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BenzieIFF,WachtelGalorS,editors.HerbalMedicine:BiomolecularandClinicalAspects.2ndedition.BocaRaton(FL):CRC
Press2011.

Chapter9 Ganodermalucidum(LingzhiorReishi)
AMedicinalMushroom
SissiWachtelGalor,JohnYuen,JohnA.Buswell,andIrisF.F.Benzie.

9.1.INTRODUCTION
Ganodermalucidum,anorientalfungus(Figure9.1),hasalonghistoryofuseforpromotinghealthandlongevityin
China,Japan,andotherAsiancountries.Itisalarge,darkmushroomwithaglossyexteriorandawoodytexture.The
Latinwordlucidusmeansshinyorbrilliantandreferstothevarnishedappearanceofthesurfaceofthemushroom.
InChina,G.lucidumiscalledlingzhi,whereasinJapanthenamefortheGanodermataceaefamilyisreishior
mannentake.
InChinese,thenamelingzhirepresentsacombinationofspiritualpotencyandessenceofimmortality,andisregardedas
theherbofspiritualpotency,symbolizingsuccess,wellbeing,divinepower,andlongevity.Amongcultivated
mushrooms,G.lucidumisuniqueinthatitspharmaceuticalratherthannutritionalvalueisparamount.Avarietyof
commercialG.lucidumproductsareavailableinvariousforms,suchaspowders,dietarysupplements,andtea.These
areproducedfromdifferentpartsofthemushroom,includingmycelia,spores,andfruitbody.Thespecificapplications
andattributedhealthbenefitsoflingzhiincludecontrolofbloodglucoselevels,modulationoftheimmunesystem,
hepatoprotection,bacteriostasis,andmore.ThevariousbeliefsregardingthehealthbenefitsofG.lucidum(Figure9.2)
arebasedlargelyonanecdotalevidence,traditionaluse,andculturalmores.However,recentreportsprovidescientific
supporttosomeoftheancientclaimsofthehealthbenefitsoflingzhi.
9.2.HISTORY:LINGZHIASAMEDICINALMUSHROOM
Lingzhihasbeenrecognizedasamedicinalmushroomforover2000years,anditspowerfuleffectshavebeen
documentedinancientscripts(Wasser2005).TheproliferationofG.lucidumimagesinartbeganin1400AD,andthey
areassociatedwithTaoism(McMeekin2005).However,G.lucidumimagesextendedbeyondreligionandappearedin
paintings,carvings,furniture,andevenwomensaccessories(Wasser2005).Thefirstbookwhollydevotedtothe
descriptionofherbsandtheirmedicinalvaluewasShenNongBenCaoJing,writtenintheEasternHandynastyof
China(25220AD).ThisbookisalsoknownasClassicoftheMateriaMedicaorShennongsHerbalClassics.It
describesbotanical,zoological,andmineralsubstances,andwascomposedinthesecondcenturyunderthepseudonym
ofShennong(theholyfarmerZhu,1998).Thebook,whichhasbeencontinuallyupdatedandextended,describes
thebeneficialeffectsofseveralmushroomswithareferencetothemedicinalmushroomG.lucidum(Zhu,1998Upton
2000Sanodiyaetal.2009).IntheSupplementtoClassicofMateriaMedica(502536AD)andtheBenCaoGangMu
byLiShinZhen,whichisconsideredtobethefirstpharmacopoeiainChina(1590ADMingdynasty),themushroom
wasattributedwiththerapeuticproperties,suchastonifyingeffects,enhancingvitalenergy,strengtheningcardiac
function,increasingmemory,andantiagingeffects.AccordingtotheStatePharmacopoeiaofthePeoplesRepublicof
China(2000),G.lucidumactstoreplenishQi,easethemind,andrelievecoughandasthma,anditisrecommendedfor
dizziness,insomnia,palpitation,andshortnessofbreath.
Wildlingzhiisrare,andintheyearsbeforeitwascultivated,onlythenobilitycouldaffordit.Itwasbelievedthatthe
sacredfungusgrewinthehomeoftheimmortalsonthethreeaislesoftheblestoffthecoastofChina(McMeekin
2005).However,itsreputationasapanaceamayhavebeenearnedmorebyvirtueofitsirregulardistribution,rarity,and
usebytherichandprivilegedmembersofChinesesocietythanbyitsactualeffects.Nevertheless,theGanoderma
speciescontinuetobeapopulartraditionalmedicineinAsiaandtheiruseisgrowingthroughouttheworld(Wachtel
Galor,Buswelletal.2004Lindequist,Niedermeyer,andJlich2005).
9.3.TAXONOMY
ThefamilyGanodermataceaedescribespolyporebasidiomycetousfungihavingadoublewalledbasidiospore(Donk

1964).Inall,219specieswithinthefamilyhavebeenassignedtothegenusGanoderma,ofwhichG.lucidum(W.
Curt.:Fr.)P.Karstenisthespeciestype(Moncalvo2000).Basidiocarpsofthisgenushavealaccate(shiny)surfacethat
isassociatedwiththepresenceofthickwalledpilocystidiaembeddedinanextracellularmelaninmatrix(Moncalvo
2000).Ganodermaspeciesarefoundallovertheworld,anddifferentcharacteristics,suchasshapeandcolor(red,
black,blue/green,white,yellow,andpurple)ofthefruitbody,hostspecificity,andgeographicalorigin,areusedto
identifyindividualmembersofthespecies(ZhaoandZhang1994Wooetal.1999Upton2000).Unfortunately,the
morphologicalcharacteristicsaresubjecttovariationresultingfrom,forexample,differencesincultivationindifferent
geographicallocationsunderdifferentclimaticconditionsandthenaturalgeneticdevelopment(e.g.,mutation,
recombination)ofindividualspecies.Consequently,theuseofmacroscopiccharacteristicshasresultedinalarge
numberofsynonymsandaconfused,overlapping,anduncleartaxonomyforthismushroom.Sometaxonomistsalso
considermacromorphologicalfeaturestobeoflimitedvalueintheidentificationofGanodermaspeciesduetoitshigh
phenotypicplasticity(Ryvarden1994ZhaoandZhang1994).Morereliablemorphologicalcharacteristicsfor
Ganodermaspeciesarethoughttoincludesporeshapeandsize,contextcolorandconsistency,andthemicroanatomy
ofthepilearcrust.Chlamydosporeproductionandshape,enzymaticstudiesand,toalesserextent,therangeandoptima
ofgrowthtemperatureshavealsobeenusedfordifferentiatingmorphologicallysimilarspecies(Gottlieb,Saidman,and
Wright1998Moncalvo2000Saltarellietal.2009).Biochemical,genetic,andmolecularapproacheshavealsobeen
usedinGanodermaspeciestaxonomy.MolecularbasedmethodologiesadoptedforidentifyingGanodermaspecies
includerecombinant(rDNA)sequencing(Moncalvoetal.1995Gottlieb,Ferref,andWright2000),randomamplified
polymorphicDNAPCR(RAPDPCRstandsforpolymerasechainreaction),internaltranscribedspacer(ITS)
sequences(Hseuetal.1996),sequencerelatedamplifiedpolymorphism(SRAPSunetal.2006),enterobacterial
repetitiveintergenicconsensus(ERIC)elements,andamplifiedfragmentlengthpolymorphism(AFLPZhengetal.
2009).OtherapproachestotheproblemofG.lucidumtaxonomyincludenondestructivenearinfrared(NIR)methods
combinedwithchemometrics(Chenetal.2008),nuclearmagneticresonance(NMR)basedmetabolomics(Wenetal.
2010),andhighperformanceliquidchromatography(HPLC)forgeneratingchemicalfingerprints(Suetal.2001Chen
etal.2008Shi,Zhangetal.2008Chenetal.2010).
9.4.CULTIVATION,GLOBALUSE,ANDMANUFACTUREOFPRODUCTS
OwingtoitsirregulardistributioninthewildandtoanincreasingdemandforG.lucidumasamedicinalherb,attempts
weremadetocultivatethemushroom(ChangandBuswell2008).DifferentmembersoftheGanodermagenusneed
differentconditionsforgrowthandcultivation(Mayzumi,Okamoto,andMizuno1997).Moreover,differenttypesare
favoredindifferentgeographicalregions.Forexample,inSouthChina,blackG.lucidumispopular,whereasredG.
lucidumispreferredinJapan.G.lucidumthrivesunderhotandhumidconditions,andmanywildvarietiesarefoundin
thesubtropicalregionsoftheOrient.Sincetheearly1970s,cultivationofG.lucidumhasbecomeamajorsourceofthe
mushroom.ArtificialcultivationofG.lucidumhasbeenachievedusingsubstratessuchasgrain,sawdust,woodlogs
(ChangandBuswell1999Wasser2005Bohetal.2007),andcorkresidues(Riu,Roig,andSancho1997).
SinceittakesseveralmonthstoculturethefruitingbodyofG.lucidum,myceliabasedandculturebrothbasedproducts
haveassumedgreaterimportanceduetodemandsforincreasedqualitycontrolandyearroundproduction(Sanodiyaet
al.2009).Theprocessesanddifferentgrowthparameters(e.g.,temperature,pH)involvedinsubmergedmycelialculture
caneasilybestandardizedundercontrolledconditions,andpurificationandotherdownstreamprocessingofactive
componentssuchaspolysaccharidesreleasedintotheculturemediumusuallyinvolverelativelysimpleprocedures.
Differentcultureconditionsandmediumcompositionshavealsobeenreportedtostronglyinfluencemycelialgrowth
andtheproductionofbiopolymers(e.g.,polysaccharides)thatareextrudedfromthecell(exopolysaccharides[EPSs]
Mayzumi,Okamoto,andMizuno1997ChangandBuswell1999HabijanicandBerovic2000FangandZhong2002
Bohetal.2007Sanodiyaetal.2009).Forexample,YangandLiau(1998)reportedthatpolysaccharideproductionby
fermentergrownmyceliaofG.lucidumwasoptimumat30C35CandapHof44.5,andtheadditionof
supplementssuchasfattyacidswasfoundtoacceleratemycelialgrowthandtheproductionofbioactivecomponents.In
asubmergedcultureofG.lucidum,theoptimumpHforcellgrowthhasbeenshowntobelowerthanthatforEPS
formation.AtwostagepHcontrolstrategy,developedtomaximizemycelialbiomassandEPSproduction,revealedthat
culturepHhadasignificanteffectonEPSyield,chemicalcompositionandmolecularweight,andmycelialmorphology
(Kim,Park,andYun2006).TheproductivemycelialmorphologicalformforEPSproductionwasadispersedpellet
(controlledpHshiftfrom3.0to6.0)ratherthanacompactpelletwithadensecore(pHmaintainedat4.5)ora
featherlikepellet(controlledpHshiftfrom6.0to3.0).ThreedifferentpolysaccharideswereobtainedundereachpH

condition,andtheirmolecularweightsandchemicalcompositionsweresignificantlydifferent(Kim,Park,andYun
2006).Morerecently,anovelthreestagelightirradiationstrategyhasbeendevelopedinsubmergedculturesofG.
lucidumfortheefficientproductionofpolysaccharidesandoneofthetriterpenecomponents,ganodericacid(Zhangand
Tang2008).
Adecadeago,morethan90brandsofG.lucidumproductswereregisteredandmarketedinternationally(Lin2000).
Worldwideconsumptionisnowestimatedatseveralthousandtonnes,andthemarketisgrowingrapidly.Althoughthere
arenorecentlypublisheddatarelatingtothetotalworldmarketvalueofganodermaproducts,in1995,thetotal
estimatedannualmarketvaluegivenbydifferentcommercialsourceswasUS$1628million(ChangandBuswell1999).
NumerousG.lucidumproducts,preparedfromdifferentpartsofthemushroom,arecurrentlyavailableonthemarket
(ChangandBuswell2008).Inmanufacturingterms,thesimplesttypeconsistsofintactfruitingbodiesgroundtopowder
andthenprocessedtocapsuleortabletform.Othernonextractedproductsarepreparedfromthefollowingthree
sources:(1)driedandpowderedmyceliaharvestedfromsubmergedliquidculturesgrowninfermentationtanks(2)
driedandpowderedcombinationsofsubstrate,mycelia,andmushroomprimordia,followinginoculationandincubation
ofasemisolidmediumwithfungalmyceliaand(3)intactfungalsporesorsporesthathavebeenbrokenbymechanical
meansorhavehadthesporewallsremoved.Althoughsporepreparationshavebeenresearchedandpromoted
vigorouslyinrecentyears,anyaddedmedicinaleffectsattributabletotheremovalorbreakageofsporewalls,which
representsanadditionalandoftencostlystepintheproductionprocess,arestillcontroversial.Otherproductsare
preparedwithmaterials(e.g.,polysaccharides,triterpenes)extracted,usuallywithhotwaterorethanol,fromfruiting
bodiesormyceliaharvestedfromsubmergedliquidculturesandthenevaporatedtodrynessandtabulated/encapsulated
eitherseparatelyorintegratedtogetherindesignatedproportions.TheadoptionofsupercriticalfluidCO2extraction
technologieshasenlargedthespectrumofextractedsubstancesduetothelowtemperaturerequiredduringprocessing.
Severalotherproductshavebeenpreparedasbinary,ternaryormorecomplexmixturesofpowderedganodermaand
othermushrooms(e.g.,Lentinulaedodes,Agaricusbrasiliensis,Grifolafrondosa,Pleurotusspp.,andFlammulina
velutipes)andevenwithothermedicinalherbs(e.g.,spirulinapowderorflowerpollengrains).
9.5.MAJORBIOACTIVECOMPONENTS
Mostmushroomsarecomposedofaround90%waterbyweight.Theremaining10%consistsof1040%protein,28%
fat,328%carbohydrate,332%fiber,810%ash,andsomevitaminsandminerals,withpotassium,calcium,
phosphorus,magnesium,selenium,iron,zinc,andcopperaccountingformostofthemineralcontent(Borchersetal.
1999).InastudyofthenonvolatilecomponentsofG.lucidum,itwasfoundthatthemushroomcontains1.8%ash,26
28%carbohydrate,35%crudefat,59%crudefiber,and78%crudeprotein(Mau,Lin,andChen2001).
Inadditiontothese,mushroomscontainawidevarietyofbioactivemolecules,suchasterpenoids,steroids,phenols,
nucleotidesandtheirderivatives,glycoproteins,andpolysaccharides.Mushroomproteinscontainalltheessentialamino
acidsandareespeciallyrichinlysineandleucine.Thelowtotalfatcontentandhighproportionofpolyunsaturatedfatty
acidsrelativetothetotalfattyacidsofmushroomsareconsideredsignificantcontributorstothehealthvalueof
mushrooms(ChangandBuswell1996Borchersetal.1999Sanodiyaetal.2009).
Polysaccharides,peptidoglycans,andtriterpenesarethreemajorphysiologicallyactiveconstituentsinG.lucidum(Boh
etal.2007Zhouetal.2007).However,theamountandpercentageofeachcomponentcanbeverydiverseinnatural
andcommercialproducts,asexemplifiedbythedatashowninTable9.1.When11randomlyselectedsamplesof
commerciallingzhiproductspurchasedinHongKongshopswereevaluatedforthetwomajoractivecomponents,
triterpenesandpolysaccharides,itwasfoundthatthetriterpenecontentrangedfromundetectableto7.8%andthe
polysaccharidecontentvariedfrom1.15.8%(ChangandBuswell2008).Suchvariationscanoccurforseveralreasons,
includingdifferencesinthespeciesorstrainsofmushroomusedanddifferencesinproductionmethods.
9.5.1.POLYSACCHARIDES ANDPEPTIDOGLYCANS

Fungiareremarkableforthevarietyofhighmolecularweightpolysaccharidestructuresthattheyproduce,andbioactive
polyglycansarefoundinallpartsofthemushroom.Polysaccharidesrepresentstructurallydiversebiological
macromoleculeswithwiderangingphysiochemicalproperties(Zhouetal.2007).Variouspolysaccharideshavebeen
extractedfromthefruitbody,spores,andmyceliaoflingzhitheyareproducedbyfungalmyceliaculturedinfermenters
andcandifferintheirsugarandpeptidecompositionsandmolecularweight(e.g.,ganoderansA,B,andC).G.lucidum
polysaccharides(GLPSs)arereportedtoexhibitabroadrangeofbioactivities,includingantiinflammatory,

hypoglycemic,antiulcer,antitumorigenic,andimmunostimulatingeffects(MiyazakiandNishijima1981Hikinoetal.
1985Tomodaetal.1986Baoetal.2001WachtelGalor,Buswelletal.2004).Polysaccharidesarenormallyobtained
fromthemushroombyextractionwithhotwaterfollowedbyprecipitationwithethanolormethanol,buttheycanalso
beextractedwithwaterandalkali.StructuralanalysesofGLPSsindicatethatglucoseistheirmajorsugarcomponent
(Baoetal.2001Wangetal.2002).However,GLPSsareheteropolymersandcanalsocontainxylose,mannose,
galactose,andfucoseindifferentconformations,including13,14,and16linkedandD(orL)substitutions
(Lee,Lee,andLee1999Baoetal.2002).Branchingconformationandsolubilitycharacteristicsaresaidtoaffectthe
antitumorigenicpropertiesofthesepolysaccharides(Baoetal.2001Zhang,Zhang,andChen2001).Themushroom
alsoconsistsofamatrixofthepolysaccharidechitin,whichislargelyindigestiblebythehumanbodyandispartly
responsibleforthephysicalhardnessofthemushroom(Upton2000).Numerousrefinedpolysaccharidepreparations
extractedfromG.lucidumarenowmarketedasoverthecountertreatmentforchronicdiseases,includingcancerand
liverdisease(Gaoetal.2005).
VariousbioactivepeptidoglycanshavealsobeenisolatedfromG.lucidum,includingG.lucidumproteoglycan(GLPG
withantiviralactivityLi,LiuandZhao2005),G.lucidumimmunomodulatingsubstance(GLISJietal.2007),PGY(a
watersolubleglycopeptidefractionatedandpurifiedfromaqueousextractsofG.lucidumfruitbodiesWuandWang
2009),GLPSpeptide(GLPPHoetal.2007),andF3(afucosecontainingglycoproteinfractionChienetal.2004).
9.5.2.T RITERPENES

Terpenesareaclassofnaturallyoccurringcompoundswhosecarbonskeletonsarecomposedofoneormoreisoprene
C5units.Examplesofterpenesarementhol(monoterpene)andcarotene(tetraterpene).Manyarealkenes,although
somecontainotherfunctionalgroups,andmanyarecyclic.Thesecompoundsarewidelydistributedthroughoutthe
plantworldandarefoundinprokaryotesaswellaseukaryotes.Terpeneshavealsobeenfoundtohaveanti
inflammatory,antitumorigenic,andhypolipidemicactivity.TerpenesinGinkgobiloba,rosemary(Rosemarinus
officinalis),andginseng(Panaxginseng)arereportedtocontributetothehealthpromotingeffectsoftheseherbs
(MahatoandSen1997Mashour,Lin,andFrishman1998Haralampidis,Trojanowska,andOsbourn2002).
TriterpenesareasubclassofterpenesandhaveabasicskeletonofC30.Ingeneral,triterpenoidshavemolecularweights
rangingfrom400to600kDaandtheirchemicalstructureiscomplexandhighlyoxidized(MahatoandSen1997Zhou
etal.2007).Manyplantspeciessynthesizetriterpenesaspartoftheirnormalprogramofgrowthanddevelopment.
Someplantscontainlargequantitiesoftriterpenesintheirlatexandresins,andthesearebelievedtocontributetodisease
resistance.Althoughhundredsoftriterpeneshavebeenisolatedfromvariousplantsandterpenesasaclasshavebeen
showntohavemanypotentiallybeneficialeffects,thereisonlylimitedapplicationoftriterpenesassuccessful
therapeuticagentstodate.Ingeneral,verylittleisknownabouttheenzymesandbiochemicalpathwaysinvolvedintheir
biosynthesis.
InG.lucidum,thechemicalstructureofthetriterpenesisbasedonlanostane,whichisametaboliteoflanosterol,the
biosynthesisofwhichisbasedoncyclizationofsqualene(Haralampidis,Trojanowska,andOsbourn2002).Extraction
oftriterpenesisusuallydonebymeansofmethanol,ethanol,acetone,chloroform,ether,oramixtureofthesesolvents.
Theextractscanbefurtherpurifiedbyvariousseparationmethods,includingnormalandreversephaseHPLC(Chenet
al.1999Suetal.2001).ThefirsttriterpenesisolatedfromG.lucidumaretheganodericacidsAandB,whichwere
identifiedbyKubotaetal.(1982).Sincethen,morethan100triterpeneswithknownchemicalcompositionsand
molecularconfigurationshavebeenreportedtooccurinG.lucidum.Amongthem,morethan50werefoundtobenew
anduniquetothisfungus.Thevastmajorityareganodericandlucidenicacids,butothertriterpenessuchasganoderals,
ganoderiols,andganodermicacidshavealsobeenidentified(Nishitobaetal.1984Satoetal.1986Budavari1989
Gonzalezetal.1999Maetal.2002Akihisaetal.2007Zhouetal.2007Jiangetal.2008Chenetal.2010).
ExamplesoftriterpenesareshowninFigure9.3.
G.lucidumisclearlyrichintriterpenes,anditisthisclassofcompoundsthatgivestheherbitsbittertasteand,itis
believed,confersonitvarioushealthbenefits,suchaslipidloweringandantioxidanteffects.However,thetriterpene
contentisdifferentindifferentpartsandgrowingstagesofthemushroom.TheprofileofthedifferenttriterpenesinG.
lucidumcanbeusedtodistinguishthismedicinalfungusfromothertaxonomicallyrelatedspecies,andcanserveas
supportingevidenceforclassification.Thetriterpenecontentcanalsobeusedasameasureofqualityofdifferent
ganodermasamples(Chenetal.1999Suetal.2001)

9.5.3.OTHERCOMPONENTS

ElementalanalysisoflogcultivatedfruitbodiesofG.lucidumrevealedphosphorus,silica,sulfur,potassium,calcium,
andmagnesiumtobetheirmainmineralcomponents.Iron,sodium,zinc,copper,manganese,andstrontiumwerealso
detectedinloweramounts,asweretheheavymetalslead,cadmium,andmercury(Chenetal.1998).Freezedriedfruit
bodiesofunidentifiedGanodermaspp.collectedfromthewildwerereportedtohaveamineralcontentof10.2%,with
potassium,calcium,andmagnesiumasthemajorcomponents(Chiuetal.2000).Significantly,nocadmiumormercury
wasdetectedinthesesamples.G.lucidumcanalsocontainupto72g/gdryweightofselenium(SeFalandysz2008)
andcanbiotransform2030%ofinorganicseleniumpresentinthegrowthsubstrateintoseleniumcontainingproteins
(Duetal.2008).
SomeattentionhasbeengiventothegermaniumcontentofGanodermaspp.Germaniumwasfifthhighestintermsof
concentration(489g/g)amongthemineralsdetectedinG.lucidumfruitbodiescollectedfromthewild(Chiuetal.
2000).Thismineralisalsopresentintheorderofpartsperbillioninmanyplantbasedfoods,includingginseng,aloe,
andgarlic(Minoetal.1980).Althoughgermaniumisnotanessentialelement,atlowdoses,ithasbeencreditedwith
immunopotentiating,antitumor,antioxidant,andantimutagenicactivities(Kolesnikova,Tuzova,andKozlov1997).
However,althoughthegermaniumcontentofG.lucidumhasbeenusedtopromoteG.lucidumbasedproducts,thereis
nofirmevidencelinkingthiselementwiththespecifichealthbenefitsassociatedwiththemushroom.
G.lucidumcontainssomeothercompoundsthatmaycontributetoitsreportedmedicinaleffect,suchasproteinsand
lectins.TheproteincontentofdriedG.lucidumwasfoundtobearound78%,whichislowerthanthatofmanyother
mushrooms(ChangandBuswell1996Mau,Lin,andChen2001).Bioactiveproteinsarereportedtocontributetothe
medicinalpropertiesofG.lucidum,includingLZ8,animmunosuppressiveproteinpurifiedfromthemycelia(VanDer
Hemetal.1995)apeptidepreparation(GLP)exhibitinghepatoprotectiveandantioxidantactivities(Sun,He,andXie
2004Shi,Sunetal.2008)anda15kDaantifungalprotein,ganodermin,whichisisolatedfromG.lucidumfruiting
bodies(WangandNg.2006).
Thecarbohydrateandcrudefibercontentofthedriedmushroomwasexaminedandfoundtobe2628%and59%,
respectively(Mau,Lin,andChen2001).Lectinswerealsoisolatedfromthefruitbodyandmyceliumofthemushroom
(Kawagishietal.1997),includinganovel114kDahexamericlectin,whichwasrevealedtobeaglycoproteinhaving
9.3%neutralsugarandshowinghemagglutinatingactivityonpronasetreatedhumanerythrocytes(Thakuretal.2007).
Lectins(fromtheLatinwordlegere,whichmeanstopickup,choose)arenonenzymaticproteinsorglycoproteinsthat
bindcarbohydrates.Manyspeciesofanimals,plants,andmicroorganismsproducelectins,andtheyexhibitawiderange
offunctions.Inanimals,forexample,lectinsareinvolvedinavarietyofcellularprocessesandthefunctioningofthe
immunesystem(Wang,Ng,andOoi1998).
OthercompoundsthathavebeenisolatedfromG.lucidumincludeenzymessuchasmetalloprotease,whichdelays
clottingtimeergosterol(provitaminD2)nucleosidesandnucleotides(adenosineandguanosineWasser2005
Paterson2006).KimandNho(2004)alsodescribedtheisolationandphysicochemicalpropertiesofahighlyspecific
andeffectivereversibleinhibitorofglucosidase,SKG3,fromG.lucidumfruitbodies.Furthermore,G.lucidum
sporeswerereportedtocontainamixtureofseverallongchainfattyacidsthatmaycontributetotheantitumoractivity
ofthemushroom(Fukuzawaetal.2008).
9.6.THERAPEUTICAPPLICATIONS
Thecombinationofbenefitwithouttoxicityrepresentsthedesiredendresultinthedevelopmentofeffectivetherapeutic
interventions.G.lucidumhasbeenusedforhundredsofyearsasahealthpromotionandtreatmentstrategythereare
nowmanypublishedstudiesthatarebasedonanimalandcellculturemodelsandoninvitroassessmentofthehealth
effectsofG.lucidum,andtherearealsosomereportsofhumantrialsinthefield.However,thereisnocohesivebodyof
research,andtheobjectiveevaluationofthistraditionaltherapyintermsofhumanhealthremainstobeclearly
established.InSections9.6.1through9.6.6,studiesonthepropertiesofG.luciduminrelationtocancer(whichhas
attractedthemostinterest),viralandbacterialinfection,diabetes,andliverinjuryarediscussed.
9.6.1.CANCER

G.lucidumisapopularsupplementtakenbyhealthyindividualtoboosttheimmunesystemandbycancerpatients
alongwithconventionaltherapies.Inthissection,thescientificstudiesofG.lucidumonitsanticancerpropertiesare

summerized.
9.6.1.1.Introduction

Cancerisaworldwideleadingcauseofdeath,anddespitecomprehensiveadvancesintheearlydiagnosisofthedisease
andchemotherapy,itremainsamajorclinicalchallenge(WHO2008).Aspartofsearchingfornewchemopreventive
andchemotherapeuticagents,hundredsofplantspecies,includingmushrooms,havebeenevaluated.Thishasresulted
intheisolationofthousandsofbioactivemoleculesthatwereshowntohaveantitumoractivityfromnumerous
mushroomspecies,includingGanodermaspecies(WasserandWeis1999Borchersetal.2008).InG.lucidum,alarge
numberofchemicalcompoundscanbeextractedfromthefruitingbody,mycelia,orspores.Manypolysaccharidesand
triterpenes,thetwomajorgroupsofcomponentsinthemushroom,exhibitchemopreventiveand/ortumoricidaleffects,
asprovedbynumerousstudiesfrominvitroexperimentsandanimalandhumaninvivostudies(YuenandGohel2005
Zaidmanetal.2005).Tumorimplantedanimalmodelshaveshowninhibitoryeffectsonangiogenesisandmetastasis.
However,evidencefromwelldesignedhumantrialsisstillscarce.
9.6.1.2.InVitroAnticancerActivities

Tomasietal.(2004)tested58basidiomycetesmushrooms,ofwhichG.lucidumwasshowntobethemosteffectivein
killingcancercells.G.luciduminducedcellcyclearrestandapoptosisinvarioushumanandrodenttumorcells,
includingmurinelymphocyticleukemiaL1210andLewislungcarcinoma(LLCMinetal.2000Tomasietal.2004),
mousereticulocytesarcomaLII(Liuetal.2002),murinesarcomaMethA(Minetal.2000Gao,Minetal.2002)and
S180(Gao,Minetal.2002Liuetal.2002),humanleukemiaHL60(Mulleretal.2006Kimetal.2007Fukuzawaet
al.2008Liuetal.2009)andU937,K562,Blin1,Nalm6,RPMI8226(Mulleretal.2006Shangetal.2009),human
hepatomaPLC/PRF/5,KB(Linetal.2003),HepG2(Liuetal.2009Wengetal.2009),Hep3B(Chungetal.2001),
Huh7(Linetal.2003Li,Chanetal.2005),humanlivertumorSMMC7721(Tangetal.2006),humanbreastcancer
MDAMB123(Jiangetal.2008Liuetal.2009Zhaoetal.2010),MCF7(Jiang,Slivova,andSliva2006Liuetal.
2009Shangetal.2009),T47D(Gao,Minetal.2002)andMT1(Wuetal.2006Xieetal.2009),humanprostate
cancerPC3(Jiangetal.2004Evansetal.2009),humancervixuteritumorHela(Liuetal.2002Tangetal.2006
Shangetal.2009),humanovariancancerSKOV4(Shangetal.2009),humancoloniccancerHT29(Hongetal.2004)
andSW480(Xieetal.2006),humanlungcarcinomaPG(CaoandLin2006Cao,Lin,andWang2007)and95D
(Tangetal.2006),humansmallcelllungcarcinomaNCIH69andmultidrugresistantstrainVPA(Sadavaetal.2009),
lowgradebladdercancerMTC11(Luetal.2004),andhumanuroepithelialHUCPC(Yuen,Gohel,andAu2008)
cells.
Throughtheregulationofexpressionofdifferentsignals,tumorcellswerearrestedbyG.lucidumatdifferentpointsof
cellcycle,forexample,breastatG0/G1phaselungatG1phaseliveratG1/G2phaseandbladder,prostate,and
leukemiaatG2phase.AseleniumenrichedextractofG.lucidummyceliawasshowntoinduceG1/Sphasearrestin
humanerythroidchronicmyeloidleukemiaK562cells(Shangetal.2009).AnotherextractinducedG0/G1phasearrest
inestrogendependentbreastMCF7cellsthroughthedownregulationofestrogenreceptorandserine/threonine
specificproteinkinaseAkt/nuclearfactorB(NFB)signaling(Jiang,Slivova,andSliva2006).Invarioushuman
cancercelllines,extractsofG.lucidumwereshowntosuppresstheprogressionoftheG1phaseincellcycle,and
apoptosiswasconfirmedbyusingterminaldeoxynucleotidyltransferasedUTPnickandlabeling(TUNEL)assay(Liu
etal.2009).Manyoftheseactivitieswereaccompaniedbyapoptosis.CaoandLin(2006)demonstratedthatafraction
ofGLPPdecreasedtheantiapoptoticproteinBcl2expressionandincreasedtheproapoptoticproteinBaxexpressionin
humanumbilicalcordvascularendothelialcells(HUVECs).AtriterpenerichextractfromG.luciduminduced
progressiveapoptosisinthepremalignantHUCPCcelllinebyincreasingtheearlyapoptosismarkerannexinVwithin
3hours.Halfthecellsstainedpositivefor7aminoactinomycinD(indicatinglateapoptosis)after8hours.Allcellswere
deadat24hours,andthiswasassociatedwiththedownregulationoftelomerase(Yuen,Gohel,andAu2008).Similar
apoptoticactivitieswerealsodemonstratedinotherhumancancercells(Fukuzawaetal.2008).AnethanolextractofG.
lucidumdecreasedcyclooxygenase2(COX)2enzymeexpressionandincreasednitricoxidesynthesisincolonHT29
cells(Hongetal.2004).Inlung95Dtumorcells,thepurecompoundganodericacidTcausedmitochondrial
dysfunction,whichresultedfromtheupregulationofproapoptoticp53andBaxexpression(Tangetal.2006).
Moreover,theuseofacombinationofG.lucidumandDuschesneaextractsupregulatedcytochromecandBax
translocationtotriggercaspase3apoptosisinleukemiaHL60cells(Kimetal.2007).Activationofcaspases7and9
byG.lucidumhasbeendemonstratedinbreastMCF7andlungH69SCLCcancercells,respectively(Huetal.2002

Sadavaetal.2009).InhepatomaHepG2cells,alucidenicacidrichG.lucidumextractwasshowntosuppress
phosphorylationofERK1/2andAktsignaling,whichdownregulatedtheirdownstreamNFBandprotooncoproteins
(cJunandcFos)activities,favoringapoptosis(Wengetal.2009).
Atumormassrequiresacontinuousnutrientsupplyvianewbloodvesselsformedbytheprocessofangiogenesis.
Invasivecancercellsspreadtodistantsitesthroughbloodandlymphoidvessels.Therefore,agentsthatinhibit
angiogenesisinhibittumorgrowthandspread.ThepotentialantiangiogenicactivitiesofG.lucidumhavebeen
demonstratedinexvivochickembryochorioallantoicmembrane(CAM)assay(CaoandLin2004Songetal.2004).
PolysaccharidepeptideandethanolextractfromG.lucidumhasbeenprovedtodecreasemicrovesselsarounda
microfiberfilterdisccontaininganembryowithintactyolks.Usingaprostatecancercellline,twoangiogenicfactors,
knownasvascularendothelialgrowthfactor(VEGF)andtransforminggrowthfactor(TGF)1,weresuppressedbyG.
lucidumthroughinhibitionoftheras/extracellularsignalregulatedkinase(Erk1/2)andAktsignalingpathways
(Johnston2005Stanleyetal.2005).Similareffectswerealsoobservedinahumanlungcancercelllinesunderhypoxic
conditionsafterexposuretoahighdoseofGLPP(CaoandLin2006).
Celladhesion,invasion,andmigrationarethekeyfactorsindeterminingtheaggressivenessofcancerhence,controlof
cellmotilityiseffectiveinavoidingcancermetastasis.ApolysaccharideextractofG.lucidummyceliainhibitedthe
formationofoncogenicrasinducedtransformedfociinanR6embryofibroblastcellline(Hsiaoetal.2004).Sporesand
thefruitingbodyofG.lucidumwereshowntoinhibittheregulatoryproteinsphosphatidylinositolandNFBinhighly
invasivebreastandprostatecancercells(Slivaetal.2002).Celladhesion,invasion,andcolonyformationofbreast
cancercellsweresignificantlyinhibitedonexposuretoG.lucidumextracts(Sliva2004).Inaddition,Luetal.(2004)
demonstratedthatwaterandethanolextractsofG.lucidummodulatedtheF/Gactinratio,which,inturn,reducedthe
formationofstressfiberandfocaladhesioncomplexesofbladdercancercells,suggestingtheactinremodelingwas
associatedwiththeinhibitionofcarcinogeninducedcellmigration.InhibitionofmitogeninducedinvasionofHepG2
cellswasdemonstratedinastudybyusingMatrigelcoatedfilterinsertsassay(Wengetal.2009).
9.6.1.3.AnimalStudies

RodentstudiesofpossibleantitumorigeniceffectsofG.lucidumcanbetracedbacktotheearly1980s.Tendaysof
intraperitoneal(i.p.)injectionsofapolysaccharidefraction(GL1)fromthefruitbodywasreportedtoinhibit(by95
98%)thegrowthoftransplantedsarcoma180tumorcellsinmice(MiyazakiandNishijima1981).Acomplexof
polysaccharidesandproteinfromthemushroomwasalsofoundtoshowsignificantantitumoractivityinasimilarstudy
conductedbyKimetal.(1980).Aninhibitionrateof88%wasreported,andtherewascompleteregressionoftumorin
athirdofthetestanimals.InastudyconductedbyHyun,Choi,andKim(1990),whichusedasimilarprotocolbutused
variousextractedpolysaccharides,inhibitionratesof5281%werefound.Ahotwaterextract(2mg/mouse)giveni.p.
for3daysresultedinanaverage74%inhibitionoftumorgrowthinmice,with3outof10animalsshowingcomplete
regression,andanoraladministration(dailyfor5weeks)showed4563%inhibition(Ohnoetal.1998).Similar
inhibitoryeffectswereshownwithimplantedsarcoma180cellsafterpolysaccharidewasgivenorallytomice(Zhang
andLin1999).Apure(13)glucanwastestedinparallelwithcrudeG.lucidumextracts,whichresultedin90%
inhibitionoftumorgrowth(Ohnoetal.1998).AdrypowderpreparationoftheantleredformofG.lucidum(knownas
deerhornlingzhiduetoitsappearance)wasshowntoinhibittumorgrowthandelongatethelifespaninbothallogeneic
sarcoma180bearingddYmiceandsynergenicMM46mammarytumorbearingC3H/Hemice(Nonakaetal.2006).
G.lucidumisamajorcomponentofmanytraditionalbotanicalformulations,suchasTBS101,whichwasdemonstrated
toinhibittumorgrowthandinvasioninPC3implantedmice(Evansetal.2009).Yun(1999)reportedthat9weeksof
oraladministrationofmycelialextractsignificantlyinhibitedlungadenomaformationinmice.Oraladministrationof
triterpenoidfractionsfor18consecutivedaysinhibitedMartigelinducedangiogenesis,whichsignificantlyreduced
tumorweightandthenumberoftumorcellcoloniesthathadmetastasizedtotheliverinfemaleC57BL/6Jstrainmice
withintrasplenicimplantationofLewislungcancercells(Kimura,Taniguchi,andBaba2002Wangetal.2007).In
maleICRnu/nunudemiceinjectedwithhepatomaHepG2cells,dailyoraladministrationoflucidenicacidrichextract
for68days(800mg/kgdosage)decreasedboththenumberandsizeoftumorsbyupto99%,andalsothenumberof
metastatictumorsoccurringinliverandlung(Wengetal.2009).Anaqueousextract(administeredi.p.at10,20,and40
mg/mouse)ofthefruitbodysignificantlyincreasedthelifespanofmiceimplantedwithLewislungcarcinomacells.
However,nodoseresponseeffectwasseen(Furusawaetal.1992).AnadditiveeffectwasseenwhenG.lucidumwas
givenincombinationwithcytotoxicantineoplasticdrugs,andtherewasasuggestionofapossiblesynergisticeffectwith

cisplatin(Furusawaetal.1992).Inanotherstudy,G.lucidumwasfoundtoalsoprolongthelifespanoftumor
transplantedmicebyinhibitingmetastasistothelung(Leeetal.1995).Whengiven1weekpriortotheadministrationof
acarcinogenicagent,ahotwaterextractofthemycelium/growthmediumcomplexdecreasedthedevelopmentof
aberrantcryptfoci(ACF)andprecancerouslesionsinthecolon(Luetal.2001Luetal.2003).Notoxicityorside
effectswereseenintheratswhentheextractwasadministeredfor3months.Whentestedwithmousecolontumor
implantedchambers,apolysaccharidemixturecontainingisoflavoneaglyconsfromculturedG.lucidummyceliawas
foundtoinhibitangiogenesisinvivo(Miuraetal.2002).
Thechemopreventiveactivitiesofthemushroomonprostatecancerweredemonstratedbyatriterpenoidrichextractof
G.lucidumthatsuppressedtheventralprostategrowthinducedbytestosterone(Liuetal.2007a).GanoderolBwas
identifiedastheactiveprinciplethatwasabletobindtoanandrogenreceptorandinhibit5reductase,suppressing
androgeninducedLNCaPcellgrowthanddownregulatingtheprostatespecificantigen(Liuetal.2007b).
9.6.1.4.HumanStudies

Inhumans,whethertheantitumoreffectoflingzhiisadirectoneorismediatedviaeffectsontheimmunesystemisa
keyquestiontoaddress.G.lucidumisoneoftheeightcomponentsofanherbalmixturecalledprostatecancerhope
(knownasPCSEPS),whichhasbeenusedasanalternativeinthetreatmentofandrogendependentandindependent
prostatecancer(GaoandZhou2009).However,onlyafewclinicaltrialshaveusedG.lucidumasasingleagenton
cancerpatients(Gao,Zhouetal.2002Gao,Zhouetal.2003Gao,Saietal.2003).Tworandomized,controlledtrials
havebeenconductedusingaGLPSrichextract(apatentedoverthecounterproduct,GanopolyGaoetal.2003Gao
andSaietal.2003).Gao,Zhouetal.(2003)recruited134patientswithadvancedcancersofdifferentsitesand
supplementedthemwithG.lucidumcapsulesatadosageof1800mg/dayfor12weeks.Cellularimmunityin80%of
thesepatientswassignificantlyenhancedintermsofelevatedplasmainterleukin(IL)2,IL6,andinterferon(IFN)
levelsandnaturalkiller(NK)cellactivity.Inanotherstudy,thesameprotocolwasfollowedwith68lungcancer
patients(Gao,Saietal.2003)inwhomimmuneparametersincludingtotalTcells,NKcells,andCD4/CD8ratiowere
significantlyenhancedintheG.lucidumtreatedgroup.Inaddition,qualityoflifeintermsofKarnofskyscorewas
improvedinabout65%ofthesepatients(Gao,Saietal.2003).Ganopolywasalsodemonstratedtoenhancemitogenic
activityandNKcellsinpatientswithadvancedcancerinabeforeandaftercomparisonstudy(Gao,Minetal.2002).
TheseresultsprovidesomeevidencethattheantitumoreffectsofG.lucidumaremediatedviaeffectsontheimmune
system.However,itmustbenotedthatallstudieswereconductedbythesameresearchgroupandthatotherdirect
antitumoreffectsofG.lucidumhavenotyetbeenstudiedonhumansinvivo.
9.6.2.IMMUNOMODULATION

Agentsthatenhancethefunctioningofthehostimmunesystemcouldbeexpectedtoenhancehealthintermsof
improvedresistanceand,thus,removalofmalignantorpremalignantcells.ManyG.lucidumproductsonthemarketare
labeledorpromotedasimmunomodulatingagents.
ThereisconsiderableevidencetosupporttheimmunostimulatingactivitiesofG.lucidumviainductionofcytokinesand
enhancementofimmunologicaleffector(Wangetal.1997ZhuandLin2006).DifferentcomponentsfromG.lucidum
wereprovedtoenhancetheproliferationandmaturationofTandBlymphocytes,splenicmononuclearcells,NKcells,
anddendriticcellsincultureinvitroandinanimalstudiesinvivo(Baoetal.2001CaoandLin2002Zhu,Chen,and
Lin2007Maetal.2008).InnormalBALB/cmice,apolysacchariderichextractofG.lucidumpromotedthe
proliferationofsplenocytesandenhancedtheactivitiesofmacrophagesandNKcells,whichresultedintheincreaseof
IL6andIFN(Changetal.2009).AlthoughacommercialG.lucidumextractdidnotstimulateproliferationof
lymphocytes,itactivatedthegeneexpressionofIL1,IL6,IL10,andtumornecrosisfactor(TNF)(Maoetal.
1999).Apolysaccharidefraction(F3)wasshowntoenhancebothadaptiveandinnateimmunitiesbytriggeringthe
productionofcytokinesIL1,IL6,IL12,IFN,TNF,andcolonystimulatingfactors(CSFs)frommouse
splenocytes(Chenetal.2004).ItwasreportedalsothatTNFandIL6productionwerestimulatedinhumanand
murinemacrophagesbyG.lucidummycelia(Kuoetal.2006).Thiseffectmightbeduetoincreasedsynthesisofnitric
oxide(NO)inducedbyDglucan(Ohnoetal.1998).Thesepolysaccharideswerealsofoundtobehighlysuppressive
totumorcellproliferationinvivowhileenhancingthehostsimmuneresponse(OoiandLiu2000).
Wangetal.(1997)foundthatapolysaccharideenrichedfractionfromG.lucidumactivatedculturedmacrophagesandT
lymphocytesinvitro,whichledtoanincreaseofIL1,TNF,andIL6intheculturemedium.Inanotherstudy

(ZhangandLin1999),incubationofmacrophagesandTlymphocyteswithapolysaccharideresultedinanincreasein
TNFandINFlevelsintheculturemedium.Thisconditionedculturemediumwasfoundtoinhibitcellgrowthand
induceapoptosisinsarcoma180andHL60cells(ZhangandLin1999).Furthermore,serumincorporatedtreatment
withapolysaccharidepeptidefractionfromG.lucidummarkedlyinhibitedtheproliferationofhumanlungcarcinoma
(PG)cells,whereasthepurefractionbyitselfdidnotinducesimilareffects(CaoandLin2004).Inadditionto
polysaccharides,alanostanetriterpenoid,ganodericacidMe,inhibitedtumorgrowthandmetastasisofLewislung
carcinomainThelper1responderC57BL/6micebyenhancingimmunefunctionintermsofIL2andIFN
expressionandNKcellactivity(Wangetal.2007).ZhuandLin(2006)usedcytokineinducedkiller(CIK)cellsto
investigatetheinteractionbetweenGLPSsandcytokines,whichmediatedcellproliferationandantitumoractivity.The
cytotoxicityofCIKcellswascorrelatedwellwiththeexpressionofperforinandgranzymeBinducedbyIL2andanti
CD3.ResultsindicatedthatGLPSsenhanceIL2andTNFproductionaswellasproteinandmessengerribonucleic
acid(mRNA)expressionofgranzymeBandperforininCIKcellsculture,andthusdecreasethedosesofIL2andanti
CD3withoutaffectingthekillingeffectsonNKresistantmouseP815mastocytomacellsandNKsensitivemouse
YAC1lymphomacells(ZhuandLin2006).
9.6.3.L INGZHI AS ANANTIOXIDANT

Consumptionofantioxidantrichplantsmayhelppreventcancerandotherchronicdiseases(Collins2005Benzieand
WachtelGalor2009).Antioxidantsprotectcellularcomponentsfromoxidativedamage,whichislikelytodecreaserisk
ofmutationsandcarcinogenesisandalsoprotectimmunecells,allowingthemtomaintainimmunesurveillanceand
response.VariouscomponentsofG.lucidum,inparticularpolysaccharidesandtriterpenoids,showantioxidantactivity
invitro(Leeetal.2001Mau,Lin,andChen2002Shietal.2002WachtelGalor,Choi,andBenzie2005Yuenand
Gohel2008Saltarellietal.2009WuandWang2009).AsshowninFigure9.4,antioxidantsfromlingzhiwerefound
tobeabsorbedquicklyafteringestion,resultinginanincreaseintheplasmatotalantioxidantactivityofhumansubjects
(Figure9.4WachtelGalor,Szetoetal.2004).
OoiandLiu(2000)reportedthatproteinboundpolysaccharide(PBP)andpolysaccharidepeptidewereabletomimic
theendogenousantioxidantsuperoxidedismutase(SOD)incancerbearinganimalsinvivo.Thesepolysaccharideswere
alsoreportedtoprotecttheimmunecellsfromoxidativedamage(OoiandLui2000).TheprotectiveeffectsofG.
lucidumonDNAstrandscissioninducedbyametalcatalyzedFentonreaction,ultravioletirradiation,andhydroxyl
radicalattackwereshowninagarosegelelectrophoresisinvitro(Leeetal.2001).HotwaterextractsofG.lucidum
significantlyprotectedRajicellsfromhydrogenperoxide(H2O2)inducedDNAdamage(Shietal.2002).Hotwater
extractsprotectedhumanlymphocyteDNAonlyatlow(<.001%w/v)concentrations,andcausedH2O2mediated
damageathigherconcentrations(>.01%w/v)(WachtelGalor,Choi,andBenzie2005).Twoantioxidantenriched
extractsfromG.lucidumactedoppositelyinpremalignantHUCPCcellsundercarcinogenicattack(YuenandGohel
2008).TheaqueousextractprotectedcellularDNAfromoxidativedamage,whereastheethanolicextractdamaged
cellularDNA,withincreasedH2O2productionandsignificantcellkillingeffectsobserved.Theresultssuggestedthat
differenteffectsofG.lucidumcouldbeexhibitedbydifferentextractablecomponentsinbladderchemoprevention.
MethanolextractsofG.lucidumwerereportedtopreventkidneydamage(inducedbytheanticancerdrugcisplatin)
throughrestorationoftherenalantioxidantdefensesystem(Sheena,Ajith,andJanardhanan2003).Incontrast,afraction
ofganodermatriterpenes(GTS)wasfoundtoenhancetheintracellularreactiveoxygenspecies(ROS)producingeffect
ofdoxorubicin(DOX)inHelacells,leadingtomoreDNAdamageandapoptosis,whereassuchsynergismwas
inhibitedbyaROSscavenger(Yueetal.2008).Inananimalstudy(diabeticrats),nonenzymicandenzymic
antioxidantslevelsincreasedandlipidperoxidationlevelsdecreasedwithG.lucidumtreatment(Jiaetal.2009).
However,adirectlinkhasnotbeenestablishedbetweentheantioxidantpropertiesofG.lucidumandits
immunomodulatoryandanticancereffects,andwhetherlingzhiactsasanantioxidantorprooxidantmaydependon
concentrationandenvironment.
9.6.4.VIRALANDBACTERIALINFECTIONS

Thegoalofresearchinthetreatmentofviralandbacterialinfectionsisthediscoveryofagentsthatspecificallyinhibit
viralandbacterialmultiplicationwithoutaffectingnormalcells.Theundesiredsideeffectsofantibioticsandantivirals
andtheappearanceofresistantandmutantstrainsmakethedevelopmentofnewagentsanurgentrequirement.Thishas
ledresearcherstoinvestigatetheantibacterialandantiviralactivityofmedicinalplantsandfungi(WasserandWeis
1999ZhongandXiao2009).Isolationofvariouswaterandmethanolsoluble,highmolecularweightPBPsfromG.

lucidumshowedinhibitoryeffectsonherpessimplexvirustype1(HSV1),herpessimplexvirustype2(HSV2),and
vesicularstomatitisvirus(VSV)NewJerseystraininatissueculturesystem.Usingtheplaquereductionmethod,a
significantinhibitoryeffectwasseenatdosesthatshowednocytotoxicity(Eoetal.1999Ohetal.2000).Inaddition,
therewasamarkedsynergisticeffectwhenPBPfromG.lucidumwasusedintissuecultureinconjunctionwith
antiherpeticagents,acyclovirorvidarabine,andwithIFN(Kimetal.2000Ohetal.2000).Similarresultswere
showninHSV1andHSV2withaGLPGisolatedfromthemyceliaofG.lucidum(Liuetal.2004Li,Liu,andZhao
2005).Thecellsweretreatedbefore,during,andafterinfection,andviraltiterinthesupernatantofcellculture48hours
postinfectionwasdetermined.TheantiviraleffectsoftheGLPGweremoreremarkablebeforeviraltreatmentthanafter
treatment.Althoughthemechanismwasnotdefined,theauthorsconcludedthatGLPGinhibitsviralreplicationby
interferingwithearlyeventsofviraladsorption(Li,Liu,andZhao2005).
SometriterpenesfromG.lucidumhavealsobeenreportedtohaveaninhibitoryeffectagainsthumanimmunodeficiency
virus(HIV)1proteaseactivity,withIC50valuesrangingfrom20tomorethan1000Mhowever,notallofthe
examinedtriterpenesshowedantiHIVactivity(ElMekkawyetal.1998Minetal.1998).Inanotherstudy,aganoderic
acidisolatedfromG.lucidumshowedinhibitoryeffectsonthereplicationofhepatitisBvirus(HBV)inHepG2215cells
(HepG2HBVproducingcellline)over8days.ProductionofHBVsurfaceantigen(HBsAg)andHBVeantigen
(HBeAg)were,respectively,20%and44%ofcontrolswithoutganodericacidtreatment(LiandWang2006).
Somesmallstudiesinhumanpatientshavealsoreportedbeneficialeffectsoflingzhiintake.Adriedhotwaterextractof
G.lucidumtakenorally(equivalentto36or72gofdriedmushroomperday)wasusedasthesoletreatmentfor
postherpetic(varicellazostervirus)neuralgiain4elderlypatients.Thistreatmentwasreportedtodramaticallydecrease
painandpromotethehealingoflesions,withoutanytoxicityevenatveryhighdoses(HijikataandYamada1998).In
anotherstudy,amixtureofG.lucidumwithotherherbsimprovedrecoverytimeinpatientswithherpesgenitalis(n=
15)andherpeslabiallis(n=13Hijikata,Yamada,andYasuhara2007).
Forevaluatingtheantibacterialeffectsofthemushroom,severalinvitroandinvivoanimalstudiesusingG.lucidum
wereperformed.MiceinjectedwithG.lucidumextract(2mg/mouse)1daypriortoinjectionwithEscherichiacoli
showedmarkedlyimprovedsurvivalrates(>80%comparedto33%incontrolsOhnoetal.1998).Inaninvitrostudy
thatusedthediskassay(Keypouretal.2008),achloroformextractofG.lucidumwasinvestigatedforitsantibacterial
effectongrampositivebacteria(Bacillussubtilis,Staphylococcusaureus,Enterococcusfaecalis)andgramnegative
bacteria(E.coli,Pseudomonasaeruginosa).Resultsshowedthattheextracthadgrowthinhibitoryeffectsontwoofthe
grampositivebacteriawithaminimalinhibitoryconcentration(MIC)of8mg/mLforS.aureusandB.subtilis.In
anotherinvitrostudy,thedirectantimicrobialeffectofaG.lucidumwaterextractwasexaminedagainst15speciesof
bacteriaaloneandincombinationwith4kindsofantibiotics(Yoonetal.1994).G.lucidumwasfoundtobemore
effectivethanantibioticsagainstE.coli,Micrococcusluteus,S.aureus,B.cereus,Proteusvulgaris,andSalmonella
typhi,butlesseffectiveagainstotherspeciestested.TheantimicrobialcombinationofG.lucidumwithfourcommonly
usedantibiotics(Yoonetal.1994)resultedinanadditiveorsynergisticeffectinmost,butnotall,instances,with
apparentantagonismagainstcefazolinandampicillineffectsonP.vulgaris.
Todate,theantimicrobialcomponentsofthetestedcrudeextractshavenotbeenidentified,althoughantimicrobial
polysaccharideshavebeenidentifiedinotherfungiandplantterpeneshavebeenreportedtohaveantimicrobialactivity
(WasserandWeis1999ZhongandXiao2009).Inaddition,thebioavailabilityofputativeantimicrobialcomponentsof
G.lucidumhasnotbeenestablished.Nonetheless,G.lucidumoffersapotentiallyeffectivetherapy.Thereisalsothe
implicationthatcombinationtherapymaybemoresafeandcosteffective,asloweramountsofcytotoxicantiviraland
antibacterialdrugscouldbeusedwithaconcomitantdecreaseintheriskofsideeffects.However,thisneedsfurther
investigationintermsofinvitrostudiesandwelldesignedclinicaltrials.
9.6.5.DIABETES MELLITUS

ComponentsofG.lucidumhavebeenprovedtohaveahypoglycemiceffectinanimals.Theadministrationof
ganoderansAandB(doseof100mg/kg),twopolysaccharidesisolatedfromfruitbodywaterextracts,byi.p.injection
tonormalandalloxaninduceddiabeticmicesignificantlydecreased(byupto50%)theplasmaglucoseconcentrations,
andthehypoglycemiceffectwasstillevidentafter24hours(Hikinoetal.1985).Usingamousemodel,ganoderanB
wasalsoreportedtoincreaseplasmainsulin,decreasehepaticglycogencontent,andmodulatetheactivityofglucose
metabolizingenzymesintheliver(Hikinoetal.1989).Thesamegroupreportedthatathirdpolysaccharide(ganoderan

C)isolatedfromG.lucidumalsoshowedsignificanthypoglycemiceffectsinmice,andthatganoderanBincreased
plasmainsulinlevelsinbothnormalandglucoseloadedmice(Hikinoetal.1989Tomodaetal.1986).
Inamorerecentstudy,oraladministrationofG.lucidumhotwaterextract(0.03and0.3g/kgBW)for4weekswas
foundtolowertheserumglucoselevelsinobese/diabetic(+db/+db)mice,witheffectsseenafterthefirstweekof
treatment(Setoetal.2009).However,theglucoselevelswerestillhigherintheseanimalsthaninthecontrolanimals,
andinsulinlevelswerenotaltered.Theextractmarkedlyreducedlevelsofphosphoenolpyruvatecarboxykinase
(PEPCK),whichareusuallyhighinobese/diabeticmice.Thesuggestedmechanism,accordingtotheauthors,isthatof
loweringtheserumglucoselevelsthroughsuppressionofthehepaticPEPCKgeneexpression.Inanotherstudy(Jiaet
al.2009),apolysaccharidesrichextractshowedbeneficialeffectsinstreptozotocininduceddiabeticrats.Thediabetic
ratsweretreatedwithG.lucidumfor30days.Followingthetreatment,seruminsulinlevelsincreased(comparedwith
thenontreateddiabeticgroup)andglucoselevelsdecreasedinadosedependentway.Treatmentwithstreptozotocin
alsoelevatedlevelsoflipidperoxidationmarkers(thiobarbituricacidreactivesubstances[TBARS]),lipid
hydroperoxides,andconjugateddienes)decreasedlevelsofnonenzymicantioxidants(vitaminC,reducedglutathione
[GSH]vitaminE)anddecreasedactivitiesoftheantioxidantenzymes,SOD,catalase,andglutathioneperoxidase
(Gpx).FollowingtreatmentwithGLPSs,levelsofnonenzymicandenzymicantioxidantsincreasedandlipid
peroxidationlevelsdecreased.Therefore,inadditiontoitsglycemicmodulation,treatmentwithG.lucidumhelpedto
decreaseoxidativestress(Jiaetal.2009).
Inonestudyreportedintheliterature,71adultpatientswithconfirmedtype2diabetesmellitus(DM)were
supplementedwithGanopoly(polysaccharidefractionsextractedfromG.lucidum).Thepatientsreceivedeither
Ganopolyorplaceboorallyat1800mg,threetimesdailyfor12weeks.Glycosylatedhemoglobin(HbA1C)andplasma
glucosedecreasedsignificantlyafter12weeks,indicatingahypoglycemiceffectoftheextract(Gao,Lanetal.2004).
Overall,thedatafromdifferentstudiessuggestthatG.lucidumintakehelpsinmodulatingbloodglucoselevels.
However,thestudieswereperformedmostlyinanimals.Moresupportfromwellplannedhumanclinicalstudiesis
neededwithandwithoutcombinationwithconventionalmedicines.
9.6.6.L IVERANDGASTRICINJURY

HotwaterandwateretherextractsofthefruitbodyofG.lucidumwerefoundtohaveapotenthepatoprotectiveeffect
onliverinjuryinducedbycarbontetrachloride(CCl4)givenorallyandintraperitoneallytorats(Linetal.1995Kimet
al.1999).Themeasuredmarkersforliverinjuryincludedaspartateandalaninetransaminases(ASTandALT)and
lactatedehydrogenase(LDH).OneactivecompoundoftheextractwasseparatedandidentifiedasganoderenicacidA.
Thiswasfoundtohaveapotentinhibitoryeffectonglucuronidase,andtheauthorssuggestthatthisinhibitoryeffect
mayhavemediatedthehepatoprotectionseenwhenthisisolatedcompoundwasgiven(Kimetal.1999).Protectionwas
alsoreportedinastudyinwhichahotwaterextractofG.lucidumwasgivenorallytomice30minutesbefore
administrationofethanol.Theextractwasfoundtohaveaninhibitoryeffectagainsttheformationofmalondialdehyde
(MDA),adegradationproductoflipidperoxides,inmouseliverandrenalhomogenate,withevidenceofadose
responseseen(Shiehetal.2001).TheMDAeffectwasalsoreportedbyShietal.(2008)whentheextractwasgiven
orallytomice(at60,120,and180mg/kg/day)for2weekspriortotreatmentwithDgalactosamine,whichinduced
hepaticinjury.Inaddition,pretreatmentwithG.lucidummaintainednormalvaluesofAST,ALT,SOD,andGSH(Shi
etal.2008).AlcoholandCCl4toxicityisassociatedwithincreasedoxidativestressandfreeradicalassociatedinjury.
Therefore,hepatoprotectionmayalsobemediatedbytheradicalscavengingpropertiesofG.lucidum.Linetal.(1995)
reportedthathotwaterextractsofG.lucidumshowedsignificantradicalscavengingactivityagainstbothsuperoxide
andhydroxylradicals.
Further,G.lucidummethanolicextractwasreportedtoshowhepaticprotection.Theextractwasgivenorallytorats
(500mg/kg/day)for30daysbeforehepaticdamagewascausedbybenzo(a)pyrene(Lakshmietal.2006).Theextract
preventedtheincreaseofserumAST,ALT,andalkalinephosphatase(ALP)activitiesthatresultfrombenzo(a)pyrene
challenge,andenhancedthelevelsofGSH,SOD,GpX,CAT,andglutathioneStransferase(GST).Protectionofliver
injuryinducedbyCCl4wasalsoobservedinmicetreatedwithganodericacid(fromG.lucidum)at10mgand30
mg/kg/daygivenbyintravenousinjectionfor7days(LiandWang2006).ThemediuminwhichG.lucidumwasgrown
wasalsoprovedtohaveliverprotectiveeffectsinananimalstudyofCCl4inducedliverdamage(Liuetal.1998).Oral
administrationofthemediuminwhichG.lucidummyceliaweregrown(butnotthemyceliaalone)hadmarked
beneficialeffects,asassessedbylowerserumASTandALTactivitiesat96hourspostinjury.Nodecreasewasseenin

theactualdamagecaused,astransaminaseactivitiesat24hourswerenotdifferentfromlevelsincontrolanimals,
implyingthatthemyceliummediummayhavepromotedrecoveryinsomeway.Thereleaseofahepatoprotective
componentfromG.lucidummyceliumwasalsoreportedbySongetal.(1998).Inthisstudy,anextracellular
peptidoglycan(apolysaccharide/aminoacidcomplexnamedWK003)producedduringmyceliumfermentationwas
administeredorallytoratsfor4dayspriortoCCl4intoxication.TheincreaseinserumALTlevelswassignificantly
decreased(by70%P<.01)at24hourspostinjurycomparedwithuntreated,intoxicatedrats.TheASTlevelsdecreased
by27%however,thiswasnotstatisticallysignificant.Thesestudiesofapossiblemycelialproductwith
hepatoprotectiveactivitybeingextrudedintotheculturemediumareofinterestbecausethemyceliaofG.lucidumare
mucheasierandlesscostlytocultivatethanthefruitbody.
PolysaccharidesextractedfromG.lucidumandgivenorallytoratsfor28dayswerefoundtoamelioratecirrhosis
inducedbybiliaryligation(Parketal.1997).Inaddition,collagen(measuredbyhydroxyproline)contentintheratliver
wasloweredandimprovedlivermorphologywasfoundincomparisonwithcontrolanimals.Thetreatmentsignificantly
decreasedligationinducedincreasesinserumbiochemicalmarkersofliverdamage(AST,ALT,ALP,andtotal
bilirubin).SimilarresultswerenoticedinastudyconductedbyWu,Fang,andLin(2010)inwhichadecreaseinhepatic
hydroxyprolinecontentandanimprovedliverhistologywerefoundinmice.Inthisstudy,liverfibrosiswasinducedby
theadministrationofthioacetamide(TAA)for12weeks,whichwasfollowedby4weeksoftreatmentwithG.lucidum
extract(0.5and1.0g/kg/day,peroraladministration).TheRTQPCRanalysisshowedtheextracttreatmentdecreased
mRNAexpressionofcollagen(1),smoothmuscleactin,andtheenzymesmetalloproteinase1andmetalloproteinase
13.Inaddition,theTAAinduceddecreaseintotalcollagenaseactivitywasreversedbytheextracttreatment,indicating
thatG.lucidumprotectionagainstinjurymayberelatedtotheenhancementofcollagenaseactivity.
Apartfromitseffectsonchemicalinducedliverinjury,theeffectsoflingzhiongastricinjuryhavealsobeen
investigated.Gastriculcerswereinducedinratsbyaceticacid(Gao,Tangetal.2004),andtreatmentwithGLPS
fractionsof0.5and1.0g/kgfor14dayssignificantlyacceleratedtheulcerhealingby40%and56%,respectively.
Treatmentwith1.0g/kgextractsignificantlyrestoredmucusandprostaglandinlevelscomparedwiththecontrolgroup.
9.7.CONCLUDINGREMARKS
G.lucidumisawellknownAsianherbalremedywithalongandimpressiverangeofapplications.Globalconsumption
ofG.lucidumishigh,andalarge,increasingseriesofpatentedandcommerciallyavailableproductsthatincorporateG.
lucidumasanactiveingredientareavailableasfoodsupplements.Theseincludeextractsandisolatedconstituentsin
variousformulations,whicharemarketedallovertheworldintheformofcapsules,creams,hairtonics,andsyrups.
Withitsgrowingpopularity,manystudiesonG.lucidumcomposition,cultivation,andreputedeffectsarebeingcarried
out,andtherearedatathatsupportitspositivehealthbenefits,includinganticancereffectsbloodglucoseregulation
antioxidant,antibacterial,andantiviraleffectsandprotectionagainstliverandgastricinjury.However,moststudies
havebeenperformedonanimalsorincellculturemodels.Humanexperimentalstudieshaveoftenbeensmall,andthe
resultsarenotalwayssupportiveoftheinvitrofindings.Now,thegreatwealthofchemicaldataandanecdotalevidence
ontheeffectsofG.lucidumneedstobecomplementedbyreliableexperimentalandclinicaldatafromwelldesigned
humantrialsinordertoclearlyestablishifthereportedhealthrelatedeffectsarevalidandsignificant.Manychallenges
areencounteredduetoarangeoffactorsfromdosagetoproductionquality.Strategiesforenhancingqualitycontrol
procedurestodefineandstandardizeG.lucidumpreparationsareneededtodeterminemechanismsofactionandtohelp
characterizetheactivecomponent(s)ofthisputativemedicinalmushroom.
ACKNOWLEDGMENTS
TheauthorsthanktheHongKongPolytechnicUniversityforfundingthisstudy.
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Figures

FIGURE9.1

(Seecolorinsert.)Thelingzhimushroom(Ganodermalucidum).(CourtesyofNorthAmericanReishi/Nammex.)

FIGURE9.2

Postulatedhealthbenefitsoflingzhi(Ganodermalucidum).

FIGURE9.3

ChemicalstructureoflanosterolandthreeofthemanytriterpenesisolatedfromGanodermalucidum.(FromKubota,T.,
Y.Asaka,I.Miura,andH.Mori.1982.HelvChimActa65:6119Nishitoba,T.,H.Sato,T.Kasai,H.Kawagishi,and
S.Sakamura.1984.AgricBiolChem48:29057Sato,H.,T.Nishitoba,S.Shirasu,K.Oda,andS.Sakamura.1986.
AgricBiolChem50:288790Budavari,S.1989.TheMerckIndex.11ed,845.NewJersey:Merck&Co.,INC.With
permission.)

FIGURE9.4

Mean+SEM(standarderrorsofthemean)changeinplasmatotalantioxidantpower(astheferricreducingabilityof
plasma[FRAP]value)at90minutespostingestionofplacebo(verticallines),1.1gofG.lucidumextract(horizontal
lines),and3.3gofG.lucidumextract(diagonallines)inahumaninterventiontrial(n=10).Asignificant(*p<.05)
increaseinplasmaFRAPwasseenafterG.lucidumadministrationcomparedwithplacebointake,indicatingan
absorptionofantioxidantcompoundsintoplasma.(FromWachtelGalor,S.,Y.T.Szeto,B.Tomlinson,andI.F.
Benzie.F.2004.IntJFoodSciNutr1:7583.Withpermission.)

Tables
TABLE9.1 ComparisonofTriterpeneandPolysaccharideContentsof11CommercialLingzhi(G.lucidum)
ProductscurrentlyavailableontheMarket

NatureofProduct

Triterpenes(%) Polysaccharide(%)

A(fruitbodyextract)

1.36

4.48

B(fruitbodyextract)

2.36

5.32

C(fruitbodyextract)

1.88

15.70

D(fruitbodyextract)

1.06

10.97

E(fruitbodyextract)

0.44

7.51

F(fruitbodyextract)

1.78

6.18

G(fruitbodyextract)

1.44

13.30

H(fruitbodyextract)

0.50

15.80

I(fruitbodyextract)

7.82

7.66

J(fruitbodypowder)

0.46

1.10

K(myceliumpowder)

Undetectable

12.78

Source:Chang,S.T.,andJ.A.Buswell.2008.Safety,qualitycontrolandregulationalaspectsrelatingtomushroomnutriceuticals.Proc.
6thIntl.Conf.MushroomBiologyandMushroomProducts,18895.Krefeld,Germany:GAMUGmbh.Withpermission.

Copyright2011byTaylorandFrancisGroup,LLC.
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