examining 2 herbs for antiviral activity & immune activity spelman - exa… · • cure •...

Examining 2 Herbs for Antiviral Activity & Immune Activity

KevinSpelman,PhD

Health,Education&Research

Ashland,OR.97520

Disclaimer

ThereisnoevidencethatanyherborproductmentionedinthispresentationiseffectiveagainstCovid-19

• DoNOTmakepublicstatementsinrelationtoCOVID-19thatusethewords:

• Prevent/Prevention•  Treat/Treatment

• Cure• ProvideImmunityto/fromCOVID-19/coronavirus

Anti-Virals

Actionisbasedonarresting

theviralreplicationcycleatvariousstages.

Le T, Bhushan V. First Aid for the USMLE Step 1 2015. McGraw-Hill Education; 2014: p. 192.

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 ___________________________________________________________________

Does Diet Make a Difference in Immune Function?

Health-protective edible plant foods have demonstrated capacity to both combat disease and optimize metabolism and performance through diverse

mechanisms of action.

TheobesegrouphadaPIvalue10.3%lowerthanthatofthenormalweightgroup

(P<0.05).PIvalueswereprogressivelylowerfrom28.6,21.6,18.8and9.5foreach

BMIquartileincrease,respectively(P=0.007).ThePIscorewasalsopositively

correlatedwiththe…oxidativestresswasinverselyrelatedtothePI.

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.

Golden Seal (Hydrastis canadensis)

Hydrastis canadensis, Traditional Use

• MajormedicinefortheCherokee,bothasabittertonicandasaneyewashforinflamedeyes

•  Iroquoisuseincludedwhoopingcough,diarrhea,pneumoniaandtuberculosis

• Widelyusedfortumorsandalsoasadermatologicaidetopicallyforulcersandskindisorders

•  Commonremedyforstagnantgastrointestinalfunctioncharacterizedbya“sour”stomach

PengellyA,BennettK,SpelmanK,TimmsM.AnAppalachianPlantMonograph.Goldenseal.HydrastiscanadensisL.AppalachianCenterforEthnobotanicalStudies.2011

Hydrastis canadensis, Traditional Use

• Appalachiansusedasastrengtheningtonic,stomachic

• Appliedtopicallyforsoreeyesandgeneralulcerationsusedtotreatarrowwounds

• Powderedpreparationiscombinedwithwaterandgargledasasorethroatremedy.


Hydrastis canadensis, Immune

Reputationforpreventing“pitting”scarsfromsmallpoxwhenappliedtopicallyinawarmbath


Hydrastis canadensis, Immune

StudiesonanimalsexposedtotheKLHantigenindicateaugmentedimmunoglobulin(IgM)responseforthefirsttwoweeksofa6weektreatment

period

Rehmanetal.,Increasedproductionofantigen-specificimmunoglobulinsGandMfollowinginvivotreatmentwiththemedicinalplantsEchinaceaangustifoliaandHydrastiscanadensis.ImmunolLett1999;68(2-3):391-5.

Hydrastis canadensis

Chemistry


HPTLC of Hydrastis canadensis


HydrastiscanadensishydroethanolicextractsSTDs

Berberine

Palmitine

Hydrastine

Canadine

Berberine

Hydrastinine

Hydrastine

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

Berberine & Gut

Improvescolitisbyinhibitingthegrowthofgram-negativeintestinalbacteria,suchasEscherichiacoli,KlebsiellapneumoniaeandProteus

mirabilis.

Besidesrepressingorkillingharmfulgutbacteria,berberinehassomepositiveeffectonbeneficialgutmicrobiota,suchasBifidobacterium

adolescentisandLactobacillusacidophilus.

CernákováM,KostálováD.FoliaMicrobiol(Praha).2002;47(4):375–8.Antimicrobialactivityofberberine–aconstituentofMahoniaaquifolium.

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.

Berberine, MOAs

InhibitsviralDNAsynthesisinHSV

ChinLW,etal.Anti-herpessimplexviruseffectsofberberinefromCoptidisrhizoma,amajorcomponentofaChineseherbalmedicine,Ching-Wei-San.ArchVirol2010;155:1933-1941

Berberine

•  Inhibitoryeffectsagainst:•  respiratorysyncytialviru•  influenzavirus,enterovirus71•  herpessimplexvirus•  Coronavirus•  cytomegalovirus

HayashiK,etal.Antiviralactivityofberberineandrelatedcompoundsagainsthumancytomegalovirus.BioorganicMedChemLett2007;17:1562–1564.

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.

OurexperimentsshowedstronginhibitionofthegrowthofH1N1influenzaAstrains(PR/8/34orWS/33)inmacrophagesandhumanlungepithelial-cells.

Inhibitionoftheproductionofinflammatorymediators(TNF-αandPGE2)athighconcentrationswasalsoobserved.

EffectsofberberineonthegrowthofinfluenzaAinmacrophages

EffectsofberberineonthegrowthofinfluenzaAinhumanlungcells

Hydrastis canadensis Pharmacokinetics&Dosage

Reference

Berberine

Zuo,F.,etal.,Pharmacokineticsofberberineanditsmainmetabolitesinconventionalandpseudogerm-freeratsdeterminedbyliquidchromatography/iontrapmassspectrometry.DrugMetabDispos,2006.34(12):p.2064-72.

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.

Hydrastis Drug-Herb Interaction

Consideringourhistoryasaspeciesthedrugsareinteractingwithplants,nottheotherwayaround

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.

Berberine Caution

ClinicalObservation:Highdosesofberberinecontainingplantsorberberinemaycausecardiacdysrhythmia

And…berberinehasbeenshowntobeusefulforatrialfibrillation

ZhengH,etal.AntimicrobialNaturalProductBerberineisEfficaciousfortheTtreatmentofAtrialFibrillation.BiomedResInt.2017;2017:3146791.

Turmeric (Curcuma longa)

Curcuma longa Chemistry

Reference

Curcuma longa, Traditional Use

Ahouseholdremedy;cough,fever,jaundice,liverdisorders,urinarydiseases

HPTLC, Turmeric & Curcuminoids

HPTLC

STDs-----TurmericExtracts-----

STDs

Curcumin

Tetrahydrocurcumin

Bisdemethoxycurcumin

Demethoxycurcumin

Curcuma longa ImmuneActivity

Reference

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.

Curcumin vs Tetrahydrocurcumin

Aggarwaletal.CurcuminDiffersfromTetrahydrocurcuminforMolecularTargets,SignalingPathwaysandCellularResponses.Molecules2015;20:185-205

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.

Holder AJ, Dept. of Chemistry, U Missouri-Kansas City, Kansas City, MO 64110

The Bilipid Membrane


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.


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.

Curcumin, Immune MOAs

JagetiaGC,etal.“SpicingUp”oftheImmuneSystembyCurcumin.JClinImmunol2007;27(1):19-35

Curcuminoids PharmacokineticsandDose

Bioavailability Enhancement

•  Strategiestoincreasecurcuminabsorptionincludecoadministrationofthenaturallyoccurringvolatileoilsfromturmericroot

AsherG,SpelmanK.Clinicalutilityofcurcuminextract.AlternTherHealthMed2013Mar-Apr;19(2):20-2.

Turmerone

Turmeric Essential Oil

ImprovesGingolideAabsorptionby62.7%

Curcumin, PK

Anandetal.,2007.Bioavailabilityofcurcumin:problemsandpromises.MolPharm2007;4(6):807-18.

Curcumin, Dose

Mostconstituentsareusuallyatactivelevelsinserumbetween0.75-6hours

Curcuminpharmacokinetics—rapidglucoronidationbyliver

Shorthalf-life,multipledosesneededperday(T-QID)

Anandetal.,2007.Bioavailabilityofcurcumin:problemsandpromises.MolPharm2007;4(6):807-18.

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

Considering Curcuma longa Essential Oils

Turmericenhancesit’sownbioavailability

InbioavailabilitystudiesturmericessentialoilImprovesGinkgolideAabsorptionby62.7%

Acknowledgements

BetsyCostilo,MS,RH(AHG)–ResearchAssistant

Thank you for your time

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examining 2 herbs for antiviral activity & immune activity spelman - exa… · • cure •...

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