurineisprotecFveincancer,heartdisease,anddiabetesi.e.,themajordiseasesofmodernFmes

TaurineplaysanessenFalroleindevelopment Taurinesmanybenefitsmaystemfromitsrolein

supplyingabufferforsulfatetothebody

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Thank you!

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*igure10inL.-.Huetal,MolPharmacol75:734,009

HydrogenSulfideProtectsMitochondria*

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Taurine-modifiedtRNAsin

Mitochondria*

* S ki t l WIRE RNA 011 376 386

Documents

Taurine 2012