Post on 16-Oct-2021
transcript
3/26/18
1
DownloadTheseSlides
h)p://people.csail.mit.edu/seneff/2018/Toronto.pptx
Sulfateisthemostcommonnutri5onaldeficiencythatyouneverheardof
StephanieSeneffMITCSAIL
March27,2018
3/26/18
2
InMemoryOfJohnBala5necz
January19,1937– August6,2017
ZenHoneycu)JackWilson
RachelParent
TonyMitra
ShivChopra SomeJohnBala5necz“Groupies”
3/26/18
3
JohnBala5neczEmailmessagetoJackWilson:
“SinceyouareasuperDIN(i.e.doitnow)person,andareeveneducaWngdoctorsoneataWme,whydon’tyoucontactDavidMathews,thea)orneyinTexas,whoisbuildingacaseagainstMonsanto(dmlawfirm.com).Hemightevenpostyourlatestpamphletinhiswebsite...Yourinfomightevenspeeduphisdecisiontostartthelawsuitofthecentury.”
Outline• IntroducWon• CholesterolSulfate• Glycocalyx&HeparanSulfate• BileAcids• Glyphosate• DiseasesLinkedtoSulfateDeficiency• CurcuminandOtherFlavonoids• PrevenWonofDiseasethroughDietandLifestyle
3/26/18
4
TheBigIdeas• Cardiovasculardiseaseisacholesterolsulfatedeficiencyproblem
• HeparansulfatedeficiencyisakeyfactorinauWsm• Mostmoderndiseasesthatareontherisearemechanismstorenewsulfatesupplytotheblood
• Glyphosate(theacWveingredientinthepervasiveherbicideRoundup)disruptsthebody’sabilitytoproperlysynthesizeanduWlizesulfate
• Taurineisastorageformofsulfate
Taurine:BriefChemistryRefresherCourse
Sulfate=SO4-2=
Taurine=C2H7NO3S= =
=
• Taurineistheonlysulfonatedaminoacid- Itdoesnotincorporateintoproteins- Itisthemostcommonfreeaminoacidinthebody- ItisstoredinlargequanWWesintheheart,brainandliver
• Humancellscannotmetabolizetaurine,butmicrobescanextractitssulfuratomtosynthesizesulfateormethionineforthehost
3/26/18
5
PerinatalTaurineisEssen5al*• TaurineaccumulatesinmaternalWssuesduringpregnancy,andisreleasedtothefetusduringtheperinatalperiod
• Mother'smilkisrichintaurine,anditaccumulatesintheneonatalbrain
• Taurinedeficiencyinthemomleadsto:– GrowthretardaWonintheoffspring(insufficientmethionine?)– Impaireddevelopmentofcentralnervoussystemandpancreas– ImpairedglucosetoleranceandvasculardysfuncWon
• GestaWonaldiabetesinoffspringtransmitstheeffectstothenextgeneraWon
*LAertsandFAVanAssche.JPerinatMed.2002;30(4):281-6.
RoundupandGMOCrops
GMORoundup-Readycorn,soy,canola,sugarbeetsco)on,tobaccoandalfalfa
Whatisglyphosate?
3/26/18
6
Glyphosatevs.OtherPes5cides:UsageintheUnitedStates*
*h)p://sustainablepulse.com/wp-content/uploads/GMO-health.pdf
Glyphosate
*Figure15,Seneffetal.,AgriculturalSciences,2015,6,42-70
Au5smPrevalence:6yearolds*
3/26/18
7
TheyKnewaLongTimeAgo*• ArWclepublishedin1960• Fedcholesteroltomonkeys– inducedatherosclerosis
• Ifsulfur-containingnutrientsareadded,atherosclerosisisprevented
• Thesenutrientsprovidesourceofsulfatetoenablecholesteroltransport
*G.V.Mannetal.,Am.J.Clin.Nutr.8,491-497,1960.
3/26/18
8
TheyKnewaLongTimeAgo*• ArWclepublishedin1960• Fedcholesteroltomonkeys– inducedatherosclerosis
• Ifsulfur-containingnutrientsareadded,atherosclerosisisprevented
• Thesenutrientsprovidesourceofsulfatetoenablecholesteroltransport
*G.V.Mannetal.,Am.J.Clin.Nutr.8,491-497,1960.
"AformofvasculardiseaseresemblinghumanatherosclerosishasbeenproducedintheNewWorldprimateCebusfatuella....Inordertoproducethesephenomena,thedietshadtoberichincholesterol,cholineandneutralfatbutrelaWvelylowinorganicsulfurcompounds.WithoutthisdeprivaWonoforganicsulfurtheresponseoftheserumlipidstocholesterolfeedingwassmall."
HeartDiseaseMortalityandSunlight*
*Grimesetal.,Q.J.Med.1996;89:579-589
3/26/18
9
• Cholesterolsulfatesuppliesoxygen,sulfur,cholesterol,energyandnegaWvechargetoalltheWssues– AlsoprotectsskinfromUVdamageandkeepsmicrobesout
• SulfateissynthesizedfromsulfideintheskinandbloodstreamuWlizingenergyinsunlight
• EndothelialNitricOxideSynthase(eNOS)performsthemagic
Theskinisasolarpoweredba)ery!
AProvoca5veProposal*
*SSeneffetal.,Entropy2012,14,2492-2530.
• Cholesterolsulfatesuppliesoxygen,sulfur,cholesterol,energyandnegaWvechargetoalltheWssues– AlsoprotectsskinfromUVdamageandkeepsmicrobesout
• SulfateissynthesizedfromsulfideintheskinandbloodstreamuWlizingenergyinsunlight
• EndothelialNitricOxideSynthase(eNOS)performsthemagic
Theskinisasolarpoweredba)ery!
AProvoca5veProposal*
*SSeneffetal.,Entropy2012,14,2492-2530.
MelaninconvertsUVlighttovisiblelight,andtheflavinsineNOSrespondtobluelightby
emiungelectrons
3/26/18
10
• Cholesterolsulfatesuppliesoxygen,sulfur,cholesterol,energyandnegaWvechargetoalltheWssues– AlsoprotectsskinfromUVdamageandkeepsmicrobesout
• SulfateissynthesizedfromsulfideintheskinandbloodstreamuWlizingenergyinsunlight
• EndothelialNitricOxideSynthase(eNOS)performsthemagic
Theskinisasolarpoweredba)ery!
AProvoca5veProposal*
*SSeneffetal.,Entropy2012,14,2492-2530.
Theseelectronsproducesuperoxidefromoxygenthatcombineswith
sulfurtoformsulfate
CholesterolandCholesterolSulfate
SULFATE
SulfaWonmakescholesterolwater-solubleandthereforemucheasiertotransport
3/26/18
11
Cholesterolsulfateprovidesnega5vecharge*
--
-
--
-
-
--
-
---
-
--
--
-
--
-
-
--
-
-
--
--
--
-
-
-
-- -
-
-- -
--
--
--
-
---
-
-
-
-
Redbloodcellsexportcholesterolsulfatetothecapillarywall,supplyingitwithcholesterol,sulfate,andnegaWvecharge
*DavidsonandSeneff,Entropy14,1399-1442,2012.
Rouleaux–InsufficientNega5veCharge*
*Dr.MarcialVega;h)ps://www.youtube.com/watch?v=9vhHe55s9rg
3/26/18
12
ArteryCrossSec5on
ExpandedView
SulfateandtheGlycocalyx
SulfateisCrucialtoMaintainStructuredWaterintheGlycocalyx
3/26/18
13
LipidPar5clesinblooddependoncholesterolsulfateto
protectthemfromoxida5veandglyca5ondamage
CholesterolSulfateinPlacentalVilli• Placentalvilliarehighlyenrichedincholesterolsulfate,especiallyinthirdtrimesterofpregnancy
• Mother’sserumcholesterolsulfatesteadilyrisesthroughpregnancy
• Inthirdtrimester,villicontain24picomol/mgofcholesterolsulfate,comparedtoonly1.5inbloodserumofanon-pregnantwoman
Linetal.,JournalofChromatographyB,704(1997)99–104
3/26/18
14
SulfateinFetalDevelopment*• Fetusdependsonmotherforsulfatesupply• SulfateisessenWalfortransporWngsterols(likeestrogenandDHEA)andsupplyingextracellularmatrixproteinseverywherewithsufficientnegaWvecharge
• SulfatedetoxifiesxenobioWcslikeacetaminophen(Tylenol)andisessenWalforexcreWngtoxinslikealuminumandmercury
• SulfateisseverelydeficientinauWsWcchildren(1/3thenormalleveloffreesulfateinbloodstream)
*Dawson,“SulfateinFetalDevelopment,”SeminCellDevBiol2011
3/26/18
15
HeparanSulfate:WonderWorker
Polymersofsugarswitha)achednitrogenandsulfates:safeglucosestorage
SulfatedGlycosaminoglycans(GAGs)
• Prominentinglycocalyx:extracellularmatrixofcells
• Amountofsulfatedependsonavailability
• Regulatesignalingandnutrientuptake
Heparansulfate
3/26/18
16
'Bo\lebrush'moleculestructures-proteincentered,carbohydratebristlestermina5ngwithsulfate/water'ac5vityareas'
Mul5pleRolesofHeparanSulfateProteoglycans(HSPGs)*
*Figure3.FEPoulainandHJYost.Development2015;142:3456-3467.
3/26/18
17
HeparinProtectsfromROSduetoIron*FreeradicalproducWon(FentonreacWon):Fe(II)+02+20H--->Fe(III)(OH)2+02-
But,intheacidenvironmentofheparin:4Fe(II)+02+4H+-->4Fe(III)+2H20
superoxide
water
*M.A.Rossetal.,Biochem.J.1992,286:717-720.
HeparinProtectsfromROSduetoIron*FreeradicalproducWon(FentonreacWon):Fe(II)+02+20H--->Fe(III)(OH)2+02-
But,intheacidenvironmentofheparin:4Fe(II)+02+4H+-->4Fe(III)+2H20
superoxide
water
*M.A.Rossetal.,Biochem.J.1992,286:717-720.
Iron’sreacWonwithoxygenisamajorcontributortothearterydamagecausedbyinflammaWon
3/26/18
18
DisruptedSignalingwhenHSPGsareDepleted*
*Figure5inPMullerandAFSchier,DevelopmentalCell21,July19,2011,145-158.
HSPGs=HeparanSulfateProteoglycans
“Theuniversalnon-specificmesenchymalreac5on”*
• StudiedincorporaWonofsulfurintoGAGsinconnecWveWssuesurroundingarterywalls,inhumansandinrats
• ShowedthatagingleadstoareducWoninuptakeofsulfurANDslowerrecyclingofGAGs
• ShowedalsothatatherosclerosisisaspecialcondiWonwheremuchmoresulfuristakenupspecificallyattheregionswherecholesterolandfathaveaccumulated
*WHHaussetal.,AnnalsNYAcadSci156,207-218,1969.
3/26/18
19
Incorpora5onofsulfurintoGAGsinarterywall*
*Figure6,WHHaussetal.,AnnalsNYAcadSci156,207-218,1969.
AtheroscleroWcarteries
Age
Sulfu
rIncorpo
raWo
nHugeamountspostnatally
Incorpora5onofsulfurintoGAGsinarterywall*
*Figure6,WHHaussetal.,AnnalsNYAcadSci156,207-218,1969.
AtheroscleroWcarteries
Age
Sulfu
rIncorpo
raWo
n
Hugeamountspostnatally
IncreasedturnoverofsulfatedGAGs
inregionswithatherosclerosis
3/26/18
20
HeparanSulfateDeficiencyandAu5sm*
• Experimentwith“designer”mice:impairedheparansulfatesynthesisinbrain
• MiceexhibitedalltheclassicfeaturesofauWsm–bothcogniWveandsocial
*F.Irieetal.,AuWsm-likesocio-communicaWvedeficitsandstereotypiesinmicelackingheparansulfate.PNASMar.27,2012,109(13),5052-5056.
Recapitula5on• Cholesterolsulfateissuppliedtothevasculaturebyred
bloodcellsandendothelialcellsinresponsetosunlight– eNOSperformsthemagic
• Sulfateplaysanimportantroleinthevasculaturetoinduceflowandprotectfromdamageduetoiron
• Theglycocalyxisacomplexstructurecontainingabundantheparansulfate,whichregulatescellularsignalingandprotectsthecellmembranefromdamage
• HeparansulfateistakenupbycellsalongwithnutrientsanditsupportsacidificaWonofthelysosometodigestnutrientsandclearcellulardebris
• HeparansulfatedeficiencyisassociatedwithauWsminamousemodel
3/26/18
21
BileAcids:ABriefTutorial• Bileacidsaresynthesizedintheliverfromcholesterol,andcirculatebetweentheliverandthedigesWvetract,withabout5%beinglosttothefeceswitheachcycle– BileacidsynthesisdependsoncytochromeP450enzymes
• Bileacidsareconjugatedwitheithertaurineorglycineando{ensulfatedbeforebeingsecreted
• Conjugatedbilesaltssitatthelipid/waterinterfaceand,attherightconcentraWon,formmicellesandsolubilizelipids
• Bileacid-containingmicellesaidlipasestodigestlipidsandbringthemneartheintesWnalbrushbordermembrane,promoWngfatabsorpWon.
3/26/18
22
Acartoondepic5onofbilecircula5on
Bacteriastripofftaurine/glycineandconvertprimarytosecondarybileacids
Bileacidsareconjugatedtoeithertaurineorglycineandthensulfatedbeforebeingshippedoutbytheliver
Modifica5onsofBileAcids
Eitherglycineortaurine
Sulfateiso{enaddedhere
Secondarybileacids
3/26/18
23
Taurolithocholicacid3-sulfate
Taurine
Sulfate
AHypothesis:Liverdeliverstaurineandglycinetobacteriatosynthesize
methionineandsulfateforthehost
Taurine
GlycineGlycinecleavagesystem
Methylfolate
Folate
Sulfite
Serine
MethionineAssimilatory
sulfitereductase
SulfateSulfiteoxidase
Methionineistheuniversalmethyldonor
3/26/18
24
Bifidobacteriamodifybileacidstoincreasegellingpoten5al*
• BifidobacteriaarethemostsignificantmicrobesinthegutfordeconjugaWngtaurineandglycinefrombileacids
• ReleaseofdeconjugatedbileacidsbyBifidobacteriacausestheaqueousmediumtogel
“IfsuchaphenomenonoccursinphysiologicalcondiWonsofhumangut,itmayimprovebacterialabilitytocolonizethegastrointesWnaltractandtheirsurvivalinthisspecificecologicalniche.”
*PJarockietal.PLOSONEDecember3,2014;9(12):e114379.
3/26/18
25
MainToxicEffectsofGlyphosate*• Killsbeneficialgutbacteriaandallowspathogenstoovergrow– BifidobacteriaareespeciallysuscepWble
• InterfereswithfuncWonofcytochromeP450(CYP)enzymes
• Chelatesimportantminerals(iron,cobalt,zinc,manganese,etc.)
• InterfereswithsynthesisofaromaWcaminoacidsandmethionine– LeadstoshortagesincriWcalneurotransmi)ersandfolate
• Disruptssulfatesynthesisandsulfatetransport
*SamselandSeneff,Entropy2013,15,1416-1463
*PlotprovidedbyDr.MarWnMichener
Clostridia Salmonella
PathogenOvergrowthinPoultryMicrobesExposedtoGlyphosate*
Bifidobacteria
3/26/18
26
Glyphosatecontamina5oninbileacids*
• Monsanto’sownearlystudiesfoundglyphosatecontaminaWoninbileacids
• Likelymechanismisitsroleasaglycineanalogue:– Glyphosateconjugatestothebileacidsinplaceofglycine
• ThiswouldbeespeciallydamagingtoBifidobacteria,becausetheydeconjugatethebileacids,thusimporWngandfreeingglyphosate
*AnthonySamsel,personalcommunicaWon
• ompF,involvedintaurinetransport,wasthemostreducedenzymeintheenWretable
• Enzymesinvolvedinbothtaurinetransport/metabolismandassimilatorysulfiteincorporaWonintomethionineweresuppressed
*AppendixinWLuetal.MolBioSyst20139:522-530.
GlyphosateimpairstaurinemetabolismbyEcoli*
3/26/18
27
Inhibi5onofCytochromeP450Enzymes(CYPs)byVariousPes5cides*
Studyinratson2,4-D,clofibrate,MCPA,andglyphosate
*EHetanenetal.,ActaPharmacol.EtToxicol.1983,53,103-112.
Bifidobacteria,acetate,NaClandSO4-2
inau5sm• AuWsWcchildrenhavelowBifidobacteria(p=0.002)*• AuWsWcchildrenarehyponatremic(lowsodium)**– Recurringdiarrhea(glyphosateinducesleakygut)***– DepleWonoftaurine(taurine-conjugatedbileacidslosttofeces)
• AuWsWcchildrenhavelowgutacetate(p=0.00002)*– Lossofacetate-producingmicrobesthatfeedonbileacids
• AuWsWcchildrenhavesulfatedeficiency****
*JBAdamsetal.BMCGastroenterology2011;11:22.**PGood.MedicalHypotheses2011;77:1015-1021.***JJGildeaetal.JournalofClinicalNutriWon&DieteWcs2017;3:1.1).****RHWaringandLVKlovrza.JNutrEnvironMed2000;10:25-32.
3/26/18
28
ABTBRMouseModelofAu5sm*Thesemicehadallthemousefeaturesofau5smTheywerefed“standardrodentchow”–glyphosatecontaminated?Somefeaturesinthegut:• Reducedlevelsofbileacids(duetoimpairedCYP7A1acWvityin
theliver)• Furtherreducedlevelsofsecondarybileacids(impaired
metabolismbygutmicrobes)• ReducedlevelsofLactobacillusandBifidobacteria– ThesemicrobesarepreferenWallykilledbyglyphosate
• Serotonindeficiency– Serotoninisderivedfromtryptophan,aproductoftheshikimatepathwaywhichglyphosatedisrupts
*AVGlubevaetal.EBioMedicine.2017Oct;24:166-178.
ABTBRMouseModelofAu5sm*Thesemicehadallthemousefeaturesofau5smTheywerefed“standardrodentchow”–glyphosatecontaminated?Somefeaturesinthegut:• Reducedlevelsofbileacids(duetoimpairedCYP7A1acWvityin
theliver)• Furtherreducedlevelsofsecondarybileacids(impaired
metabolismbygutmicrobes)• ReducedlevelsofLactobacillusandBifidobacteria– ThesemicrobesarepreferenWallykilledbyglyphosate
• Serotonindeficiency– Serotoninisderivedfromtryptophan,aproductoftheshikimatepathwaywhichglyphosatedisrupts
*AVGlubevaetal.EBioMedicine.2017Oct;24:166-178.
TheseBTBRmicealsohadheparansulfatedeficiencyinthebrainventriclesandamissingcorpuscallosum
3/26/18
29
HormonesEnhanceSulfateLevels*• Sulfateisthefourthmostcommonanioninthebody
• Serumsulfateiselevatedininfants,youngchildrenandpregnantwomen.
• Estrogen,progesterone,growthhormoneandinsulin-likegrowthfactorallenhancetheexpressionofthesodium-sulfatecotransporter,increasingserumsulfatelevels.
*HJLeeetal.ProcSocExpBiolMed.2000;225(1):49-57.
HormonesEnhanceSulfateLevels*• Sulfateisthefourthmostcommonanioninthebody
• Serumsulfateiselevatedininfants,youngchildrenandpregnantwomen.
• Estrogen,progesterone,growthhormoneandinsulin-likegrowthfactorallenhancetheexpressionofthesodium-sulfatecotransporter,increasingserumsulfatelevels.
*HJLeeetal.ProcSocExpBiolMed.2000;225(1):49-57.
Aromatase,anenzymethatconvertstestosteronetoestrogen,isaCYPenzyme
thatisinhibitedbyglyphosate.
ThiscouldparWallyexplaintheincreasedrisktoauWsminboys.
3/26/18
30
SulfateDeficientMice*Micemissingthesodiumsulfatecotransportergene(NaSi-/-mice)survivedinuterobutexhibitedseveralmetabolicproblems:• Severelyreducedserumsulfatelevels(75%reducWon)• Significantlyreducedli)ersizeandmiscarriages• Aseizuredisorder• Stuntedgrowth• Increasedliversize• 1.5to2-foldincreasedphenolsulfotransferaseacWvity
*PADawsonetal.PNAS2003;100(23):13704-13709.
SulfateDeficientMice*Micemissingthesodiumsulfatecotransportergene(NaSi-/-mice)survivedinuterobutexhibitedseveralmetabolicproblems:• Severelyreducedserumsulfatelevels(75%reducWon)• Significantlyreducedli)ersizeandmiscarriages• Aseizuredisorder• Stuntedgrowth• Increasedliversize• 1.5to2-foldincreasedphenolsulfotransferaseacWvity
*PADawsonetal.PNAS2003;100(23):13704-13709.
Toxicphenol-sulfatemetabolitesareimplicatedinauWsm**
3/26/18
31
eNOSisVeryVulnerable*
*S.Seneffetal.,Entropy2012,14,2492-2530
• eNOSdependson:– Cobalamin(vitaminB12,cobalt)– Hemeiron,sulfur,zinc,oxygen– Glutathione– Sunlight/melanin– Tryptophan:sourceofNAD
• eNOSisacytochromeP450enzyme:– Highlyvulnerabletovariousenvironmentaltoxicantslikemercury,aluminum,glyphosate,etc.
*S.Seneffetal.,Entropy2012,14,2492-2530.
eNOSisVeryVulnerable*
3/26/18
32
• eNOSdependson:– Cobalamin(vitaminB12,cobalt)– Hemeiron,sulfur,zinc,oxygen– Glutathione– Sunlight/melanin– Tryptophan:sourceofNAD
• eNOSisacytochromeP450enzyme:– Highlyvulnerabletovariousenvironmentaltoxicantslikemercury,aluminum,glyphosate,etc.
*S.Seneffetal.,Entropy2012,14,2492-2530.
GlyphosatedisruptseNOSfuncWoninmulWpleways
eNOSisVeryVulnerable*
GlyphosatedisruptseNOS!• Glyphosatechelatescobalt,zincandiron,makingthemunavailable
• Glyphosateinterfereswiththesynthesisofpyrrole,theprecursortoheme(ineNOS)
• Glyphosatedepletesglutathionebyinterferingwithmethioninesynthesisbygutmicrobes
• Glyphosatedepletesmelaninintheskin(productofshikimatepathway)– ImpairedconversionofUVlighttovisiblelight
• Glyphosatedisruptstryptophansynthesis,depleWngNAD• eNOShastwohighlyconservedglycineresidues– EssenWalfora)achingtothemembraneandformingadimer
3/26/18
33
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
0
20
40
60
80
100
120
140
160
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Hospital Discharge Diagnoses of Hyperlipidemia (ICD 272.0-4)& Glyphosate applied to corn & soy crops
R = 0.9662, p<1.797e-5Sources: CDC; USDA
hyperlipidemia per 10,000
Total glyphosate / total acreage (lb/acre; corn & soy)
Year
Nu
mbe
r o
f d
isch
arg
e d
iag
no
se
s o
f h
ype
rlip
ide
mia
pe
r 1
00
00
Tota
l g
lyph
osa
te a
pplica
tio
ns/ T
ota
l a
cre
ag
e (
lbs/a
cre
)
HighSerumLipidsisCorrelatedwithGlyphosateUsageonCornandSoyCrops
CollaboraWonwithDr.ChenLiandDr.NancySwanson
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
0
20
40
60
80
100
120
140
160
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Hospital Discharge Diagnoses of Hyperlipidemia (ICD 272.0-4)& Glyphosate applied to corn & soy crops
R = 0.9662, p<1.797e-5Sources: CDC; USDA
hyperlipidemia per 10,000
Total glyphosate / total acreage (lb/acre; corn & soy)
Year
Nu
mbe
r o
f d
isch
arg
e d
iag
no
se
s o
f h
ype
rlip
ide
mia
pe
r 1
00
00
Tota
l g
lyph
osa
te a
pplica
tio
ns/ T
ota
l a
cre
ag
e (
lbs/a
cre
)
HighSerumLipidsisCorrelatedwithGlyphosateUsageonCornandSoyCrops
CollaboraWonwithDr.ChenLiandDr.NancySwanson
GlyphosatedisruptsbileacidsynthesisandforceslivertodistributecholesterolasLDLparWclesinstead
3/26/18
34
ElevatedHomocysteineandHeartDisease*
• 587paWentswithcoronaryarterydiseasefollowedovermedianperiodof4.6years
• Homocysteine>15μmol/Literà6.5-foldincreaseindeathratecomparedto
homocysteine<10μmol/Liter
*P.O.Limetal.,JournalofHumanHypertension(2002)16,411–415.
Sulfur
3/26/18
35
Hypothesis:Homocysteinebecomeselevatedwhensulfatesuppliesaredepletedbecauseit
canbeasourceofnewsulfate
PathwayfromHomocysteinetoSulfate*
homocysteinethiolactone
VitaminA
thioreWnamide
VitaminC
alphaketobutyrate Sulfite
oxidase
reWnoicacid
sulfate
sulfite
*McCully,AnnalsofClinicalandLaboratoryScience41:4,300-313,2011
WhenfolateandB12aredeficient,nearlyallhomocysteineisconvertedtohomocysteinethiolactone
Superoxide:ReacWveoxygenspecies
(ROS)
PAPS
3/26/18
36
PathwayfromHomocysteinetoSulfate*
GAGs=glycosaminoglycans!
*McCully,AnnalsofClinicalandLaboratoryScience41:4,300-313,2011
GAG-sulfate
*Seneffetal.,JournalofBiologicalPhysicsandChemistry17;2017:53-76
*
Paperexplainshowthecomplexsignalingcascadethattakesplaceinthegoutytoejointisacarefullyorchestratedplantosynthesizecholesterolsulfateandsupplyittoinvadingimmunecells.
3/26/18
37
*Seneffetal.,JournalofBiologicalPhysicsandChemistry17;2017:53-76
HeparanSulfateDeficiencyinAu5smHumans:“HeparansulfatedeficiencyinauWsWcpostmortembrainWssuefromthesubventricularzoneofthelateralventricles”*Mice:“Hippocampus/amygdalaalteraWons,lossofheparansulfates,fractonesandventriclewallreducWoninadultBTBRT+�/Jmice,animalmodelforauWsm”**
*BLPearsonetal.BehavBrainRes.2013;243:138–145**FMercieretal.NeurosciLe)2012;506(2):208-13.
3/26/18
38
Chroniclow-gradeencephalopathy(braininflammaWon)characterizesauWsm.
Signalingcascadeinthebrainleadstotaurinereleaseandhypothesizedsynthesisofsulfate
fromtaurinebymicrobes
VariousFactorsthatIncreaseSulfate*Anincreaseofthe35S-sulfatedepositiseffectedregularlybyinfecWons,byinjecWonsoftoxinsandproteins,byhypoxemia,dieteWcinfluence,muscularover-exerWon,weatherinfluenceandincreaseofthebloodpressure.
SMPS=Sulfatedmucopolysaccharides=glycosaminoglycans
*ReportbyBernhardMuschlien
*FirstpublishedintheGermanlanguageintheSANUM-Postmagazine(17/1991)
SMPS=Sulfatedmucopolysaccharides(GAGs)
3/26/18
39
Chlamydiapneumoniae
• Causepneumoniawhentheyinfectthelungs
• Showupfrequentlyincardiovascularplaque
• ShowupfrequentlyinAlzheimer’splaque
Whataretheydoingthere???
ChlamydiaProduceHeparanSulfate!*
• Chlamydiaareviableonlyinsidehostcells
• Theysetuphousekeepinginvacuoleswithinthecell(e.g.,amacrophageintheplaque)
• Theyproduceaglucosamine-containingsulphatedpolysaccharidethatisnearlyindisWnguishablefromheparansulfate
• Theyhaveauniquesetofenzymesforthis*S.J.Rasmussen-Lathropetal,CellMicrobiol.2000Apr,2(2),137-44.
3/26/18
40
ChlamydiaProduceHeparanSulfate!*
• Chlamydiaareviableonlyinsidehostcells
• Theysetuphousekeepinginvacuoleswithinthecell(e.g.,amacrophageintheplaque)
• Theyproduceaglucosamine-containingsulphatedpolysaccharidethatisnearlyindisWnguishablefromheparansulfate
• Theyhaveauniquesetofenzymesforthis*S.J.Rasmussen-Lathropetal,CellMicrobiol.2000Apr,2(2),137-44.
AretheyassisWngthehostbyboosWngheparansulfatelevelsinthearterywall?
SulfiteMetabolism:SulfurSensi5vity
Sulfite
Sulfiteoxidase
DissimilatorySulfitereductase
AssimilatorySulfitereductase
Methionine HydrogenSulfide
Sulfate
InhibitedinEcolibyglyphosate
Desulfovibrioovergrowth
Dependsonmolybdenumandhemeandahighlyconserved
glycineresidue
VeryToxic!
Sulfite
HydrogenSulfide
3/26/18
41
SulfiteMetabolism:SulfurSensi5vity
Sulfite
Sulfiteoxidase
DissimilatorySulfitereductase
AssimilatorySulfitereductase
Methionine HydrogenSulfide
Sulfate
InhibitedinEcolibyglyphosate
Desulfovibrioovergrowth
Dependsonmolybdenumandhemeandahighlyconserved
glycineresidue
VeryToxic!
Sulfite
HydrogenSulfide
DesulfovibrioovergrowthislinkedtoauWsm.
Desulfovibrioconvertmercurytoaverytoxicorganicmethylmercurymetabolite.
ColonCancer*• Clostridia(overgrowthwithglyphosateexposure)leadstoinflammaWoninthegut
• AssimilatorysulfitereducWonisdisturbedbyglyphosate,allowingovergrowthofsulfur-reducingbacteriaandexcessiveproducWonofhydrogensulfide
• ThisincreasesrisktocoliWsand,overWme,leadstocoloncancer,anepidemicinAmerica
*JMRidlonetal.GutMicrobes2016;7(3):201-215.
3/26/18
42
• Suppressescarcinogenesisinskin,stomach,colon,breastandliver
• Inducesapoptosisinawidevarietyoftumorcells
• Downregulatesvariousproinflammatorycytokines
*SKVaridetal,CancerEpidemiolBiomarkersPrev2008;17:1411-1417.
ThereisalowincidenceofcolorectalcancerinIndiawherecurcuminisheavilyusedincurries
CurcuminHasManyBenefits*
3/26/18
43
*SKVaridetal,CancerEpidemiolBiomarkersPrev2008;17:1411-1417.
CurcuminHasManyBenefits*
Anintractablemyelomawassentintoremissionwithcurcumintherapy(8g/day)and
hyperbaricoxygen
*ZaidiA,etal.BMJCaseRepApril162017.doi:10.1136/bcr-2016-218148
• Lossofbodyfatandadipose-associatedmacrophages
• Reducedinflammatory-relatedatherogenesis
• AnWdiabeWceffect– LowerHemoglobinA1c
• LowertotalcholesterolandLDL-C• HigherHDL-C.
*SCuengsamarnaetal.,journalofNutriWonalBiochemistry25(2014)144–150.
CurcuminHasManyBenefits*
3/26/18
44
ThreeFormsofCurcumin*
*Figure1inSKVaridetal,CancerEpidemiolBiomarkersPrev2008;17:1411-1417.
CurcuminGoesAroundandAroundDeliveringSulfatetoLiver!
curcumin
3/26/18
45
CurcuminPreventsDiabetes*
CONCLUSIONS:“A9-monthcurcuminintervenWoninaprediabeWcpopulaWonsignificantlyloweredthenumberofprediabeWcindividualswhoeventuallydevelopedtype2diabetes.InaddiWon,thecurcumintreatmentappearedtoimproveoverallfuncWonof[pancreaWc]beta-cells,withveryminoradverseeffects.”
*SChuengsamarnetal.,DiabetesCar35,2012,2121-2127
Glucosinolates!
• Naturalcomponentsofmanypungentplantssuchasmustard,cabbageandhorseradish
• Contributetoplantdefenseagainstpestsanddiseases
3/26/18
46
BroccoliSprouts*
*arWcles.mercola.com/sites/arWcles/archive/2014/06/30/broccoli-sprout-detox.aspx
• Sproutscontain30xnutrientsoforganicvegetables
• Growyourownandeatthemraw!
glucoraphaninControlledstudyinChina:• Benzeneandacroleindetoxedintourine• Thesearechemicalsindirtyairfromcar
exhaustandburningfuels
Querce5n:ASulfateTransporter*
SulfateGlucuronate
Neteffect:gutdeliverssulfatetotheliver
*IRRowland,ToxicolPathol198816:147-153.
3/26/18
47
Cholinesulfate!!*• Producedbyplants,lichens,algae,fungi,andseveralbacterialspecies
• ExperimentdemonstratedthatithadsuperiorcapabiliWestoinhibitamyloidformaWoninpancreaWcbetacells– AmyloidinbetacellsisakintoamyloidbetainAlzheimer‘sdiseaseandplaysamajorroleintype-IIdiabetes
*M.Hagiharaetal.,FEBSOpenBio2(2012)20–25.
3/26/18
48
MostImportant:GoOrganic!
HowMuchDoesitCost?
Food Organic Conven5onalcelery 2.99 1.99cauliflower 4.99 2.99Bartle)pears 2.69 1.99orangejuice 3.99 2.99eggs 5.69 3.99milk 4.69 2.99cereal 4.56 3.91
TOTAL 29.60 20.85
increasebillby~40%
3/26/18
49
Probio5cs!–MaintainHealthyGut
• Sauerkrautandapplecidervinegarcontainacetobacter,oneoftheveryfewmicrobesthatcanmetabolizeglyphosate
• Yogurtandkimchiprobablydotoo
3/26/18
50
AreWeGepngEnoughSulfurinOurDiet?*
• Mostabundantmineralelementbehindcalciumandphosphorus
• ChondroiWnsulfate,glucosaminesulfate,etc.usedtotreatdiseasesofthejoints
“OutofthisstudycameinformaWonthatsuggestedthatasignificantproporWonofthepopulaWonthatincludeddisproporWonallytheaged,maynotbereceivingsufficientsulfurandthatthesedietarysupplements,wereverylikelyexhibiWngtheirpharmacologicalacWonsbysupplyinginorganicsulfur.”
*MENimnietal.,NutriVon&Metabolism2007,4:24
EatFoodsContainingSulfur
3/26/18
51
Somesulfur-containingsupplements
• BioWn• Taurine• N-acetylCysteine• Glutathione• S-adenosylMethionine• AlphaLipoicAcid• DMSO(dimethylsulfoxide)• MSM(methylsulfonylmethane)• DMPS(chelaWngagent)• EpsomSalts
FlavonoidsandPolyphenols!
3/26/18
52
Escapetoasunnyplaceinwinter!
IfyouLiveinCanada,UseaSunlamp!
3/26/18
53
EpsomSalts!MagnesiumSulfateinhotbathwaterisacheapandeasywaytogetsulfatesupplytotheskin
Infraredheatalsobeneficial!
Trea5ngGlyphosatePoisoninginAnimals(e.g.,cows)*
BentoniteClayFulvicAcid
*HGerlachetal.,JEnvironAnalToxicol2014,5:2
AcWvatedCharcoal
SauerkrautJuice
AcWvatedcharcoal,bentoniteclay,humicandfulvicacids,andsauerkrautjuicehavebeenshowntobeeffecWveinreducingurinarylevelsofglyphosateandimprovinganimalhealth
3/26/18
54
Summary• CholesterolsulfateisanessenWalmoleculeinthebodyto
maintainvascularhealth– Producedintheskinuponsunlightexposure
• HeparansulfateplaysmulWplerolesinthebodyanditsdeficiencyislinkedtoauWsm
• BileacidsplayanessenWalroleinsupplyingtaurinetothebody,andtaurineisanessenWalstorageformofsulfate– TaurinedeficiencymaybeakeyfactorinauWsm
• GlyphosateisapervasivetoxicantthatiscausingamajorhealthcrisisintheUS– MuchofitstoxicityrelatestodisrupWonofgutmicrobes
• Anorganicwholefoodsdietrichinsulfur,cholesterolandpolyphenolshasmanyhealthbenefits
• ItisessenWaltogetabundantsunlightexposuretotheskinwithoutsunscreen