Solidago virgaurea L.: A Review of Its Ethnomedicinal Uses, Phytochemistry, and Pharmacological Activities

Abstract

Solidago virgaurea L. (European goldenrod, Woundwort), Asteraceae, is a familiar medicinal plant in Europe and other parts of the world, widely used and among the most researched species from its genus. The aerial parts of European goldenrod have long been used for urinary tract conditions and as an anti-inflammatory agent in the traditional medicine of different peoples. Its main chemical constituents are flavonoids (mainly derived from quercetin and kaempferol), C6-C1 and C6-C3 compounds, terpenes (mostly from the essential oil), and a large number of saponin molecules (mainly virgaureasaponins and solidagosaponins). Published research on its potential activities is critically reviewed here: antioxidant, anti-inflammatory, analgesic, spasmolitic, antihypertensive, diuretic, antibacterial, antifungal, antiparasite, cytotoxic and antitumor, antimutagenic, antiadipogenic, antidiabetic, cardioprotective, and antisenescence. The evidence concerning its potential benefits is mainly derived from non-clinical studies, some effects are rather modest, whereas others are more promising, but need more confirmation in both non-clinical models and clinical trials.

Full text

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Biomolecules2020,10,1619;doi:10.3390/biom10121619www.mdpi.com/journal/biomolecules
Review
SolidagovirgaureaL.:AReviewofIts
EthnomedicinalUses,Phytochemistry,
andPharmacologicalActivities
CorneliaFursenco
1,2,†
,TatianaCalalb
1,†
,LiviaUncu
2,3
,MihaelaDinu
4,
*andRobertAncuceanu
4

1
DepartamentofPharmacognosyandPharmaceuticalBotany,FacultyofPharmacy,NicolaeTestemitanu
SUMPh,66MălinaMicăStreet,MD‐2025Chisinau,Moldova;cornelia.fursenco@usmf.md(C.F.);
tatiana.calalb@usmf.md(T.C.)
2
FacultyofPharmacy,ScientificCenterofMedicines,NicolaeTestemitanuSUMPh,66MălinaMicăStreet,
MD‐2025Chisinau,Moldova;livia.uncu@usmf.md
3
FacultyofPharmacy,Departamentofpharmaceuticalandtoxicologicalchemistry,NicolaeTestemitanu
SUMPh,66MălinaMicăStreet,MD‐2025Chisinau,Moldova
4
DepartmentofPharmaceuticalBotanyandCellBiology,FacultyofPharmacy,CarolDavilaUniversityof
MedicineandPharmacy,6TraianVuiaStreet,Sector2,020956Bucharest,Romania;
robert.ancuceanu@umfcd.ro
*Correspondence:mihaela.dinu@umfcd.ro
†Denotesequalcontribution.
Received:13October2020;Accepted:26November2020;Published:30November2020
Abstract:SolidagovirgaureaL.(Europeangoldenrod,Woundwort),Asteraceae,isafamiliar
medicinalplantinEuropeandotherpartsoftheworld,widelyusedandamongthemostresearched
speciesfromitsgenus.TheaerialpartsofEuropeangoldenrodhavelongbeenusedforurinarytract
conditionsandasananti‐inflammatoryagentinthetraditionalmedicineofdifferentpeoples.Its
mainchemicalconstituentsareflavonoids(mainlyderivedfromquercetinandkaempferol),C6‐C1
andC6‐C3compounds,terpenes(mostlyfromtheessentialoil),andalargenumberofsaponin
molecules(mainlyvirgaureasaponinsandsolidagosaponins).Publishedresearchonitspotential
activitiesiscriticallyreviewedhere:antioxidant,anti‐inflammatory,analgesic,spasmolitic,
antihypertensive,diuretic,antibacterial,antifungal,antiparasite,cytotoxicandantitumor,
antimutagenic,antiadipogenic,antidiabetic,cardioprotective,andantisenescence.Theevidence
concerningitspotentialbenefitsismainlyderivedfromnon‐clinicalstudies,someeffectsarerather
modest,whereasothersaremorepromising,butneedmoreconfirmationinbothnon‐clinical
modelsandclinicaltrials.
Keywords:SolidagovigaureaL.;Europeangoldenrod;asteraceae;ethnomedicinal;phytochemistry;
distribution;pharmacologicalactivity

1.Introduction
ThegenusSolidagoincludesabout190speciesandinfraspecifictaxons(subspeciesandvarieties)
withanacceptedstatusandabout330speciesandintraspecifictaxonswithanambiguousstatus[1].
Theyarewidespreadthroughouttheworld,mostofthemoriginatingfromNorthAmericaor
confinedtothispartoftheworld[2].MostofSolidagospeciesareherbaceousfloweringplants,which
occurinthespontaneousfloraorarecultivatedasdecorativeplants[3].Rawmaterialsofgoldenrods
havealongandwideusehistoryinthetraditionalmedicineofdifferentpartsoftheworld:S.
virgaureaL.(Europeangoldenrod)isthemostusedinEuropeandAsia;S.canadensisL.(Canadian
goldenrod),S.giganteaAiton(Giantgoldenrod),andS.odoraAiton—inNorthAmerica;S.chilensis

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Meyen−inSouthAmerica[4,5].AccordingtotheFloraEuropaea,onthecontinent,thereare5
representativesofthegenusSolidago:S.virgaureaL.,S.canadensisL.,S.giganteaAiton.,S.altissimaL.,
andS.graminifoliaL.Salisb.)[6].Today,S.graminifoliaisconsideredasynonymforEuthamia
graminifolia(L.)Nutt.[7].S.canadensisandS.gigantea,althoughofNorthAmericanorigin,have
becomewidespreadacrossEuropeandareconsidered“seriousinvaders”,whereasS.rugosa,ofthe
sameorigins,hasbeenreportedonlyinafewWesternEuropeancountries[8].
TheaerialpartsofEuropeangoldenrodhavebeenknownandusedforcenturiesasanti‐
inflammatory,spasmolytic,anddiureticremediesinthetraditionalmedicineforthetreatmentof
numerousdiseases,especiallyasaurologicalagentinkidneyandbladderinflammation,urolithiasis,
andcystitis[3,4,8–12].AccordingtotheEuropeanMedicinesAgency,S.virgaureaisoneofthemost
usedandstudiedspeciesoftheSolidagogenusinEurope[9].
ThegrowinginterestforthespeciesS.virgaureaasamedicinalplantledustocarryoutthis
reviewusingthemostrelevantandrecentinternationalresearchstudies.Thescientificcommunity
interestinS.virgaureaisbooming.Figure1depictsthecumulativenumberofarticles(totalof580)
publishedonS.virgaureaintheperiod1944–2020.Forthispurpose,twowell‐knownandworldwide
appliedscientificdatabases(MEDLINE(PubMed)andHINARI),aswellasGoogleScholar,were
used.Thenumberofpublishedpaperonthisspecieshasescalatedinthelasttwodecades(2000–
2020).

Figure1.CumulativenumberofcitationsonS.virgaurea.Source:PubMed.
2.GeneralDescription,Taxonomy,andDistribution
S.virgaureaisaperennialherbprovidedwithanoblique,woodyrhizome,ofacylindricalshape
anddevoidofknots,onwhichstemscarsarevisible(Figure2A).Theround,erectstemmayachieve
aheightofupto1m,andisramifiedandpubescentatthetopside.Theleaves,withanalternate
arrangement,aresimple,slightlypubescentontheadaxialface,andpubescentontheabaxialone.
Basalleaveshaveovateorovate‐ellipticbladeswithanacutetipandawingedpetiole,whereasupper
leaveshaveshortstalksandlinear‐lanceolateorellipticblades,withmarginseitherserratedorentire
(Figure2B,C).Theradiateflowerheadshavemorphologicallydistinguishedray(female,tongue‐like)
anddiscyellowflorets(hermaphrodite,tubular).Theflowerscapitulaaregroupedinasimpleraceme
orinpanicles(Figure2D).Thereceptacleisglossyandflat.Thefruitisacylindrically‐shapedachene,
with8–10ribsandapappusderivedfromthemodifiedcalyx[13].

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Arecentmorpho‐anatomicallocalstudyfocusedonthemorphologicalandanatomical
investigationofS.virgaureafromfloraoftheRepublicofMoldova,anditsherbalproductSolidaginis
virgaureaeherba,wasdonebyCalalbT.etal.[13].Theanatomicalfeaturesofthehighestinterestfor
theexactidentificationofS.virgaurea,establishedinthisstudy,include:repartitionofstomataon
bothsidesoftheleaf,anomocyticarrangementofstomata,cone‐shapedorfan‐shapedmulticellular
trichomesonbothepidermises,aswellasglandulartrichomes,dorsiventralstructureoftheleafwith
vascularbundlescollateralandopen,andsecretoryductsinthestem.Theanomocyticstomata
reportedfortheleafisconsistentwiththefindingsofSzymuraM.andWolskyK.[14],whoalso
establishedthatanomotetracyticstomatawerethemostwidespreadtypeinotherSolidagotaxa
collectedfromPoland.Thepresenceoftwocategoriesofmulticellulartrichomes(cone‐shapedand
fan‐shaped)onthegoldenrodleafwasalsoreportedbyothersources[14,15]:byBuynovMV.onS.
dahuricaleaf[16],byDouglasM.etal.onS.chilensisleaf[17],andbyFedotovaVV.onS.caucasicaleaf
[18].Careisneededforacorrectidentification,becauseinthe19thcentury,ascientificpaperwritten
byamedicaldoctor(basedonhispersonalexperiencerepeatedseveraltimes)drewtheattentionto
therisksofconfusingthismedicinalplantwithanon‐effective(andlikelydangerousforthehealth)
SenecionemorensisL.[19]

Figure2.S.virgaurea(originalphoto):(A)obliquerhizome,(B)basalleaves,(C)caulineleaves,(D)
radiateflowerheads.
Accordingtoanumberofsources[20,21],S.virgaureaisregardedasataxonomicgroupor
complex,anditconsistsofperennialherbaceousspeciesextensivelydistributedfromEuropetoEast
Asia.Asagroup,itisgenerallydividedlongitudinally:inEuropethegenusisrepresentedbyS.
virgaureaL.,inSiberiaandmostoftheFarEastbyS.dahurica(Kitag.)Kitag.exJuz.TogetherwithS.
spiraeifoliaFisch.exHerder,whereasintheFarEastregionofRussia,knownasChukotkaandin
NorthAmerica,thegenusisrepresentedbyS.multiradiataAit.[22].
TheEuropeanS.virgaureaL.hasbeendescribedas“anexceedinglypolymorphictaxon”,anda
multitudeofnarrowlyrelatedtaxahavebeenincludedwithinitatdifferentlevels(varieties,
subspecies,andevenspecies)[22,23].InaEuropeancountry(CzechRepublic)flora,discussingthe
variability,S.Slavik(2004)hasidentified17taxaasbelongingtotheS.virgaureaL.group(leaving
asidetaxafromJapan),ofwhichanumberofsixarequalifiedassubspecies,whereasanumberof
elevenas“microspecies”[22,24]).TheAtlasoftheBritishandIrishflora[25]describesS.virgaureaas
highlyvariable,withmanydistinctformsfordistincthabitats(ecotypes).Strongcorrelationshave
beenclaimedbetweenS.virgaureagenotypesandtheirgeography,andastrongabilitytorapidly
evolveandecologicallydiversifyhasbeenrecognizedforthespecies[26].

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3.SynonymsandCommonNames
AccordingtotheAssessmentReportonSolidagovirgaurea,realizedbytheEuropeanMedicines
Agency[9]andtheWorldFloraOnline[1],themainsynonymsinuseare:Amphiraphisleiocarpa
Benth.,AmphiraphispubescensDC.,Astervirgaurea(L.)Kuntze,DectisdecurrensRafin.(Lour.),and
DoriavirgaureaScop.S.patagonicaPhil.iscurrentlyanacceptedname[1],althoughitwasreported
thatoneArgentinespecimenidentifiedasS.patagonicawasinfactanescapedcultivarofS.virgaurea
[27].
ThemostoftenusedcommonnameforS.virgaurea,aswellasforotherSolidagospeciesis
goldenrod.Sometimesthe“European”qualifierisaddedtothisvernacularnameandinthispaper,
inordertoavoidconfusionwithotherspeciesofthegenus,wewillhereafterusethisname(European
goldenrod).AccordingtotheAmericanBotanicalCouncil,othercommonnamesinuseare:Solidago,
Virgaurea,Woundwort,Aaron’srod,andYellowweed[28].Thedriedfloweringabovegroundparts
arethesubjectofaEuropeanherbalmonograph[29].
4.EthnomedicinalUses
S.virgaureahasadiversityofmedicinalusesintheterritorieswhereitisspread.Probablyits
mostwidelyknownethnopharmacologicalusesarerelatedtokidneydisorders(beingoftenfoundin
teasintendedtohelppasskidneycalculi),urinarytractinfections,theoveractivebladdersyndrome,
andprostaticdiseases[30–32],theurologicusesoftheplantgoingbackatleasttothewritingsof
ArnoldvonVillanova(1240–1311)[33].Traditionally,theaerialpartsoftheplanthavebeenusedfor
healingandantisepticproperties[9],aswellasforthetreatmentofdiabetes,allergies,andgastro‐
intestinaldisorders[8,32].Likewise,infusionsordecoctionspreparedfromEuropeangoldenrodis
usedinthetraditionalmedicineinmanypartsoftheworldforitsantibacterialandanti‐inflammatory
effects[34],includinginflammationoftheoralcavityandthroat,whenusedasamouthrinse[32].
FurtherscientificstudieshaveshownthegrowingimportanceofEuropeangoldenrodasasourcefor
herbaldrugs[35].InmanyEuropeancountries,theherbalproductderivedfromthespecieshasoften
beenincombinationproducts[9].
4.1.Germany
HieronymusBock(1498–1554),oneofthefirstmodernbotanistsinGermany,conjecturedthat
Germanictribeshadbeenusingtheplantformedicinalpurposes,mentioningthattheyregardedit
asa“miracleherb”(Wunderkraut)[36].ItisbelievedthattheGermanfatherofReformation,Martin
Luther(1438‐1546),hadagoodopinionongoldenrodanduseditoftentocareforhisphysical
infirmities[33].Oneofthefirstreportsonitsdiureticandanti‐inflammatoryeffectsareascribedto
the“fatherofGermanbotany“(1525–1590),JacobusTheodorusTabernaemontanus[37],whostated
thatit“alsocleansesthekidneysandurinarytractofallcoarsemucus”[36].ThenameHeydnisch
Wundkraut(heathenwoundwort),employedintheGermanterritoriesduringtheMiddleAgesfor
theplant,evokesthehealingpropertiesoftheherb.AnothervernacularGermanname,Unsegenkraut
(curseherb),indicatesbeliefatthattimeinitsmagicabilities,inanerawherediseasewasoften
attributedtowitchcraftandmetaphysicalcauses,andindirectlythenamemightstillpointtowards
itspotentialmedicinalproperties[38].InGermanfolkmedicine,goldenrodwasusedforthe
treatmentofurinaryretention,kidneystones,andhemorrhoids[36].Sincethemiddle19thcentury,
itsusewasslowlyforgotteninGermany,toberevivedonlyrelativelyrecentlywiththerenewed
interestfortheherbaltherapy[36].
Currently,awell‐establisheduseisacceptedinGermanyforinflammatorydiseasesofthe
urinarytractcollectionsystem,urolithiasisandrenalgravel.Avarietyofextractsareused,
particularlydriedextractsobtainedfromtheaerialparts(Solidaginisvirgaureaeherba)using30–60%
ethanolasanextractionsolvent[9].AmonographofthespecieswasintroducedinDABin2002,
whichalsoacknowledgedS.canadensisandS.giganteaasvalidspecies,despitecertaindifferencesin
thespectrumoftheirphytochemicals[33].

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4.2.CzechRepublic
TheherbaldrugobtainedfromS.virgaureaisincludedintheCzechPharmacopoeia2009[39].A
drinkobtainedfromtheaerialpartsoftheplantisusedasanadjuvanttreatmentininflammatory
conditionsoftheurinarysystem,aswellasforthepreventionofkidneyandbladdercalculi[9].Itis
notclear,though,whethersuchusesrepresentanoldCzechtradition,asaCzechpaperonthespecies
onlycitedforeignsourceswhenreferringtothetraditionalmedicinaluseofthespecies[39].
4.3.Poland
Traditionally,theinfusionpreparedofdriedaerialpartsofS.virgaureahasbeenusedasa
diureticandasanadjuvantintreatmentofminorcomplaintsoftheurinarytract[9].InaPolish
source,itisstatedthatrawmaterialofthisherbischaracterizedbydiuretic,detoxifying,anti‐
inflammatory,andbilesecretionenhancingproperties[35].APolishsourcementionsitsdisinfectant
propertiesasthemostimportantamongthetraditionaluses,butalsoitsusefuleffectsinaccelerating
woundhealingandinskincare[40].
4.4.RussianFederation
InRussianfolkmedicine,Europeangoldenrodisusedforavarietyofconditions,fromgallstone
diseasetoindigestion,andfromrheumatismtogout.Forexternaluse,freshleavesarerecommended
inabscessesandboils[41].OtherRussiansources[35,42]statethatmostcommonusesofthisspecies
includepreventionandtreatmentofvariousdiseasesofthekidneys,bladder,andprostategland(i.e.,
thetraditionalusemostwidelyacknowledgedinEurope).IntheRussianfolktradition,theEuropean
goldenrodisalsoknownasahemostaticandastringentagent,aswellasagoodremedyfor
respiratorydiseases(tonsillitis,laryngitis,acuterespiratorydiseases),gallstonediseases,and
pulmonarytuberculosis[41].
4.5.Ukraine
TheuseintuberculosisisalsowellestablishedintheUkrainefolkmedicine,wherethenameof
theplant,zolotushnik,alludestoitsuseindecoctionsas“agoodremedyagainstscrofula(zolotukha)”,
buttheplantwasalsobelievedtohavediureticeffects[43].
4.6.Bulgaria
AccordingtoaBulgariansource,theaerialpartsofS.vigaureaL.areusedasadiuretic,
antihypertensive,andexpectorant,aswellasinthetherapyofrenaldeficiencyandgout[44].
4.7.RomaniaandtheRepublicofMoldova
S.virgaureahasalonghistoryofuseintheRomaniantraditionalphytotherapy.Theherbal
productSolidaginisvirgaureaeherbahasbeenusedinherbaltherapyandmarketedbyspecialized
outletssince1990[45].Ethnopharmacologicalusesofthisplantaremostlyrelatedtomaintainingthe
healthoftheurinarytractandthenormalfunctioningofthedigestivesystem.Traditionally,itis
recommendedasadiuretic,saluretic,anti‐inflammatory,antiseptic,healing,orasedativeagent.For
externaluse,themostcommonapplicationconsistsinadministeringaninfusionordecoctionofthe
aerialpartsorbloomingtopsinthetreatmentofwoundsorulcersoftheoralcavity[46,47].The
externaluseinrickets,alsoacknowledgedbyRomaniantraditionalsources[48],doesnotseemto
havegreatbenefit,consideringthecurrentknowledgeofthisdiseaseanditscauses.
4.8.Korea
TherootandaerialpartsofS.virgaureasubsp.gigantea(Nakai)Kitamhavebeenusedasan
appetitestimulantanddiureticinKoreanfolkmedicine,whereastheimmatureaerialpartsareused
inthesameareaasfood[49,50].

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4.9.China
Decoctionsobtainedfromthewholeplantwereusedfortheirantibacterialactivity,andin
respiratorytractinfectionsforitsexpectorantandanti‐inflammatoryproperties[51].
4.10.OtherUses
Besidesitsmedicinaluses,S.virgaureahasbeenrecognizedasafirst‐classalternativesourcefor
thefloriculturebusiness,bothontheoldcontinentandinthenewworld[32].Ithasalsobeen
proposedtobeusedasarotationcropasameansofcontainingnoxiousweedsinanorganic
agriculturecontext[35].Solidagospp.,includingS.virgaurea,havebeenclaimedtohavepotential
utilityforphytoremediationpurposes,basedontheirabilitytotransferironfromsoiltoplantsnear
ironprocessingindustrialsites[35];however,studiesonotheroligo‐elements(suchaszinc)havenot
identifiedparticularhyperaccumulatorpropertiesfortheplant[52],andwhereasanumberofpapers
havebeenpublishedonthephytoremediationpotentialofS.canadensis[53,54],wecouldfindnone
onS.virgaurea.Thepollenofthelatterisofgoodquality,anditsavailabilitymaycontributetolong‐
livedbeesbeingabletosurviveahardwinter[55].
5.Phytochemistry
ExtractsofS.virgaureacontainC6‐C1glycosides(virgaureoside,leiocarposide)andaglycones
(vanillicacid,gallicacid)[4,9,56–58],C6‐C3polyphenolicacids(caffeic,chlorogenic,ferulic,synapic,
3‐hydroxyphenylaceticacid,3,4‐dihydroxyphenylacetic,homovanilic,acids)[3,9,10,45,53–57],a
numberofflavonoidmolecules(mostlyquercetinandkaempferolglycosides,aswellasthefree
aglyconsandsmallamountsofcyanidinderivatives)[3,4,9,45,49,59–65],oleanane‐typetriterpene
saponins[9,66–73],essentialoilscontainingmonoterpenes(alpha‐andbeta‐pinene,myrcene,
limonene,sabinene)[35,74–77]andsesquiterpenes(germacreneDβ‐caryophyllene,α‐humulene,),
clerodane‐typediterpenes[78],polysaccharides[79],andpolyacetylenes[80](Table1).TheEuropean
PharmacopoeiamonographforSolidaginisvirgaureaeherbaregardsflavonoidsasqualitymarkersand
fortheproductrequiresacontentofatleast0.5%andmaximum1.5%,expressedashyperoside[81].
Table1.ChemicalcompoundsidentifiedinS.virgaurea.
ChemicalCompoundsPlace/CountryofCollectionReferences
Flavonoids(Figure3)
Quercetin,
Quercetin‐3‐O‐glucoside(isoquercitrin)
Quercetin‐3‐O‐galactoside(hyperoside)
Quercetin‐3‐O‐rhamnoside(quercitrin)
Quercetin‐3‐O‐rutinoside(rutin)
Quercetin‐3‐O‐arabinopyranoside(avicularin)
Kaempferol‐3‐O‐glucoside(astragalin)
Kaempferol‐3‐O‐rhamnoside(afzelin)
Kaempferol‐3‐O‐rutinoside(nicotiflorin)
Kaempferol‐3‐O‐robinobioside(biorobin)
Myricetin3‐rhamnoside(myricitrin)
Isorhamnetin‐3‐O‐rutinoside(narcissin)
Cyanidin‐3‐gentiobiosidemono‐C‐
glycosylflavones(?)
di‐C‐glycosylflavones(?)
Poland,Italy,Hungary,
Korea,Romania,Lithuania
FuchsL.[82],
BudzianowskiJ.etal.
[61],
BorkowskiB.and
SkrzypczakowaL.[60],
ChoderaA.etal.[65],
RoslonW.etal.[59],
PiettaP.etal.[62],
ApátiP.etal.[83],
ChoiSZ.etal.[49],
TamasM.[63],
DobjanschiL.etal.
[45,64],
KraujalieneV.etal.[84]
C6‐C1Compounds(Figure4)

Biomolecules2020,10,16197of31
Benzoicacid
3‐Hydroxybenzoicacid
4‐Hydroxybenzoicacid
3,4‐Dihydroxybenzoic(protocatechuic)acid
Salicylicacid
Gentisicacid
Vanillicacid
Gallicacid
Leiocarposide
2‐methoxybenzyl‐2,6‐dimethoxybenzoate
Poland
Egypt
Korea
KalembaD.[85],
AbdelMotaalA.etal.
[10],
ChoiSZ.etal.[49],
Thiem,B.etal.[58],
BajkaczS.etal.[86],
SungJHetal.[50],
C6‐C2andC6‐C3Compounds(Figure5)
Caffeicacid,
Chlorogenicacid
5‐O‐caffeoylquinic(neochlorogenic)acid
3,5‐di‐O‐caffeoylquinicacid
3,4‐di‐O‐caffeoylquinicacid
4,5‐di‐O‐caffeoylquinicacid
3,4,5‐tri‐O‐caffeoylquinicacid
Methyl3,5‐di‐O‐caffeoylquinate
3‐hydroxyphenylaceticacid3,4‐
dihydroxyphenylaceticacid
5‐p‐Coumaroylquinicacid
Homovanilicacid
p‐Coumaricacid
Ferulicacid
Sinapicacid
Rosmarinicacid
Poland
Egypt
Korea
Iran
KalembaD.[85],
AbdelMotaalA.etal.
[10],
ChoiSZ.etal.[49],
ThiemB.etal.[58],
BajkaczS.etal.[86],
HaghiG.,HatamiA.[87],
RoslonW.etal.[59],
KraujalienėVetal.[84],
M.Marksaetal.[88],
D.Fraisseetal.[89],
BorkowskiB.and
SkrzypczakowaL.[60],
JaiswalR.etal.[90]
Coumarins
7‐hydroxy‐coumarin(umbelliferone)CzechRepublicDobiasP.etal.[91]
TerpeneDerivatives(Figure6)
α‐Pinene,
β‐Pinene,
Sabinene
Myrcene
Limonene
β‐Ocimene
Germacrene‐D,
β‐Caryophyllene,
α‐Humulene,
Clerodanediterpenes
2,8‐(cis)‐(cis)‐MatricariaesterMatricariaγ‐
lactones
Lachnophyllumlactone
ent‐germacra‐4(15),5,10(14)‐trien‐1β‐ol
β‐dictyopterol
Poland,Japan,
Italy,
RussianFederation,
USA
Denmark
Korea
KalembaD.[74],
KalembaD.andThiemB.
[75],
FujitaS.[76],
BertoliA.etal.[77],
TkachevAV.etal.[35],
GoswamiAetal.[92],
StarksCM.etal.[78],
LamJ.[80],
ChoiS.[49]
Saponins(Figure7)
Virgaureasaponins1–6
SolidagosaponinsX‐XXIX
BellisaponinBA2
Erythrodiol‐3‐acetate
Germany,
France,Romania
Japan
BaderG.etal.[34,56–59],
ChevalierM.etal.[86],
LaurençonL.etal.[61],
DobjanschiL.etal.[85],
InoseY.etal.[60],
SungJHetal.[50]
CarbohydratesandOther
Compounds
Polysaccharides
α‐tocopherolquinone
2‐phyten‐1‐ol
RussianFederation
Korea
PychenkovaPA.[66],
SungJHetal.[50]

Biomolecules2020,10,16198of31
Ithasbeenspeculated[3]thatanumberoftheactivecompoundsofS.virgaureaextracts
(leiocarposide,polyphenolicacids,flavonoids,saponins)exertasynergisticactivityindisplayingthe
reportedanti‐inflammatoryeffectsoftheproduct[56,93].Theantioxidantactivityhasbeenattributed
tothepolyphenoliccompounds[3,94–96],whileflavonoidsarethoughttoberesponsibleforthe
spasmolyticeffects[3,31,97].
5.1.Flavonoids
Amongtheflavonoids,rutin,quercetrin,astragalin,nicotiflorin,biorobin,andnarcissinhave
beenconsidered“themostrepresentative”[62],andtheyareaccompaniedbytheiraglycons[49,84].
Morerecently,flavanonesaglyconesandglycosideshavealsobeendetectedandquantifiedinthe
differentpartsoftheplant:eriodictyol(thelargestamountintheflowers,followedbyleavesand
thenstems,mostlyasglycosides),naringenin(similarquantitativedistributioninflowers,leaves,and
stems,mostlyasglycosides),andverysmallamountsofhesperitin(notassessedseparatelyineach
aerialparts)[98].EriodictyolandnaringeninarepresentintheformofbothRandSenantiomers,
whereashesperitinwasdetectedonlyastheSenantiomer[98].Allflavonoidheterosidesseemtobe
3‐O‐glycosides,asforthemajorityofSolidagospecies(thenotableexceptionbeingS.graminifolia(L.)
Salisb,inwhichmono‐anddi‐C‐glycosylflavonoidshavealsobeenreported[58],butwhichnowis
consideredasynonymfortheEuthamiagraminifolia(L.)Nutt[1]).Thepresenceofflavonoid‐C‐
heterosidesinS.virgaureahasalsobeenoccasionallyclaimedinsecondarysources[59],butwecould
notlocateaprimaryreferencereportingthem.Cyanidin‐3‐gentiobiosideisthemainanthocyanin
presentintheleaves,butatleastoneothercyaniding‐glycosydewasreportedinverysmallamounts
[99].Flavonoidglycosidestendtobebetterextractedinethanolof70%orhigherconcentrations[83].
Asmentionedabove,hyperosideisconsideredthekeyflavonoidbytheEuropeanPharmacopoeia
[81].However,inonepaper,quercitrinwasthemajorphytochemicalfromaquantitativestandpoint
[84],whereasothersourcesreportedrutinasthedominantflavonoid[59,60](ameancontent196.42
mg100g−1reportedby[59]).Aqualitativeandquantitativecomparativestudyofflavonoidsfrom
extractsoffourSolidagospp.reportedinRomanianflorawascarriedoutbyDobjanschiL.etal.
[38,49],whofoundatotalflavonoidcontentforS.virgaureaof4.06%,expressedasrutin.Theyalso
foundthatforS.virgaurea,specificwasthepresenceofrutinandhyperoside,whereasquercitrin
(unlikethefindingsofV.Kraujalienėetal.)wasabsent[45,64].Spasmolyticeffects(asdiscussed
below)[31,97],diureticactivity[10],havebeenattributedtotheflavonoids,andothereffectshave
alsobeenspecificallyascribed(atleastpartially)tosomeflavonoids,e.g.,antiadipogeniceffectsto
kaempferol‐3‐O‐rutinoside[100].

Biomolecules2020,10,16199of31

Figure3.RepresentativeflavonoidsfromS.virgaureaL.
5.2.C6‐C1Compounds
SeveralmaincompoundswithaC6–C1haveapparentlybeenreporteduptodateinS.virgaurea,
twoglycosidesandtwoaglycones:virgaureosideA,abis‐desmosidicglycosidederivedfrombenzoic
acid(2‐beta‐D‐glucopyranosyloxybenzoicacid‐2′‐beta‐D‐glucopyranosyloxybenzylester)[101],
leiocarposide(2′‐hydroxybenzyl‐3‐methoxybenzoate2′,4‐diglucoside)[56],vanillicacid,gallicacid
[9,102],benzoicacid,3‐hydroxybenzoicacid,4‐hydroxybenzoicacid,3,4‐dihydroxybenzoic
(protocatechuic)acid,and2,5‐dihydroxibenzoic(gentisic)acid[85,86].Suchderivativesofthe
benzoicacidareoftenoccurringinthefamilyAsteraceae[103].
Asomewhatdetailedhistoryofthediscoveryofthetwophenolicglycosideswasprovidedby
L.Skrzypczaketal.[103].Leiocarposideiscurrentlyconsideredthemostimportantandwasfound
tobemaximallybiosynthesizedintheflowerbuds(1.60%)andinthetwo‐yearleaves,post‐blooming
(1.05%)[104].Similarcontents(0.4–1.6%)werereportedbyotherresearchers,dependingonanumber

Biomolecules2020,10,161910of31
ofvariablessuchasplantheightatharvest,collectiontime,orthenaturalstateoftheherbalsamples
[58].Leiocarposidehasattractedinterestforitspharmacologicalpotential,beingexploredforits
hypothesizedanti‐inflammatory,analgesic,antilithiatic,anddiureticeffects,asdiscussedbelow.For
plantscultivatedinvitro,thecontentofleiocarposideislowerthanthatofnaturallygrowingplants
(0.18%vs.0.2–1.0%)[58].

Figure4.C6‐C1compoundsfromS.virgaureaL.
5.3.C6‐C2andC6‐C3Compounds
AvarietyofC6–C3phenolicacidshavebeenidentifiedindifferentstudies.Amongthemost
importantarethecaffeoylquinicderivatives(chlorogenicacid,butalso5‐O‐caffeoylquinic
(neochlorogenic)acid,5‐p‐coumaroylquinicacid,3,5‐di‐O‐caffeoylquinic,3,4‐di‐O‐caffeoylquinic,
4,5‐di‐O‐caffeoylquinicacids,methyl3,5‐di‐O‐caffeoylquinate,and3,4,5‐tri‐O‐caffeoylquinicacid,
thelattershowingsuperioranti‐inflammatoryeffectsoverthedi‐caffeoylquinicderivatives.)
[10,49,58,59,86,90].Caffeic,p‐coumaric,ferulic,sinapic,3‐hydroxyphenylacetic,3,4‐
dihydroxyphenylacetic(DOPAC),andhomovanilicacidswerealsoreportedinphytochemical
studiesofS.virgaureaL[86].Inonestudy,whereaschlorogenicacidwasdetectedandmeasured(by
HPLC),ellagicandrosmarinicacidscouldnotbedetected[87].Chlorogenicacidcontentmayvary
considerably,asshowninonestudythatmeasureditinsamplescollectedfrom20sites,whichfound
concentrationsaslowas158.99mg/100gandashighas441.50mg/kg[59].Similarly,rosmarinicacid
variedinthesamestudybetween256.38mg/100gand898.70mg/100g[59],whereas(asmentioned)
inadifferentstudy,itcouldnotbedetectedatall[87].Asalreadydiscussedintheliterature[88],a
numberofvariables,suchastheherbalpart,ontogeneticdevelopmentstage,andambientconditions
haveaconsiderableinfluenceonthequalitativeandquantitativecontentinphenoliccompoundsof
thespecies.

Biomolecules2020,10,161911of31

Figure5.C6–C2andC6–C3compoundsfromS.virgaureaL.
5.4.Coumarins
Uptodate,asinglepaper[91]reportedthepresenceofacoumarinecompoundinSolidago
virgaurea:umbeliferone(7‐hydroxy‐coumarin).Esculetinandscopoletinwerenotdetectedinthe
species[91].
5.5.TerpeneDerivatives
Anumberofover60compoundshavebeendescribedintheessentialoilobtainedfromthe
floweringtopsofS.virgaureaLcollectedinPoland[74],whereasinspecimensfromLithuania,106
compoundswereidentifiedinflowersand95inleaves[105].Thekeycompounds(asfoundinthree
samplesfromthreedifferentsitesofPoland)werethemonoterpenesα‐pinene(27.4–34.1%),myrcene
(7.8–17.9%),β‐pinene(5.4–7.5%),limonene(3.0–14.1%),andsabinene(0.4–11.8%),aswellasthe
sesquiterpenesgermacreneD(8.2–17.0%),andinsmalleramountsα–humulene,β‐caryophyllene,
andα–muurolene[74].InLithuaninspecimens,thecompositionreportedrecentlywasrather
different:intheleaves,themostimportantcompoundsdetectedwerecaryophylleneoxide,trans‐
verbenol,spathulenol,humuleneepoxideII,α–pinene(only5.21%),andgermacreneD;inflowers
ofthesameorigin,themostimportantcompoundswerecaryophylleneoxide,humuleneepoxideII,
germacreneD,trans‐verbenol,spathulenol,andbornylacetate[105].Detailedinformationonthe
chemicalconstituentsoftheessentialoilispresentedinTable2.


Biomolecules2020,10,161912of31
Table2.DetailedcompositionoftheessentialoilobtainedfromS.virgaureaL.floweringtops.
CompoundProportion(%)Reference(s)
α‐Pinene0.47–36.5[35,76–78]
Camphene0.02–0.6[35,76–78]
Sabinene0.06–11.8[35,76–78]
Myrcene0.05–17.9[35,76–78]
β‐Pinene0.16–13.3[35,76–78]
3‐Carene0.1–0.7[35,76]
α‐Terpinene Tr.*–0.3[76]
Limonene0.07–14.8[35,76–78]
p‐Cymene Tr.*–0.77[76–78]
(E)‐β‐Ocimene 0.02–4.7[35,76,78,79]
Linalol0.3–0.8[76]
NonanalTr.**–1.4[76,77]
trans‐VerbenolTr.*–0.7[76,77]
trans‐Pinocarveol0.09–0.2[76,77]
Decanal0.04–0.7[35,76,77]
Terpinen‐4‐ol 0.1–1.1[76–78]
Borneol Tr.*[76,77]
α‐Terpineol 0.13–1.89[76–78]
γ‐Terpineol 0.04–0.2[76]
p‐Cymen‐8‐ol 0.03–0.51[76,78]
trans‐Carveol 0.05–0.3[76,77]
Myrtenal Tr.*–0.06[76,77]
Geraniol0.02–0.45[76,78]
VerbenoneTr.*–0.6[76,77]
α‐Cubebene Tr.*–2.35[76–78]
δ‐ElemeneTr.*–9.38[35,76–78]
Bornylacetate0.13–4.52[35,76–78]
Carvone Tr.*–0.4[76,77]
α‐Copaene Tr.*–0.64[35,76–78]
β
‐Bourbonene
0.2–7.28*
[76–78]
β‐Cubebene [76–78]
β
‐Elemene [35,76–78]
GeranylacetateTr.*–0.2[35,76]
IsobutylbenzoateTr.*[76]
(Z)‐β‐FarneseneTr.*–0.6[76–78]
β
‐Caryophyllene0.1–10.5[35,76–78]
α‐Humulene0.1–4.1[35,76–78]
γ‐MuuroleneTr.*–1.86[35,76–78]
Germacrene‐D0.1–17.68[35,76–78]
Isoamylbenzoate0.08–0.4[35,76]
α‐MuuroleneTr.*–3.6[35,76–78]
BicyclogermacreneTr.*–0.9[35,76,77]
γ‐CadineneTr.*–0.7[35,76]
Nerolidol 0.07–0.6[35,76–78]
CalameneneA Tr.*–0.2[76–78]
Caryophylleneepoxide0.4–1.6[76,77]
Spathulenol0.29–11.33[76,78]
(Z)‐hex‐3‐enylbenzoate0.08–0.8[76,77]
TorreyolTr.*–0.6[76,77]
T‐Muurolol0.2–1.16[76,77]
Humuleneepoxide0.2–0.5[76,77]
α‐CadinolTr.**–3.06[35,76–78]
(Z)‐hex‐3‐enylsalicylate0.09–0.3[76,77]

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Eudesma‐4(15),7‐dien0.1–0.2[76]
MintsulphideTr.*[76]
Cyclocolorenone Tr.*–0.3[76,77]
BenzylbenzoateTr.*–57.0[35,76–78]
GeranylbenzoateTr.*–0.1[76]
Benzylsalicylate0.02–1.14[35,76–78]
β‐Phenylethylsalicylate0.1–0.6[76,77]
α‐ThujeneTr.*[77]
Linalool0.23–2.0[77,78]
Perillene0.3[77]
Campholenealdehyde0.6[77]
Pinocarvone0.5[77]
ar‐Curcumene0.5[77]
Spathulenol1.6[77]
Salvial‐4(14)‐en‐1‐one0.1[77]
Torilenol0.8[77]
Junenol0.2[77]
Eudesma‐4(15),7‐dien‐1β‐ol0.1[77]
Acetone0.02–0.62[78]
Ethylacetate0.02–2.27[78]
Ethylalcohol0.03–1.62[78]
α‐PhellandrenTr.*–1.12[78]
β‐Phellandren0.07–0.26***[35,78]
TerpinoleneTr.*–0.2[35,78]
n‐Hexanol0.02–0.10[78]
cis‐3‐hexen‐1‐ol0.16–1.52[78]
trans‐Linalool‐oxideTr.*–0.11[78]
trans‐sabinen‐hydrateTr.*–0.26[78]
cis‐Linalool‐oxideTr.*–0.06[78]
Benzaldehyde0.13–0.40[78]
γ‐ElemeneTr.*–0.06[78]
Aromadendrene0.03–0.20[78]
AcetophenoneTr.*–0.19[78]
SalicylaldehideTr.*–0.02[78]
trans‐β‐Farnesene0.07–4.80[35,78]
Germacrene‐B0.03–16.63[78]
cis‐α‐FarneseneTr.*–0.41[78]
δ‐Cadinene0.2–7.87[35,78]
Cubenene0.02–0.25[78]
Benzylalcohol0.19–1.80[78]
2‐Phenylethylalcohol0.09–1.18[78]
o‐Methoxybenzaldehyde0.02–0.38[78]
Caryophylleneoxide0.1–4.30[35,78]
Epi‐cubenol0.04–2.79[78]
o‐Methoxybenzylalcohol0.07–1.29[78]
T‐Cadinol0.12–0.76[78]
T‐Muurolol0.25–1.16[78]
δ‐Cadinol0.15–0.73[78]
n‐TetracosaneTr.*–0.24[78]
n‐PentacosaneTr.*–0.50[78]
Phytol0.02–1.07[78]
n‐hexacosaneTr.*–0.30[78]
MyristicacidTr.*–1.30[78]
β
‐Ocimene‐Y/(Z)‐
β
‐ocimene0.02–3.0[35,78,79]
γ‐TerpineneTr.**[35]
1‐undeceneTr.**–0.1[35]

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4,8‐dimethyl‐1,3,7‐nonatriene0.1[35]
CamphorTr.**–0.2[35]
Zingiberene0.4–1.1[35]
GermacreneA0.1–0.7[35]
(E,E)‐α‐farnesene1.0–2.7[35]
β‐sesquiphellandrene0.1–0.2[35]
(Z)‐3‐hexenylbenzoate0.1–0.4[35]
β‐EudesmolTr.**–0.1[35]
Neophytadiene0.1–0.2[35]
2‐phenylethylbenzoateTr.**–0.4[35]
*Tr.—traces(<0.02%);**Tr.—traces(<0.1%)(differentcut‐offlevelswereusedindifferentpapersto
define“traces”).***“limonene+β‐phellandrene(2:1)”:1.8–6.4%[35].
Lookingatallcompoundsgroupedbychemicalstructure,thelargestproportioninthePolish
samplesconsistedofmonoterpenehydrocarbons(58–73%)andsesquiterpenehydrocarbons(17–
31%);oxygenatedmonoterpenesandsesquiterpenes(about3%each),benzoicacidandsalicilycacids
(about1%)representlessthan10%ofthetotaloil[74].Theessentialoilofspecimenscultivatedin
vitrobymicropropagationwassimilarinitsmonoterpenecontents,butthesesquiterpeneswere
apparentlylessrepresentedforS.virgaureaL.inthiscase[75].A.V.Tkachevetal.(2006)compared
thecompositionoftheessentialoilfromtheaerialpartsharvestedfromtwodifferentheightsinthe
RussianAltaiandfoundthattheproductharvestedatalowerheight(290m)arericherinessential
oil(0.22%),whichcontainshigheramountsofα‐pineneandmyrceneascomparedtotheoil(0.07%)
obtainedfromplantsharvestedatamoreelevatedheight(650m)[35].Thekeycompoundsinthis
studywerealmostthesameasinthespecimensfromPoland,theonlynotableexceptionbeinga
highercontentinβ‐caryophylleneforbothspecimens(maximumcontentinthePolishspecimens
was3.3%,whereasintheRussianspecimenstheminimumcontentwas6.3%)[35,74].
Besidestheessentialoilterpenes,fromtheaerialpartsofS.virgaureaL.,anumberofatleast12
cis‐clerodanelactoneswerereportedinthe1980s,eightofwhichwerenewatthetimeofreporting
[92].In2010,anadditionalsetofninenewclerodaneswereisolatedfromthespecies(mostlikelythe
aerialpart,althoughuptodate,manyclerodaneshavebeenisolatedfromrootsofdifferentSolidago
species),sevenofwhichhavetherelativelyatypicalfeatureofacarboxylicacidatC‐19(solidagoic
acidsC‐I)[78].
Anumberofpolyacetylenecompoundshavebeenreportedintherootsofthespecies(matricaria
ester,twomatricaria‐γ‐lactones,onelachnophyllumlactone),thatshowconsiderableseasonal
variation[80].Onlythematricariaestercouldbedetectedintheabovegroundshoots,whereasthe
othercompoundsareabsentfromtheaerialparts[80].

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
Figure6.TerpenesfromS.virgaureaL.
5.6.Saponins
ThesaponinsofS.virgaureaL.havebeenanobjectofstudyasearlyasthe1930s,butthefirst
dataontheirstructurewereprovidedbyK.Hilleretal.in1975[106].Inthe1980s,G.Baderetal.
wereamongthefirsttoisolateandestablishthechemicalstructuresofdeacylatedsaponinsfoundin
theaerialparts,namedbytheauthorsvirgaureasponins1–3[37,66,68,107].Aroundthesametime,in
Japan,Y.Inoseetal.isolatedandelucidated,fromsamplesofJapaneseorigin,thestructuresof
oleanane‐typesolidagosaponinsI‐XX,manyofthemglycosylatedinposition16oftheaglyconealone
orbesidesposition3[51,70],andlaterthesamegroupfurtheridentifiedsolidagosaponinsXXI‐XXIX
[108].ThesameJapaneseresearchersreportedthepresenceofbellisaponinBA2[108],whichhadbeen
isolatedpreviouslyfromBellisperennisL.[109].Later,anotherEuropeangroupisolated
virgaureasaponins4–6fromS.virgaureassp.alpestris[73].Quantitatively,thesaponincontentis
similarbetweenS.virgaurea,S.gigantean,andS.canadensis[71].UnlikeS.canadensisandS.gigantea,
whicharederivedfrombyogeninandhavemorecomplexsugarchains,thesaponinsisolatedfrom
S.virgaureaarederivedfrompolygalacicacidandareacylatedbycarboxylicacids[37].Asformany
phytochemicals,someofthesaponinshavemultiplesynonyms,sometimesconfusing;forinstance,
solidagosaponinXVIIIisalsoknownasvirgaureasaponinC[73].

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


Figure7.SaponinsfromS.virgaureaL.
5.7.Polysaccharides
BothinflorescencesandleavesofS.virgaureaL.containpolysaccharides.Thoseisolatedfrom
inflorescencescontainuronicacids(over40%,mostlygalacturonicacid),galactose(13–18%),glucose
(7–12.5%),rhamnose(4–7.5%),arabinose(2–8%),andxylose(1–2%)residues[79].Theamountand
theproportionamongthecomponentsvaryalongthegrowingstagesoftheplant[79].J.Saluk‐
Juszczak(2010)reportedquitedifferentproportionsofsugarsforthepolyphenolic‐polysaccharide

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conjugatesisolatedfromtheflowerheads(rhamnose22.4%,fucose5.0%,arabinose19.2%,xylose
2.6%,mannose1.3%,glucose13.0%,galactose14.0%)[110].
6.Pharmacology
6.1.AntioxidantProperties
Joiningthenutritionalvocabularyofthemassesatleastthreedecadesago,theconceptof
“antioxidants”remainsonepoorlyunderstoodinthefieldoflifesciences,andtheclinicalrelevance
ofantioxidantsisstillratherfuzzy,withmanyknowledgegaps[111].However,partlybecausethe
assessmentofantioxidantpotentialiseasilyaccessibleandrelativelycheap,formanyherbal
products,theantioxidantpropertiesareevaluatedrepeatedly,andS.virgaureamakesnoexception,
thefirststudyonthistopicdatingfrom1995[96].Inthisstudy,ethanolicextractsoftheplantwere
showninvitrotoinhibitlipoxygenaseandxanthineoxidasepathways[96].Amethanolextract
obtainedfromtheyoungshootsandleaveshadstrongerantioxidanteffects(measuredinvitrowith
aDPPH‐basedassay)thananextractpreparedwithhotwater[95].Autoclavingofan80%ethanol
extractresultedindecreasedscavengingeffectsonDPPHandABTS(associatedwithadeclinein
polyphenolandflavonoidcontents),butitincreasedthechelatingeffectsonferrousions[112].
Althoughaslightlyhigherantioxidanteffectwasobservedwhenusingpressurizedfluidextraction
overtheultrasonicextractionmethodonS.virgaureaL.leaves(94.0%vs.89.0%inhibition),the
differencewasnotstatisticallysignificant[91].Bothleafandstempowders,aswellasextracts
obtainedfromthoseparts,preventedlipidoxidationwhenappliedongroundporksamples
[113,114].Among23herbalspeciesexaminedfortheirantioxidanteffectinonestudy,S.vigaureaL.
hadanaverageantioxidantactivity(indecreasingorder,itoccupiedthe11thpositionoutof23)[44].
ThekeycomponentandmarkeroftheantioxidantpropertiesofS.virgaureawasfoundbyM.
Marksaetal.(2020)tobe3,5‐dicaffeoylquinicacid(abouthalfofthewholescavengingactivity,asfor
S.canadensisandS.×niederederi,butunlikeS.gigantea,forwhichthemaincomponentresponsibleis
chlorogenicacid)[88].ForseveralSolidagospeciestested,thescavengingactivitieswerestrongerfor
theleafproductsthanfortheinflorescences[88].Theradicalneutralizingpropertiesofquercetin
derivativesfromSolidagospecieswasshowntobeconsiderablylowertothatofthecafeoylquinic
derivatives,butitishigherthanthatofkaempferolderivatives,whoseantioxidantpotentialis
insignificant[88].Di‐caffeoylquinicacidshaveastrongerradicalscavengingeffectthanmono‐
caffeoylquinicacids[88].
6.2.Anti‐InflammatoryEffects
Theanti‐inflammatoryactivityofS.virgaureaextractsorcomponentsisolatedfromthespecies
hasbeenrepeatedlyevaluated,confirmed,andascribedtodifferentphytochemicalsfromits
composition.Inaratmodel,H.J.Jackeretal.(1981)showedthatatriterpenesaponinfraction
administeredi.v.atalowdose(1.25–2.5mg/kg)causedasignificantdecreaseofedema,asmeasured
bypletysmograph[9,115].AlthoughJ.Metzneretal.(1984)reportedsomeanti‐inflammatoryeffect
forleiocarposide(200mg/kg)inacarrageenan‐inducededemamodelinrats,theeffectwasobviously
inferiortothatofphenylbutazone(e.g.,3%vs.53%twohourspost‐administrationand27%vs.54%
reductionfivehourspost‐administration)[9,56].Rutinandquercetin,aswellas3,5‐dicaffeoylquinic
acidwereshownbyM.Melzigetal.(2000)toinhibitleukocyteelastase,aneffectconsidered
synergisticwiththeradicalscavengingofthesamemoleculesinexertingtheiranti‐inflammatory
activity[33,93].Instead,saponinsandleiocarposidedidnotdemonstrateanysuchelastaseinhibition;
thesameauthorsclaimedthatestersaponinsstimulatethereleaseofACTHbytheirinteractionwith
cellmembranesofthepituitarycells,andthus,consecutively,glucocorticoidswithanti‐inflammatory
effects[33,93].3,4,5‐O‐tricaffeoylquinicacidwasidentifiedamongphenoliccompoundsfromS.
virgaureaashavingthehighestanti‐inflammatoryeffect(88%ofthatofindomethacin)inrats
(carrageenan‐basedratpawedema)andtoinhibitTNF‐αandIL‐1β[10].Ontheotherhand,other
studiesreportedstimulationofTNF‐α secretionbymacrophages,aneffectinducedbydifferent
phytochemicalsofthespecies(2‐methoxybenzyl‐2‐hydroxybenzoate,benzyl‐2‐hydroxy‐6‐

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methoxybenzoate)[116],anditremainstobeinvestigatedinwhatcontextsandundertheinfluence
ofwhatvariablesoneortheothereffectwillpredominate.
AqueousandethanolicextractsofS.virguareahavedemonstratedanabilitytoreducepaw
edemaandarthriticpawvolumeinratmodelsofinflammation[117].Someinhibitionof
dihydrofolatereductasehasbeendescribedforahydroalcoholicextractofthespecies,andthishas
beensuggestedascontributingtotheanti‐inflammatoryeffectsoftheS.virgaureaextracts,being
knownthatinhibitorsoftheenzyme,suchasmethotrexate,dohaveanti‐inflammatoryactivity[118–
120].
AstandardizedcombinationofalcoholicextractsofS.vigaurea,PopulustremulaL.,andFraxinus
excelsiorL.hasbeendevelopedasananti‐rheumaticdrugandhasbeenrelativelyextensively
investigated[117,121,122].
6.3.AnalgesicActivity
Aninvitrostudyevaluatedtheanalgesicpotentialofamethanolseedextractbyassessingits
affinityforthreereceptorsinvolvedinacutepainsignaling(bradykinin,neurokinin1,andcalcitonin
generelatedpeptide).Theextractexhibitedsubstantialbindingtothebradykininreceptor,butthis
effectwascanceledbyPVPtreatment,allowingtheauthorstospeculatethatitshouldprobablybe
ascribedtonon‐specificbindingoftanninsorotherpolyphenols[123].Inthehotplatetestonmice,
leiocarposidedemonstratedverysimilaranalgesiceffectstoaminophenazoneforthefirsthour,but
thoseeffectsalmostdisappearedpost‐administrationafterthesecondhour[56].
6.4.SpasmolyticandAntihypertensiveActivity
Exvivodataobtainedonisolatedsmoothmusclesfromguineapiggutshowedamodest
spasmolyticeffectforaS.virgaureaethanolextract(lessthan15%ofthepapaverineeffect)[9,124].As
mentionedbelow,extractsofS.virgaureahavedemonstratedanti‐muscariniceffectsonisolated
bladder,inhibitingtheM2andM3receptors[31].Ithasbeenstatedthatallspeciesofthegenushave
“hypotensiveactivity”,includingS.virgaurea,whichdemonstratedsuchaneffectindogs,foraleaf
extract,atadoseof150/kg[119,125,126].Aqueousextractsfromflowersandfromleaves,
administeredbyi.v.routeinrats,atdosesof180and360mg/kgfoundnoreductionofbloodpressure
afterthefirst2–5min,forbothextracts[127],despiteisolatedinterpretationstothecontrary[119].
Thishasbeenspeculativelyrelatedtoapotentialcontributionofflavonoids,basedonthereported
vasodilatoryeffectsmediatedbytheinhibitionofproteinkinaseCresultingintherelaxationofthe
arterialsmoothmuscle[97].Inthatstudy,flavonolshadastrongereffectthanflavones,whichintheir
turnhadamorepotenteffectthanflavanols[97],andasshownabove,S.virgaureakeyflavonoidsare
derivativesofflavonols(quercetinandkaempferol).
6.5.DiureticEffectsandBenefitsinOtherUrinaryTractConditions
Asshownabove,manyfolktraditionsattributeadiureticactivitytoextractspreparedfromS.
virgaureaL.Inacademicsources,itismentionedatleaststartingwiththe17thcentury,when
Shcroeder’s“Thesauruspharmacologicus”pointsouttoit;throughoutthe20thcentury,different
sourcesalsocitethispharmacologicaleffectinrelationshiptoS.virgaureaproducts[9].
Thediureticeffectshavebeenattributedtotheflavonoidfraction(particularlyquercetinandits
derivatives),whichwasshowntoinhibittheneutralendopeptidase,resultinginanenhancedurinary
flow[88,93].Theinhibitionofneutralendopeptidaseleadstoanincreaseintheplasmaconcentration
ofnatriureticpeptides,whichhavestrongnatriureticproperties[128].A.Choderaetal.(1991)found
thatthisflavonoidfraction(25mg/kgb.w.)increasestheurineoutputinratsbyabout88%,and
causesadecreaseintheexcretionofsodiumandpotassium,accompaniedbyanincreaseincalcium
excretion[9,65].TheseresultsareincontradictionwiththosereportedlaterbyU.Kaspersetal.(1998),
whofoundnoincreaseinurinevolumeorelectrolytesfortheflavonoidfraction[9,129].Instead,they
reportedthatthehydroxycinnamicacidfraction(100mg/kg)andthesaponinfraction(25–100mg/kg)
hadaneffectcomparablewiththoseoffurosemide[9,129],includinganincreaseinsodiumand

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potassiumexcretion,unlikethedatareportedbyA.Choderaetal.(1991),whichclaimedadecrease
intheexcretionoftheseions[9,65].
Besidestheflavonoidicfraction,leiocarposide(25mg/kg,i.p.)wasalsoshownbyA.Choderaet
al.(1985)tohavediureticactivity,equivalenttoabout75%ofthefurosemideeffect[9,130].Thesame
authorshavedemonstratedthatthei.p.routeresultsinhigherefficacy(about30%)thantheoral
route,thatithasaslowonset(around5h),anditlastsforupto24h[9,119,131].Theaglyconepartof
theglycoside(leiocarpicacid)isdevoidofdiureticactivity(atthesamedose,25mg/kgi.p.)[9,132].
Besidestheassumeddiureticeffects,S.virgaureahasbeendeclared“theplantthatismost
frequentlyextractedtoyieldpreparationsforthetreatmentofbladderdysfunctionincludingthe
overactivebladdersyndrome”[31].Inthissense,clinicaldatainpatientswithdysuriahaveclaimed
thatS.virgaureareducesthefrequencyofurination(aswellasthepainassociatedwithit).Ina
relativelylarge(n=512patients),butopen‐labelanduncontrolledstudyofpatientswithchronic
recurrentoveractivebladder,96%ofthesubjectsreceiving424.8mgofS.vigraureaextract,t.i.d.,
reportedanimprovementintheclinicalglobalimpressionandasignificantdropinpainful
micturitionandintheneedtourinate[133].Inasmallerstudy(n=74),alsoopen‐label,carriedout
onfemalepatientswithdysuria,areductionofthesamesymptomswasobservedin69%ofthe
patients[133].Theseresultsaresomewhatpuzzlingbecausediureticstendtoratherincreasethe
frequencyofurination,butthediureticdatacomefromnon‐clinicalstudieswithanisolated
compound(leiocarposide)ortheflavonoidfraction,andnotwithanextractassuch.Ontheother
hand,theopen‐labelcharacterandthelackofacontrolgroupindicatealowqualityofthesedataand
strongerevidenceisneededtoconcludeontheeffectS.virgaureahaveontheurinarytract.Invitro
datahavedemonstratedthatextractsoftheplanthaveanti‐muscariniceffectsontheM2andM3
receptors,whichresultsintheinhibitionofthebladdercontraction[31].
Leiocarposide(25mg/kgp.o.)administeredforsixweekssignificantlyinhibitedthegrowthof
human‐derivedurinarycalculitransferredintotheratbladder[57].
6.6.AntibacterialActivity
Aninvestigationoftheantibacterialpotentialoftwoextracts,onealcoholicandonelipophilic
(withhexane),foundthatthealcoholichadthelowestMICforStaphyllococcusaureus,whereasthe
lipophiliconeforS.aureusandP.aeruginosa[134].TheMICvaluesvariedbetween2.95and11.8
mg/mLfortheethanolic;forthehexaneextract,MICwas3.5mg/mLforStaphyllococcusaureus,
Staphyllococcusfaecalis,andPseudomonasaeruginosa,andhigherthan3.5mg/mLfortheother
microorganismstested[134].Althoughvalueslowerthan16mg/mLhavebeenconsideredsometimes
asshowingastrongantibacterialeffect[135],otherauthorshaveusedmorestringentcriteria:MIC
values<100 μg/mLhavebeenproposedtobehighlyactive,thosebetween100and500 μg/mLactive,
thosebetween500and1000μg/mLmoderatelyactive,thosebetween1000and200μg/mLoflow
activity,andthosewithMIC>2000 μg/mLinactive[136,137].Ithasalsobeensuggestedthatinorder
to“beconsideredapromisingactivity,acrudeextractmustdemonstrateaMICunder100μg/mL”
(andapurecompoundlessthan16μg/mL)[138].Otherstudieshavealsoassessedvariousextracts
fortheirantimicrobialeffects,butMICorMBC(minimalbactericidalconcentration)wasalsoformost
specieshigherthan2000μg/mL[139–141].Inthelightofthesecriteriafromtheliterature,the
activitiesobservedinthisstudyarenot“promising”andbecausetheyarehigherthan2000μg/mL,
shouldratherbeconsideredinactive.
Inastudycomparing(amongothers)theethanolandaqueousextractsobtainedfromleavesand
stemsofS.virgaurea(agardiscdiffusionmethod),inhibitionzonesweredetectedonlyfortheethanol
extractandonlyonBacillussubtilis,Micrococcusflavus(Gram‐positive),andtheGram‐negative
Morganellamorganii[142].Anotherstudyalsoreportednoinhibitoryeffectonseveralmicrobial
speciesofanaqueousextract[72].Ithasbeensuggestedthatinhibitionzonessmallerthan9mm
shouldbeconsideredinactive,thoserangingbetween9and12mm,moderatelyactive,thoseranging
between13and18mm,active,andthoselargerthan18mmshouldbeclassifiedasveryactive
[136,143].Since,inthisstudy,allinhibitionzoneswerelessthan9mminsize[142],theethanolextract
shouldalsoberegardedasvirtuallyinactive.A.BrantnerandJ.Grein(1994),though,reported