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Abstract and Figures

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.
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Biomolecules2020,10,1619;doi:10.3390/biom10121619www.mdpi.com/journal/biomolecules
Review
SolidagovirgaureaL.:AReviewofIts
EthnomedicinalUses,Phytochemistry,
andPharmacologicalActivities
CorneliaFursenco
1,2,†
,TatianaCalalb
1,†
,LiviaUncu
2,3
,MihaelaDinu
4,
*andRobertAncuceanu
4
1
DepartamentofPharmacognosyandPharmaceuticalBotany,FacultyofPharmacy,NicolaeTestemitanu
SUMPh,66MălinaMicăStreet,MD2025Chisinau,Moldova;cornelia.fursenco@usmf.md(C.F.);
tatiana.calalb@usmf.md(T.C.)
2
FacultyofPharmacy,ScientificCenterofMedicines,NicolaeTestemitanuSUMPh,66MălinaMicăStreet,
MD2025Chisinau,Moldova;livia.uncu@usmf.md
3
FacultyofPharmacy,Departamentofpharmaceuticalandtoxicologicalchemistry,NicolaeTestemitanu
SUMPh,66MălinaMicăStreet,MD2025Chisinau,Moldova
4
DepartmentofPharmaceuticalBotanyandCellBiology,FacultyofPharmacy,CarolDavilaUniversityof
MedicineandPharmacy,6TraianVuiaStreet,Sector2,020956Bucharest,Romania;
robert.ancuceanu@umfcd.ro
*Correspondence:mihaela.dinu@umfcd.ro
Denotesequalcontribution.
Received:13October2020;Accepted:26November2020;Published:30November2020
Abstract:SolidagovirgaureaL.(Europeangoldenrod,Woundwort),Asteraceae,isafamiliar
medicinalplantinEuropeandotherpartsoftheworld,widelyusedandamongthemostresearched
speciesfromitsgenus.TheaerialpartsofEuropeangoldenrodhavelongbeenusedforurinarytract
conditionsandasanantiinflammatoryagentinthetraditionalmedicineofdifferentpeoples.Its
mainchemicalconstituentsareflavonoids(mainlyderivedfromquercetinandkaempferol),C6C1
andC6C3compounds,terpenes(mostlyfromtheessentialoil),andalargenumberofsaponin
molecules(mainlyvirgaureasaponinsandsolidagosaponins).Publishedresearchonitspotential
activitiesiscriticallyreviewedhere:antioxidant,antiinflammatory,analgesic,spasmolitic,
antihypertensive,diuretic,antibacterial,antifungal,antiparasite,cytotoxicandantitumor,
antimutagenic,antiadipogenic,antidiabetic,cardioprotective,andantisenescence.Theevidence
concerningitspotentialbenefitsismainlyderivedfromnonclinicalstudies,someeffectsarerather
modest,whereasothersaremorepromising,butneedmoreconfirmationinbothnonclinical
modelsandclinicaltrials.
Keywords:SolidagovigaureaL.;Europeangoldenrod;asteraceae;ethnomedicinal;phytochemistry;
distribution;pharmacologicalactivity
1.Introduction
ThegenusSolidagoincludesabout190speciesandinfraspecifictaxons(subspeciesandvarieties)
withanacceptedstatusandabout330speciesandintraspecifictaxonswithanambiguousstatus[1].
Theyarewidespreadthroughouttheworld,mostofthemoriginatingfromNorthAmericaor
confinedtothispartoftheworld[2].MostofSolidagospeciesareherbaceousfloweringplants,which
occurinthespontaneousfloraorarecultivatedasdecorativeplants[3].Rawmaterialsofgoldenrods
havealongandwideusehistoryinthetraditionalmedicineofdifferentpartsoftheworld:S.
virgaureaL.(Europeangoldenrod)isthemostusedinEuropeandAsia;S.canadensisL.(Canadian
goldenrod),S.giganteaAiton(Giantgoldenrod),andS.odoraAiton—inNorthAmerica;S.chilensis
Biomolecules2020,10,16192of31
MeyeninSouthAmerica[4,5].AccordingtotheFloraEuropaea,onthecontinent,thereare5
representativesofthegenusSolidago:S.virgaureaL.,S.canadensisL.,S.giganteaAiton.,S.altissimaL.,
andS.graminifoliaL.Salisb.)[6].Today,S.graminifoliaisconsideredasynonymforEuthamia
graminifolia(L.)Nutt.[7].S.canadensisandS.gigantea,althoughofNorthAmericanorigin,have
becomewidespreadacrossEuropeandareconsidered“seriousinvaders”,whereasS.rugosa,ofthe
sameorigins,hasbeenreportedonlyinafewWesternEuropeancountries[8].
TheaerialpartsofEuropeangoldenrodhavebeenknownandusedforcenturiesasanti
inflammatory,spasmolytic,anddiureticremediesinthetraditionalmedicineforthetreatmentof
numerousdiseases,especiallyasaurologicalagentinkidneyandbladderinflammation,urolithiasis,
andcystitis[3,4,8–12].AccordingtotheEuropeanMedicinesAgency,S.virgaureaisoneofthemost
usedandstudiedspeciesoftheSolidagogenusinEurope[9].
ThegrowinginterestforthespeciesS.virgaureaasamedicinalplantledustocarryoutthis
reviewusingthemostrelevantandrecentinternationalresearchstudies.Thescientificcommunity
interestinS.virgaureaisbooming.Figure1depictsthecumulativenumberofarticles(totalof580)
publishedonS.virgaureaintheperiod1944–2020.Forthispurpose,twowellknownandworldwide
appliedscientificdatabases(MEDLINE(PubMed)andHINARI),aswellasGoogleScholar,were
used.Thenumberofpublishedpaperonthisspecieshasescalatedinthelasttwodecades(2000–
2020).
Figure1.CumulativenumberofcitationsonS.virgaurea.Source:PubMed.
2.GeneralDescription,Taxonomy,andDistribution
S.virgaureaisaperennialherbprovidedwithanoblique,woodyrhizome,ofacylindricalshape
anddevoidofknots,onwhichstemscarsarevisible(Figure2A).Theround,erectstemmayachieve
aheightofupto1m,andisramifiedandpubescentatthetopside.Theleaves,withanalternate
arrangement,aresimple,slightlypubescentontheadaxialface,andpubescentontheabaxialone.
Basalleaveshaveovateorovateellipticbladeswithanacutetipandawingedpetiole,whereasupper
leaveshaveshortstalksandlinearlanceolateorellipticblades,withmarginseitherserratedorentire
(Figure2B,C).Theradiateflowerheadshavemorphologicallydistinguishedray(female,tonguelike)
anddiscyellowflorets(hermaphrodite,tubular).Theflowerscapitulaaregroupedinasimpleraceme
orinpanicles(Figure2D).Thereceptacleisglossyandflat.Thefruitisacylindricallyshapedachene,
with8–10ribsandapappusderivedfromthemodifiedcalyx[13].
Biomolecules2020,10,16193of31
Arecentmorphoanatomicallocalstudyfocusedonthemorphologicalandanatomical
investigationofS.virgaureafromfloraoftheRepublicofMoldova,anditsherbalproductSolidaginis
virgaureaeherba,wasdonebyCalalbT.etal.[13].Theanatomicalfeaturesofthehighestinterestfor
theexactidentificationofS.virgaurea,establishedinthisstudy,include:repartitionofstomataon
bothsidesoftheleaf,anomocyticarrangementofstomata,coneshapedorfanshapedmulticellular
trichomesonbothepidermises,aswellasglandulartrichomes,dorsiventralstructureoftheleafwith
vascularbundlescollateralandopen,andsecretoryductsinthestem.Theanomocyticstomata
reportedfortheleafisconsistentwiththefindingsofSzymuraM.andWolskyK.[14],whoalso
establishedthatanomotetracyticstomatawerethemostwidespreadtypeinotherSolidagotaxa
collectedfromPoland.Thepresenceoftwocategoriesofmulticellulartrichomes(coneshapedand
fanshaped)onthegoldenrodleafwasalsoreportedbyothersources[14,15]:byBuynovMV.onS.
dahuricaleaf[16],byDouglasM.etal.onS.chilensisleaf[17],andbyFedotovaVV.onS.caucasicaleaf
[18].Careisneededforacorrectidentification,becauseinthe19thcentury,ascientificpaperwritten
byamedicaldoctor(basedonhispersonalexperiencerepeatedseveraltimes)drewtheattentionto
therisksofconfusingthismedicinalplantwithanoneffective(andlikelydangerousforthehealth)
SenecionemorensisL.[19]
Figure2.S.virgaurea(originalphoto):(A)obliquerhizome,(B)basalleaves,(C)caulineleaves,(D)
radiateflowerheads.
Accordingtoanumberofsources[20,21],S.virgaureaisregardedasataxonomicgroupor
complex,anditconsistsofperennialherbaceousspeciesextensivelydistributedfromEuropetoEast
Asia.Asagroup,itisgenerallydividedlongitudinally:inEuropethegenusisrepresentedbyS.
virgaureaL.,inSiberiaandmostoftheFarEastbyS.dahurica(Kitag.)Kitag.exJuz.TogetherwithS.
spiraeifoliaFisch.exHerder,whereasintheFarEastregionofRussia,knownasChukotkaandin
NorthAmerica,thegenusisrepresentedbyS.multiradiataAit.[22].
TheEuropeanS.virgaureaL.hasbeendescribedas“anexceedinglypolymorphictaxon”,anda
multitudeofnarrowlyrelatedtaxahavebeenincludedwithinitatdifferentlevels(varieties,
subspecies,andevenspecies)[22,23].InaEuropeancountry(CzechRepublic)flora,discussingthe
variability,S.Slavik(2004)hasidentified17taxaasbelongingtotheS.virgaureaL.group(leaving
asidetaxafromJapan),ofwhichanumberofsixarequalifiedassubspecies,whereasanumberof
elevenas“microspecies”[22,24]).TheAtlasoftheBritishandIrishflora[25]describesS.virgaureaas
highlyvariable,withmanydistinctformsfordistincthabitats(ecotypes).Strongcorrelationshave
beenclaimedbetweenS.virgaureagenotypesandtheirgeography,andastrongabilitytorapidly
evolveandecologicallydiversifyhasbeenrecognizedforthespecies[26].
Biomolecules2020,10,16194of31
3.SynonymsandCommonNames
AccordingtotheAssessmentReportonSolidagovirgaurea,realizedbytheEuropeanMedicines
Agency[9]andtheWorldFloraOnline[1],themainsynonymsinuseare:Amphiraphisleiocarpa
Benth.,AmphiraphispubescensDC.,Astervirgaurea(L.)Kuntze,DectisdecurrensRafin.(Lour.),and
DoriavirgaureaScop.S.patagonicaPhil.iscurrentlyanacceptedname[1],althoughitwasreported
thatoneArgentinespecimenidentifiedasS.patagonicawasinfactanescapedcultivarofS.virgaurea
[27].
ThemostoftenusedcommonnameforS.virgaurea,aswellasforotherSolidagospeciesis
goldenrod.Sometimesthe“European”qualifierisaddedtothisvernacularnameandinthispaper,
inordertoavoidconfusionwithotherspeciesofthegenus,wewillhereafterusethisname(European
goldenrod).AccordingtotheAmericanBotanicalCouncil,othercommonnamesinuseare:Solidago,
Virgaurea,Woundwort,Aaron’srod,andYellowweed[28].Thedriedfloweringabovegroundparts
arethesubjectofaEuropeanherbalmonograph[29].
4.EthnomedicinalUses
S.virgaureahasadiversityofmedicinalusesintheterritorieswhereitisspread.Probablyits
mostwidelyknownethnopharmacologicalusesarerelatedtokidneydisorders(beingoftenfoundin
teasintendedtohelppasskidneycalculi),urinarytractinfections,theoveractivebladdersyndrome,
andprostaticdiseases[30–32],theurologicusesoftheplantgoingbackatleasttothewritingsof
ArnoldvonVillanova(1240–1311)[33].Traditionally,theaerialpartsoftheplanthavebeenusedfor
healingandantisepticproperties[9],aswellasforthetreatmentofdiabetes,allergies,andgastro
intestinaldisorders[8,32].Likewise,infusionsordecoctionspreparedfromEuropeangoldenrodis
usedinthetraditionalmedicineinmanypartsoftheworldforitsantibacterialandantiinflammatory
effects[34],includinginflammationoftheoralcavityandthroat,whenusedasamouthrinse[32].
FurtherscientificstudieshaveshownthegrowingimportanceofEuropeangoldenrodasasourcefor
herbaldrugs[35].InmanyEuropeancountries,theherbalproductderivedfromthespecieshasoften
beenincombinationproducts[9].
4.1.Germany
HieronymusBock(1498–1554),oneofthefirstmodernbotanistsinGermany,conjecturedthat
Germanictribeshadbeenusingtheplantformedicinalpurposes,mentioningthattheyregardedit
asa“miracleherb”(Wunderkraut)[36].ItisbelievedthattheGermanfatherofReformation,Martin
Luther(14381546),hadagoodopinionongoldenrodanduseditoftentocareforhisphysical
infirmities[33].Oneofthefirstreportsonitsdiureticandantiinflammatoryeffectsareascribedto
the“fatherofGermanbotany“(1525–1590),JacobusTheodorusTabernaemontanus[37],whostated
thatit“alsocleansesthekidneysandurinarytractofallcoarsemucus”[36].ThenameHeydnisch
Wundkraut(heathenwoundwort),employedintheGermanterritoriesduringtheMiddleAgesfor
theplant,evokesthehealingpropertiesoftheherb.AnothervernacularGermanname,Unsegenkraut
(curseherb),indicatesbeliefatthattimeinitsmagicabilities,inanerawherediseasewasoften
attributedtowitchcraftandmetaphysicalcauses,andindirectlythenamemightstillpointtowards
itspotentialmedicinalproperties[38].InGermanfolkmedicine,goldenrodwasusedforthe
treatmentofurinaryretention,kidneystones,andhemorrhoids[36].Sincethemiddle19thcentury,
itsusewasslowlyforgotteninGermany,toberevivedonlyrelativelyrecentlywiththerenewed
interestfortheherbaltherapy[36].
Currently,awellestablisheduseisacceptedinGermanyforinflammatorydiseasesofthe
urinarytractcollectionsystem,urolithiasisandrenalgravel.Avarietyofextractsareused,
particularlydriedextractsobtainedfromtheaerialparts(Solidaginisvirgaureaeherba)using30–60%
ethanolasanextractionsolvent[9].AmonographofthespecieswasintroducedinDABin2002,
whichalsoacknowledgedS.canadensisandS.giganteaasvalidspecies,despitecertaindifferencesin
thespectrumoftheirphytochemicals[33].
Biomolecules2020,10,16195of31
4.2.CzechRepublic
TheherbaldrugobtainedfromS.virgaureaisincludedintheCzechPharmacopoeia2009[39].A
drinkobtainedfromtheaerialpartsoftheplantisusedasanadjuvanttreatmentininflammatory
conditionsoftheurinarysystem,aswellasforthepreventionofkidneyandbladdercalculi[9].Itis
notclear,though,whethersuchusesrepresentanoldCzechtradition,asaCzechpaperonthespecies
onlycitedforeignsourceswhenreferringtothetraditionalmedicinaluseofthespecies[39].
4.3.Poland
Traditionally,theinfusionpreparedofdriedaerialpartsofS.virgaureahasbeenusedasa
diureticandasanadjuvantintreatmentofminorcomplaintsoftheurinarytract[9].InaPolish
source,itisstatedthatrawmaterialofthisherbischaracterizedbydiuretic,detoxifying,anti
inflammatory,andbilesecretionenhancingproperties[35].APolishsourcementionsitsdisinfectant
propertiesasthemostimportantamongthetraditionaluses,butalsoitsusefuleffectsinaccelerating
woundhealingandinskincare[40].
4.4.RussianFederation
InRussianfolkmedicine,Europeangoldenrodisusedforavarietyofconditions,fromgallstone
diseasetoindigestion,andfromrheumatismtogout.Forexternaluse,freshleavesarerecommended
inabscessesandboils[41].OtherRussiansources[35,42]statethatmostcommonusesofthisspecies
includepreventionandtreatmentofvariousdiseasesofthekidneys,bladder,andprostategland(i.e.,
thetraditionalusemostwidelyacknowledgedinEurope).IntheRussianfolktradition,theEuropean
goldenrodisalsoknownasahemostaticandastringentagent,aswellasagoodremedyfor
respiratorydiseases(tonsillitis,laryngitis,acuterespiratorydiseases),gallstonediseases,and
pulmonarytuberculosis[41].
4.5.Ukraine
TheuseintuberculosisisalsowellestablishedintheUkrainefolkmedicine,wherethenameof
theplant,zolotushnik,alludestoitsuseindecoctionsas“agoodremedyagainstscrofula(zolotukha)”,
buttheplantwasalsobelievedtohavediureticeffects[43].
4.6.Bulgaria
AccordingtoaBulgariansource,theaerialpartsofS.vigaureaL.areusedasadiuretic,
antihypertensive,andexpectorant,aswellasinthetherapyofrenaldeficiencyandgout[44].
4.7.RomaniaandtheRepublicofMoldova
S.virgaureahasalonghistoryofuseintheRomaniantraditionalphytotherapy.Theherbal
productSolidaginisvirgaureaeherbahasbeenusedinherbaltherapyandmarketedbyspecialized
outletssince1990[45].Ethnopharmacologicalusesofthisplantaremostlyrelatedtomaintainingthe
healthoftheurinarytractandthenormalfunctioningofthedigestivesystem.Traditionally,itis
recommendedasadiuretic,saluretic,antiinflammatory,antiseptic,healing,orasedativeagent.For
externaluse,themostcommonapplicationconsistsinadministeringaninfusionordecoctionofthe
aerialpartsorbloomingtopsinthetreatmentofwoundsorulcersoftheoralcavity[46,47].The
externaluseinrickets,alsoacknowledgedbyRomaniantraditionalsources[48],doesnotseemto
havegreatbenefit,consideringthecurrentknowledgeofthisdiseaseanditscauses.
4.8.Korea
TherootandaerialpartsofS.virgaureasubsp.gigantea(Nakai)Kitamhavebeenusedasan
appetitestimulantanddiureticinKoreanfolkmedicine,whereastheimmatureaerialpartsareused
inthesameareaasfood[49,50].
Biomolecules2020,10,16196of31
4.9.China
Decoctionsobtainedfromthewholeplantwereusedfortheirantibacterialactivity,andin
respiratorytractinfectionsforitsexpectorantandantiinflammatoryproperties[51].
4.10.OtherUses
Besidesitsmedicinaluses,S.virgaureahasbeenrecognizedasafirstclassalternativesourcefor
thefloriculturebusiness,bothontheoldcontinentandinthenewworld[32].Ithasalsobeen
proposedtobeusedasarotationcropasameansofcontainingnoxiousweedsinanorganic
agriculturecontext[35].Solidagospp.,includingS.virgaurea,havebeenclaimedtohavepotential
utilityforphytoremediationpurposes,basedontheirabilitytotransferironfromsoiltoplantsnear
ironprocessingindustrialsites[35];however,studiesonotheroligoelements(suchaszinc)havenot
identifiedparticularhyperaccumulatorpropertiesfortheplant[52],andwhereasanumberofpapers
havebeenpublishedonthephytoremediationpotentialofS.canadensis[53,54],wecouldfindnone
onS.virgaurea.Thepollenofthelatterisofgoodquality,anditsavailabilitymaycontributetolong
livedbeesbeingabletosurviveahardwinter[55].
5.Phytochemistry
ExtractsofS.virgaureacontainC6C1glycosides(virgaureoside,leiocarposide)andaglycones
(vanillicacid,gallicacid)[4,9,56–58],C6C3polyphenolicacids(caffeic,chlorogenic,ferulic,synapic,
3hydroxyphenylaceticacid,3,4dihydroxyphenylacetic,homovanilic,acids)[3,9,10,45,53–57],a
numberofflavonoidmolecules(mostlyquercetinandkaempferolglycosides,aswellasthefree
aglyconsandsmallamountsofcyanidinderivatives)[3,4,9,45,49,59–65],oleananetypetriterpene
saponins[9,66–73],essentialoilscontainingmonoterpenes(alphaandbetapinene,myrcene,
limonene,sabinene)[35,74–77]andsesquiterpenes(germacreneDβ‐caryophyllene,αhumulene,),
clerodanetypediterpenes[78],polysaccharides[79],andpolyacetylenes[80](Table1).TheEuropean
PharmacopoeiamonographforSolidaginisvirgaureaeherbaregardsflavonoidsasqualitymarkersand
fortheproductrequiresacontentofatleast0.5%andmaximum1.5%,expressedashyperoside[81].
Table1.ChemicalcompoundsidentifiedinS.virgaurea.
ChemicalCompoundsPlace/CountryofCollectionReferences
Flavonoids(Figure3)
Quercetin,
Quercetin3Oglucoside(isoquercitrin)
Quercetin3Ogalactoside(hyperoside)
Quercetin3Orhamnoside(quercitrin)
Quercetin3Orutinoside(rutin)
Quercetin3Oarabinopyranoside(avicularin)
Kaempferol3Oglucoside(astragalin)
Kaempferol3Orhamnoside(afzelin)
Kaempferol3Orutinoside(nicotiflorin)
Kaempferol3Orobinobioside(biorobin)
Myricetin3rhamnoside(myricitrin)
Isorhamnetin3Orutinoside(narcissin)
Cyanidin3gentiobiosidemonoC
glycosylflavones(?)
diCglycosylflavones(?)
Poland,Italy,Hungary,
Korea,Romania,Lithuania
FuchsL.[82],
BudzianowskiJ.etal.
[61],
BorkowskiB.and
SkrzypczakowaL.[60],
ChoderaA.etal.[65],
RoslonW.etal.[59],
PiettaP.etal.[62],
ApátiP.etal.[83],
ChoiSZ.etal.[49],
TamasM.[63],
DobjanschiL.etal.
[45,64],
KraujalieneV.etal.[84]
C6C1Compounds(Figure4)
Biomolecules2020,10,16197of31
Benzoicacid
3Hydroxybenzoicacid
4Hydroxybenzoicacid
3,4Dihydroxybenzoic(protocatechuic)acid
Salicylicacid
Gentisicacid
Vanillicacid
Gallicacid
Leiocarposide
2methoxybenzyl2,6dimethoxybenzoate
Poland
Egypt
Korea
KalembaD.[85],
AbdelMotaalA.etal.
[10],
ChoiSZ.etal.[49],
Thiem,B.etal.[58],
BajkaczS.etal.[86],
SungJHetal.[50],
C6C2andC6C3Compounds(Figure5)
Caffeicacid,
Chlorogenicacid
5Ocaffeoylquinic(neochlorogenic)acid
3,5diOcaffeoylquinicacid
3,4diOcaffeoylquinicacid
4,5diOcaffeoylquinicacid
3,4,5triOcaffeoylquinicacid
Methyl3,5diOcaffeoylquinate
3hydroxyphenylaceticacid3,4
dihydroxyphenylaceticacid
5pCoumaroylquinicacid
Homovanilicacid
pCoumaricacid
Ferulicacid
Sinapicacid
Rosmarinicacid
Poland
Egypt
Korea
Iran
KalembaD.[85],
AbdelMotaalA.etal.
[10],
ChoiSZ.etal.[49],
ThiemB.etal.[58],
BajkaczS.etal.[86],
HaghiG.,HatamiA.[87],
RoslonW.etal.[59],
KraujalienėVetal.[84],
M.Marksaetal.[88],
D.Fraisseetal.[89],
BorkowskiB.and
SkrzypczakowaL.[60],
JaiswalR.etal.[90]
Coumarins
7hydroxycoumarin(umbelliferone)CzechRepublicDobiasP.etal.[91]
TerpeneDerivatives(Figure6)
α‐Pinene,
β‐Pinene,
Sabinene
Myrcene
Limonene
β‐Ocimene
GermacreneD,
β‐Caryophyllene,
α‐Humulene,
Clerodanediterpenes
2,8(cis)(cis)MatricariaesterMatricariaγ‐
lactones
Lachnophyllumlactone
entgermacra4(15),5,10(14)trien1β‐ol
β‐dictyopterol
Poland,Japan,
Italy,
RussianFederation,
USA
Denmark
Korea
KalembaD.[74],
KalembaD.andThiemB.
[75],
FujitaS.[76],
BertoliA.etal.[77],
TkachevAV.etal.[35],
GoswamiAetal.[92],
StarksCM.etal.[78],
LamJ.[80],
ChoiS.[49]
Saponins(Figure7)
Virgaureasaponins1–6
SolidagosaponinsXXXIX
BellisaponinBA2
Erythrodiol3acetate
Germany,
France,Romania
Japan
BaderG.etal.[34,56–59],
ChevalierM.etal.[86],
LaurençonL.etal.[61],
DobjanschiL.etal.[85],
InoseY.etal.[60],
SungJHetal.[50]
CarbohydratesandOther
Compounds
Polysaccharides
α‐tocopherolquinone
2phyten1ol
RussianFederation
Korea
PychenkovaPA.[66],
SungJHetal.[50]
Biomolecules2020,10,16198of31
Ithasbeenspeculated[3]thatanumberoftheactivecompoundsofS.virgaureaextracts
(leiocarposide,polyphenolicacids,flavonoids,saponins)exertasynergisticactivityindisplayingthe
reportedantiinflammatoryeffectsoftheproduct[56,93].Theantioxidantactivityhasbeenattributed
tothepolyphenoliccompounds[3,94–96],whileflavonoidsarethoughttoberesponsibleforthe
spasmolyticeffects[3,31,97].
5.1.Flavonoids
Amongtheflavonoids,rutin,quercetrin,astragalin,nicotiflorin,biorobin,andnarcissinhave
beenconsidered“themostrepresentative”[62],andtheyareaccompaniedbytheiraglycons[49,84].
Morerecently,flavanonesaglyconesandglycosideshavealsobeendetectedandquantifiedinthe
differentpartsoftheplant:eriodictyol(thelargestamountintheflowers,followedbyleavesand
thenstems,mostlyasglycosides),naringenin(similarquantitativedistributioninflowers,leaves,and
stems,mostlyasglycosides),andverysmallamountsofhesperitin(notassessedseparatelyineach
aerialparts)[98].EriodictyolandnaringeninarepresentintheformofbothRandSenantiomers,
whereashesperitinwasdetectedonlyastheSenantiomer[98].Allflavonoidheterosidesseemtobe
3Oglycosides,asforthemajorityofSolidagospecies(thenotableexceptionbeingS.graminifolia(L.)
Salisb,inwhichmono‐anddiCglycosylflavonoidshavealsobeenreported[58],butwhichnowis
consideredasynonymfortheEuthamiagraminifolia(L.)Nutt[1]).ThepresenceofflavonoidC
heterosidesinS.virgaureahasalsobeenoccasionallyclaimedinsecondarysources[59],butwecould
notlocateaprimaryreferencereportingthem.Cyanidin3gentiobiosideisthemainanthocyanin
presentintheleaves,butatleastoneothercyanidingglycosydewasreportedinverysmallamounts
[99].Flavonoidglycosidestendtobebetterextractedinethanolof70%orhigherconcentrations[83].
Asmentionedabove,hyperosideisconsideredthekeyflavonoidbytheEuropeanPharmacopoeia
[81].However,inonepaper,quercitrinwasthemajorphytochemicalfromaquantitativestandpoint
[84],whereasothersourcesreportedrutinasthedominantflavonoid[59,60](ameancontent196.42
mg100g1reportedby[59]).Aqualitativeandquantitativecomparativestudyofflavonoidsfrom
extractsoffourSolidagospp.reportedinRomanianflorawascarriedoutbyDobjanschiL.etal.
[38,49],whofoundatotalflavonoidcontentforS.virgaureaof4.06%,expressedasrutin.Theyalso
foundthatforS.virgaurea,specificwasthepresenceofrutinandhyperoside,whereasquercitrin
(unlikethefindingsofV.Kraujalienėetal.)wasabsent[45,64].Spasmolyticeffects(asdiscussed
below)[31,97],diureticactivity[10],havebeenattributedtotheflavonoids,andothereffectshave
alsobeenspecificallyascribed(atleastpartially)tosomeflavonoids,e.g.,antiadipogeniceffectsto
kaempferol3Orutinoside[100].
Biomolecules2020,10,16199of31
Figure3.RepresentativeflavonoidsfromS.virgaureaL.
5.2.C6C1Compounds
SeveralmaincompoundswithaC6–C1haveapparentlybeenreporteduptodateinS.virgaurea,
twoglycosidesandtwoaglycones:virgaureosideA,abisdesmosidicglycosidederivedfrombenzoic
acid(2betaDglucopyranosyloxybenzoicacid2′‐betaDglucopyranosyloxybenzylester)[101],
leiocarposide(2′‐hydroxybenzyl3methoxybenzoate2,4diglucoside)[56],vanillicacid,gallicacid
[9,102],benzoicacid,3hydroxybenzoicacid,4hydroxybenzoicacid,3,4dihydroxybenzoic
(protocatechuic)acid,and2,5dihydroxibenzoic(gentisic)acid[85,86].Suchderivativesofthe
benzoicacidareoftenoccurringinthefamilyAsteraceae[103].
Asomewhatdetailedhistoryofthediscoveryofthetwophenolicglycosideswasprovidedby
L.Skrzypczaketal.[103].Leiocarposideiscurrentlyconsideredthemostimportantandwasfound
tobemaximallybiosynthesizedintheflowerbuds(1.60%)andinthetwoyearleaves,postblooming
(1.05%)[104].Similarcontents(0.4–1.6%)werereportedbyotherresearchers,dependingonanumber
Biomolecules2020,10,161910of31
ofvariablessuchasplantheightatharvest,collectiontime,orthenaturalstateoftheherbalsamples
[58].Leiocarposidehasattractedinterestforitspharmacologicalpotential,beingexploredforits
hypothesizedantiinflammatory,analgesic,antilithiatic,anddiureticeffects,asdiscussedbelow.For
plantscultivatedinvitro,thecontentofleiocarposideislowerthanthatofnaturallygrowingplants
(0.18%vs.0.2–1.0%)[58].
Figure4.C6C1compoundsfromS.virgaureaL.
5.3.C6C2andC6C3Compounds
AvarietyofC6–C3phenolicacidshavebeenidentifiedindifferentstudies.Amongthemost
importantarethecaffeoylquinicderivatives(chlorogenicacid,butalso5Ocaffeoylquinic
(neochlorogenic)acid,5pcoumaroylquinicacid,3,5diOcaffeoylquinic,3,4diOcaffeoylquinic,
4,5diOcaffeoylquinicacids,methyl3,5diOcaffeoylquinate,and3,4,5triOcaffeoylquinicacid,
thelattershowingsuperiorantiinflammatoryeffectsoverthedicaffeoylquinicderivatives.)
[10,49,58,59,86,90].Caffeic,pcoumaric,ferulic,sinapic,3hydroxyphenylacetic,3,4
dihydroxyphenylacetic(DOPAC),andhomovanilicacidswerealsoreportedinphytochemical
studiesofS.virgaureaL[86].Inonestudy,whereaschlorogenicacidwasdetectedandmeasured(by
HPLC),ellagicandrosmarinicacidscouldnotbedetected[87].Chlorogenicacidcontentmayvary
considerably,asshowninonestudythatmeasureditinsamplescollectedfrom20sites,whichfound
concentrationsaslowas158.99mg/100gandashighas441.50mg/kg[59].Similarly,rosmarinicacid
variedinthesamestudybetween256.38mg/100gand898.70mg/100g[59],whereas(asmentioned)
inadifferentstudy,itcouldnotbedetectedatall[87].Asalreadydiscussedintheliterature[88],a
numberofvariables,suchastheherbalpart,ontogeneticdevelopmentstage,andambientconditions
haveaconsiderableinfluenceonthequalitativeandquantitativecontentinphenoliccompoundsof
thespecies.
Biomolecules2020,10,161911of31
Figure5.C6–C2andC6–C3compoundsfromS.virgaureaL.
5.4.Coumarins
Uptodate,asinglepaper[91]reportedthepresenceofacoumarinecompoundinSolidago
virgaurea:umbeliferone(7hydroxycoumarin).Esculetinandscopoletinwerenotdetectedinthe
species[91].
5.5.TerpeneDerivatives
Anumberofover60compoundshavebeendescribedintheessentialoilobtainedfromthe
floweringtopsofS.virgaureaLcollectedinPoland[74],whereasinspecimensfromLithuania,106
compoundswereidentifiedinflowersand95inleaves[105].Thekeycompounds(asfoundinthree
samplesfromthreedifferentsitesofPoland)werethemonoterpenesα‐pinene(27.4–34.1%),myrcene
(7.8–17.9%),βpinene(5.4–7.5%),limonene(3.0–14.1%),andsabinene(0.4–11.8%),aswellasthe
sesquiterpenesgermacreneD(8.2–17.0%),andinsmalleramountsα–humulene,βcaryophyllene,
andα–muurolene[74].InLithuaninspecimens,thecompositionreportedrecentlywasrather
different:intheleaves,themostimportantcompoundsdetectedwerecaryophylleneoxide,trans
verbenol,spathulenol,humuleneepoxideII,α–pinene(only5.21%),andgermacreneD;inflowers
ofthesameorigin,themostimportantcompoundswerecaryophylleneoxide,humuleneepoxideII,
germacreneD,transverbenol,spathulenol,andbornylacetate[105].Detailedinformationonthe
chemicalconstituentsoftheessentialoilispresentedinTable2.
Biomolecules2020,10,161912of31
Table2.DetailedcompositionoftheessentialoilobtainedfromS.virgaureaL.floweringtops.
CompoundProportion(%)Reference(s)
α‐Pinene0.47–36.5[35,76–78]
Camphene0.02–0.6[35,76–78]
Sabinene0.06–11.8[35,76–78]
Myrcene0.05–17.9[35,76–78]
β‐Pinene0.16–13.3[35,76–78]
3Carene0.1–0.7[35,76]
α‐Terpinene Tr.*–0.3[76]
Limonene0.07–14.8[35,76–78]
pCymene Tr.*–0.77[76–78]
(E)‐β‐Ocimene 0.02–4.7[35,76,78,79]
Linalol0.3–0.8[76]
NonanalTr.**–1.4[76,77]
transVerbenolTr.*–0.7[76,77]
transPinocarveol0.09–0.2[76,77]
Decanal0.04–0.7[35,76,77]
Terpinen4ol 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]
pCymen8ol 0.03–0.51[76,78]
transCarveol 0.05–0.3[76,77]
Myrtenal Tr.*–0.06[76,77]
Geraniol0.02–0.45[76,78]
VerbenoneTr.*–0.6[76,77]
α‐Cubebene Tr.*–2.35[76–78]
δ‐ElemeneTr.*–9.38[35,76–78]
Bornylacetate0.13–4.52[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]
GeranylacetateTr.*–0.2[35,76]
IsobutylbenzoateTr.*[76]
(Z)‐β‐FarneseneTr.*–0.6[76–78]
β
Caryophyllene0.1–10.5[35,76–78]
α‐Humulene0.1–4.1[35,76–78]
γ‐MuuroleneTr.*–1.86[35,76–78]
GermacreneD0.1–17.68[35,76–78]
Isoamylbenzoate0.08–0.4[35,76]
α‐MuuroleneTr.*–3.6[35,76–78]
BicyclogermacreneTr.*–0.9[35,76,77]
γ‐CadineneTr.*–0.7[35,76]
Nerolidol 0.07–0.6[35,76–78]
CalameneneA Tr.*–0.2[76–78]
Caryophylleneepoxide0.4–1.6[76,77]
Spathulenol0.29–11.33[76,78]
(Z)hex3enylbenzoate0.08–0.8[76,77]
TorreyolTr.*–0.6[76,77]
TMuurolol0.2–1.16[76,77]
Humuleneepoxide0.2–0.5[76,77]
α‐CadinolTr.**–3.06[35,76–78]
(Z)hex3enylsalicylate0.09–0.3[76,77]
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Eudesma4(15),7dien0.1–0.2[76]
MintsulphideTr.*[76]
Cyclocolorenone Tr.*–0.3[76,77]
BenzylbenzoateTr.*–57.0[35,76–78]
GeranylbenzoateTr.*–0.1[76]
Benzylsalicylate0.02–1.14[35,76–78]
β‐Phenylethylsalicylate0.1–0.6[76,77]
α‐ThujeneTr.*[77]
Linalool0.23–2.0[77,78]
Perillene0.3[77]
Campholenealdehyde0.6[77]
Pinocarvone0.5[77]
arCurcumene0.5[77]
Spathulenol1.6[77]
Salvial4(14)en1one0.1[77]
Torilenol0.8[77]
Junenol0.2[77]
Eudesma4(15),7dien1β‐ol0.1[77]
Acetone0.02–0.62[78]
Ethylacetate0.02–2.27[78]
Ethylalcohol0.03–1.62[78]
α‐PhellandrenTr.*–1.12[78]
β‐Phellandren0.07–0.26***[35,78]
TerpinoleneTr.*–0.2[35,78]
nHexanol0.02–0.10[78]
cis3hexen1ol0.16–1.52[78]
transLinalooloxideTr.*–0.11[78]
transsabinenhydrateTr.*–0.26[78]
cisLinalooloxideTr.*–0.06[78]
Benzaldehyde0.13–0.40[78]
γ‐ElemeneTr.*–0.06[78]
Aromadendrene0.03–0.20[78]
AcetophenoneTr.*–0.19[78]
SalicylaldehideTr.*–0.02[78]
trans‐β‐Farnesene0.07–4.80[35,78]
GermacreneB0.03–16.63[78]
cis‐α‐FarneseneTr.*–0.41[78]
δ‐Cadinene0.2–7.87[35,78]
Cubenene0.02–0.25[78]
Benzylalcohol0.19–1.80[78]
2Phenylethylalcohol0.09–1.18[78]
oMethoxybenzaldehyde0.02–0.38[78]
Caryophylleneoxide0.1–4.30[35,78]
Epicubenol0.04–2.79[78]
oMethoxybenzylalcohol0.07–1.29[78]
TCadinol0.12–0.76[78]
TMuurolol0.25–1.16[78]
δ‐Cadinol0.15–0.73[78]
nTetracosaneTr.*–0.24[78]
nPentacosaneTr.*–0.50[78]
Phytol0.02–1.07[78]
nhexacosaneTr.*–0.30[78]
MyristicacidTr.*–1.30[78]
β
OcimeneY/(Z)‐
β
ocimene0.02–3.0[35,78,79]
γ‐TerpineneTr.**[35]
1undeceneTr.**–0.1[35]
Biomolecules2020,10,161914of31
4,8dimethyl1,3,7nonatriene0.1[35]
CamphorTr.**–0.2[35]
Zingiberene0.4–1.1[35]
GermacreneA0.1–0.7[35]
(E,E)‐α‐farnesene1.0–2.7[35]
β‐sesquiphellandrene0.1–0.2[35]
(Z)3hexenylbenzoate0.1–0.4[35]
β‐EudesmolTr.**–0.1[35]
Neophytadiene0.1–0.2[35]
2phenylethylbenzoateTr.**–0.4[35]
*Tr.—traces(<0.02%);**Tr.—traces(<0.1%)(differentcutofflevelswereusedindifferentpapersto
define“traces”).***“limonene+β‐phellandrene(2:1)”:1.8–6.4%[35].
Lookingatallcompoundsgroupedbychemicalstructure,thelargestproportioninthePolish
samplesconsistedofmonoterpenehydrocarbons(58–73%)andsesquiterpenehydrocarbons(17–
31%);oxygenatedmonoterpenesandsesquiterpenes(about3%each),benzoicacidandsalicilycacids
(about1%)representlessthan10%ofthetotaloil[74].Theessentialoilofspecimenscultivatedin
vitrobymicropropagationwassimilarinitsmonoterpenecontents,butthesesquiterpeneswere
apparentlylessrepresentedforS.virgaureaL.inthiscase[75].A.V.Tkachevetal.(2006)compared
thecompositionoftheessentialoilfromtheaerialpartsharvestedfromtwodifferentheightsinthe
RussianAltaiandfoundthattheproductharvestedatalowerheight(290m)arericherinessential
oil(0.22%),whichcontainshigheramountsofα‐pineneandmyrceneascomparedtotheoil(0.07%)
obtainedfromplantsharvestedatamoreelevatedheight(650m)[35].Thekeycompoundsinthis
studywerealmostthesameasinthespecimensfromPoland,theonlynotableexceptionbeinga
highercontentinβcaryophylleneforbothspecimens(maximumcontentinthePolishspecimens
was3.3%,whereasintheRussianspecimenstheminimumcontentwas6.3%)[35,74].
Besidestheessentialoilterpenes,fromtheaerialpartsofS.virgaureaL.,anumberofatleast12
cisclerodanelactoneswerereportedinthe1980s,eightofwhichwerenewatthetimeofreporting
[92].In2010,anadditionalsetofninenewclerodaneswereisolatedfromthespecies(mostlikelythe
aerialpart,althoughuptodate,manyclerodaneshavebeenisolatedfromrootsofdifferentSolidago
species),sevenofwhichhavetherelativelyatypicalfeatureofacarboxylicacidatC19(solidagoic
acidsCI)[78].
Anumberofpolyacetylenecompoundshavebeenreportedintherootsofthespecies(matricaria
ester,twomatricaria‐γ‐lactones,onelachnophyllumlactone),thatshowconsiderableseasonal
variation[80].Onlythematricariaestercouldbedetectedintheabovegroundshoots,whereasthe
othercompoundsareabsentfromtheaerialparts[80].
Biomolecules2020,10,161915of31
Figure6.TerpenesfromS.virgaureaL.
5.6.Saponins
ThesaponinsofS.virgaureaL.havebeenanobjectofstudyasearlyasthe1930s,butthefirst
dataontheirstructurewereprovidedbyK.Hilleretal.in1975[106].Inthe1980s,G.Baderetal.
wereamongthefirsttoisolateandestablishthechemicalstructuresofdeacylatedsaponinsfoundin
theaerialparts,namedbytheauthorsvirgaureasponins1–3[37,66,68,107].Aroundthesametime,in
Japan,Y.Inoseetal.isolatedandelucidated,fromsamplesofJapaneseorigin,thestructuresof
oleananetypesolidagosaponinsIXX,manyofthemglycosylatedinposition16oftheaglyconealone
orbesidesposition3[51,70],andlaterthesamegroupfurtheridentifiedsolidagosaponinsXXIXXIX
[108].ThesameJapaneseresearchersreportedthepresenceofbellisaponinBA2[108],whichhadbeen
isolatedpreviouslyfromBellisperennisL.[109].Later,anotherEuropeangroupisolated
virgaureasaponins4–6fromS.virgaureassp.alpestris[73].Quantitatively,thesaponincontentis
similarbetweenS.virgaurea,S.gigantean,andS.canadensis[71].UnlikeS.canadensisandS.gigantea,
whicharederivedfrombyogeninandhavemorecomplexsugarchains,thesaponinsisolatedfrom
S.virgaureaarederivedfrompolygalacicacidandareacylatedbycarboxylicacids[37].Asformany
phytochemicals,someofthesaponinshavemultiplesynonyms,sometimesconfusing;forinstance,
solidagosaponinXVIIIisalsoknownasvirgaureasaponinC[73].
Biomolecules2020,10,161916of31
Figure7.SaponinsfromS.virgaureaL.
5.7.Polysaccharides
BothinflorescencesandleavesofS.virgaureaL.containpolysaccharides.Thoseisolatedfrom
inflorescencescontainuronicacids(over40%,mostlygalacturonicacid),galactose(13–18%),glucose
(7–12.5%),rhamnose(4–7.5%),arabinose(2–8%),andxylose(1–2%)residues[79].Theamountand
theproportionamongthecomponentsvaryalongthegrowingstagesoftheplant[79].J.Saluk
Juszczak(2010)reportedquitedifferentproportionsofsugarsforthepolyphenolicpolysaccharide
Biomolecules2020,10,161917of31
conjugatesisolatedfromtheflowerheads(rhamnose22.4%,fucose5.0%,arabinose19.2%,xylose
2.6%,mannose1.3%,glucose13.0%,galactose14.0%)[110].
6.Pharmacology
6.1.AntioxidantProperties
Joiningthenutritionalvocabularyofthemassesatleastthreedecadesago,theconceptof
“antioxidants”remainsonepoorlyunderstoodinthefieldoflifesciences,andtheclinicalrelevance
ofantioxidantsisstillratherfuzzy,withmanyknowledgegaps[111].However,partlybecausethe
assessmentofantioxidantpotentialiseasilyaccessibleandrelativelycheap,formanyherbal
products,theantioxidantpropertiesareevaluatedrepeatedly,andS.virgaureamakesnoexception,
thefirststudyonthistopicdatingfrom1995[96].Inthisstudy,ethanolicextractsoftheplantwere
showninvitrotoinhibitlipoxygenaseandxanthineoxidasepathways[96].Amethanolextract
obtainedfromtheyoungshootsandleaveshadstrongerantioxidanteffects(measuredinvitrowith
aDPPHbasedassay)thananextractpreparedwithhotwater[95].Autoclavingofan80%ethanol
extractresultedindecreasedscavengingeffectsonDPPHandABTS(associatedwithadeclinein
polyphenolandflavonoidcontents),butitincreasedthechelatingeffectsonferrousions[112].
Althoughaslightlyhigherantioxidanteffectwasobservedwhenusingpressurizedfluidextraction
overtheultrasonicextractionmethodonS.virgaureaL.leaves(94.0%vs.89.0%inhibition),the
differencewasnotstatisticallysignificant[91].Bothleafandstempowders,aswellasextracts
obtainedfromthoseparts,preventedlipidoxidationwhenappliedongroundporksamples
[113,114].Among23herbalspeciesexaminedfortheirantioxidanteffectinonestudy,S.vigaureaL.
hadanaverageantioxidantactivity(indecreasingorder,itoccupiedthe11thpositionoutof23)[44].
ThekeycomponentandmarkeroftheantioxidantpropertiesofS.virgaureawasfoundbyM.
Marksaetal.(2020)tobe3,5dicaffeoylquinicacid(abouthalfofthewholescavengingactivity,asfor
S.canadensisandS.×niederederi,butunlikeS.gigantea,forwhichthemaincomponentresponsibleis
chlorogenicacid)[88].ForseveralSolidagospeciestested,thescavengingactivitieswerestrongerfor
theleafproductsthanfortheinflorescences[88].Theradicalneutralizingpropertiesofquercetin
derivativesfromSolidagospecieswasshowntobeconsiderablylowertothatofthecafeoylquinic
derivatives,butitishigherthanthatofkaempferolderivatives,whoseantioxidantpotentialis
insignificant[88].Dicaffeoylquinicacidshaveastrongerradicalscavengingeffectthanmono
caffeoylquinicacids[88].
6.2.AntiInflammatoryEffects
TheantiinflammatoryactivityofS.virgaureaextractsorcomponentsisolatedfromthespecies
hasbeenrepeatedlyevaluated,confirmed,andascribedtodifferentphytochemicalsfromits
composition.Inaratmodel,H.J.Jackeretal.(1981)showedthatatriterpenesaponinfraction
administeredi.v.atalowdose(1.25–2.5mg/kg)causedasignificantdecreaseofedema,asmeasured
bypletysmograph[9,115].AlthoughJ.Metzneretal.(1984)reportedsomeantiinflammatoryeffect
forleiocarposide(200mg/kg)inacarrageenaninducededemamodelinrats,theeffectwasobviously
inferiortothatofphenylbutazone(e.g.,3%vs.53%twohourspostadministrationand27%vs.54%
reductionfivehourspostadministration)[9,56].Rutinandquercetin,aswellas3,5dicaffeoylquinic
acidwereshownbyM.Melzigetal.(2000)toinhibitleukocyteelastase,aneffectconsidered
synergisticwiththeradicalscavengingofthesamemoleculesinexertingtheirantiinflammatory
activity[33,93].Instead,saponinsandleiocarposidedidnotdemonstrateanysuchelastaseinhibition;
thesameauthorsclaimedthatestersaponinsstimulatethereleaseofACTHbytheirinteractionwith
cellmembranesofthepituitarycells,andthus,consecutively,glucocorticoidswithantiinflammatory
effects[33,93].3,4,5OtricaffeoylquinicacidwasidentifiedamongphenoliccompoundsfromS.
virgaureaashavingthehighestantiinflammatoryeffect(88%ofthatofindomethacin)inrats
(carrageenanbasedratpawedema)andtoinhibitTNF‐αandIL1β[10].Ontheotherhand,other
studiesreportedstimulationofTNF‐α secretionbymacrophages,aneffectinducedbydifferent
phytochemicalsofthespecies(2methoxybenzyl2hydroxybenzoate,benzyl2hydroxy6
Biomolecules2020,10,161918of31
methoxybenzoate)[116],anditremainstobeinvestigatedinwhatcontextsandundertheinfluence
ofwhatvariablesoneortheothereffectwillpredominate.
AqueousandethanolicextractsofS.virguareahavedemonstratedanabilitytoreducepaw
edemaandarthriticpawvolumeinratmodelsofinflammation[117].Someinhibitionof
dihydrofolatereductasehasbeendescribedforahydroalcoholicextractofthespecies,andthishas
beensuggestedascontributingtotheantiinflammatoryeffectsoftheS.virgaureaextracts,being
knownthatinhibitorsoftheenzyme,suchasmethotrexate,dohaveantiinflammatoryactivity[118–
120].
AstandardizedcombinationofalcoholicextractsofS.vigaurea,PopulustremulaL.,andFraxinus
excelsiorL.hasbeendevelopedasanantirheumaticdrugandhasbeenrelativelyextensively
investigated[117,121,122].
6.3.AnalgesicActivity
Aninvitrostudyevaluatedtheanalgesicpotentialofamethanolseedextractbyassessingits
affinityforthreereceptorsinvolvedinacutepainsignaling(bradykinin,neurokinin1,andcalcitonin
generelatedpeptide).Theextractexhibitedsubstantialbindingtothebradykininreceptor,butthis
effectwascanceledbyPVPtreatment,allowingtheauthorstospeculatethatitshouldprobablybe
ascribedtononspecificbindingoftanninsorotherpolyphenols[123].Inthehotplatetestonmice,
leiocarposidedemonstratedverysimilaranalgesiceffectstoaminophenazoneforthefirsthour,but
thoseeffectsalmostdisappearedpostadministrationafterthesecondhour[56].
6.4.SpasmolyticandAntihypertensiveActivity
Exvivodataobtainedonisolatedsmoothmusclesfromguineapiggutshowedamodest
spasmolyticeffectforaS.virgaureaethanolextract(lessthan15%ofthepapaverineeffect)[9,124].As
mentionedbelow,extractsofS.virgaureahavedemonstratedantimuscariniceffectsonisolated
bladder,inhibitingtheM2andM3receptors[31].Ithasbeenstatedthatallspeciesofthegenushave
“hypotensiveactivity”,includingS.virgaurea,whichdemonstratedsuchaneffectindogs,foraleaf
extract,atadoseof150/kg[119,125,126].Aqueousextractsfromflowersandfromleaves,
administeredbyi.v.routeinrats,atdosesof180and360mg/kgfoundnoreductionofbloodpressure
afterthefirst2–5min,forbothextracts[127],despiteisolatedinterpretationstothecontrary[119].
Thishasbeenspeculativelyrelatedtoapotentialcontributionofflavonoids,basedonthereported
vasodilatoryeffectsmediatedbytheinhibitionofproteinkinaseCresultingintherelaxationofthe
arterialsmoothmuscle[97].Inthatstudy,flavonolshadastrongereffectthanflavones,whichintheir
turnhadamorepotenteffectthanflavanols[97],andasshownabove,S.virgaureakeyflavonoidsare
derivativesofflavonols(quercetinandkaempferol).
6.5.DiureticEffectsandBenefitsinOtherUrinaryTractConditions
Asshownabove,manyfolktraditionsattributeadiureticactivitytoextractspreparedfromS.
virgaureaL.Inacademicsources,itismentionedatleaststartingwiththe17thcentury,when
Shcroeder’s“Thesauruspharmacologicus”pointsouttoit;throughoutthe20thcentury,different
sourcesalsocitethispharmacologicaleffectinrelationshiptoS.virgaureaproducts[9].
Thediureticeffectshavebeenattributedtotheflavonoidfraction(particularlyquercetinandits
derivatives),whichwasshowntoinhibittheneutralendopeptidase,resultinginanenhancedurinary
flow[88,93].Theinhibitionofneutralendopeptidaseleadstoanincreaseintheplasmaconcentration
ofnatriureticpeptides,whichhavestrongnatriureticproperties[128].A.Choderaetal.(1991)found
thatthisflavonoidfraction(25mg/kgb.w.)increasestheurineoutputinratsbyabout88%,and
causesadecreaseintheexcretionofsodiumandpotassium,accompaniedbyanincreaseincalcium
excretion[9,65].TheseresultsareincontradictionwiththosereportedlaterbyU.Kaspersetal.(1998),
whofoundnoincreaseinurinevolumeorelectrolytesfortheflavonoidfraction[9,129].Instead,they
reportedthatthehydroxycinnamicacidfraction(100mg/kg)andthesaponinfraction(25–100mg/kg)
hadaneffectcomparablewiththoseoffurosemide[9,129],includinganincreaseinsodiumand
Biomolecules2020,10,161919of31
potassiumexcretion,unlikethedatareportedbyA.Choderaetal.(1991),whichclaimedadecrease
intheexcretionoftheseions[9,65].
Besidestheflavonoidicfraction,leiocarposide(25mg/kg,i.p.)wasalsoshownbyA.Choderaet
al.(1985)tohavediureticactivity,equivalenttoabout75%ofthefurosemideeffect[9,130].Thesame
authorshavedemonstratedthatthei.p.routeresultsinhigherefficacy(about30%)thantheoral
route,thatithasaslowonset(around5h),anditlastsforupto24h[9,119,131].Theaglyconepartof
theglycoside(leiocarpicacid)isdevoidofdiureticactivity(atthesamedose,25mg/kgi.p.)[9,132].
Besidestheassumeddiureticeffects,S.virgaureahasbeendeclared“theplantthatismost
frequentlyextractedtoyieldpreparationsforthetreatmentofbladderdysfunctionincludingthe
overactivebladdersyndrome”[31].Inthissense,clinicaldatainpatientswithdysuriahaveclaimed
thatS.virgaureareducesthefrequencyofurination(aswellasthepainassociatedwithit).Ina
relativelylarge(n=512patients),butopenlabelanduncontrolledstudyofpatientswithchronic
recurrentoveractivebladder,96%ofthesubjectsreceiving424.8mgofS.vigraureaextract,t.i.d.,
reportedanimprovementintheclinicalglobalimpressionandasignificantdropinpainful
micturitionandintheneedtourinate[133].Inasmallerstudy(n=74),alsoopenlabel,carriedout
onfemalepatientswithdysuria,areductionofthesamesymptomswasobservedin69%ofthe
patients[133].Theseresultsaresomewhatpuzzlingbecausediureticstendtoratherincreasethe
frequencyofurination,butthediureticdatacomefromnonclinicalstudieswithanisolated
compound(leiocarposide)ortheflavonoidfraction,andnotwithanextractassuch.Ontheother
hand,theopenlabelcharacterandthelackofacontrolgroupindicatealowqualityofthesedataand
strongerevidenceisneededtoconcludeontheeffectS.virgaureahaveontheurinarytract.Invitro
datahavedemonstratedthatextractsoftheplanthaveantimuscariniceffectsontheM2andM3
receptors,whichresultsintheinhibitionofthebladdercontraction[31].
Leiocarposide(25mg/kgp.o.)administeredforsixweekssignificantlyinhibitedthegrowthof
humanderivedurinarycalculitransferredintotheratbladder[57].
6.6.AntibacterialActivity
Aninvestigationoftheantibacterialpotentialoftwoextracts,onealcoholicandonelipophilic
(withhexane),foundthatthealcoholichadthelowestMICforStaphyllococcusaureus,whereasthe
lipophiliconeforS.aureusandP.aeruginosa[134].TheMICvaluesvariedbetween2.95and11.8
mg/mLfortheethanolic;forthehexaneextract,MICwas3.5mg/mLforStaphyllococcusaureus,
Staphyllococcusfaecalis,andPseudomonasaeruginosa,andhigherthan3.5mg/mLfortheother
microorganismstested[134].Althoughvalueslowerthan16mg/mLhavebeenconsideredsometimes
asshowingastrongantibacterialeffect[135],otherauthorshaveusedmorestringentcriteria:MIC
values<100 μg/mLhavebeenproposedtobehighlyactive,thosebetween100and500 μg/mLactive,
thosebetween500and1000μg/mLmoderatelyactive,thosebetween1000and200μg/mLoflow
activity,andthosewithMIC>2000 μg/mLinactive[136,137].Ithasalsobeensuggestedthatinorder
to“beconsideredapromisingactivity,acrudeextractmustdemonstrateaMICunder100μg/mL”
(andapurecompoundlessthan16μg/mL)[138].Otherstudieshavealsoassessedvariousextracts
fortheirantimicrobialeffects,butMICorMBC(minimalbactericidalconcentration)wasalsoformost
specieshigherthan2000μg/mL[139–141].Inthelightofthesecriteriafromtheliterature,the
activitiesobservedinthisstudyarenot“promising”andbecausetheyarehigherthan2000μg/mL,
shouldratherbeconsideredinactive.
Inastudycomparing(amongothers)theethanolandaqueousextractsobtainedfromleavesand
stemsofS.virgaurea(agardiscdiffusionmethod),inhibitionzonesweredetectedonlyfortheethanol
extractandonlyonBacillussubtilis,Micrococcusflavus(Grampositive),andtheGramnegative
Morganellamorganii[142].Anotherstudyalsoreportednoinhibitoryeffectonseveralmicrobial
speciesofanaqueousextract[72].Ithasbeensuggestedthatinhibitionzonessmallerthan9mm
shouldbeconsideredinactive,thoserangingbetween9and12mm,moderatelyactive,thoseranging
between13and18mm,active,andthoselargerthan18mmshouldbeclassifiedasveryactive
[136,143].Since,inthisstudy,allinhibitionzoneswerelessthan9mminsize[142],theethanolextract
shouldalsoberegardedasvirtuallyinactive.A.BrantnerandJ.Grein(1994),though,reported