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Is psoriasis a bowel disease? HainesElyM.D.

ClinicalProfessorofDermatologyUCDavis

Rxderm-L An Interna8onal Dermatology on line discussion group •  Tojoinwritetome:

• hainesely@hotmail.com

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Is psoriasis a bowel disease?

•  Ifyou’dliketoleaveearly:Theanswerisyes• PsoriasisisasystemicdiseasecausedbytheabsorpJonofbacterialpepJdoglycansandendotoxin(LPS)fromthegut(beginningatthemouth,tonsils)Thereisincreasedgutpermeability.• DysbiosisandovergrowthofanJgenicbacteria(streppyogenes)• BileacidabnormaliJesinliverandbile• AbnormalliverfuncJon,faSyliver,fibrosis,micronodularcirrhosis• Metabolicsyndromeistheresult,psoriasisisacatharJcevent

Pathogenesis of Psoriasis, Ely, 1981

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Treatment

• Alterbowelfloratowardnormal:ProbioJcs,S.boulardii,anJbioJcsAzithromycin,clindamycinhavehadsuccess• Breakupendotoxininbowelwithbileacids•  InhibitabsorpJonofendotoxin/pepJdoglycanswithbioflavonoids(myriceJn,querceJn,curcumin,orangejuice)NoETOHorpepper•  Inhibitphosphorylkinasewithcurcumin,myriceJn,querceJn• Healliverwithsilymarin(alsophosphodiesteraseinhibitorlikeapremilast)

Today’s concept of psoriasis

• AnimmunologicabnormalityrelatedtooverproducJonofinflammatorycytokinesbyTcells• GeneJcpredisposiJon•  ExacerbatedbybacterialsuperanJgens• NomenJonoftheprimaryanJgenwhichiniJatesTcellresponse

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Targe8ng key psoriasis pathways

Current therapy targets only the end result not the cause of psoria8c inflamma8on

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Psoriasis is a systemic disease with many comorbidi8es

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How can we relate the comorbidi8es of psoriasis to the bowel?

AmJClinNutr.Apr2010;91(4):940–949.PublishedonlineMar3,2010

Orangejuiceneutralizestheproinflammatoryeffectofahigh-fat,high-carbohydratemealandpreventsendotoxinincreaseandToll-likereceptorexpression1,2,3HusamGhanim,ChangLingSia,MannishUpadhyay,KellyKorzeniewski,PrabhakarViswanathan,SanaaAbuaysheh,PriyaMohanty,andPareshDandonacorrespondingauthor

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Background:Theintakeofglucoseorahigh-fat,high-carbohydrate(HFHC)meal,butnotorangejuice,inducesanincreaseininflammaJonandoxidaJvestressincirculaJngmononuclearcells(MNCs)ofnormal-weightsubjects.Objec0ve:WeinvesJgatedtheeffectoforangejuiceonHFHCmeal–inducedinflammaJonandoxidaJvestressandtheexpressionofplasmaendotoxinandToll-likereceptors(TLRs).Design:Threegroups(10subjectsineachgroup)ofnormal,healthysubjectswereaskedtodrinkwateror300kcalglucoseororangejuiceincombinaJonwitha900-kcalHFHCmeal.Bloodsampleswereobtainedbeforeand1,3,and5hakerthedrinksandmealcombinaJonswereconsumed.

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Conclusions:ThecombinaJonofglucoseorwaterandtheHFHCmealinducedoxidaJveandinflammatorystressandanincreaseinTLRexpressionandplasmaendotoxinconcentraJons.Incontrast,orangejuiceintakewiththeHFHCmealpreventedmeal-inducedoxidaJveandinflammatorystress,includingtheincreaseinendotoxinandTLRexpression.TheseobservaJonsmayhelpexplainthemechanismsunderlyingpostprandialoxidaJvestressandinflammaJon,pathogenesisofinsulinresistance,andatherosclerosis.

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“Herewereportthat,inmice,relaJvelylowconcentraJonsoftwocommonlyusedemulsifiersnamelycarboxymethylcelluloseandpolysorbate-80,inducedlow-gradeinflammaJonandobesity/metabolicsyndromeinwild-typehostsandproducedrobustcoliJsinmicepredisposedtothisdisorder.”

Chronic systemic inflamma8on and metabolic syndrome are caused by systemic absorp8on of endotoxin from the gut. Atherosclerosis is also caused by deposi8on of bacterial pep8doglycans in the arterial walls. References at the end of presenta8on

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The pep8doglycan of all bacteria is essen8ally the same. Responsible for cell wall rigidity

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Fat ladies in my prac8ce 1975

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Skin tes8ng with bacterial an8gens

Klebsiella and e.coli

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Strep pyogenes and proteus vulgaris

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The Bowel Bypass Syndrome:

• PepJdoglycananJbodiespresentinalmostallpaJents• PsoriaJcpaJentsusedascontrols•  20%ofpsoriaJcshadhighJtersofpepJdoglycananJbodiesEly,PH,Thebowelbypasssyndrome:aresponsetobacterialpepJdoglycansJAAD1980:2:473-487

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IS PG an Endotoxin?

Similari8es between acute psoriasis and endotoxemia •  Fever•  Leukocytosis•  Increasedcapillarypermeability•  ElevatedliverfuncJonenzymes• Decreasedcomplementlevels• AbnormaliJesoflipidmetabolism• Riseoflysosomalenzymes

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Sources of Endotoxin: Teeth Quantification of endotoxins in necrotic root canals from symptomatic and asymptomatic teeth Samples were collected from root canals of 50 patients requiring endodontic treatment due to necrosis of the pulpal tissue. Endotoxin was present in all the samples studied [range 2390.0 to 22100.0 endotoxin units (EU) ml. The mean concentration of endotoxin in samples from patients with spontaneous pain was 18540.0 EU ml while in asymptomatic cases it was 12030.0 EU ml

Source of pep8doglycans: Infected tonsils

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Psoria8cs have increased gut permeability

PsoriaJcpaJentshavemeasuredcirculaJngendotoxinlevelswhichhavebeendemonstratedinnumerousstudiesTheyhaveabnormal51CR-labeledEDTAabsorpJontestresults(excreJngmore51CR-labeledEDTAthancontrols)67-80%ofpsoriaJcshavecirculaJngIGAimmunecomplexes

Cutaneous polyamines in psoriasis

• OrnithinedecarboxylaseacJvityisincreasedinpsoriaJcskin

•  Thisenzymebreaksdownputrecine,spermidine,andspermineTheseenzymesareelevatedinpsoriaJcskinandcauseepidermalproliferaJon.UrinarylevelsfallaspsoriaJcplaquesresolveTheycomefrombacteriaintheintesJnallumen

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Recent data confirms the presence of gut derived bacterial DNA in psoria8c blood

OnlineFirstResearchLeSer|March11,2015Iden0fica0onofBacterialDNAinthePeripheralBloodofPa0entsWithAc0vePsoriasisAnaRamírez-Boscá,MD1,2;VicenteNavarro-López,MD2,3;AsunciónMartnez-Andrés,MD1,2;JoséSuch,MD4,5,6;RubénFrancés,PhD4,5;JoséHorgadelaParte,MD7;ManuelAsín-Llorca,MD1JAMADermatol.PublishedonlineMarch11,2015.

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Fiky-fourpaJentswithpsoriasisand27controlswereincludedinthestudy.ThebaselinecharacterisJcsoftheseparJcipantsareshowninTable1.BloodbactDNAwaspresentin16paJentswithpsoriasis,allofwhomshowedthephenotypeofplaquepsoriasis(16of45[35.5%]),whereas6paJentswithguSatepsoriasis,3withinversepsoriasis,andall27controlsdidnothavebactDNAintheblood.SpeciesidenJficaJoncorrespondedtoEscherichiacoli(n=9),Klebsiellapneumoniae(n=2),Enterococcusfaecalis(n=2),Proteusmirabilis(n=1),Streptococuspyogenes(n=1),andShigellafresneli(n=1).

AhigherproporJonoffindingsofbactDNAinthebloodwasobservedinpaJentswithplaquepsoriasiscomparedwithpaJentswithotherpsoriasisphenotypes(35.5%vs0%;P<.05).ThepaJent’sageatdiagnosisofpsoriasisandyearssincethefirstepisodeofpsoriasisshowedstaJsJcallysignificantdifferencesinpaJentswithandwithoutbactDNAintheblood.ThesystemicinflammatoryresponsewassignificantlyhigherinpaJentswithbactDNAcomparedwithotherpaJentsandcontrols

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NucleoJdesequencingrevealedthatEcoliwasthemostprevalentsourceofbactDNA(9of16isolates).Therestofthebacterialspecies’originofthedetectedgenomicfragmentsalsocorrespondedtothetypeoffloracommonlyfoundintheintesJnallumen.Therefore,thebactDNAdetectedinourpaJentswithpsoriasismayhavetheiroriginintheintesJnallumen.

Kidney Interna&onal 2001(59):1580-89 Historical concept of “catharsis” through skin

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Psoria8cs have abnormal liver func8on and abnormal bile composi8on

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Peslyak, M: Model of pathogenesis of psoriasis, online www.psoriasis.info.com •  213psoriaJcsexamined• Diseaseofliverandbileductsdiagnosedin88• Bileof67psoriaJcsfromduodenalintubaJonanalyzed•  1stgroup(28persons)includedpsoriaJcswithhepatobiliarysystemdisorders•  2ndgroup(39persons)psoriaJcswithoutsuchdisorder• Bothgroups(comparedto15controls)hadsignificantreducJonofbileacidlevelsinbile

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Peslyak, M: Model of pathogenesis of psoriasis, online www.psoriasis.info.com •  50psoriaJcsexamined• HighBAlevels(10-20Jmeshigherthanstandard)correlatedwithdiseaseseverityandstability•  FreesecondaryDC-BAlevelsindicatedisorderedenterohepaJccirculaJonbecausemainsiteofformaJonismicrofloraofsmallintesJne

Peslyak, M: Model of pathogenesis of psoriasis, online www.psoriasis.info.com •  IncreaseofprimaryC-BA,synthesizedbyhepaJccells,isasignofconjugaJondisorderand/ordisorderofpatencyofbileducts•  Studiesofbilelithogenicityshowedlevelsofbileacidsandphospholipidsinbileweresignificantlydecreasedandlithogenicindexeswere2-4JmesincreasedinpsoriaJcs.

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The psoria8c intes8nal microbiome: Dysbiosis

The gut is the largest lymphoid organ in the body.

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ScherJU,UbedaC,ArtachoA,ASurM,IsaacS,ReddySM,etal.DecreasedbacterialdiversitycharacterizesthealteredgutmicrobiotainpaJentswithpsoriaJcarthriJs,resemblingdysbiosisininflammatoryboweldisease.ArthriJsRheumatol.2015;67(1):128–39.Epub2014/10/17.

ThegutmicrobiotaofpaJentswithpsoriasiswascharacterizedbyareducedrelaJveabundanceofthegeneraParabacteroidesandCoprobacillusComparisonbetweenthePsAandpsoriasisgroupsrevealedthatthehighertaxonomiclevelsofAkkermansiaandRuminococcus(includingFirmicutes/ClostridialesandVerrucomicrobiales,respecJvely)weresignificantlylessabundantinPsApaJentswhereastheBacteroidetesphylumandCoprobacillusgenuswerelessabundantinpsoriasispaJents.

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Conclusion

PaJentswithPsAandpaJentswithskinpsoriasishadalowerrelaJveabundanceofmulJpleintesJnalbacteria.AlthoughsomegenerawereconcomitantlydecreasedinbothcondiJons,PsAsampleshadalowerabundanceofreportedlybeneficialtaxa.ThisgutmicrobiotaprofileinPsAwassimilartothatpreviouslydescribedinpaJentswithinflammatoryboweldiseaseandwasassociatedwithchangesinspecificinflammatoryproteinsuniquetothisgroup,anddisJnctfromthatinpaJentswithskinpsoriasisandhealthycontrols.Thus,theroleofthegutmicrobiomeintheconJnuumofpsoriasis–PsApathogenesisandtheassociatedimmuneresponsemeritsfurtherstudy.

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2009-2012. Peslyak MY, Model of pathogenesis of psoriasis. Part 1

•  75%ofpsoriaJcswithmoderatediseaseand97%withseverediseasehad“maximumdisturbancesofcolonicmicroflora”andthechangesincreasedwithduraJonofdisease

2009-2012. Peslyak MY, Model of pathogenesis of psoriasis. Part 1 (Colon bacteria found in small intes8ne)

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2009-2012. Peslyak MY, Model of pathogenesis of psoriasis. Part 1 Blastocystosis present in 79% of psoria8cs

Blastocystosis (Blastocys8s hominis) •  Afewofmostcommonlyreportedsymptomsare:•  abdominalpain[15]•  itching,usuallyanalitching[15]•  consJpaJon[15]•  diarrhea[15]•  wateryorloosestools[15]•  weightloss[15]•  faJgue•  flatulence[15]•  Somelesscommonlyreportedsymptomsinclude:•  SkinRash[16][17][18][19][20][21]•  Headache,[9][17]depression[9]•  ArthriJcsymptomsandjointpain[22][23]•  IntesJnalinflammaJon[24

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Treatment

• Alterbowelfloratowardnormal:ProbioJcs,S.boulardii,anJbioJcsSulfasalazine,Azithromycin,clindamycinhavehadsuccess• Breakupendotoxininbowelwithbileacids•  InhibitabsorpJonofendotoxin/pepJdoglycanswithbioflavonoids(myriceJn,querceJn,curcumin,orangejuice)NoETOHorpepper•  Inhibitphosphorylkinasewithcurcumin,myriceJn,querceJn• Healliverwithsilymarin(alsophosphodiesteraseinhibitorlikeapremilast)

Treatment of BLE + psoria8cs

• MiconazoleandquinacrinehavebeenreportedaseffecJveagentsagainstBlastocysJsgrowthin-vitro.[79][86]Rifaximin,[87]andalbendazolehaveshownpromiseashasivermecJnwhichdemonstratedhigheffecJvenessagainstblastocysJshominisisolatesinaninvitrostudy.[88]ThereisalsoevidencethattheprobioJcyeastSaccharomycesboulardii,[82]andtheplantmallotusopposiJfolius[89]maybeeffecJveagainstBlastocysJsinfecJons

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Treatment

• Alterbowelfloratowardnormal:ProbioJcs,S.boulardii,anJbioJcsSulfasalazine,Azithromycin,clindamycinhavehadsuccess• Breakupendotoxininbowelwithbileacids•  InhibitabsorpJonofendotoxin/pepJdoglycanswithbioflavonoids(myriceJn,querceJn,curcumin,orangejuice)NoETOHorpepper•  Inhibitphosphorylkinasewithcurcumin,myriceJn,querceJn• Healliverwithsilymarin(alsophosphodiesteraseinhibitorlikeapremilast)

SulfasalazineImprovesPsoriasisADouble-blindAnalysisAdityaK.Gupta,MD,FRCPC;CharlesN.Ellis,MD;MichaelT.Siegel,MD;ElizabethA.Duell,PhD;ChristopherE.M.Griffiths,BSc,MB,MRCP;TedA.Hamilton,MS;BrianJ.Nickoloff,MD,PhD;JohnJ.Voorhees,MDArchDermatol.1990;126(4):487-493.

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Inan8-weekdouble-blindtrialofsulfasalazineforthetreatmentofmoderate-to-severepsoriasis,23and27paJentsreceivedtheacJveandplacebotablets,respecJvely.Attheendofthedouble-blindphase,therewere17assessablepaJentsreceivingsulfasalazine;7(41%)hadmarkedimprovement,7(41%)hadmoderateimprovement,and3(18%)demonstratedminimalchange.Only1paJentreceivingplacebodemonstratedmoderateimprovement,whereastheresthadminimalimprovementorworseningofpsoriasis.WhentherandomizaJoncodewasbroken,paJentsreceivingsulfasalazinewereallowedtoconJnuetherapyforanaddiJonal4weeksinanopenmanner,whilethoseusingplacebolekthestudy.Sixof23paJentsdisconJnuedsulfasalazinetherapyduringthedouble-blindphasebecauseofsideeffects,4duetothedevelopmentofacutaneouserupJonand2duetonausea.Fourteenof17paJents,whowereassessableattheendofthe8-weekdouble-blindphase,completedtheaddiJonal4weeksofsulfasalazinetherapy.Ofthese14paJents,markedimprovementoccurredin8(57%),moderateimprovementin2(14%),andminimalimprovementin4(29%),comparedwithpretherapy.ThelowincidenceofseveresideeffectsmakessulfasalazineaconsideraJonfororaltherapyinpaJentswhosediseaseseveritydoesnotjusJfyuseofmethotrexate,etreJnate,orpsoralenplusUV-A,butwhosediseaseseverityistoowidespreadforsafeandpracJcaluseoftopicalcorJcosteroids.(ArchDermatol.1990;126:487-493)

Sulfasalazine

• AzoreducJvecleavagebycolonbacteriaresultsinformaJonof5-aminosalicylicacidandsulfapyridine• InhibitsnuclearfactorKappaB• (NF-kB)isatranscripJonfactorthatgovernstheexpressionofgenesencodinginflammatorycytokines

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SSZ inhibits TNF-a binding

•  Immunopharmacology.1990Nov-Dec;20(3):217-24.•  SulfasalazineinhibitsthebindingofTNFalphatoitsreceptor.ShanahanF,NiederlehnerA,CarramanzanaN,AntonP.

Treatment

• Alterbowelfloratowardnormal:ProbioJcs,S.boulardii,anJbioJcsSulfasalazine,Azithromycin,Clindamycinhavehadsuccess• Breakupendotoxininbowelwithbileacids•  InhibitabsorpJonofendotoxin/pepJdoglycanswithbioflavonoids(myriceJn,querceJn,curcumin,orangejuice)NoETOHorpepper•  Inhibitphosphorylkinasewithcurcumin,myriceJn,querceJn• Healliverwithsilymarin(alsophosphodiesteraseinhibitorlikeapremilast)

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Annals Immunologiae Hungaricae XVII

Bile Detoxifica8on of LPS

• Commonbileductofratscannulated• BiledeprivedratsdiewhengivenLPSorally• RadiolabeledLPSisfoundintheirblood•  IntesJnalabsorpJonofLPSinbiledeprivedratscanbepreventedbysodiumdeoxycholate

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Pathophysiology, 2003;10(1):57-61

• Bileacidssplitentericendotoxinsintonontoxicfragments.Bileacidsarealsobactericidal•  800psoriasisptsinstudy,500Rxedwithdehydrocholicacid1-8weeks•  434pts(78.8%)becameasymptomaJc

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Pathophysiology 10 (2003) 57-61

Why no pepper?

• Bothpepperandalcoholwillruinad-xyloseabsorpJontest.•  Ifd-xyloseisgivenbymouththeamountfoundinurineindicatesintesJnalpermeability.VeryliSlegetsintourine.IfalcoholorpepperisgivenatthesameJmeahugeamountofd-xyloseendsupinurine.

• Amoremodernversionisthe(Cr51)EDTAexcreJontestpreviouslymenJoned

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Pathophysiology, 2003;10(1):57-61

• Of249ptswhoreceivedconvenJonaltherapyonly62(24.9%)showedclinicalrecoveryoverthesameJmeframe• BileacidRxofacutepsoriasis95.1%completerecovery•  Twoyearslater319of551ptsRxedwithbileacids(57.9%)wereasymptomaJc

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DehydrocholicacidHungarianpaper

DeoxycholicacidFromcholicacidingut

UrsodeoxycholicacidJapanesepaper

Bile Acid Rx of Psoriasis

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Before Bile Acid Rx

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Bile One Month Rx

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Arm Pre Bile

One month

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From Bill Danby M.D.

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Treatment

• Alterbowelfloratowardnormal:ProbioJcs,S.boulardii,anJbioJcsAzithromycin,clindamycinhavehadsuccess• Breakupendotoxininbowelwithbileacids•  InhibitabsorpJonofendotoxin/pepJdoglycanswithbioflavonoids(myriceJn,querceJn,curcumin,orangejuice)NoETOHorpepper•  Inhibitphosphorylkinasewithcurcumin,myriceJn,querceJn• Healliverwithsilymarin(alsophosphodiesteraseinhibitorlikeapremilast)

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JNutrBiochem.2011Jan;22(1):53-9.Epub2010Mar20.Emulsifiedlipidsincreaseendotoxemia:possibleroleinearlypostprandiallow-gradeinflamma0on.LaugereSeF1,VorsC,GéloënA,ChauvinMA,SoulageC,Lambert-PorcheronS,Pere|N,AlligierM,BurcelinR,LavilleM,VidalH,MichalskiMC.

AbstractLow-gradeinflammaJonisariskfactorfortheonsetofatherosclerosis.LiSleisknownabouttheinvolvementofendotoxinabsorpJonfromthegutduringthedigesJonoflipids.Inthepresentstudy,wefirstinvesJgatedinhumanstheimpactofamixedmealcontainingdispersedlipidsonpostprandialendotoxemiaandinflammaJon.WetheninvesJgatedtheeffectof(i)oilemulsificaJoninvivoinratsand(ii)faSyacidamountsinvitrousingCaco-2cellsonpostprandialendotoxemia.Inhumans,postprandialendotoxemiaincreasedearlyakerthemeal.Moreover,weevidencedthattheendotoxinreceptorsCD14increasedduringdigesJonandthatchylomicronscouldcontributetoabsorbedendotoxintransport.ThiscouldexplainthesignificantpeakofinflammatorycytokineIL-6thatweobserved2hakerthemixedmeal.InteresJngly,inrats,theemulsionledtobothhigherendotoxemiaandhypertriglyceridemiathanoilandcomparedtoacontrolsalineload.Invitro,incubaJonofCaco-2cellswithincreasingfaSyacidconcentraJonsenhancedepithelialabsorpJonofendotoxin.Toourknowledge,thisisthefirststudyevidencinginhealthyhumansthat,followingamixedmealcontaininglipids,increasedendotoxemiaisassociatedwithraisedsCD14andapeakofIL-6.Onarepeatedbasis,thismaythusbeatriggeringcascadefortheonsetofatherosclerosis.Inthisrespect,opJmizingbothdietaryfatamountandstructurecouldbeapossiblestrategytolimitsuchlow-gradeendotoxemiaandinflammaJonbythecontrolofpostprandiallipemia

PlantFoodsHumNutr.2013Mar;68(1):1-10..

An0-inflammatoryproper0esoforangejuice:possiblefavorablemolecularandmetaboliceffects.CoelhoRC1,HermsdorffHH,BressanJ.Authorinforma0on

AbstractThelow-gradeinflammaJonhasbeenrecognizedasthelinkbetweenadiposityandtheriskofchronicmetabolicdisorders.Thus,increasedconcentraJonsofinflammatorymarkers,suchasinterleukinsandtumornecrosisfactoralphahavebeenfoundinobeseindividuals.Inturn,dietcanposiJvelyornegaJvelyinfluenceontheriskofchronicmetabolicdiseasesbymodulaJngtheinflammatorystatus.Inthiscontext,orangejuiceconsumpJoncanplayaroleinmodulaJonofinflammatorymarkersthroughbioacJvecompounds,suchastheflavonoids(hesperidin,naringenin).Accordingtothisreview,orangejuiceappearstomediatetheinflammatoryresponseinplasmalevelandgeneexpression,andinpostprandialandchronic(≥7consecuJvedays)periods.ThecurrentfindingssuggestthatorangejuicecouldbeadietaryfeatureforprevenJonandtreatmentofchronicdiseases,

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Flavonoids

QUERCITIN

•  “Backbone”forotherflavonoidsie:• RuJn• Hesperidin• Naringin•  TangeriJn

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Querci8n

• PotentanJoxidant•  Inhibitsmanufactureandreleaseofhistamine• AnJinflammatory•  Inhibitscollagenase,preventscollagenbreakdown

Querci8n prevents Metabolic syndrome

• PfeufferM,AuingerA,BleyU,etal.,EffectofquerceJnontraitsofthemetabolicsyndrome,endothelialfuncJonandinflammaJoninmenwithdifferentAPOEisoforms.NutrMetabolCardiovascDis.2013;23(5):403-9

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Querci8n prevents metabolic syndrome

•  EgertS,Bosy-WestphalA,SeiberlJ.,etalQuerciJnreducessystemicbloodpressureandplasmaoxidizedlowdensitylipoproteinconcentraJonsinoverweightsubjectswithahigh-cardiovasculardiseaseriskphenotype:Adoubleblindedplacebo-controlledcross-overstudy.BrJNutr.2009;102(7):1065-74

Treatment

• Alterbowelfloratowardnormal:ProbioJcs,S.boulardii,anJbioJcsAzithromycin,clindamycinhavehadsuccess• Breakupendotoxininbowelwithbileacids•  InhibitabsorpJonofendotoxin/pepJdoglycanswithbioflavonoids(myriceJn,querceJn,curcumin,orangejuice)NoETOHorpepper•  Someofthesebioflavonoidsarealsophosphodiesteraseinhibitors•  Inhibitphosphorylkinasewithcurcumin,myriceJn,querceJn• Healliverwithsilymarin(alsophosphodiesteraseinhibitorlikeapremilast)

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InvestNewDrugs.2008Oct;26(5):417-24.doi:10.1007/s10637-008-9114-7.Epub2008Feb9.

Inhibitoryeffectsofquerce0nderiva0vesonphosphodiesteraseisozymesandhigh-affinity[(3)H]-roliprambindinginguineapig0ssues.

ChanAL1,HuangHL,ChienHC,ChenCM,LinCN,KoWC.

Authorinforma0on

Abstract

Rolipramhashigh(PDE4(H))andlow(PDE4(L))affiniJesforphosphodiesterase(PDE)-4,respecJvely.Ingeneral,itisbelievedthatinhibiJonsbyPDE4(H)andPDE4(L)arerespecJvelyassociatedwithanadverseresponseandwithanJ-inflammatoryandbronchodilaJngeffects.ThishasprovidedaraJonalbasisfordesigningnewcompoundswithhighPDE4(H)/PDE4(L)raJos.Inthepresentstudy,weaSemptedtodeterminethePDE4(H)/PDE4(L)raJosofquerceJn(1),TheacJviJesofPDE1approximately5,whichwereparJallyseparatedfromhomogenatesofguineapiglungsandhearts,weremeasuredbyatwo-stepprocedureusingadenosine3',5'-cyclicmonophosphate(cAMP)with[(3)H]-cAMPorguanosine3',5'-cyclicmonophosphate(cGMP)with[(3)H]-cGMPassubstrates..TheanJ-inflammatoryeffectsofPDE4inhibitorswerereportedtobeassociatedwithinhibiJonofPDE4catalyJcacJvity.Therefore,theseIC(50)valuesforPDE4inhibiJonweretakenasthePDE4(L)values.TheeffecJveconcentraJon(EC(50)),atwhichonehalfofthe[(3)H]-rolipramboundtohigh-affinityroliprambindingsites(HARBSs)ofbraincellmembraneswasreplaced,wasdefinedasthePDE4(H)value.Inthepresentresults,thePDE4(H)/PDE4(L)raJosofquerceJn(1),ayanin(3),andQPME(5)were>30,>19,and11,respecJvely(Table1),whicharehigherthanorequaltothatofAWD12-281,theselecJvePDE4inhibitorwiththegreatestpotenJalcurrentlyundergoingclinicaltrialsfortreaJngasthmaandchronicobstrucJvepulmonarydisease.

BiochemPharmacol.2004Nov15;68(10):2087-94.Inhibitoryeffectsofflavonoidsonphosphodiesteraseisozymesfromguineapigandtheirstructure-ac0vityrela0onships.KoWC1,ShihCM,LaiYH,ChenJH,HuangHL.Authorinforma0onAbstractThestructure-acJvityrelaJonshipsofflavonoidswithregardtotheirinhibitoryeffectsonphosphodiesterase(PDE)isozymesareliSleknown.TheacJviJesofPDE1-5weremeasuredbyatwo-stepprocedureusingcAMPwith[(3)H]-cAMPorcGMPwith[(3)H]-cGMPassubstrates.Inthepresentresults,PDE1,5,2,and4isozymeswereparJallypurifiedfromguineapiglungsinthatorder,andPDE3wasfromtheheart.TheIC(50)valuesofPDE1-5weregreaterthanthosereportedpreviouslyforthereferencedrugs,vinpoceJn,EHNA,milrinone,Ro20-1724,andzaprinast,by5-,5-,7-,5-,and3-fold,respecJvely.AsshowninTable2,luteolinrevealednon-selecJveinhibiJonofPDE1-5withIC(50)valuesinarangeof10-20microM,asdidgenisteinexceptwithalowpotencyonPDE5.Daidzein,aninacJveanalogueofgenisteinintyrosinekinaseinhibiJon,showedselecJveinhibiJonofPDE3withanIC(50)valueofaround30microM,asdideriodictyolwithanIC(50)valueofaround50microM.HespereJnandpruneJnexhibitedmore-selecJveinhibiJonofPDE4withIC(50)valuesofaround30and60microM,respecJvely.Luteolin-7-glucosideexhibiteddualinhibiJonofPDE2/PDE4withanIC(50)valueofaround40microM.DiosmeJnmore-selecJvelyinhibitedPDE2(IC(50)of4.8microM)thanPDE1,PDE4,orPDE5.However,biochaninAmore-selecJvelyinhibitedPDE4(IC(50)of8.5microM)thanPDE1orPDE2.ApigenininhibitedPDE1-3withIC(50)valuesofaround10-25microM.MyriceJninhibitedPDE1-4withIC(50)valuesofaround10-40microM.ThesamewastrueforquerceJn,butweratherconsiderthatitmore-selecJvelyinhibitedPDE3andPDE4(IC(50)of<10microM).Inconclusion,itispossibletosynthesizeusefuldrugsthroughelucidaJngthestructure-acJvityrelaJonshipsofflavonoidswithrespecttoinhibiJonofPDEisozymesatconcentraJonsusedinthisinvitrostudy.

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1054SpecialiaExperienJa34/8FlavonoidcompoundsarepotentinhibitorsofcyclicAMPphosphodiesteraseA.Beretz,R.AntonandJ.C.StocletFacult~dePharmacie,Universit~LouisPasteur,LaboratoiredePharmacognosie,andLaboratoiredePharmacodynamie(CNRS,ERA787)F-67083Strasbourg(France),29December1977Summary.TheinhibitoryacJvityof19flavonoidmoleculesoncyclicAMPbreakdownbyacommercial,~beefheartphosphodiesterasepreparaJonisreported.7compoundsareacJveinthemicromolarrange,2ofwhichhaveapotencyequivalenttothatofpapaverine.SomestructureacJvityrelaJonshipsaredrawn

Commercially available

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Treatment

• Alterbowelfloratowardnormal:ProbioJcs,S.boulardii,anJbioJcsAzithromycin,clindamycinhavehadsuccess• Breakupendotoxininbowelwithbileacids•  InhibitabsorpJonofendotoxin/pepJdoglycanswithbioflavonoids(myriceJn,querceJn,curcumin,orangejuice)NoETOHorpepper•  Inhibitphosphorylkinasewithcurcumin,myriceJn,querceJn• Healliverwithsilymarin(alsophosphodiesteraseinhibitorlikeapremilast)

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MethodsFindExpClinPharmacol.1985Aug;7(8):409-13.Silymarin:potentinhibitorofcyclicAMPphosphodiesterase.KochHP,BachnerJ,LöfflerE.AbstractSilymarin,theacJveprincipleoftheMilkThistle(SilybummarianumGaertner),isaverypotentinhibitorofcyclicAMPbreakdowninvitrobyacommercialbeefheartphosphodiesterasepreparaJon.ItsmainconsJtuents,silybin,silydianinandsilychrisJn,are12.66to52.06JmesmoreacJvethantheophyllineand0.77to3.17JmesmoreacJvethanpapaverineinthisrespect.UsinganovelHPLCtechnique,theenzymekineJcalanalysiscanbeperformedmuchfasterthanbytheclassicalmethods.

Silymarin is a potent phosphodiesterase inhibitor: 50 8mes more potent than theophyline

United States Patent: 5,196,448 March 23, 1993 (Antiinflammatory compositions and method of use: esters of silybin with dicarboxylic acids)

Ely, H., Therapies You’ve Probably Never Heard Of, Dermatologic Clinics, 1989: 7(1): 19-35.

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NFI but I have found this one to work the best in PCT compared to many brands

Hepatology 1997:26(3):643-49

SilymarinRetardsCollagenAccumulaJoninEarlyandAdvancedBiliaryFibrosisSecondarytoCompleteBileDuctObliteraJoninRatsGABRIELEBOIGK,1LUTZSTROEDTER,2HERMANNHERBST,3JU¨RGENWALDSCHMIDT,2ERNSTOTTORIECKEN,1ANDDETLEFSCHUPPAN1

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Trea8ng psoriasis star8ng in the gut

•  S.BoulardiionecapTIDforonemonthtostart•  Sulfasalazine500mgTID• Bileacids(Oxbile)onecapTIDastolerated• Bioflavinoids(myreciJn,querceJn,orangejuice)witheachmeal• Decreaseinflammatoryfoodssuchasgluten• Avoidspicyfoodsandalcohol• Helptheliverwithsilymarin140mgBID• CurcuminoralandtopicalrecommendedbyMadelineHengM.D.

Pathogenesis of Psoriasis 2016 no change!

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The following references were lem out of talk for sake of 8me

20% or more of Psoria8cs Have Circula8ng Bacterial Pep8doglycan An8bodies

•  Ely,P.H.,ImmunopathologyoftheBowelBypassSyndrome,inImmunodermatology,D.M.MacDonald,ed.,BuSerworthandCo.,London,1984.287-89.

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Intes8nal Permeability in Psoriasis

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Leners to editor: Arch Dermatol vol 118 March 1982, 143 Endotoxemia in Psoriasis • PatriciaW.Belew,PhD•  E.WilliamRosenberg,MD• RobertB.Skinner,Jr,MD• WayneM.Marley,MD• Memphis

Leners to editor: Arch Dermatol vol 118 March 1982, 143 Endotoxemia in Psoriasis EndotoxemiainPsoriasisTotheEditor:WehavebeenabletodetectcirculaJngendotoxininsixof11paJentswithpsoriasis.OurinterestinthepossibilityofendotoxemiainpsoriasisfollowedrecentdemonstraJonsofalteraJonsinlevelsofalternaJvecomplementpathwaycomponentsandofcirculaJngIgAimmunecomplexesinpsoriasis.EndotoxinandimmuneIgAcomplexeseachacJvatethealternaJvecomplementpathway.

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Circula8ng IGA Immune complexes in psoriasis •  InthenextthreearJcles67to80%ofpsoriaJcshadcirculaJngIGAimmunecomplexes•  IGAissecretedinthegut,shouldnotbehighintheserum

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Polyamines

• Putrescine• Cadaverine• Spermidine• Allcomefromthegut

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ScherJU,UbedaC,ArtachoA,ASurM,IsaacS,ReddySM,etal.DecreasedbacterialdiversitycharacterizesthealteredgutmicrobiotainpaJentswithpsoriaJcarthriJs,resemblingdysbiosisininflammatoryboweldisease.ArthriJsRheumatol.2015;67(1):128–39.Epub2014/10/17.

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2009-2012. Peslyak MY, Model of pathogenesis of psoriasis. Part 1

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Figure5.

CorrelaJonsbetweengutmicrobiotaandmetadata.TherelaJveabundanceofgutmicrobiotawasassessedforcorrelaJonswiththelevelsofvariousproteinsandfaSyacids(FAs)intheserumand/orfecalsamplesfrompaJentswithpsoriaJcarthriJs,paJentswithpsoriasis,andhealthycontrols.HeatmapsshowthecorrelaJonsbetweenpaJentmetadataandintesJnalmicrobiotaatthegenuslevel(A)oroperaJonaltaxonomicunit(OTU)level(B).CirclesizesandcolorintensityrepresentthemagnitudeofcorrelaJon.Bluecircles=posiJvecorrelaJons;redcircles=negaJvecorrelaJons.sIgA=secretoryIgA;OPG=osteoprotegerin;CFAs=short-andmedium-chainFAs.

DDeeccrreeaasseedd BBaacctteerriiaall DDiivveerrssiittyy CChhaarraacctteerriizzeess tthhee AAlltteerreedd GGuutt MMiiccrroobbiioottaa iinn PPaa88eennttss WWiitthh PPssoorriiaa88cc AArrtthhrrii88ss,, RReesseemmbblliinngg DDyyssbbiioossiiss iinn IInnflflaammmmaattoorryy BBoowweell DDiisseeaassee

Arthri0s&RheumatologyVolume67,Issue1,pages128-139,27DEC2014DOI:10.1002/art.38892hSp://onlinelibrary.wiley.com/doi/10.1002/art.38892/full#art38892-fig-0005

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DDeeccrreeaasseedd BBaacctteerriiaall DDiivveerrssiittyy CChhaarraacctteerriizzeess tthhee AAlltteerreedd GGuutt MMiiccrroobbiioottaa iinn PPaa88eennttss WWiitthh PPssoorriiaa88cc AArrtthhrrii88ss,, RReesseemmbblliinngg DDyyssbbiioossiiss iinn IInnflflaammmmaattoorryy BBoowweell DDiisseeaassee

Arthri0s&RheumatologyVolume67,Issue1,pages128-139,27DEC2014DOI:10.1002/art.38892hSp://onlinelibrary.wiley.com/doi/10.1002/art.38892/full#art38892-fig-0004

2009-2012. Peslyak MY, Model of pathogenesis of psoriasis. Part 1

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2009-2012. Peslyak MY, Model of pathogenesis of psoriasis. Part 1 (Colon bacteria found in small intes8ne)

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An8bio8c to change gut flora?

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