Ganoderma Lucidum (Lingzhi or Reishi) - Herbal Medicine - NCBI

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Ganodermalucidum(LingzhiorReishi)HerbalMedicineNCBIBookshelf
NCBIBookshelf.AserviceoftheNationalLibraryofMedicine,NationalInstitutesofHealth.
BenzieIFF,WachtelGalorS,editors.HerbalMedicine:BiomolecularandClinicalAspects.2ndedition.Boca
Raton(FL):CRCPress2011.
Chapter9 Ganodermalucidum(LingzhiorReishi)
AMedicinalMushroom
SissiWachtelGalor,JohnYuen,JohnA.Buswell,andIrisF.F.Benzie.
9.1.INTRODUCTION
Ganodermalucidum,anorientalfungus(Figure9.1),hasalonghistoryofuseforpromoting
healthandlongevityinChina,Japan,andotherAsiancountries.Itisalarge,darkmushroomwith
aglossyexteriorandawoodytexture.TheLatinwordlucidusmeansshinyorbrilliantand
referstothevarnishedappearanceofthesurfaceofthemushroom.InChina,G.lucidumiscalled
lingzhi,whereasinJapanthenamefortheGanodermataceaefamilyisreishiormannentake.
FIGURE9.1
(Seecolorinsert.)Thelingzhimushroom(Ganoderma
lucidum).(CourtesyofNorthAmericanReishi/Nammex.)
InChinese,thenamelingzhirepresentsacombinationofspiritualpotencyandessenceof
immortality,andisregardedastheherbofspiritualpotency,symbolizingsuccess,wellbeing,
divinepower,andlongevity.Amongcultivatedmushrooms,G.lucidumisuniqueinthatits
pharmaceuticalratherthannutritionalvalueisparamount.AvarietyofcommercialG.lucidum
productsareavailableinvariousforms,suchaspowders,dietarysupplements,andtea.Theseare
producedfromdifferentpartsofthemushroom,includingmycelia,spores,andfruitbody.The
specificapplicationsandattributedhealthbenefitsoflingzhiincludecontrolofbloodglucose
levels,modulationoftheimmunesystem,hepatoprotection,bacteriostasis,andmore.Thevarious
beliefsregardingthehealthbenefitsofG.lucidum(Figure9.2)arebasedlargelyonanecdotal
evidence,traditionaluse,andculturalmores.However,recentreportsprovidescientificsupportto
someoftheancientclaimsofthehealthbenefitsoflingzhi.
FIGURE9.2
Postulatedhealthbenefitsoflingzhi(Ganodermalucidum).
9.2.HISTORY:LINGZHIASAMEDICINALMUSHROOM
Lingzhihasbeenrecognizedasamedicinalmushroomforover2000years,anditspowerful
effectshavebeendocumentedinancientscripts(Wasser2005).TheproliferationofG.lucidum
imagesinartbeganin1400AD,andtheyareassociatedwithTaoism(McMeekin2005).
However,G.lucidumimagesextendedbeyondreligionandappearedinpaintings,carvings,
furniture,andevenwomensaccessories(Wasser2005).Thefirstbookwhollydevotedtothe
descriptionofherbsandtheirmedicinalvaluewasShenNongBenCaoJing,writtenintheEastern
HandynastyofChina(25220AD).ThisbookisalsoknownasClassicoftheMateriaMedica
orShennongsHerbalClassics.Itdescribesbotanical,zoological,andmineralsubstances,and
wascomposedinthesecondcenturyunderthepseudonymofShennong(theholyfarmerZhu,
1998).Thebook,whichhasbeencontinuallyupdatedandextended,describesthebeneficial
http://www.ncbi.nlm.nih.gov/books/NBK92757/
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effectsofseveralmushroomswithareferencetothemedicinalmushroomG.lucidum(Zhu,1998
Upton2000Sanodiyaetal.2009).IntheSupplementtoClassicofMateriaMedica(502536AD)
andtheBenCaoGangMubyLiShinZhen,whichisconsideredtobethefirstpharmacopoeiain
China(1590ADMingdynasty),themushroomwasattributedwiththerapeuticproperties,suchas
tonifyingeffects,enhancingvitalenergy,strengtheningcardiacfunction,increasingmemory,and
antiagingeffects.AccordingtotheStatePharmacopoeiaofthePeoplesRepublicofChina
(2000),G.lucidumactstoreplenishQi,easethemind,andrelievecoughandasthma,anditis
recommendedfordizziness,insomnia,palpitation,andshortnessofbreath.
Wildlingzhiisrare,andintheyearsbeforeitwascultivated,onlythenobilitycouldaffordit.It
wasbelievedthatthesacredfungusgrewinthehomeoftheimmortalsonthethreeaislesofthe
blestoffthecoastofChina(McMeekin2005).However,itsreputationasapanaceamayhave
beenearnedmorebyvirtueofitsirregulardistribution,rarity,andusebytherichandprivileged
membersofChinesesocietythanbyitsactualeffects.Nevertheless,theGanodermaspecies
continuetobeapopulartraditionalmedicineinAsiaandtheiruseisgrowingthroughouttheworld
(WachtelGalor,Buswelletal.2004Lindequist,Niedermeyer,andJlich2005).
9.3.TAXONOMY
ThefamilyGanodermataceaedescribespolyporebasidiomycetousfungihavingadoublewalled
basidiospore(Donk1964).Inall,219specieswithinthefamilyhavebeenassignedtothegenus
Ganoderma,ofwhichG.lucidum(W.Curt.:Fr.)P.Karstenisthespeciestype(Moncalvo2000).
Basidiocarpsofthisgenushavealaccate(shiny)surfacethatisassociatedwiththepresenceof
thickwalledpilocystidiaembeddedinanextracellularmelaninmatrix(Moncalvo2000).
Ganodermaspeciesarefoundallovertheworld,anddifferentcharacteristics,suchasshapeand
color(red,black,blue/green,white,yellow,andpurple)ofthefruitbody,hostspecificity,and
geographicalorigin,areusedtoidentifyindividualmembersofthespecies(ZhaoandZhang1994
Wooetal.1999Upton2000).Unfortunately,themorphologicalcharacteristicsaresubjectto
variationresultingfrom,forexample,differencesincultivationindifferentgeographicallocations
underdifferentclimaticconditionsandthenaturalgeneticdevelopment(e.g.,mutation,
recombination)ofindividualspecies.Consequently,theuseofmacroscopiccharacteristicshas
resultedinalargenumberofsynonymsandaconfused,overlapping,anduncleartaxonomyfor
thismushroom.Sometaxonomistsalsoconsidermacromorphologicalfeaturestobeoflimited
valueintheidentificationofGanodermaspeciesduetoitshighphenotypicplasticity(Ryvarden
1994ZhaoandZhang1994).MorereliablemorphologicalcharacteristicsforGanodermaspecies
arethoughttoincludesporeshapeandsize,contextcolorandconsistency,andthemicroanatomy
ofthepilearcrust.Chlamydosporeproductionandshape,enzymaticstudiesand,toalesserextent,
therangeandoptimaofgrowthtemperatureshavealsobeenusedfordifferentiating
morphologicallysimilarspecies(Gottlieb,Saidman,andWright1998Moncalvo2000Saltarelliet
al.2009).Biochemical,genetic,andmolecularapproacheshavealsobeenusedinGanoderma
speciestaxonomy.MolecularbasedmethodologiesadoptedforidentifyingGanodermaspecies
includerecombinant(rDNA)sequencing(Moncalvoetal.1995Gottlieb,Ferref,andWright
2000),randomamplifiedpolymorphicDNAPCR(RAPDPCRstandsforpolymerasechain
reaction),internaltranscribedspacer(ITS)sequences(Hseuetal.1996),sequencerelated
amplifiedpolymorphism(SRAPSunetal.2006),enterobacterialrepetitiveintergenicconsensus
(ERIC)elements,andamplifiedfragmentlengthpolymorphism(AFLPZhengetal.2009).Other
approachestotheproblemofG.lucidumtaxonomyincludenondestructivenearinfrared(NIR)
methodscombinedwithchemometrics(Chenetal.2008),nuclearmagneticresonance(NMR)
basedmetabolomics(Wenetal.2010),andhighperformanceliquidchromatography(HPLC)for
generatingchemicalfingerprints(Suetal.2001Chenetal.2008Shi,Zhangetal.2008Chenet
al.2010).
9.4.CULTIVATION,GLOBALUSE,ANDMANUFACTUREOFPRODUCTS
OwingtoitsirregulardistributioninthewildandtoanincreasingdemandforG.lucidumasa
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medicinalherb,attemptsweremadetocultivatethemushroom(ChangandBuswell2008).
DifferentmembersoftheGanodermagenusneeddifferentconditionsforgrowthandcultivation
(Mayzumi,Okamoto,andMizuno1997).Moreover,differenttypesarefavoredindifferent
geographicalregions.Forexample,inSouthChina,blackG.lucidumispopular,whereasredG.
lucidumispreferredinJapan.G.lucidumthrivesunderhotandhumidconditions,andmanywild
varietiesarefoundinthesubtropicalregionsoftheOrient.Sincetheearly1970s,cultivationofG.
lucidumhasbecomeamajorsourceofthemushroom.ArtificialcultivationofG.lucidumhasbeen
achievedusingsubstratessuchasgrain,sawdust,woodlogs(ChangandBuswell1999Wasser
2005Bohetal.2007),andcorkresidues(Riu,Roig,andSancho1997).
SinceittakesseveralmonthstoculturethefruitingbodyofG.lucidum,myceliabasedandculture
brothbasedproductshaveassumedgreaterimportanceduetodemandsforincreasedquality
controlandyearroundproduction(Sanodiyaetal.2009).Theprocessesanddifferentgrowth
parameters(e.g.,temperature,pH)involvedinsubmergedmycelialculturecaneasilybe
standardizedundercontrolledconditions,andpurificationandotherdownstreamprocessingof
activecomponentssuchaspolysaccharidesreleasedintotheculturemediumusuallyinvolve
relativelysimpleprocedures.Differentcultureconditionsandmediumcompositionshavealsobeen
reportedtostronglyinfluencemycelialgrowthandtheproductionofbiopolymers(e.g.,
polysaccharides)thatareextrudedfromthecell(exopolysaccharides[EPSs]Mayzumi,Okamoto,
andMizuno1997ChangandBuswell1999HabijanicandBerovic2000FangandZhong2002
Bohetal.2007Sanodiyaetal.2009).Forexample,YangandLiau(1998)reportedthat
polysaccharideproductionbyfermentergrownmyceliaofG.lucidumwasoptimumat30C35C
andapHof44.5,andtheadditionofsupplementssuchasfattyacidswasfoundtoaccelerate
mycelialgrowthandtheproductionofbioactivecomponents.InasubmergedcultureofG.
lucidum,theoptimumpHforcellgrowthhasbeenshowntobelowerthanthatforEPSformation.
AtwostagepHcontrolstrategy,developedtomaximizemycelialbiomassandEPSproduction,
revealedthatculturepHhadasignificanteffectonEPSyield,chemicalcompositionandmolecular
weight,andmycelialmorphology(Kim,Park,andYun2006).Theproductivemycelial
morphologicalformforEPSproductionwasadispersedpellet(controlledpHshiftfrom3.0to6.0)
ratherthanacompactpelletwithadensecore(pHmaintainedat4.5)orafeatherlikepellet
(controlledpHshiftfrom6.0to3.0).ThreedifferentpolysaccharideswereobtainedundereachpH
condition,andtheirmolecularweightsandchemicalcompositionsweresignificantlydifferent
(Kim,Park,andYun2006).Morerecently,anovelthreestagelightirradiationstrategyhasbeen
developedinsubmergedculturesofG.lucidumfortheefficientproductionofpolysaccharidesand
oneofthetriterpenecomponents,ganodericacid(ZhangandTang2008).
Adecadeago,morethan90brandsofG.lucidumproductswereregisteredandmarketed
internationally(Lin2000).Worldwideconsumptionisnowestimatedatseveralthousandtonnes,
andthemarketisgrowingrapidly.Althoughtherearenorecentlypublisheddatarelatingtothe
totalworldmarketvalueofganodermaproducts,in1995,thetotalestimatedannualmarketvalue
givenbydifferentcommercialsourceswasUS$1628million(ChangandBuswell1999).
NumerousG.lucidumproducts,preparedfromdifferentpartsofthemushroom,arecurrently
availableonthemarket(ChangandBuswell2008).Inmanufacturingterms,thesimplesttype
consistsofintactfruitingbodiesgroundtopowderandthenprocessedtocapsuleortabletform.
Othernonextractedproductsarepreparedfromthefollowingthreesources:(1)driedand
powderedmyceliaharvestedfromsubmergedliquidculturesgrowninfermentationtanks(2)dried
andpowderedcombinationsofsubstrate,mycelia,andmushroomprimordia,followinginoculation
andincubationofasemisolidmediumwithfungalmyceliaand(3)intactfungalsporesorspores
thathavebeenbrokenbymechanicalmeansorhavehadthesporewallsremoved.Althoughspore
preparationshavebeenresearchedandpromotedvigorouslyinrecentyears,anyaddedmedicinal
effectsattributabletotheremovalorbreakageofsporewalls,whichrepresentsanadditionaland
oftencostlystepintheproductionprocess,arestillcontroversial.Otherproductsarepreparedwith
materials(e.g.,polysaccharides,triterpenes)extracted,usuallywithhotwaterorethanol,from
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fruitingbodiesormyceliaharvestedfromsubmergedliquidculturesandthenevaporatedtodryness
andtabulated/encapsulatedeitherseparatelyorintegratedtogetherindesignatedproportions.The
adoptionofsupercriticalfluidCO2extractiontechnologieshasenlargedthespectrumofextracted
substancesduetothelowtemperaturerequiredduringprocessing.Severalotherproductshave
beenpreparedasbinary,ternaryormorecomplexmixturesofpowderedganodermaandother
mushrooms(e.g.,Lentinulaedodes,Agaricusbrasiliensis,Grifolafrondosa,Pleurotusspp.,and
Flammulinavelutipes)andevenwithothermedicinalherbs(e.g.,spirulinapowderorflower
pollengrains).
9.5.MAJORBIOACTIVECOMPONENTS
Mostmushroomsarecomposedofaround90%waterbyweight.Theremaining10%consistsof
1040%protein,28%fat,328%carbohydrate,332%fiber,810%ash,andsomevitaminsand
minerals,withpotassium,calcium,phosphorus,magnesium,selenium,iron,zinc,andcopper
accountingformostofthemineralcontent(Borchersetal.1999).Inastudyofthenonvolatile
componentsofG.lucidum,itwasfoundthatthemushroomcontains1.8%ash,2628%
carbohydrate,35%crudefat,59%crudefiber,and78%crudeprotein(Mau,Lin,andChen
2001).
Inadditiontothese,mushroomscontainawidevarietyofbioactivemolecules,suchasterpenoids,
steroids,phenols,nucleotidesandtheirderivatives,glycoproteins,andpolysaccharides.Mushroom
proteinscontainalltheessentialaminoacidsandareespeciallyrichinlysineandleucine.Thelow
totalfatcontentandhighproportionofpolyunsaturatedfattyacidsrelativetothetotalfattyacidsof
mushroomsareconsideredsignificantcontributorstothehealthvalueofmushrooms(Changand
Buswell1996Borchersetal.1999Sanodiyaetal.2009).
Polysaccharides,peptidoglycans,andtriterpenesarethreemajorphysiologicallyactiveconstituents
inG.lucidum(Bohetal.2007Zhouetal.2007).However,theamountandpercentageofeach
componentcanbeverydiverseinnaturalandcommercialproducts,asexemplifiedbythedata
showninTable9.1.When11randomlyselectedsamplesofcommerciallingzhiproducts
purchasedinHongKongshopswereevaluatedforthetwomajoractivecomponents,triterpenes
andpolysaccharides,itwasfoundthatthetriterpenecontentrangedfromundetectableto7.8%and
thepolysaccharidecontentvariedfrom1.15.8%(ChangandBuswell2008).Suchvariationscan
occurforseveralreasons,includingdifferencesinthespeciesorstrainsofmushroomusedand
differencesinproductionmethods.
TABLE9.1
ComparisonofTriterpeneandPolysaccharideContentsof11
CommercialLingzhi(G.lucidum)Productscurrentlyavailable
ontheMarket.
9.5.1.POLYSACCHARIDES ANDPEPTIDOGLYCANS
Fungiareremarkableforthevarietyofhighmolecularweightpolysaccharidestructuresthatthey
produce,andbioactivepolyglycansarefoundinallpartsofthemushroom.Polysaccharides
representstructurallydiversebiologicalmacromoleculeswithwiderangingphysiochemical
properties(Zhouetal.2007).Variouspolysaccharideshavebeenextractedfromthefruitbody,
spores,andmyceliaoflingzhitheyareproducedbyfungalmyceliaculturedinfermentersandcan
differintheirsugarandpeptidecompositionsandmolecularweight(e.g.,ganoderansA,B,and
C).G.lucidumpolysaccharides(GLPSs)arereportedtoexhibitabroadrangeofbioactivities,
includingantiinflammatory,hypoglycemic,antiulcer,antitumorigenic,andimmunostimulating
effects(MiyazakiandNishijima1981Hikinoetal.1985Tomodaetal.1986Baoetal.2001
WachtelGalor,Buswelletal.2004).Polysaccharidesarenormallyobtainedfromthemushroom
byextractionwithhotwaterfollowedbyprecipitationwithethanolormethanol,buttheycanalso
beextractedwithwaterandalkali.StructuralanalysesofGLPSsindicatethatglucoseistheir
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majorsugarcomponent(Baoetal.2001Wangetal.2002).However,GLPSsareheteropolymers
andcanalsocontainxylose,mannose,galactose,andfucoseindifferentconformations,including
13,14,and16linkedandD(orL)substitutions(Lee,Lee,andLee1999Baoetal.2002).
Branchingconformationandsolubilitycharacteristicsaresaidtoaffecttheantitumorigenic
propertiesofthesepolysaccharides(Baoetal.2001Zhang,Zhang,andChen2001).The
mushroomalsoconsistsofamatrixofthepolysaccharidechitin,whichislargelyindigestibleby
thehumanbodyandispartlyresponsibleforthephysicalhardnessofthemushroom(Upton2000).
NumerousrefinedpolysaccharidepreparationsextractedfromG.lucidumarenowmarketedas
overthecountertreatmentforchronicdiseases,includingcancerandliverdisease(Gaoetal.
2005).
VariousbioactivepeptidoglycanshavealsobeenisolatedfromG.lucidum,includingG.lucidum
proteoglycan(GLPGwithantiviralactivityLi,LiuandZhao2005),G.lucidum
immunomodulatingsubstance(GLISJietal.2007),PGY(awatersolubleglycopeptide
fractionatedandpurifiedfromaqueousextractsofG.lucidumfruitbodiesWuandWang2009),
GLPSpeptide(GLPPHoetal.2007),andF3(afucosecontainingglycoproteinfractionChien
etal.2004).
9.5.2.T RITERPENES
Terpenesareaclassofnaturallyoccurringcompoundswhosecarbonskeletonsarecomposedof
oneormoreisopreneC5units.Examplesofterpenesarementhol(monoterpene)andcarotene
(tetraterpene).Manyarealkenes,althoughsomecontainotherfunctionalgroups,andmanyare
cyclic.Thesecompoundsarewidelydistributedthroughouttheplantworldandarefoundin
prokaryotesaswellaseukaryotes.Terpeneshavealsobeenfoundtohaveantiinflammatory,
antitumorigenic,andhypolipidemicactivity.TerpenesinGinkgobiloba,rosemary(Rosemarinus
officinalis),andginseng(Panaxginseng)arereportedtocontributetothehealthpromotingeffects
oftheseherbs(MahatoandSen1997Mashour,Lin,andFrishman1998Haralampidis,
Trojanowska,andOsbourn2002).
TriterpenesareasubclassofterpenesandhaveabasicskeletonofC30.Ingeneral,triterpenoids
havemolecularweightsrangingfrom400to600kDaandtheirchemicalstructureiscomplexand
highlyoxidized(MahatoandSen1997Zhouetal.2007).Manyplantspeciessynthesize
triterpenesaspartoftheirnormalprogramofgrowthanddevelopment.Someplantscontainlarge
quantitiesoftriterpenesintheirlatexandresins,andthesearebelievedtocontributetodisease
resistance.Althoughhundredsoftriterpeneshavebeenisolatedfromvariousplantsandterpenesas
aclasshavebeenshowntohavemanypotentiallybeneficialeffects,thereisonlylimited
applicationoftriterpenesassuccessfultherapeuticagentstodate.Ingeneral,verylittleisknown
abouttheenzymesandbiochemicalpathwaysinvolvedintheirbiosynthesis.
InG.lucidum,thechemicalstructureofthetriterpenesisbasedonlanostane,whichisametabolite
oflanosterol,thebiosynthesisofwhichisbasedoncyclizationofsqualene(Haralampidis,
Trojanowska,andOsbourn2002).Extractionoftriterpenesisusuallydonebymeansofmethanol,
ethanol,acetone,chloroform,ether,oramixtureofthesesolvents.Theextractscanbefurther
purifiedbyvariousseparationmethods,includingnormalandreversephaseHPLC(Chenetal.
1999Suetal.2001).ThefirsttriterpenesisolatedfromG.lucidumaretheganodericacidsAand
B,whichwereidentifiedbyKubotaetal.(1982).Sincethen,morethan100triterpeneswith
knownchemicalcompositionsandmolecularconfigurationshavebeenreportedtooccurinG.
lucidum.Amongthem,morethan50werefoundtobenewanduniquetothisfungus.Thevast
majorityareganodericandlucidenicacids,butothertriterpenessuchasganoderals,ganoderiols,
andganodermicacidshavealsobeenidentified(Nishitobaetal.1984Satoetal.1986Budavari
1989Gonzalezetal.1999Maetal.2002Akihisaetal.2007Zhouetal.2007Jiangetal.2008
Chenetal.2010).ExamplesoftriterpenesareshowninFigure9.3.
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FIGURE9.3
Chemicalstructureoflanosterolandthreeofthemanytriterpenesisolatedfrom
Ganodermalucidum.(FromKubota,T.,Y.Asaka,I.Miura,andH.Mori.1982.
HelvChimActa65:6119Nishitoba,T.,H.Sato,T.Kasai,H.Kawagishi,and
S.Sakamura.(more...)
G.lucidumisclearlyrichintriterpenes,anditisthisclassofcompoundsthatgivestheherbits
bittertasteand,itisbelieved,confersonitvarioushealthbenefits,suchaslipidloweringand
antioxidanteffects.However,thetriterpenecontentisdifferentindifferentpartsandgrowing
stagesofthemushroom.TheprofileofthedifferenttriterpenesinG.lucidumcanbeusedto
distinguishthismedicinalfungusfromothertaxonomicallyrelatedspecies,andcanserveas
supportingevidenceforclassification.Thetriterpenecontentcanalsobeusedasameasureof
qualityofdifferentganodermasamples(Chenetal.1999Suetal.2001)
9.5.3.OTHERCOMPONENTS
ElementalanalysisoflogcultivatedfruitbodiesofG.lucidumrevealedphosphorus,silica,sulfur,
potassium,calcium,andmagnesiumtobetheirmainmineralcomponents.Iron,sodium,zinc,
copper,manganese,andstrontiumwerealsodetectedinloweramounts,asweretheheavymetals
lead,cadmium,andmercury(Chenetal.1998).Freezedriedfruitbodiesofunidentified
Ganodermaspp.collectedfromthewildwerereportedtohaveamineralcontentof10.2%,with
potassium,calcium,andmagnesiumasthemajorcomponents(Chiuetal.2000).Significantly,no
cadmiumormercurywasdetectedinthesesamples.G.lucidumcanalsocontainupto72g/gdry
weightofselenium(SeFalandysz2008)andcanbiotransform2030%ofinorganicselenium
presentinthegrowthsubstrateintoseleniumcontainingproteins(Duetal.2008).
SomeattentionhasbeengiventothegermaniumcontentofGanodermaspp.Germaniumwasfifth
highestintermsofconcentration(489g/g)amongthemineralsdetectedinG.lucidumfruit
bodiescollectedfromthewild(Chiuetal.2000).Thismineralisalsopresentintheorderofparts
perbillioninmanyplantbasedfoods,includingginseng,aloe,andgarlic(Minoetal.1980).
Althoughgermaniumisnotanessentialelement,atlowdoses,ithasbeencreditedwith
immunopotentiating,antitumor,antioxidant,andantimutagenicactivities(Kolesnikova,Tuzova,
andKozlov1997).However,althoughthegermaniumcontentofG.lucidumhasbeenusedto
promoteG.lucidumbasedproducts,thereisnofirmevidencelinkingthiselementwiththespecific
healthbenefitsassociatedwiththemushroom.
G.lucidumcontainssomeothercompoundsthatmaycontributetoitsreportedmedicinaleffect,
suchasproteinsandlectins.TheproteincontentofdriedG.lucidumwasfoundtobearound7
8%,whichislowerthanthatofmanyothermushrooms(ChangandBuswell1996Mau,Lin,and
Chen2001).BioactiveproteinsarereportedtocontributetothemedicinalpropertiesofG.
lucidum,includingLZ8,animmunosuppressiveproteinpurifiedfromthemycelia(VanDerHem
etal.1995)apeptidepreparation(GLP)exhibitinghepatoprotectiveandantioxidantactivities
(Sun,He,andXie2004Shi,Sunetal.2008)anda15kDaantifungalprotein,ganodermin,
whichisisolatedfromG.lucidumfruitingbodies(WangandNg.2006).
Thecarbohydrateandcrudefibercontentofthedriedmushroomwasexaminedandfoundtobe
2628%and59%,respectively(Mau,Lin,andChen2001).Lectinswerealsoisolatedfromthe
fruitbodyandmyceliumofthemushroom(Kawagishietal.1997),includinganovel114kDa
hexamericlectin,whichwasrevealedtobeaglycoproteinhaving9.3%neutralsugarandshowing
hemagglutinatingactivityonpronasetreatedhumanerythrocytes(Thakuretal.2007).Lectins
(fromtheLatinwordlegere,whichmeanstopickup,choose)arenonenzymaticproteinsor
glycoproteinsthatbindcarbohydrates.Manyspeciesofanimals,plants,andmicroorganisms
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producelectins,andtheyexhibitawiderangeoffunctions.Inanimals,forexample,lectinsare
involvedinavarietyofcellularprocessesandthefunctioningoftheimmunesystem(Wang,Ng,
andOoi1998).
OthercompoundsthathavebeenisolatedfromG.lucidumincludeenzymessuchas
metalloprotease,whichdelaysclottingtimeergosterol(provitaminD2)nucleosidesand
nucleotides(adenosineandguanosineWasser2005Paterson2006).KimandNho(2004)also
describedtheisolationandphysicochemicalpropertiesofahighlyspecificandeffectivereversible
inhibitorofglucosidase,SKG3,fromG.lucidumfruitbodies.Furthermore,G.lucidumspores
werereportedtocontainamixtureofseverallongchainfattyacidsthatmaycontributetothe
antitumoractivityofthemushroom(Fukuzawaetal.2008).
9.6.THERAPEUTICAPPLICATIONS
Thecombinationofbenefitwithouttoxicityrepresentsthedesiredendresultinthedevelopmentof
effectivetherapeuticinterventions.G.lucidumhasbeenusedforhundredsofyearsasahealth
promotionandtreatmentstrategytherearenowmanypublishedstudiesthatarebasedonanimal
andcellculturemodelsandoninvitroassessmentofthehealtheffectsofG.lucidum,andthereare
alsosomereportsofhumantrialsinthefield.However,thereisnocohesivebodyofresearch,and
theobjectiveevaluationofthistraditionaltherapyintermsofhumanhealthremainstobeclearly
established.InSections9.6.1through9.6.6,studiesonthepropertiesofG.luciduminrelationto
cancer(whichhasattractedthemostinterest),viralandbacterialinfection,diabetes,andliverinjury
arediscussed.
9.6.1.CANCER
G.lucidumisapopularsupplementtakenbyhealthyindividualtoboosttheimmunesystemand
bycancerpatientsalongwithconventionaltherapies.Inthissection,thescientificstudiesofG.
lucidumonitsanticancerpropertiesaresummerized.
9.6.1.1.Introduction
Cancerisaworldwideleadingcauseofdeath,anddespitecomprehensiveadvancesintheearly
diagnosisofthediseaseandchemotherapy,itremainsamajorclinicalchallenge(WHO2008).As
partofsearchingfornewchemopreventiveandchemotherapeuticagents,hundredsofplant
species,includingmushrooms,havebeenevaluated.Thishasresultedintheisolationofthousands
ofbioactivemoleculesthatwereshowntohaveantitumoractivityfromnumerousmushroom
species,includingGanodermaspecies(WasserandWeis1999Borchersetal.2008).InG.
lucidum,alargenumberofchemicalcompoundscanbeextractedfromthefruitingbody,mycelia,
orspores.Manypolysaccharidesandtriterpenes,thetwomajorgroupsofcomponentsinthe
mushroom,exhibitchemopreventiveand/ortumoricidaleffects,asprovedbynumerousstudies
frominvitroexperimentsandanimalandhumaninvivostudies(YuenandGohel2005Zaidman
etal.2005).Tumorimplantedanimalmodelshaveshowninhibitoryeffectsonangiogenesisand
metastasis.However,evidencefromwelldesignedhumantrialsisstillscarce.
9.6.1.2.InVitroAnticancerActivities
Tomasietal.(2004)tested58basidiomycetesmushrooms,ofwhichG.lucidumwasshowntobe
themosteffectiveinkillingcancercells.G.luciduminducedcellcyclearrestandapoptosisin
varioushumanandrodenttumorcells,includingmurinelymphocyticleukemiaL1210andLewis
lungcarcinoma(LLCMinetal.2000Tomasietal.2004),mousereticulocytesarcomaLII(Liu
etal.2002),murinesarcomaMethA(Minetal.2000Gao,Minetal.2002)andS180(Gao,Min
etal.2002Liuetal.2002),humanleukemiaHL60(Mulleretal.2006Kimetal.2007
Fukuzawaetal.2008Liuetal.2009)andU937,K562,Blin1,Nalm6,RPMI8226(Mulleretal.
2006Shangetal.2009),humanhepatomaPLC/PRF/5,KB(Linetal.2003),HepG2(Liuetal.
2009Wengetal.2009),Hep3B(Chungetal.2001),Huh7(Linetal.2003Li,Chanetal.
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2005),humanlivertumorSMMC7721(Tangetal.2006),humanbreastcancerMDAMB123
(Jiangetal.2008Liuetal.2009Zhaoetal.2010),MCF7(Jiang,Slivova,andSliva2006Liu
etal.2009Shangetal.2009),T47D(Gao,Minetal.2002)andMT1(Wuetal.2006Xieetal.
2009),humanprostatecancerPC3(Jiangetal.2004Evansetal.2009),humancervixuteritumor
Hela(Liuetal.2002Tangetal.2006Shangetal.2009),humanovariancancerSKOV4(Shang
etal.2009),humancoloniccancerHT29(Hongetal.2004)andSW480(Xieetal.2006),human
lungcarcinomaPG(CaoandLin2006Cao,Lin,andWang2007)and95D(Tangetal.2006),
humansmallcelllungcarcinomaNCIH69andmultidrugresistantstrainVPA(Sadavaetal.
2009),lowgradebladdercancerMTC11(Luetal.2004),andhumanuroepithelialHUCPC
(Yuen,Gohel,andAu2008)cells.
Throughtheregulationofexpressionofdifferentsignals,tumorcellswerearrestedbyG.lucidum
atdifferentpointsofcellcycle,forexample,breastatG0/G1phaselungatG1phaseliverat
G1/G2phaseandbladder,prostate,andleukemiaatG2phase.AseleniumenrichedextractofG.
lucidummyceliawasshowntoinduceG1/Sphasearrestinhumanerythroidchronicmyeloid
leukemiaK562cells(Shangetal.2009).AnotherextractinducedG0/G1phasearrestinestrogen
dependentbreastMCF7cellsthroughthedownregulationofestrogenreceptorand
serine/threoninespecificproteinkinaseAkt/nuclearfactorB(NFB)signaling(Jiang,Slivova,
andSliva2006).Invarioushumancancercelllines,extractsofG.lucidumwereshownto
suppresstheprogressionoftheG1phaseincellcycle,andapoptosiswasconfirmedbyusing
terminaldeoxynucleotidyltransferasedUTPnickandlabeling(TUNEL)assay(Liuetal.2009).
Manyoftheseactivitieswereaccompaniedbyapoptosis.CaoandLin(2006)demonstratedthata
fractionofGLPPdecreasedtheantiapoptoticproteinBcl2expressionandincreasedthe
proapoptoticproteinBaxexpressioninhumanumbilicalcordvascularendothelialcells
(HUVECs).AtriterpenerichextractfromG.luciduminducedprogressiveapoptosisinthe
premalignantHUCPCcelllinebyincreasingtheearlyapoptosismarkerannexinVwithin3
hours.Halfthecellsstainedpositivefor7aminoactinomycinD(indicatinglateapoptosis)after8
hours.Allcellsweredeadat24hours,andthiswasassociatedwiththedownregulationof
telomerase(Yuen,Gohel,andAu2008).Similarapoptoticactivitieswerealsodemonstratedin
otherhumancancercells(Fukuzawaetal.2008).AnethanolextractofG.lucidumdecreased
cyclooxygenase2(COX)2enzymeexpressionandincreasednitricoxidesynthesisincolonHT
29cells(Hongetal.2004).Inlung95Dtumorcells,thepurecompoundganodericacidTcaused
mitochondrialdysfunction,whichresultedfromtheupregulationofproapoptoticp53andBax
expression(Tangetal.2006).Moreover,theuseofacombinationofG.lucidumandDuschesnea
extractsupregulatedcytochromecandBaxtranslocationtotriggercaspase3apoptosisinleukemia
HL60cells(Kimetal.2007).Activationofcaspases7and9byG.lucidumhasbeen
demonstratedinbreastMCF7andlungH69SCLCcancercells,respectively(Huetal.2002
Sadavaetal.2009).InhepatomaHepG2cells,alucidenicacidrichG.lucidumextractwasshown
tosuppressphosphorylationofERK1/2andAktsignaling,whichdownregulatedtheirdownstream
NFBandprotooncoproteins(cJunandcFos)activities,favoringapoptosis(Wengetal.2009).
Atumormassrequiresacontinuousnutrientsupplyvianewbloodvesselsformedbytheprocess
ofangiogenesis.Invasivecancercellsspreadtodistantsitesthroughbloodandlymphoidvessels.
Therefore,agentsthatinhibitangiogenesisinhibittumorgrowthandspread.Thepotential
antiangiogenicactivitiesofG.lucidumhavebeendemonstratedinexvivochickembryo
chorioallantoicmembrane(CAM)assay(CaoandLin2004Songetal.2004).Polysaccharide
peptideandethanolextractfromG.lucidumhasbeenprovedtodecreasemicrovesselsarounda
microfiberfilterdisccontaininganembryowithintactyolks.Usingaprostatecancercellline,two
angiogenicfactors,knownasvascularendothelialgrowthfactor(VEGF)andtransforminggrowth
factor(TGF)1,weresuppressedbyG.lucidumthroughinhibitionoftheras/extracellularsignal
regulatedkinase(Erk1/2)andAktsignalingpathways(Johnston2005Stanleyetal.2005).Similar
effectswerealsoobservedinahumanlungcancercelllinesunderhypoxicconditionsafter
exposuretoahighdoseofGLPP(CaoandLin2006).
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Celladhesion,invasion,andmigrationarethekeyfactorsindeterminingtheaggressivenessof
cancerhence,controlofcellmotilityiseffectiveinavoidingcancermetastasis.Apolysaccharide
extractofG.lucidummyceliainhibitedtheformationofoncogenicrasinducedtransformedfociin
anR6embryofibroblastcellline(Hsiaoetal.2004).SporesandthefruitingbodyofG.lucidum
wereshowntoinhibittheregulatoryproteinsphosphatidylinositolandNFBinhighlyinvasive
breastandprostatecancercells(Slivaetal.2002).Celladhesion,invasion,andcolonyformation
ofbreastcancercellsweresignificantlyinhibitedonexposuretoG.lucidumextracts(Sliva2004).
Inaddition,Luetal.(2004)demonstratedthatwaterandethanolextractsofG.lucidummodulated
theF/Gactinratio,which,inturn,reducedtheformationofstressfiberandfocaladhesion
complexesofbladdercancercells,suggestingtheactinremodelingwasassociatedwiththe
inhibitionofcarcinogeninducedcellmigration.InhibitionofmitogeninducedinvasionofHepG2
cellswasdemonstratedinastudybyusingMatrigelcoatedfilterinsertsassay(Wengetal.2009).
9.6.1.3.AnimalStudies
RodentstudiesofpossibleantitumorigeniceffectsofG.lucidumcanbetracedbacktotheearly
1980s.Tendaysofintraperitoneal(i.p.)injectionsofapolysaccharidefraction(GL1)fromthe
fruitbodywasreportedtoinhibit(by9598%)thegrowthoftransplantedsarcoma180tumorcells
inmice(MiyazakiandNishijima1981).Acomplexofpolysaccharidesandproteinfromthe
mushroomwasalsofoundtoshowsignificantantitumoractivityinasimilarstudyconductedby
Kimetal.(1980).Aninhibitionrateof88%wasreported,andtherewascompleteregressionof
tumorinathirdofthetestanimals.InastudyconductedbyHyun,Choi,andKim(1990),which
usedasimilarprotocolbutusedvariousextractedpolysaccharides,inhibitionratesof5281%were
found.Ahotwaterextract(2mg/mouse)giveni.p.for3daysresultedinanaverage74%
inhibitionoftumorgrowthinmice,with3outof10animalsshowingcompleteregression,andan
oraladministration(dailyfor5weeks)showed4563%inhibition(Ohnoetal.1998).Similar
inhibitoryeffectswereshownwithimplantedsarcoma180cellsafterpolysaccharidewasgiven
orallytomice(ZhangandLin1999).Apure(13)glucanwastestedinparallelwithcrudeG.
lucidumextracts,whichresultedin90%inhibitionoftumorgrowth(Ohnoetal.1998).Adry
powderpreparationoftheantleredformofG.lucidum(knownasdeerhornlingzhiduetoits
appearance)wasshowntoinhibittumorgrowthandelongatethelifespaninbothallogeneic
sarcoma180bearingddYmiceandsynergenicMM46mammarytumorbearingC3H/Hemice
(Nonakaetal.2006).
G.lucidumisamajorcomponentofmanytraditionalbotanicalformulations,suchasTBS101,
whichwasdemonstratedtoinhibittumorgrowthandinvasioninPC3implantedmice(Evanset
al.2009).Yun(1999)reportedthat9weeksoforaladministrationofmycelialextractsignificantly
inhibitedlungadenomaformationinmice.Oraladministrationoftriterpenoidfractionsfor18
consecutivedaysinhibitedMartigelinducedangiogenesis,whichsignificantlyreducedtumor
weightandthenumberoftumorcellcoloniesthathadmetastasizedtotheliverinfemale
C57BL/6JstrainmicewithintrasplenicimplantationofLewislungcancercells(Kimura,
Taniguchi,andBaba2002Wangetal.2007).InmaleICRnu/nunudemiceinjectedwith
hepatomaHepG2cells,dailyoraladministrationoflucidenicacidrichextractfor68days(800
mg/kgdosage)decreasedboththenumberandsizeoftumorsbyupto99%,andalsothenumber
ofmetastatictumorsoccurringinliverandlung(Wengetal.2009).Anaqueousextract
(administeredi.p.at10,20,and40mg/mouse)ofthefruitbodysignificantlyincreasedthelifespan
ofmiceimplantedwithLewislungcarcinomacells.However,nodoseresponseeffectwasseen
(Furusawaetal.1992).AnadditiveeffectwasseenwhenG.lucidumwasgivenincombination
withcytotoxicantineoplasticdrugs,andtherewasasuggestionofapossiblesynergisticeffectwith
cisplatin(Furusawaetal.1992).Inanotherstudy,G.lucidumwasfoundtoalsoprolongthelife
spanoftumortransplantedmicebyinhibitingmetastasistothelung(Leeetal.1995).Whengiven
1weekpriortotheadministrationofacarcinogenicagent,ahotwaterextractofthe
mycelium/growthmediumcomplexdecreasedthedevelopmentofaberrantcryptfoci(ACF)and
precancerouslesionsinthecolon(Luetal.2001Luetal.2003).Notoxicityorsideeffectswere
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seenintheratswhentheextractwasadministeredfor3months.Whentestedwithmousecolon
tumorimplantedchambers,apolysaccharidemixturecontainingisoflavoneaglyconsfromcultured
G.lucidummyceliawasfoundtoinhibitangiogenesisinvivo(Miuraetal.2002).
Thechemopreventiveactivitiesofthemushroomonprostatecancerweredemonstratedbya
triterpenoidrichextractofG.lucidumthatsuppressedtheventralprostategrowthinducedby
testosterone(Liuetal.2007a).GanoderolBwasidentifiedastheactiveprinciplethatwasableto
bindtoanandrogenreceptorandinhibit5reductase,suppressingandrogeninducedLNCaPcell
growthanddownregulatingtheprostatespecificantigen(Liuetal.2007b).
9.6.1.4.HumanStudies
Inhumans,whethertheantitumoreffectoflingzhiisadirectoneorismediatedviaeffectsonthe
immunesystemisakeyquestiontoaddress.G.lucidumisoneoftheeightcomponentsofan
herbalmixturecalledprostatecancerhope(knownasPCSEPS),whichhasbeenusedasan
alternativeinthetreatmentofandrogendependentandindependentprostatecancer(Gaoand
Zhou2009).However,onlyafewclinicaltrialshaveusedG.lucidumasasingleagentoncancer
patients(Gao,Zhouetal.2002Gao,Zhouetal.2003Gao,Saietal.2003).Tworandomized,
controlledtrialshavebeenconductedusingaGLPSrichextract(apatentedoverthecounter
product,GanopolyGaoetal.2003GaoandSaietal.2003).Gao,Zhouetal.(2003)recruited
134patientswithadvancedcancersofdifferentsitesandsupplementedthemwithG.lucidum
capsulesatadosageof1800mg/dayfor12weeks.Cellularimmunityin80%ofthesepatients
wassignificantlyenhancedintermsofelevatedplasmainterleukin(IL)2,IL6,andinterferon
(IFN)levelsandnaturalkiller(NK)cellactivity.Inanotherstudy,thesameprotocolwas
followedwith68lungcancerpatients(Gao,Saietal.2003)inwhomimmuneparameters
includingtotalTcells,NKcells,andCD4/CD8ratioweresignificantlyenhancedintheG.
lucidumtreatedgroup.Inaddition,qualityoflifeintermsofKarnofskyscorewasimprovedin
about65%ofthesepatients(Gao,Saietal.2003).Ganopolywasalsodemonstratedtoenhance
mitogenicactivityandNKcellsinpatientswithadvancedcancerinabeforeandaftercomparison
study(Gao,Minetal.2002).TheseresultsprovidesomeevidencethattheantitumoreffectsofG.
lucidumaremediatedviaeffectsontheimmunesystem.However,itmustbenotedthatallstudies
wereconductedbythesameresearchgroupandthatotherdirectantitumoreffectsofG.lucidum
havenotyetbeenstudiedonhumansinvivo.
9.6.2.IMMUNOMODULATION
Agentsthatenhancethefunctioningofthehostimmunesystemcouldbeexpectedtoenhance
healthintermsofimprovedresistanceand,thus,removalofmalignantorpremalignantcells.Many
G.lucidumproductsonthemarketarelabeledorpromotedasimmunomodulatingagents.
ThereisconsiderableevidencetosupporttheimmunostimulatingactivitiesofG.lucidumvia
inductionofcytokinesandenhancementofimmunologicaleffector(Wangetal.1997Zhuand
Lin2006).DifferentcomponentsfromG.lucidumwereprovedtoenhancetheproliferationand
maturationofTandBlymphocytes,splenicmononuclearcells,NKcells,anddendriticcellsin
cultureinvitroandinanimalstudiesinvivo(Baoetal.2001CaoandLin2002Zhu,Chen,and
Lin2007Maetal.2008).InnormalBALB/cmice,apolysacchariderichextractofG.lucidum
promotedtheproliferationofsplenocytesandenhancedtheactivitiesofmacrophagesandNK
cells,whichresultedintheincreaseofIL6andIFN(Changetal.2009).Althoughacommercial
G.lucidumextractdidnotstimulateproliferationoflymphocytes,itactivatedthegeneexpression
ofIL1,IL6,IL10,andtumornecrosisfactor(TNF)(Maoetal.1999).Apolysaccharide
fraction(F3)wasshowntoenhancebothadaptiveandinnateimmunitiesbytriggeringthe
productionofcytokinesIL1,IL6,IL12,IFN,TNF,andcolonystimulatingfactors(CSFs)
frommousesplenocytes(Chenetal.2004).ItwasreportedalsothatTNFandIL6production
werestimulatedinhumanandmurinemacrophagesbyG.lucidummycelia(Kuoetal.2006).This
effectmightbeduetoincreasedsynthesisofnitricoxide(NO)inducedbyDglucan(Ohnoetal.
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1998).Thesepolysaccharideswerealsofoundtobehighlysuppressivetotumorcellproliferation
invivowhileenhancingthehostsimmuneresponse(OoiandLiu2000).
Wangetal.(1997)foundthatapolysaccharideenrichedfractionfromG.lucidumactivated
culturedmacrophagesandTlymphocytesinvitro,whichledtoanincreaseofIL1,TNF,and
IL6intheculturemedium.Inanotherstudy(ZhangandLin1999),incubationofmacrophages
andTlymphocyteswithapolysaccharideresultedinanincreaseinTNFandINFlevelsinthe
culturemedium.Thisconditionedculturemediumwasfoundtoinhibitcellgrowthandinduce
apoptosisinsarcoma180andHL60cells(ZhangandLin1999).Furthermore,serum
incorporatedtreatmentwithapolysaccharidepeptidefractionfromG.lucidummarkedlyinhibited
theproliferationofhumanlungcarcinoma(PG)cells,whereasthepurefractionbyitselfdidnot
inducesimilareffects(CaoandLin2004).Inadditiontopolysaccharides,alanostanetriterpenoid,
ganodericacidMe,inhibitedtumorgrowthandmetastasisofLewislungcarcinomainThelper1
responderC57BL/6micebyenhancingimmunefunctionintermsofIL2andIFNexpression
andNKcellactivity(Wangetal.2007).ZhuandLin(2006)usedcytokineinducedkiller(CIK)
cellstoinvestigatetheinteractionbetweenGLPSsandcytokines,whichmediatedcell
proliferationandantitumoractivity.ThecytotoxicityofCIKcellswascorrelatedwellwiththe
expressionofperforinandgranzymeBinducedbyIL2andantiCD3.ResultsindicatedthatGL
PSsenhanceIL2andTNFproductionaswellasproteinandmessengerribonucleicacid
(mRNA)expressionofgranzymeBandperforininCIKcellsculture,andthusdecreasethedoses
ofIL2andantiCD3withoutaffectingthekillingeffectsonNKresistantmouseP815
mastocytomacellsandNKsensitivemouseYAC1lymphomacells(ZhuandLin2006).
9.6.3.L INGZHI AS ANANTIOXIDANT
Consumptionofantioxidantrichplantsmayhelppreventcancerandotherchronicdiseases
(Collins2005BenzieandWachtelGalor2009).Antioxidantsprotectcellularcomponentsfrom
oxidativedamage,whichislikelytodecreaseriskofmutationsandcarcinogenesisandalsoprotect
immunecells,allowingthemtomaintainimmunesurveillanceandresponse.Variouscomponents
ofG.lucidum,inparticularpolysaccharidesandtriterpenoids,showantioxidantactivityinvitro
(Leeetal.2001Mau,Lin,andChen2002Shietal.2002WachtelGalor,Choi,andBenzie
2005YuenandGohel2008Saltarellietal.2009WuandWang2009).AsshowninFigure9.4,
antioxidantsfromlingzhiwerefoundtobeabsorbedquicklyafteringestion,resultinginan
increaseintheplasmatotalantioxidantactivityofhumansubjects(Figure9.4WachtelGalor,
Szetoetal.2004).
FIGURE9.4
Mean+SEM(standarderrorsofthemean)changeinplasma
totalantioxidantpower(astheferricreducingabilityofplasma
[FRAP]value)at90minutespostingestionofplacebo(vertical
lines),1.1gofG.lucidumextract(horizontallines),and3.3g
(more...)
OoiandLiu(2000)reportedthatproteinboundpolysaccharide(PBP)andpolysaccharidepeptide
wereabletomimictheendogenousantioxidantsuperoxidedismutase(SOD)incancerbearing
animalsinvivo.Thesepolysaccharideswerealsoreportedtoprotecttheimmunecellsfrom
oxidativedamage(OoiandLui2000).TheprotectiveeffectsofG.lucidumonDNAstrand
scissioninducedbyametalcatalyzedFentonreaction,ultravioletirradiation,andhydroxylradical
attackwereshowninagarosegelelectrophoresisinvitro(Leeetal.2001).HotwaterextractsofG.
lucidumsignificantlyprotectedRajicellsfromhydrogenperoxide(H2O2)inducedDNAdamage
(Shietal.2002).HotwaterextractsprotectedhumanlymphocyteDNAonlyatlow(<.001%w/v)
concentrations,andcausedH2O2mediateddamageathigherconcentrations(>.01%w/v)
(WachtelGalor,Choi,andBenzie2005).TwoantioxidantenrichedextractsfromG.lucidum
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actedoppositelyinpremalignantHUCPCcellsundercarcinogenicattack(YuenandGohel2008).
TheaqueousextractprotectedcellularDNAfromoxidativedamage,whereastheethanolicextract
damagedcellularDNA,withincreasedH2O2productionandsignificantcellkillingeffects
observed.TheresultssuggestedthatdifferenteffectsofG.lucidumcouldbeexhibitedbydifferent
extractablecomponentsinbladderchemoprevention.MethanolextractsofG.lucidumwere
reportedtopreventkidneydamage(inducedbytheanticancerdrugcisplatin)throughrestorationof
therenalantioxidantdefensesystem(Sheena,Ajith,andJanardhanan2003).Incontrast,afraction
ofganodermatriterpenes(GTS)wasfoundtoenhancetheintracellularreactiveoxygenspecies
(ROS)producingeffectofdoxorubicin(DOX)inHelacells,leadingtomoreDNAdamageand
apoptosis,whereassuchsynergismwasinhibitedbyaROSscavenger(Yueetal.2008).Inan
animalstudy(diabeticrats),nonenzymicandenzymicantioxidantslevelsincreasedandlipid
peroxidationlevelsdecreasedwithG.lucidumtreatment(Jiaetal.2009).However,adirectlink
hasnotbeenestablishedbetweentheantioxidantpropertiesofG.lucidumandits
immunomodulatoryandanticancereffects,andwhetherlingzhiactsasanantioxidantorpro
oxidantmaydependonconcentrationandenvironment.
9.6.4.VIRALANDBACTERIALINFECTIONS
Thegoalofresearchinthetreatmentofviralandbacterialinfectionsisthediscoveryofagentsthat
specificallyinhibitviralandbacterialmultiplicationwithoutaffectingnormalcells.Theundesired
sideeffectsofantibioticsandantiviralsandtheappearanceofresistantandmutantstrainsmakethe
developmentofnewagentsanurgentrequirement.Thishasledresearcherstoinvestigatethe
antibacterialandantiviralactivityofmedicinalplantsandfungi(WasserandWeis1999Zhong
andXiao2009).Isolationofvariouswaterandmethanolsoluble,highmolecularweightPBPs
fromG.lucidumshowedinhibitoryeffectsonherpessimplexvirustype1(HSV1),herpes
simplexvirustype2(HSV2),andvesicularstomatitisvirus(VSV)NewJerseystraininatissue
culturesystem.Usingtheplaquereductionmethod,asignificantinhibitoryeffectwasseenatdoses
thatshowednocytotoxicity(Eoetal.1999Ohetal.2000).Inaddition,therewasamarked
synergisticeffectwhenPBPfromG.lucidumwasusedintissuecultureinconjunctionwith
antiherpeticagents,acyclovirorvidarabine,andwithIFN(Kimetal.2000Ohetal.2000).
SimilarresultswereshowninHSV1andHSV2withaGLPGisolatedfromthemyceliaofG.
lucidum(Liuetal.2004Li,Liu,andZhao2005).Thecellsweretreatedbefore,during,andafter
infection,andviraltiterinthesupernatantofcellculture48hourspostinfectionwasdetermined.
TheantiviraleffectsoftheGLPGweremoreremarkablebeforeviraltreatmentthanaftertreatment.
Althoughthemechanismwasnotdefined,theauthorsconcludedthatGLPGinhibitsviral
replicationbyinterferingwithearlyeventsofviraladsorption(Li,Liu,andZhao2005).
SometriterpenesfromG.lucidumhavealsobeenreportedtohaveaninhibitoryeffectagainst
humanimmunodeficiencyvirus(HIV)1proteaseactivity,withIC50valuesrangingfrom20to
morethan1000Mhowever,notalloftheexaminedtriterpenesshowedantiHIVactivity(El
Mekkawyetal.1998Minetal.1998).Inanotherstudy,aganodericacidisolatedfromG.
lucidumshowedinhibitoryeffectsonthereplicationofhepatitisBvirus(HBV)inHepG2215cells
(HepG2HBVproducingcellline)over8days.ProductionofHBVsurfaceantigen(HBsAg)and
HBVeantigen(HBeAg)were,respectively,20%and44%ofcontrolswithoutganodericacid
treatment(LiandWang2006).
Somesmallstudiesinhumanpatientshavealsoreportedbeneficialeffectsoflingzhiintake.A
driedhotwaterextractofG.lucidumtakenorally(equivalentto36or72gofdriedmushroomper
day)wasusedasthesoletreatmentforpostherpetic(varicellazostervirus)neuralgiain4elderly
patients.Thistreatmentwasreportedtodramaticallydecreasepainandpromotethehealingof
lesions,withoutanytoxicityevenatveryhighdoses(HijikataandYamada1998).Inanother
study,amixtureofG.lucidumwithotherherbsimprovedrecoverytimeinpatientswithherpes
genitalis(n=15)andherpeslabiallis(n=13Hijikata,Yamada,andYasuhara2007).
Forevaluatingtheantibacterialeffectsofthemushroom,severalinvitroandinvivoanimalstudies
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usingG.lucidumwereperformed.MiceinjectedwithG.lucidumextract(2mg/mouse)1dayprior
toinjectionwithEscherichiacolishowedmarkedlyimprovedsurvivalrates(>80%comparedto
33%incontrolsOhnoetal.1998).Inaninvitrostudythatusedthediskassay(Keypouretal.
2008),achloroformextractofG.lucidumwasinvestigatedforitsantibacterialeffectongram
positivebacteria(Bacillussubtilis,Staphylococcusaureus,Enterococcusfaecalis)andgram
negativebacteria(E.coli,Pseudomonasaeruginosa).Resultsshowedthattheextracthadgrowth
inhibitoryeffectsontwoofthegrampositivebacteriawithaminimalinhibitoryconcentration
(MIC)of8mg/mLforS.aureusandB.subtilis.Inanotherinvitrostudy,thedirectantimicrobial
effectofaG.lucidumwaterextractwasexaminedagainst15speciesofbacteriaaloneandin
combinationwith4kindsofantibiotics(Yoonetal.1994).G.lucidumwasfoundtobemore
effectivethanantibioticsagainstE.coli,Micrococcusluteus,S.aureus,B.cereus,Proteus
vulgaris,andSalmonellatyphi,butlesseffectiveagainstotherspeciestested.Theantimicrobial
combinationofG.lucidumwithfourcommonlyusedantibiotics(Yoonetal.1994)resultedinan
additiveorsynergisticeffectinmost,butnotall,instances,withapparentantagonismagainst
cefazolinandampicillineffectsonP.vulgaris.
Todate,theantimicrobialcomponentsofthetestedcrudeextractshavenotbeenidentified,
althoughantimicrobialpolysaccharideshavebeenidentifiedinotherfungiandplantterpeneshave
beenreportedtohaveantimicrobialactivity(WasserandWeis1999ZhongandXiao2009).In
addition,thebioavailabilityofputativeantimicrobialcomponentsofG.lucidumhasnotbeen
established.Nonetheless,G.lucidumoffersapotentiallyeffectivetherapy.Thereisalsothe
implicationthatcombinationtherapymaybemoresafeandcosteffective,asloweramountsof
cytotoxicantiviralandantibacterialdrugscouldbeusedwithaconcomitantdecreaseintheriskof
sideeffects.However,thisneedsfurtherinvestigationintermsofinvitrostudiesandwelldesigned
clinicaltrials.
9.6.5.DIABETES MELLITUS
ComponentsofG.lucidumhavebeenprovedtohaveahypoglycemiceffectinanimals.The
administrationofganoderansAandB(doseof100mg/kg),twopolysaccharidesisolatedfrom
fruitbodywaterextracts,byi.p.injectiontonormalandalloxaninduceddiabeticmicesignificantly
decreased(byupto50%)theplasmaglucoseconcentrations,andthehypoglycemiceffectwasstill
evidentafter24hours(Hikinoetal.1985).Usingamousemodel,ganoderanBwasalsoreported
toincreaseplasmainsulin,decreasehepaticglycogencontent,andmodulatetheactivityofglucose
metabolizingenzymesintheliver(Hikinoetal.1989).Thesamegroupreportedthatathird
polysaccharide(ganoderanC)isolatedfromG.lucidumalsoshowedsignificanthypoglycemic
effectsinmice,andthatganoderanBincreasedplasmainsulinlevelsinbothnormalandglucose
loadedmice(Hikinoetal.1989Tomodaetal.1986).
Inamorerecentstudy,oraladministrationofG.lucidumhotwaterextract(0.03and0.3g/kgBW)
for4weekswasfoundtolowertheserumglucoselevelsinobese/diabetic(+db/+db)mice,with
effectsseenafterthefirstweekoftreatment(Setoetal.2009).However,theglucoselevelswere
stillhigherintheseanimalsthaninthecontrolanimals,andinsulinlevelswerenotaltered.The
extractmarkedlyreducedlevelsofphosphoenolpyruvatecarboxykinase(PEPCK),whichare
usuallyhighinobese/diabeticmice.Thesuggestedmechanism,accordingtotheauthors,isthatof
loweringtheserumglucoselevelsthroughsuppressionofthehepaticPEPCKgeneexpression.In
anotherstudy(Jiaetal.2009),apolysaccharidesrichextractshowedbeneficialeffectsin
streptozotocininduceddiabeticrats.ThediabeticratsweretreatedwithG.lucidumfor30days.
Followingthetreatment,seruminsulinlevelsincreased(comparedwiththenontreateddiabetic
group)andglucoselevelsdecreasedinadosedependentway.Treatmentwithstreptozotocinalso
elevatedlevelsoflipidperoxidationmarkers(thiobarbituricacidreactivesubstances[TBARS]),
lipidhydroperoxides,andconjugateddienes)decreasedlevelsofnonenzymicantioxidants
(vitaminC,reducedglutathione[GSH]vitaminE)anddecreasedactivitiesoftheantioxidant
enzymes,SOD,catalase,andglutathioneperoxidase(Gpx).FollowingtreatmentwithGLPSs,
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levelsofnonenzymicandenzymicantioxidantsincreasedandlipidperoxidationlevelsdecreased.
Therefore,inadditiontoitsglycemicmodulation,treatmentwithG.lucidumhelpedtodecrease
oxidativestress(Jiaetal.2009).
Inonestudyreportedintheliterature,71adultpatientswithconfirmedtype2diabetesmellitus
(DM)weresupplementedwithGanopoly(polysaccharidefractionsextractedfromG.lucidum).
ThepatientsreceivedeitherGanopolyorplaceboorallyat1800mg,threetimesdailyfor12
weeks.Glycosylatedhemoglobin(HbA1C)andplasmaglucosedecreasedsignificantlyafter12
weeks,indicatingahypoglycemiceffectoftheextract(Gao,Lanetal.2004).Overall,thedata
fromdifferentstudiessuggestthatG.lucidumintakehelpsinmodulatingbloodglucoselevels.
However,thestudieswereperformedmostlyinanimals.Moresupportfromwellplannedhuman
clinicalstudiesisneededwithandwithoutcombinationwithconventionalmedicines.
9.6.6.L IVERANDGASTRICINJURY
HotwaterandwateretherextractsofthefruitbodyofG.lucidumwerefoundtohaveapotent
hepatoprotectiveeffectonliverinjuryinducedbycarbontetrachloride(CCl4)givenorallyand
intraperitoneallytorats(Linetal.1995Kimetal.1999).Themeasuredmarkersforliverinjury
includedaspartateandalaninetransaminases(ASTandALT)andlactatedehydrogenase(LDH).
OneactivecompoundoftheextractwasseparatedandidentifiedasganoderenicacidA.Thiswas
foundtohaveapotentinhibitoryeffectonglucuronidase,andtheauthorssuggestthatthis
inhibitoryeffectmayhavemediatedthehepatoprotectionseenwhenthisisolatedcompoundwas
given(Kimetal.1999).ProtectionwasalsoreportedinastudyinwhichahotwaterextractofG.
lucidumwasgivenorallytomice30minutesbeforeadministrationofethanol.Theextractwas
foundtohaveaninhibitoryeffectagainsttheformationofmalondialdehyde(MDA),adegradation
productoflipidperoxides,inmouseliverandrenalhomogenate,withevidenceofadoseresponse
seen(Shiehetal.2001).TheMDAeffectwasalsoreportedbyShietal.(2008)whentheextract
wasgivenorallytomice(at60,120,and180mg/kg/day)for2weekspriortotreatmentwithD
galactosamine,whichinducedhepaticinjury.Inaddition,pretreatmentwithG.lucidummaintained
normalvaluesofAST,ALT,SOD,andGSH(Shietal.2008).AlcoholandCCl4toxicityis
associatedwithincreasedoxidativestressandfreeradicalassociatedinjury.Therefore,
hepatoprotectionmayalsobemediatedbytheradicalscavengingpropertiesofG.lucidum.Linet
al.(1995)reportedthathotwaterextractsofG.lucidumshowedsignificantradicalscavenging
activityagainstbothsuperoxideandhydroxylradicals.
Further,G.lucidummethanolicextractwasreportedtoshowhepaticprotection.Theextractwas
givenorallytorats(500mg/kg/day)for30daysbeforehepaticdamagewascausedbybenzo(a)
pyrene(Lakshmietal.2006).TheextractpreventedtheincreaseofserumAST,ALT,andalkaline
phosphatase(ALP)activitiesthatresultfrombenzo(a)pyrenechallenge,andenhancedthelevelsof
GSH,SOD,GpX,CAT,andglutathioneStransferase(GST).Protectionofliverinjuryinduced
byCCl4wasalsoobservedinmicetreatedwithganodericacid(fromG.lucidum)at10mgand30
mg/kg/daygivenbyintravenousinjectionfor7days(LiandWang2006).Themediuminwhich
G.lucidumwasgrownwasalsoprovedtohaveliverprotectiveeffectsinananimalstudyofCCl4
inducedliverdamage(Liuetal.1998).OraladministrationofthemediuminwhichG.lucidum
myceliaweregrown(butnotthemyceliaalone)hadmarkedbeneficialeffects,asassessedby
lowerserumASTandALTactivitiesat96hourspostinjury.Nodecreasewasseenintheactual
damagecaused,astransaminaseactivitiesat24hourswerenotdifferentfromlevelsincontrol
animals,implyingthatthemyceliummediummayhavepromotedrecoveryinsomeway.The
releaseofahepatoprotectivecomponentfromG.lucidummyceliumwasalsoreportedbySonget
al.(1998).Inthisstudy,anextracellularpeptidoglycan(apolysaccharide/aminoacidcomplex
namedWK003)producedduringmyceliumfermentationwasadministeredorallytoratsfor4
dayspriortoCCl4intoxication.TheincreaseinserumALTlevelswassignificantlydecreased(by
70%P<.01)at24hourspostinjurycomparedwithuntreated,intoxicatedrats.TheASTlevels
decreasedby27%however,thiswasnotstatisticallysignificant.Thesestudiesofapossible
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mycelialproductwithhepatoprotectiveactivitybeingextrudedintotheculturemediumareof
interestbecausethemyceliaofG.lucidumaremucheasierandlesscostlytocultivatethanthefruit
body.
PolysaccharidesextractedfromG.lucidumandgivenorallytoratsfor28dayswerefoundto
amelioratecirrhosisinducedbybiliaryligation(Parketal.1997).Inaddition,collagen(measured
byhydroxyproline)contentintheratliverwasloweredandimprovedlivermorphologywasfound
incomparisonwithcontrolanimals.Thetreatmentsignificantlydecreasedligationinduced
increasesinserumbiochemicalmarkersofliverdamage(AST,ALT,ALP,andtotalbilirubin).
SimilarresultswerenoticedinastudyconductedbyWu,Fang,andLin(2010)inwhicha
decreaseinhepatichydroxyprolinecontentandanimprovedliverhistologywerefoundinmice.In
thisstudy,liverfibrosiswasinducedbytheadministrationofthioacetamide(TAA)for12weeks,
whichwasfollowedby4weeksoftreatmentwithG.lucidumextract(0.5and1.0g/kg/day,per
oraladministration).TheRTQPCRanalysisshowedtheextracttreatmentdecreasedmRNA
expressionofcollagen(1),smoothmuscleactin,andtheenzymesmetalloproteinase1and
metalloproteinase13.Inaddition,theTAAinduceddecreaseintotalcollagenaseactivitywas
reversedbytheextracttreatment,indicatingthatG.lucidumprotectionagainstinjurymaybe
relatedtotheenhancementofcollagenaseactivity.
Apartfromitseffectsonchemicalinducedliverinjury,theeffectsoflingzhiongastricinjuryhave
alsobeeninvestigated.Gastriculcerswereinducedinratsbyaceticacid(Gao,Tangetal.2004),
andtreatmentwithGLPSfractionsof0.5and1.0g/kgfor14dayssignificantlyacceleratedthe
ulcerhealingby40%and56%,respectively.Treatmentwith1.0g/kgextractsignificantlyrestored
mucusandprostaglandinlevelscomparedwiththecontrolgroup.
9.7.CONCLUDINGREMARKS
G.lucidumisawellknownAsianherbalremedywithalongandimpressiverangeofapplications.
GlobalconsumptionofG.lucidumishigh,andalarge,increasingseriesofpatentedand
commerciallyavailableproductsthatincorporateG.lucidumasanactiveingredientareavailableas
foodsupplements.Theseincludeextractsandisolatedconstituentsinvariousformulations,which
aremarketedallovertheworldintheformofcapsules,creams,hairtonics,andsyrups.
Withitsgrowingpopularity,manystudiesonG.lucidumcomposition,cultivation,andreputed
effectsarebeingcarriedout,andtherearedatathatsupportitspositivehealthbenefits,including
anticancereffectsbloodglucoseregulationantioxidant,antibacterial,andantiviraleffectsand
protectionagainstliverandgastricinjury.However,moststudieshavebeenperformedonanimals
orincellculturemodels.Humanexperimentalstudieshaveoftenbeensmall,andtheresultsare
notalwayssupportiveoftheinvitrofindings.Now,thegreatwealthofchemicaldataand
anecdotalevidenceontheeffectsofG.lucidumneedstobecomplementedbyreliable
experimentalandclinicaldatafromwelldesignedhumantrialsinordertoclearlyestablishifthe
reportedhealthrelatedeffectsarevalidandsignificant.Manychallengesareencounteredduetoa
rangeoffactorsfromdosagetoproductionquality.Strategiesforenhancingqualitycontrol
procedurestodefineandstandardizeG.lucidumpreparationsareneededtodeterminemechanisms
ofactionandtohelpcharacterizetheactivecomponent(s)ofthisputativemedicinalmushroom.
ACKNOWLEDGMENTS
TheauthorsthanktheHongKongPolytechnicUniversityforfundingthisstudy.
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