examining 2 herbs for antiviral activity & immune activity spelman - exa… · • cure •...
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Examining 2 Herbs for Antiviral Activity & Immune Activity
KevinSpelman,PhD
Health,Education&Research
Ashland,OR.97520
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Disclaimer
ThereisnoevidencethatanyherborproductmentionedinthispresentationiseffectiveagainstCovid-19
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• DoNOTmakepublicstatementsinrelationtoCOVID-19thatusethewords:
• Prevent/Prevention• Treat/Treatment
• Cure• ProvideImmunityto/fromCOVID-19/coronavirus
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Anti-Virals
Actionisbasedonarresting
theviralreplicationcycleatvariousstages.
Le T, Bhushan V. First Aid for the USMLE Step 1 2015. McGraw-Hill Education; 2014: p. 192.
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Le T, Bhushan V. First Aid for the USMLE Step 1 2015. McGraw-Hill Education; 2014: p. 192.
Modes of Activity for Anti-Viral Agents ___________________________________________________________________
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Does Diet Make a Difference in Immune Function?
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Health-protective edible plant foods have demonstrated capacity to both combat disease and optimize metabolism and performance through diverse
mechanisms of action.
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TheobesegrouphadaPIvalue10.3%lowerthanthatofthenormalweightgroup
(P<0.05).PIvalueswereprogressivelylowerfrom28.6,21.6,18.8and9.5foreach
BMIquartileincrease,respectively(P=0.007).ThePIscorewasalsopositively
correlatedwiththe…oxidativestresswasinverselyrelatedtothePI.
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Innate lymphoid cells could be controlled by leafy greens in your diet.
Proteins in green leafy (cruciferous) vegetables result in the production of IL-22, which can protect the body from invading bacteria and possibly food allergies, inflammatory diseases and obesity and bowel cancers.
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Golden Seal (Hydrastis canadensis)
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Hydrastis canadensis, Traditional Use
• MajormedicinefortheCherokee,bothasabittertonicandasaneyewashforinflamedeyes
• Iroquoisuseincludedwhoopingcough,diarrhea,pneumoniaandtuberculosis
• Widelyusedfortumorsandalsoasadermatologicaidetopicallyforulcersandskindisorders
• Commonremedyforstagnantgastrointestinalfunctioncharacterizedbya“sour”stomach
PengellyA,BennettK,SpelmanK,TimmsM.AnAppalachianPlantMonograph.Goldenseal.HydrastiscanadensisL.AppalachianCenterforEthnobotanicalStudies.2011
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Hydrastis canadensis, Traditional Use
• Appalachiansusedasastrengtheningtonic,stomachic
• Appliedtopicallyforsoreeyesandgeneralulcerationsusedtotreatarrowwounds
• Powderedpreparationiscombinedwithwaterandgargledasasorethroatremedy.
PengellyA,BennettK,SpelmanK,TimmsM.AnAppalachianPlantMonograph.Goldenseal.HydrastiscanadensisL.AppalachianCenterforEthnobotanicalStudies.2011
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Hydrastis canadensis, Immune
Reputationforpreventing“pitting”scarsfromsmallpoxwhenappliedtopicallyinawarmbath
PengellyA,BennettK,SpelmanK,TimmsM.AnAppalachianPlantMonograph.Goldenseal.HydrastiscanadensisL.AppalachianCenterforEthnobotanicalStudies.2011
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Hydrastis canadensis, Immune
StudiesonanimalsexposedtotheKLHantigenindicateaugmentedimmunoglobulin(IgM)responseforthefirsttwoweeksofa6weektreatment
period
Rehmanetal.,Increasedproductionofantigen-specificimmunoglobulinsGandMfollowinginvivotreatmentwiththemedicinalplantsEchinaceaangustifoliaandHydrastiscanadensis.ImmunolLett1999;68(2-3):391-5.
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Hydrastis canadensis
Chemistry
PengellyA,BennettK,SpelmanK,TimmsM.AnAppalachianPlantMonograph.Goldenseal.HydrastiscanadensisL.AppalachianCenterforEthnobotanicalStudies.2011
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HPTLC of Hydrastis canadensis
PengellyA,BennettK,SpelmanK,TimmsM.AnAppalachianPlantMonograph.Goldenseal.HydrastiscanadensisL.AppalachianCenterforEthnobotanicalStudies.2011
HydrastiscanadensishydroethanolicextractsSTDs
Berberine
Palmitine
Hydrastine
Canadine
Berberine
Hydrastinine
Hydrastine
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Alkaloids in Hydrastis
(Upton, 2001; Hwang, Roberts, Chadwick, Wu, & Kinghorn, 2003)
MAJORALKALOIDS MINORALKALOIDS
Berberine Hydrastinine
(—)-(β)-hydrastine Canadaline
(—)-canadine Isohydrastidine
1-β-hydrastine
5-hydroxytetrahydroberberine
(S)-corypalmine
(S)-isocorypalmine
(S)-tetrahydropalmatine
Berberastine
8-oxotetrahydrothalifendine
Canadinicacid
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Berberine & Gut
Improvescolitisbyinhibitingthegrowthofgram-negativeintestinalbacteria,suchasEscherichiacoli,KlebsiellapneumoniaeandProteus
mirabilis.
Besidesrepressingorkillingharmfulgutbacteria,berberinehassomepositiveeffectonbeneficialgutmicrobiota,suchasBifidobacterium
adolescentisandLactobacillusacidophilus.
CernákováM,KostálováD.FoliaMicrobiol(Praha).2002;47(4):375–8.Antimicrobialactivityofberberine–aconstituentofMahoniaaquifolium.
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Berberine, Gut
Berberinemaymodulatethegutmicrobiotathroughenrichingshort-chainfattyacid(SCFA)-producingbacteriaandreducingmicrobial
diversity• immuneregulatoryeffects• anti-inflammatoryeffects• inhibitsdietarypolysaccharidedegradation• decreasescaloricintakeinthegut• improveenergymetabolismandintestinalhealth• IncreasedproductionofSCFAs
MaslowskiK,etal.RegulationofinflammatoryresponsesbygutmicrobiotaandchemoattractantreceptorGPR43.Nature.2009;461(7268):1282–6.SuzukiT,etal.Physiologicalconcentrationsofshort-chainfattyacidsimmediatelysuppresscolonicepithelialpermeability.BrJNutr.2008;100(2):297–305.TilgH,KaserA.Gutmicrobiome,obesity,andmetabolicdysfunction.JClinInvest.2011;121:2126–32.WangY,etal.Berberine-inducedbioactivemetabolitesofthegutmicrobiotaimproveenergymetabolism.Metabolism.2017;70:72–84.
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Berberine, MOAs
InhibitsviralDNAsynthesisinHSV
ChinLW,etal.Anti-herpessimplexviruseffectsofberberinefromCoptidisrhizoma,amajorcomponentofaChineseherbalmedicine,Ching-Wei-San.ArchVirol2010;155:1933-1941
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Berberine
• Inhibitoryeffectsagainst:• respiratorysyncytialviru• influenzavirus,enterovirus71• herpessimplexvirus• Coronavirus• cytomegalovirus
HayashiK,etal.Antiviralactivityofberberineandrelatedcompoundsagainsthumancytomegalovirus.BioorganicMedChemLett2007;17:1562–1564.
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Berberine has Broad Spectrum Effects
• Targets:downregulationof• cellularc-JunN-terminalproteinkinase(JNK)• NF-kappaBactivation
• Targets:Suppressionof• mitogen-activatedproteinkinase(MAPK)• MAPK/ERKkinase1(MEK)/extracellularsignal-regulatedkinase(ERK)signaling
• EV71-inducedautophagybyactivatingtheAKTproteinandinhibitingthephosphorylationofJNKandphosphatidylinositol-4,5-bisphosphate3-kinaseIII(PI3KIII)
HayashiK,etal.Antiviralactivityofberberineandrelatedcompoundsagainsthumancytomegalovirus.BioorganicMedChemLett2007;17:1562–1564.
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OurexperimentsshowedstronginhibitionofthegrowthofH1N1influenzaAstrains(PR/8/34orWS/33)inmacrophagesandhumanlungepithelial-cells.
Inhibitionoftheproductionofinflammatorymediators(TNF-αandPGE2)athighconcentrationswasalsoobserved.
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EffectsofberberineonthegrowthofinfluenzaAinmacrophages
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EffectsofberberineonthegrowthofinfluenzaAinhumanlungcells
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Hydrastis canadensis Pharmacokinetics&Dosage
Reference
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Berberine
Zuo,F.,etal.,Pharmacokineticsofberberineanditsmainmetabolitesinconventionalandpseudogerm-freeratsdeterminedbyliquidchromatography/iontrapmassspectrometry.DrugMetabDispos,2006.34(12):p.2064-72.
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Berberine
• Pharmacokinetics:• Human:Asingleoraldoseof300mgberberine,itsconcentration-timecurvefittedone-compartmentopenmodel.
• T1/2absorption0.87±0.03h• T1/2elimination2.94±0.14h• T(peak)2.37±0.04h• C(max)394.7±155.4mug/L• AUC2799.0±1128.5mug/L·h.
Li,B.,M.Zhang,andL.Bao,Studyonthepharmacokineticsofberberineafteroraladministrationinhumanbeing.Ha'erbinyikedaxuexuebao=JournalofHarbinMedicalUniversity=Harbinyikedaxuexuebao,1995.29(5):p.
382-385.
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Hydrastis Drug-Herb Interaction
Consideringourhistoryasaspeciesthedrugsareinteractingwithplants,nottheotherwayaround
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Hydrastis canadensis, Drug-Herb Interaction
• HumanTrial:NostatisticallysignificanteffectsondigoxinPKwereobservedfollowingsupplementationwithgoldenseal(3210mg/dx14d)
• ThissuggestthatgoldensealisnotapotentmodulatorsofP-gpinvivo
• HumanTrial:NosignificantalterationsinthePKofindinavir(po2280mg/dayofgoldensealrootextractx2wk
Gurley,B.J.,Swain,A.,Barone,G.W.,Williams,D.K.,Breen,P.,Yates,C.R.,...Cheboyina,S.Effectofgoldenseal(Hydrastiscanadensis)andkavakava(Pipermethysticum)supplementationondigoxinpharmacokineticsinhumans.
DrugMetabDispos,2007;35(2),240-245.Sandhu,R.S.,Prescilla,R.P.,Simonelli,T.M.,&Edwards,D.J.Influenceofgoldensealrootonthepharmacokinetics
ofindinavir.JClinPharmacol2003;43(11),1283-1288.
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Berberine Caution
ClinicalObservation:Highdosesofberberinecontainingplantsorberberinemaycausecardiacdysrhythmia
And…berberinehasbeenshowntobeusefulforatrialfibrillation
ZhengH,etal.AntimicrobialNaturalProductBerberineisEfficaciousfortheTtreatmentofAtrialFibrillation.BiomedResInt.2017;2017:3146791.
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Turmeric (Curcuma longa)
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Curcuma longa Chemistry
Reference
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Curcuma longa, Traditional Use
Ahouseholdremedy;cough,fever,jaundice,liverdisorders,urinarydiseases
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HPTLC, Turmeric & Curcuminoids
HPTLC
STDs-----TurmericExtracts-----
STDs
Curcumin
Tetrahydrocurcumin
Bisdemethoxycurcumin
Demethoxycurcumin
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Curcuma longa ImmuneActivity
Reference
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Curcumin
• Immunetargets:• Indendriticcells:decreasematuration;decreaseCD80,CD86;decreaseIL-12,MAPK,NFkB;increaseSTAT3
• Inmurinemacrophage:decreaseIL-6,TNF-a,PTGS-2,P38MAPK;increasesSOCS1,SOCS3
• InBV2microgliacells:decreaseNFkB,iNOS,IL-6,TNF-a,IL-1B,COX-2,HO-1,MAPK,NO,PGE-2
• invivo:increasesserumIgM,IgG,concanavalinA;decreasesTNF-a,IL-1B,NO,MPO
• activatesperoxisomeproliferator-activatedreceptor-γ,deactivatestype1response,inhibitsinduciblenitricoxidesynthase
Catanzaro,M.,etal.,ImmunomodulatorsInspiredbyNature:AReviewonCurcuminandEchinacea.Molecules,2018.23(11).Adapala,N.andM.M.Chan,Long-termuseofanantiinflammatory,curcumin,suppressedtype1immunityandexacerbatedvisceralleishmaniasisina
chronicexperimentalmodel.LabInvest,2008.88(12):p.1329-39.
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Curcumin vs Tetrahydrocurcumin
Aggarwaletal.CurcuminDiffersfromTetrahydrocurcuminforMolecularTargets,SignalingPathwaysandCellularResponses.Molecules2015;20:185-205
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Curcumin, Antiviral MOAs
• InhibitsHCVentryindependentofthegenotypeandinprimaryhumanhepatocytesbyaffectingmembranefluidity,therebyimpairingvirusbindingandfusion(Anggakusumaetal,2014)
• Down-regulatesEGFR,thismayblockHCVentry(Lupbergeretal,2011)
Anggakusuma,etal.TurmericcurcumininhibitsentryofallhepatitisCvirusgenotypesintohumanlivercells.Gut2014;63:1137–1149.LupbergerJ,etal.EGFRandEphA2arehostfactorsforhepatitisCvirusentryandpossibletargetsforantiviraltherapy.NatMed2011;17:589–595.
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Holder AJ, Dept. of Chemistry, U Missouri-Kansas City, Kansas City, MO 64110
The Bilipid Membrane
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Curcumin, Antiviral MOAs
CurcumininhibitstypeAinfluenzavirusinfectionbyinterferingwithviralhemagglutinationactivity
(Chenetal,2010;Chenetal,2013;Ouetal,2013)
Chen,DY,etal.Curcumininhibitsinfluenzavirusinfectionandhaemagglutinationactivity.FoodChem2010:119:1346–1351.ChenT.Y,etal.InhibitionofEnvelopedVirusesInfectivitybyCurcumin.PLoSOne2013;8:e62482.Ou,JL,etal.Structure-activityrelationshipanalysisofcurcuminanaloguesonanti-influenzavirusactivity.FEBSJ2013;280:5829–5840.
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Curcumin, Antiviral MOAs
Viraltranscriptionsuppressorviadown-regulationofthecoactivatorPGC-1a(Recthmanetal.,2010)
HCVreplicationinhibitorviasuppressingAkt-SREBP-1pathway(Kimetal.,2010)
RechtmanMM,etal.CurcumininhibitshepatitisBvirusviadown-regulationofthemetaboliccoactivatorPGC-1alpha.FEBS
Lett2010;584:2485-2490.Kim,K,etal.CurcumininhibitshepatitisCvirusreplicationviasuppressingtheAkt-SREBP-1pathway.FEBSLett2010;584:707-712.
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Curcumin, Immune MOAs
JagetiaGC,etal.“SpicingUp”oftheImmuneSystembyCurcumin.JClinImmunol2007;27(1):19-35
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Curcuminoids PharmacokineticsandDose
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Bioavailability Enhancement
• Strategiestoincreasecurcuminabsorptionincludecoadministrationofthenaturallyoccurringvolatileoilsfromturmericroot
AsherG,SpelmanK.Clinicalutilityofcurcuminextract.AlternTherHealthMed2013Mar-Apr;19(2):20-2.
Turmerone
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Turmeric Essential Oil
ImprovesGingolideAabsorptionby62.7%
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Curcumin, PK
Anandetal.,2007.Bioavailabilityofcurcumin:problemsandpromises.MolPharm2007;4(6):807-18.
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Curcumin, Dose
Mostconstituentsareusuallyatactivelevelsinserumbetween0.75-6hours
Curcuminpharmacokinetics—rapidglucoronidationbyliver
Shorthalf-life,multipledosesneededperday(T-QID)
Anandetal.,2007.Bioavailabilityofcurcumin:problemsandpromises.MolPharm2007;4(6):807-18.
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Curcumin, Drug-Herb Interactions
• HumanTrial:Nosignificantchangeswereobservedinmidazolam,fluriprofen,orparacetamolplasmaCmax,AUC,clearance,eliminationhalf-life,ormetabolitelevelsofthedrugsafter4gcurcuminoidsQIDx2d
• Animalmodel:Oraladministrationofcurcuminproducenosignificanteffectonthepharmacodynamicsofwarfarinandclopidogrel(25,50and100mg/kgfor7days).
• Pretreatmentwith100mg/kgincreasedboththeAUCandCmaxofthetwodrugs
Volak,L.P.,Hanley,M.J.,Masse,G.,Hazarika,S.,Harmatz,J.S.,Badmaev,V.,...Court,M.H.(2013).Effectofaherbalextractcontainingcurcuminandpiperineonmidazolam,flurbiprofenandparacetamol(acetaminophen)pharmacokineticsinhealthyvolunteers.BrJClinPharmacol,75(2),450-462.LiuAC,etal.CurcuminaltersthepharmacokineticsofwarfarinandclopidogrelinWistarratsbuthasnoeffectonanticoagulationorantiplatelet
aggregation.PlantaMed2013;79(11):971-977.doi:10.1055/s-0032-1328652
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Considering Curcuma longa Essential Oils
Turmericenhancesit’sownbioavailability
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InbioavailabilitystudiesturmericessentialoilImprovesGinkgolideAabsorptionby62.7%
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Acknowledgements
BetsyCostilo,MS,RH(AHG)–ResearchAssistant
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Thank you for your time
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