NCBIBookshelf.AserviceoftheNationalLibraryofMedicine,NationalInstitutesofHealth.

BenzieIFF,WachtelGalorS,editors.HerbalMedicine:BiomolecularandClinicalAspects.2ndedition.BocaRaton(FL):CRCPress2011.

Chapter9 Ganodermalucidum(LingzhiorReishi)AMedicinalMushroom

SissiWachtelGalor,JohnYuen,JohnA.Buswell,andIrisF.F.Benzie.

9.1.INTRODUCTION

Ganodermalucidum,anorientalfungus(Figure9.1),hasalonghistoryofuseforpromotinghealthandlongevityinChina,Japan,andotherAsiancountries.Itisalarge,darkmushroomwithaglossyexteriorandawoodytexture.TheLatinwordlucidusmeansshinyorbrilliantandreferstothevarnishedappearanceofthesurfaceofthemushroom.InChina,G.lucidumiscalledlingzhi,whereasinJapanthenamefortheGanodermataceaefamilyisreishiormannentake.

InChinese,thenamelingzhirepresentsacombinationofspiritualpotencyandessenceofimmortality,andisregardedastheherbofspiritualpotency,symbolizingsuccess,wellbeing,divinepower,andlongevity.Amongcultivatedmushrooms,G.lucidumisuniqueinthatitspharmaceuticalratherthannutritionalvalueisparamount.AvarietyofcommercialG.lucidumproductsareavailableinvariousforms,suchaspowders,dietarysupplements,andtea.Theseareproducedfromdifferentpartsofthemushroom,includingmycelia,spores,andfruitbody.Thespecificapplicationsandattributedhealthbenefitsoflingzhiincludecontrolofbloodglucoselevels,modulationoftheimmunesystem,hepatoprotection,bacteriostasis,andmore.ThevariousbeliefsregardingthehealthbenefitsofG.lucidum(Figure9.2)arebasedlargelyonanecdotalevidence,traditionaluse,andculturalmores.However,recentreportsprovidescientificsupporttosomeoftheancientclaimsofthehealthbenefitsoflingzhi.

9.2.HISTORY:LINGZHIASAMEDICINALMUSHROOM

Lingzhihasbeenrecognizedasamedicinalmushroomforover2000years,anditspowerfuleffectshavebeendocumentedinancientscripts(Wasser2005).TheproliferationofG.lucidumimagesinartbeganin1400AD,andtheyareassociatedwithTaoism(McMeekin2005).However,G.lucidumimagesextendedbeyondreligionandappearedinpaintings,carvings,furniture,andevenwomensaccessories(Wasser2005).ThefirstbookwhollydevotedtothedescriptionofherbsandtheirmedicinalvaluewasShenNongBenCaoJing,writtenintheEasternHandynastyofChina(25220AD).ThisbookisalsoknownasClassicoftheMateriaMedicaorShennongsHerbalClassics.Itdescribesbotanical,zoological,andmineralsubstances,andwascomposedinthesecondcenturyunderthepseudonymofShennong(theholyfarmerZhu,1998).Thebook,whichhasbeencontinuallyupdatedandextended,describesthebeneficialeffectsofseveralmushroomswithareferencetothemedicinalmushroomG.lucidum(Zhu,1998Upton2000Sanodiyaetal.2009).IntheSupplementtoClassicofMateriaMedica(502536AD)andtheBenCaoGangMubyLiShinZhen,whichisconsideredtobethefirstpharmacopoeiainChina(1590ADMingdynasty),themushroomwasattributedwiththerapeuticproperties,suchastonifyingeffects,enhancingvitalenergy,strengtheningcardiacfunction,increasingmemory,andantiagingeffects.AccordingtotheStatePharmacopoeiaofthePeoplesRepublicofChina(2000),G.lucidumactstoreplenishQi,easethemind,andrelievecoughandasthma,anditisrecommendedfordizziness,insomnia,palpitation,andshortnessofbreath.

Wildlingzhiisrare,andintheyearsbeforeitwascultivated,onlythenobilitycouldaffordit.ItwasbelievedthatthesacredfungusgrewinthehomeoftheimmortalsonthethreeaislesoftheblestoffthecoastofChina(McMeekin2005).However,itsreputationasapanaceamayhavebeenearnedmorebyvirtueofitsirregulardistribution,rarity,andusebytherichandprivilegedmembersofChinesesocietythanbyitsactualeffects.Nevertheless,theGanodermaspeciescontinuetobeapopulartraditionalmedicineinAsiaandtheiruseisgrowingthroughouttheworld(WachtelGalor,Buswelletal.2004Lindequist,Niedermeyer,andJlich2005).

9.3.TAXONOMY

ThefamilyGanodermataceaedescribespolyporebasidiomycetousfungihavingadoublewalledbasidiospore(Donk

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1964).Inall,219specieswithinthefamilyhavebeenassignedtothegenusGanoderma,ofwhichG.lucidum(W.Curt.:Fr.)P.Karstenisthespeciestype(Moncalvo2000).Basidiocarpsofthisgenushavealaccate(shiny)surfacethatisassociatedwiththepresenceofthickwalledpilocystidiaembeddedinanextracellularmelaninmatrix(Moncalvo2000).Ganodermaspeciesarefoundallovertheworld,anddifferentcharacteristics,suchasshapeandcolor(red,black,blue/green,white,yellow,andpurple)ofthefruitbody,hostspecificity,andgeographicalorigin,areusedtoidentifyindividualmembersofthespecies(ZhaoandZhang1994Wooetal.1999Upton2000).Unfortunately,themorphologicalcharacteristicsaresubjecttovariationresultingfrom,forexample,differencesincultivationindifferentgeographicallocationsunderdifferentclimaticconditionsandthenaturalgeneticdevelopment(e.g.,mutation,recombination)ofindividualspecies.Consequently,theuseofmacroscopiccharacteristicshasresultedinalargenumberofsynonymsandaconfused,overlapping,anduncleartaxonomyforthismushroom.SometaxonomistsalsoconsidermacromorphologicalfeaturestobeoflimitedvalueintheidentificationofGanodermaspeciesduetoitshighphenotypicplasticity(Ryvarden1994ZhaoandZhang1994).MorereliablemorphologicalcharacteristicsforGanodermaspeciesarethoughttoincludesporeshapeandsize,contextcolorandconsistency,andthemicroanatomyofthepilearcrust.Chlamydosporeproductionandshape,enzymaticstudiesand,toalesserextent,therangeandoptimaofgrowthtemperatureshavealsobeenusedfordifferentiatingmorphologicallysimilarspecies(Gottlieb,Saidman,andWright1998Moncalvo2000Saltarellietal.2009).Biochemical,genetic,andmolecularapproacheshavealsobeenusedinGanodermaspeciestaxonomy.MolecularbasedmethodologiesadoptedforidentifyingGanodermaspeciesincluderecombinant(rDNA)sequencing(Moncalvoetal.1995Gottlieb,Ferref,andWright2000),randomamplifiedpolymorphicDNAPCR(RAPDPCRstandsforpolymerasechainreaction),internaltranscribedspacer(ITS)sequences(Hseuetal.1996),sequencerelatedamplifiedpolymorphism(SRAPSunetal.2006),enterobacterialrepetitiveintergenicconsensus(ERIC)elements,andamplifiedfragmentlengthpolymorphism(AFLPZhengetal.2009).OtherapproachestotheproblemofG.lucidumtaxonomyincludenondestructivenearinfrared(NIR)methodscombinedwithchemometrics(Chenetal.2008),nuclearmagneticresonance(NMR)basedmetabolomics(Wenetal.2010),andhighperformanceliquidchromatography(HPLC)forgeneratingchemicalfingerprints(Suetal.2001Chenetal.2008Shi,Zhangetal.2008Chenetal.2010).

9.4.CULTIVATION,GLOBALUSE,ANDMANUFACTUREOFPRODUCTS

OwingtoitsirregulardistributioninthewildandtoanincreasingdemandforG.lucidumasamedicinalherb,attemptsweremadetocultivatethemushroom(ChangandBuswell2008).DifferentmembersoftheGanodermagenusneeddifferentconditionsforgrowthandcultivation(Mayzumi,Okamoto,andMizuno1997).Moreover,differenttypesarefavoredindifferentgeographicalregions.Forexample,inSouthChina,blackG.lucidumispopular,whereasredG.lucidumispreferredinJapan.G.lucidumthrivesunderhotandhumidconditions,andmanywildvarietiesarefoundinthesubtropicalregionsoftheOrient.Sincetheearly1970s,cultivationofG.lucidumhasbecomeamajorsourceofthemushroom.ArtificialcultivationofG.lucidumhasbeenachievedusingsubstratessuchasgrain,sawdust,woodlogs(ChangandBuswell1999Wasser2005Bohetal.2007),andcorkresidues(Riu,Roig,andSancho1997).

SinceittakesseveralmonthstoculturethefruitingbodyofG.lucidum,myceliabasedandculturebrothbasedproductshaveassumedgreaterimportanceduetodemandsforincreasedqualitycontrolandyearroundproduction(Sanodiyaetal.2009).Theprocessesanddifferentgrowthparameters(e.g.,temperature,pH)involvedinsubmergedmycelialculturecaneasilybestandardizedundercontrolledconditions,andpurificationandotherdownstreamprocessingofactivecomponentssuchaspolysaccharidesreleasedintotheculturemediumusuallyinvolverelativelysimpleprocedures.Differentcultureconditionsandmediumcompositionshavealsobeenreportedtostronglyinfluencemycelialgrowthandtheproductionofbiopolymers(e.g.,polysaccharides)thatareextrudedfromthecell(exopolysaccharides[EPSs]Mayzumi,Okamoto,andMizuno1997ChangandBuswell1999HabijanicandBerovic2000FangandZhong2002Bohetal.2007Sanodiyaetal.2009).Forexample,YangandLiau(1998)reportedthatpolysaccharideproductionbyfermentergrownmyceliaofG.lucidumwasoptimumat30C35CandapHof44.5,andtheadditionofsupplementssuchasfattyacidswasfoundtoacceleratemycelialgrowthandtheproductionofbioactivecomponents.InasubmergedcultureofG.lucidum,theoptimumpHforcellgrowthhasbeenshowntobelowerthanthatforEPSformation.AtwostagepHcontrolstrategy,developedtomaximizemycelialbiomassandEPSproduction,revealedthatculturepHhadasignificanteffectonEPSyield,chemicalcompositionandmolecularweight,andmycelialmorphology(Kim,Park,andYun2006).TheproductivemycelialmorphologicalformforEPSproductionwasadispersedpellet(controlledpHshiftfrom3.0to6.0)ratherthanacompactpelletwithadensecore(pHmaintainedat4.5)orafeatherlikepellet(controlledpHshiftfrom6.0to3.0).ThreedifferentpolysaccharideswereobtainedundereachpH

condition,andtheirmolecularweightsandchemicalcompositionsweresignificantlydifferent(Kim,Park,andYun2006).Morerecently,anovelthreestagelightirradiationstrategyhasbeendevelopedinsubmergedculturesofG.lucidumfortheefficientproductionofpolysaccharidesandoneofthetriterpenecomponents,ganodericacid(ZhangandTang2008).

Adecadeago,morethan90brandsofG.lucidumproductswereregisteredandmarketedinternationally(Lin2000).Worldwideconsumptionisnowestimatedatseveralthousandtonnes,andthemarketisgrowingrapidly.Althoughtherearenorecentlypublisheddatarelatingtothetotalworldmarketvalueofganodermaproducts,in1995,thetotalestimatedannualmarketvaluegivenbydifferentcommercialsourceswasUS$1628million(ChangandBuswell1999).NumerousG.lucidumproducts,preparedfromdifferentpartsofthemushroom,arecurrentlyavailableonthemarket(ChangandBuswell2008).Inmanufacturingterms,thesimplesttypeconsistsofintactfruitingbodiesgroundtopowderandthenprocessedtocapsuleortabletform.Othernonextractedproductsarepreparedfromthefollowingthreesources:(1)driedandpowderedmyceliaharvestedfromsubmergedliquidculturesgrowninfermentationtanks(2)driedandpowderedcombinationsofsubstrate,mycelia,andmushroomprimordia,followinginoculationandincubationofasemisolidmediumwithfungalmyceliaand(3)intactfungalsporesorsporesthathavebeenbrokenbymechanicalmeansorhavehadthesporewallsremoved.Althoughsporepreparationshavebeenresearchedandpromotedvigorouslyinrecentyears,anyaddedmedicinaleffectsattributabletotheremovalorbreakageofsporewalls,whichrepresentsanadditionalandoftencostlystepintheproductionprocess,arestillcontroversial.Otherproductsarepreparedwithmaterials(e.g.,polysaccharides,triterpenes)extracted,usuallywithhotwaterorethanol,fromfruitingbodiesormyceliaharvestedfromsubmergedliquidculturesandthenevaporatedtodrynessandtabulated/encapsulatedeitherseparatelyorintegratedtogetherindesignatedproportions.TheadoptionofsupercriticalfluidCO extractiontechnologieshasenlargedthespectrumofextractedsubstancesduetothelowtemperaturerequiredduringprocessing.Severalotherproductshavebeenpreparedasbinary,ternaryormorecomplexmixturesofpowderedganodermaandothermushrooms(e.g.,Lentinulaedodes,Agaricusbrasiliensis,Grifolafrondosa,Pleurotusspp.,andFlammulinavelutipes)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,2628%carbohydrate,35%crudefat,59%crudefiber,and78%crudeprotein(Mau,Lin,andChen2001).

Inadditiontothese,mushroomscontainawidevarietyofbioactivemolecules,suchasterpenoids,steroids,phenols,nucleotidesandtheirderivatives,glycoproteins,andpolysaccharides.Mushroomproteinscontainalltheessentialaminoacidsandareespeciallyrichinlysineandleucine.Thelowtotalfatcontentandhighproportionofpolyunsaturatedfattyacidsrelativetothetotalfattyacidsofmushroomsareconsideredsignificantcontributorstothehealthvalueofmushrooms(ChangandBuswell1996Borchersetal.1999Sanodiyaetal.2009).

Polysaccharides,peptidoglycans,andtriterpenesarethreemajorphysiologicallyactiveconstituentsinG.lucidum(Bohetal.2007Zhouetal.2007).However,theamountandpercentageofeachcomponentcanbeverydiverseinnaturalandcommercialproducts,asexemplifiedbythedatashowninTable9.1.When11randomlyselectedsamplesofcommerciallingzhiproductspurchasedinHongKongshopswereevaluatedforthetwomajoractivecomponents,triterpenesandpolysaccharides,itwasfoundthatthetriterpenecontentrangedfromundetectableto7.8%andthepolysaccharidecontentvariedfrom1.15.8%(ChangandBuswell2008).Suchvariationscanoccurforseveralreasons,includingdifferencesinthespeciesorstrainsofmushroomusedanddifferencesinproductionmethods.

9.5.1.POLYSACCHARIDESANDPEPTIDOGLYCANS

Fungiareremarkableforthevarietyofhighmolecularweightpolysaccharidestructuresthattheyproduce,andbioactivepolyglycansarefoundinallpartsofthemushroom.Polysaccharidesrepresentstructurallydiversebiologicalmacromoleculeswithwiderangingphysiochemicalproperties(Zhouetal.2007).Variouspolysaccharideshavebeenextractedfromthefruitbody,spores,andmyceliaoflingzhitheyareproducedbyfungalmyceliaculturedinfermentersandcandifferintheirsugarandpeptidecompositionsandmolecularweight(e.g.,ganoderansA,B,andC).G.lucidumpolysaccharides(GLPSs)arereportedtoexhibitabroadrangeofbioactivities,includingantiinflammatory,

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hypoglycemic,antiulcer,antitumorigenic,andimmunostimulatingeffects(MiyazakiandNishijima1981Hikinoetal.1985Tomodaetal.1986Baoetal.2001WachtelGalor,Buswelletal.2004).Polysaccharidesarenormallyobtainedfromthemushroombyextractionwithhotwaterfollowedbyprecipitationwithethanolormethanol,buttheycanalsobeextractedwithwaterandalkali.StructuralanalysesofGLPSsindicatethatglucoseistheirmajorsugarcomponent(Baoetal.2001Wangetal.2002).However,GLPSsareheteropolymersandcanalsocontainxylose,mannose,galactose,andfucoseindifferentconformations,including13,14,and16linkedandD(orL)substitutions(Lee,Lee,andLee1999Baoetal.2002).Branchingconformationandsolubilitycharacteristicsaresaidtoaffecttheantitumorigenicpropertiesofthesepolysaccharides(Baoetal.2001Zhang,Zhang,andChen2001).Themushroomalsoconsistsofamatrixofthepolysaccharidechitin,whichislargelyindigestiblebythehumanbodyandispartlyresponsibleforthephysicalhardnessofthemushroom(Upton2000).NumerousrefinedpolysaccharidepreparationsextractedfromG.lucidumarenowmarketedasoverthecountertreatmentforchronicdiseases,includingcancerandliverdisease(Gaoetal.2005).

VariousbioactivepeptidoglycanshavealsobeenisolatedfromG.lucidum,includingG.lucidumproteoglycan(GLPGwithantiviralactivityLi,LiuandZhao2005),G.lucidumimmunomodulatingsubstance(GLISJietal.2007),PGY(awatersolubleglycopeptidefractionatedandpurifiedfromaqueousextractsofG.lucidumfruitbodiesWuandWang2009),GLPSpeptide(GLPPHoetal.2007),andF3(afucosecontainingglycoproteinfractionChienetal.2004).

9.5.2.TRITERPENES

TerpenesareaclassofnaturallyoccurringcompoundswhosecarbonskeletonsarecomposedofoneormoreisopreneC units.Examplesofterpenesarementhol(monoterpene)andcarotene(tetraterpene).Manyarealkenes,althoughsomecontainotherfunctionalgroups,andmanyarecyclic.Thesecompoundsarewidelydistributedthroughouttheplantworldandarefoundinprokaryotesaswellaseukaryotes.Terpeneshavealsobeenfoundtohaveantiinflammatory,antitumorigenic,andhypolipidemicactivity.TerpenesinGinkgobiloba,rosemary(Rosemarinusofficinalis),andginseng(Panaxginseng)arereportedtocontributetothehealthpromotingeffectsoftheseherbs(MahatoandSen1997Mashour,Lin,andFrishman1998Haralampidis,Trojanowska,andOsbourn2002).

TriterpenesareasubclassofterpenesandhaveabasicskeletonofC .Ingeneral,triterpenoidshavemolecularweightsrangingfrom400to600kDaandtheirchemicalstructureiscomplexandhighlyoxidized(MahatoandSen1997Zhouetal.2007).Manyplantspeciessynthesizetriterpenesaspartoftheirnormalprogramofgrowthanddevelopment.Someplantscontainlargequantitiesoftriterpenesintheirlatexandresins,andthesearebelievedtocontributetodiseaseresistance.Althoughhundredsoftriterpeneshavebeenisolatedfromvariousplantsandterpenesasaclasshavebeenshowntohavemanypotentiallybeneficialeffects,thereisonlylimitedapplicationoftriterpenesassuccessfultherapeuticagentstodate.Ingeneral,verylittleisknownabouttheenzymesandbiochemicalpathwaysinvolvedintheirbiosynthesis.

InG.lucidum,thechemicalstructureofthetriterpenesisbasedonlanostane,whichisametaboliteoflanosterol,thebiosynthesisofwhichisbasedoncyclizationofsqualene(Haralampidis,Trojanowska,andOsbourn2002).Extractionoftriterpenesisusuallydonebymeansofmethanol,ethanol,acetone,chloroform,ether,oramixtureofthesesolvents.Theextractscanbefurtherpurifiedbyvariousseparationmethods,includingnormalandreversephaseHPLC(Chenetal.1999Suetal.2001).ThefirsttriterpenesisolatedfromG.lucidumaretheganodericacidsAandB,whichwereidentifiedbyKubotaetal.(1982).Sincethen,morethan100triterpeneswithknownchemicalcompositionsandmolecularconfigurationshavebeenreportedtooccurinG.lucidum.Amongthem,morethan50werefoundtobenewanduniquetothisfungus.Thevastmajorityareganodericandlucidenicacids,butothertriterpenessuchasganoderals,ganoderiols,andganodermicacidshavealsobeenidentified(Nishitobaetal.1984Satoetal.1986Budavari1989Gonzalezetal.1999Maetal.2002Akihisaetal.2007Zhouetal.2007Jiangetal.2008Chenetal.2010).ExamplesoftriterpenesareshowninFigure9.3.

G.lucidumisclearlyrichintriterpenes,anditisthisclassofcompoundsthatgivestheherbitsbittertasteand,itisbelieved,confersonitvarioushealthbenefits,suchaslipidloweringandantioxidanteffects.However,thetriterpenecontentisdifferentindifferentpartsandgrowingstagesofthemushroom.TheprofileofthedifferenttriterpenesinG.lucidumcanbeusedtodistinguishthismedicinalfungusfromothertaxonomicallyrelatedspecies,andcanserveassupportingevidenceforclassification.Thetriterpenecontentcanalsobeusedasameasureofqualityofdifferentganodermasamples(Chenetal.1999Suetal.2001)

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9.5.3.OTHERCOMPONENTS

ElementalanalysisoflogcultivatedfruitbodiesofG.lucidumrevealedphosphorus,silica,sulfur,potassium,calcium,andmagnesiumtobetheirmainmineralcomponents.Iron,sodium,zinc,copper,manganese,andstrontiumwerealsodetectedinloweramounts,asweretheheavymetalslead,cadmium,andmercury(Chenetal.1998).FreezedriedfruitbodiesofunidentifiedGanodermaspp.collectedfromthewildwerereportedtohaveamineralcontentof10.2%,withpotassium,calcium,andmagnesiumasthemajorcomponents(Chiuetal.2000).Significantly,nocadmiumormercurywasdetectedinthesesamples.G.lucidumcanalsocontainupto72g/gdryweightofselenium(SeFalandysz2008)andcanbiotransform2030%ofinorganicseleniumpresentinthegrowthsubstrateintoseleniumcontainingproteins(Duetal.2008).

SomeattentionhasbeengiventothegermaniumcontentofGanodermaspp.Germaniumwasfifthhighestintermsofconcentration(489g/g)amongthemineralsdetectedinG.lucidumfruitbodiescollectedfromthewild(Chiuetal.2000).Thismineralisalsopresentintheorderofpartsperbillioninmanyplantbasedfoods,includingginseng,aloe,andgarlic(Minoetal.1980).Althoughgermaniumisnotanessentialelement,atlowdoses,ithasbeencreditedwithimmunopotentiating,antitumor,antioxidant,andantimutagenicactivities(Kolesnikova,Tuzova,andKozlov1997).However,althoughthegermaniumcontentofG.lucidumhasbeenusedtopromoteG.lucidumbasedproducts,thereisnofirmevidencelinkingthiselementwiththespecifichealthbenefitsassociatedwiththemushroom.

G.lucidumcontainssomeothercompoundsthatmaycontributetoitsreportedmedicinaleffect,suchasproteinsandlectins.TheproteincontentofdriedG.lucidumwasfoundtobearound78%,whichislowerthanthatofmanyothermushrooms(ChangandBuswell1996Mau,Lin,andChen2001).BioactiveproteinsarereportedtocontributetothemedicinalpropertiesofG.lucidum,includingLZ8,animmunosuppressiveproteinpurifiedfromthemycelia(VanDerHemetal.1995)apeptidepreparation(GLP)exhibitinghepatoprotectiveandantioxidantactivities(Sun,He,andXie2004Shi,Sunetal.2008)anda15kDaantifungalprotein,ganodermin,whichisisolatedfromG.lucidumfruitingbodies(WangandNg.2006).

Thecarbohydrateandcrudefibercontentofthedriedmushroomwasexaminedandfoundtobe2628%and59%,respectively(Mau,Lin,andChen2001).Lectinswerealsoisolatedfromthefruitbodyandmyceliumofthemushroom(Kawagishietal.1997),includinganovel114kDahexamericlectin,whichwasrevealedtobeaglycoproteinhaving9.3%neutralsugarandshowinghemagglutinatingactivityonpronasetreatedhumanerythrocytes(Thakuretal.2007).Lectins(fromtheLatinwordlegere,whichmeanstopickup,choose)arenonenzymaticproteinsorglycoproteinsthatbindcarbohydrates.Manyspeciesofanimals,plants,andmicroorganismsproducelectins,andtheyexhibitawiderangeoffunctions.Inanimals,forexample,lectinsareinvolvedinavarietyofcellularprocessesandthefunctioningoftheimmunesystem(Wang,Ng,andOoi1998).

OthercompoundsthathavebeenisolatedfromG.lucidumincludeenzymessuchasmetalloprotease,whichdelaysclottingtimeergosterol(provitaminD )nucleosidesandnucleotides(adenosineandguanosineWasser2005Paterson2006).KimandNho(2004)alsodescribedtheisolationandphysicochemicalpropertiesofahighlyspecificandeffectivereversibleinhibitorofglucosidase,SKG3,fromG.lucidumfruitbodies.Furthermore,G.lucidumsporeswerereportedtocontainamixtureofseverallongchainfattyacidsthatmaycontributetotheantitumoractivityofthemushroom(Fukuzawaetal.2008).

9.6.THERAPEUTICAPPLICATIONS

Thecombinationofbenefitwithouttoxicityrepresentsthedesiredendresultinthedevelopmentofeffectivetherapeuticinterventions.G.lucidumhasbeenusedforhundredsofyearsasahealthpromotionandtreatmentstrategytherearenowmanypublishedstudiesthatarebasedonanimalandcellculturemodelsandoninvitroassessmentofthehealtheffectsofG.lucidum,andtherearealsosomereportsofhumantrialsinthefield.However,thereisnocohesivebodyofresearch,andtheobjectiveevaluationofthistraditionaltherapyintermsofhumanhealthremainstobeclearlyestablished.InSections9.6.1through9.6.6,studiesonthepropertiesofG.luciduminrelationtocancer(whichhasattractedthemostinterest),viralandbacterialinfection,diabetes,andliverinjuryarediscussed.

9.6.1.CANCER

G.lucidumisapopularsupplementtakenbyhealthyindividualtoboosttheimmunesystemandbycancerpatientsalongwithconventionaltherapies.Inthissection,thescientificstudiesofG.lucidumonitsanticancerpropertiesare

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summerized.

9.6.1.1.Introduction

Cancerisaworldwideleadingcauseofdeath,anddespitecomprehensiveadvancesintheearlydiagnosisofthediseaseandchemotherapy,itremainsamajorclinicalchallenge(WHO2008).Aspartofsearchingfornewchemopreventiveandchemotherapeuticagents,hundredsofplantspecies,includingmushrooms,havebeenevaluated.Thishasresultedintheisolationofthousandsofbioactivemoleculesthatwereshowntohaveantitumoractivityfromnumerousmushroomspecies,includingGanodermaspecies(WasserandWeis1999Borchersetal.2008).InG.lucidum,alargenumberofchemicalcompoundscanbeextractedfromthefruitingbody,mycelia,orspores.Manypolysaccharidesandtriterpenes,thetwomajorgroupsofcomponentsinthemushroom,exhibitchemopreventiveand/ortumoricidaleffects,asprovedbynumerousstudiesfrominvitroexperimentsandanimalandhumaninvivostudies(YuenandGohel2005Zaidmanetal.2005).Tumorimplantedanimalmodelshaveshowninhibitoryeffectsonangiogenesisandmetastasis.However,evidencefromwelldesignedhumantrialsisstillscarce.

9.6.1.2.InVitroAnticancerActivities

Tomasietal.(2004)tested58basidiomycetesmushrooms,ofwhichG.lucidumwasshowntobethemosteffectiveinkillingcancercells.G.luciduminducedcellcyclearrestandapoptosisinvarioushumanandrodenttumorcells,includingmurinelymphocyticleukemiaL1210andLewislungcarcinoma(LLCMinetal.2000Tomasietal.2004),mousereticulocytesarcomaLII(Liuetal.2002),murinesarcomaMethA(Minetal.2000Gao,Minetal.2002)andS180(Gao,Minetal.2002Liuetal.2002),humanleukemiaHL60(Mulleretal.2006Kimetal.2007Fukuzawaetal.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.2005),humanlivertumorSMMC7721(Tangetal.2006),humanbreastcancerMDAMB123(Jiangetal.2008Liuetal.2009Zhaoetal.2010),MCF7(Jiang,Slivova,andSliva2006Liuetal.2009Shangetal.2009),T47D(Gao,Minetal.2002)andMT1(Wuetal.2006Xieetal.2009),humanprostatecancerPC3(Jiangetal.2004Evansetal.2009),humancervixuteritumorHela(Liuetal.2002Tangetal.2006Shangetal.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.lucidumatdifferentpointsofcellcycle,forexample,breastatG0/G1phaselungatG1phaseliveratG1/G2phaseandbladder,prostate,andleukemiaatG2phase.AseleniumenrichedextractofG.lucidummyceliawasshowntoinduceG1/SphasearrestinhumanerythroidchronicmyeloidleukemiaK562cells(Shangetal.2009).AnotherextractinducedG0/G1phasearrestinestrogendependentbreastMCF7cellsthroughthedownregulationofestrogenreceptorandserine/threoninespecificproteinkinaseAkt/nuclearfactorB(NFB)signaling(Jiang,Slivova,andSliva2006).Invarioushumancancercelllines,extractsofG.lucidumwereshowntosuppresstheprogressionoftheG1phaseincellcycle,andapoptosiswasconfirmedbyusingterminaldeoxynucleotidyltransferasedUTPnickandlabeling(TUNEL)assay(Liuetal.2009).Manyoftheseactivitieswereaccompaniedbyapoptosis.CaoandLin(2006)demonstratedthatafractionofGLPPdecreasedtheantiapoptoticproteinBcl2expressionandincreasedtheproapoptoticproteinBaxexpressioninhumanumbilicalcordvascularendothelialcells(HUVECs).AtriterpenerichextractfromG.luciduminducedprogressiveapoptosisinthepremalignantHUCPCcelllinebyincreasingtheearlyapoptosismarkerannexinVwithin3hours.Halfthecellsstainedpositivefor7aminoactinomycinD(indicatinglateapoptosis)after8hours.Allcellsweredeadat24hours,andthiswasassociatedwiththedownregulationoftelomerase(Yuen,Gohel,andAu2008).Similarapoptoticactivitieswerealsodemonstratedinotherhumancancercells(Fukuzawaetal.2008).AnethanolextractofG.lucidumdecreasedcyclooxygenase2(COX)2enzymeexpressionandincreasednitricoxidesynthesisincolonHT29cells(Hongetal.2004).Inlung95Dtumorcells,thepurecompoundganodericacidTcausedmitochondrialdysfunction,whichresultedfromtheupregulationofproapoptoticp53andBaxexpression(Tangetal.2006).Moreover,theuseofacombinationofG.lucidumandDuschesneaextractsupregulatedcytochromecandBaxtranslocationtotriggercaspase3apoptosisinleukemiaHL60cells(Kimetal.2007).Activationofcaspases7and9byG.lucidumhasbeendemonstratedinbreastMCF7andlungH69SCLCcancercells,respectively(Huetal.2002

Sadavaetal.2009).InhepatomaHepG2cells,alucidenicacidrichG.lucidumextractwasshowntosuppressphosphorylationofERK1/2andAktsignaling,whichdownregulatedtheirdownstreamNFBandprotooncoproteins(cJunandcFos)activities,favoringapoptosis(Wengetal.2009).

Atumormassrequiresacontinuousnutrientsupplyvianewbloodvesselsformedbytheprocessofangiogenesis.Invasivecancercellsspreadtodistantsitesthroughbloodandlymphoidvessels.Therefore,agentsthatinhibitangiogenesisinhibittumorgrowthandspread.ThepotentialantiangiogenicactivitiesofG.lucidumhavebeendemonstratedinexvivochickembryochorioallantoicmembrane(CAM)assay(CaoandLin2004Songetal.2004).PolysaccharidepeptideandethanolextractfromG.lucidumhasbeenprovedtodecreasemicrovesselsaroundamicrofiberfilterdisccontaininganembryowithintactyolks.Usingaprostatecancercellline,twoangiogenicfactors,knownasvascularendothelialgrowthfactor(VEGF)andtransforminggrowthfactor(TGF)1,weresuppressedbyG.lucidumthroughinhibitionoftheras/extracellularsignalregulatedkinase(Erk1/2)andAktsignalingpathways(Johnston2005Stanleyetal.2005).SimilareffectswerealsoobservedinahumanlungcancercelllinesunderhypoxicconditionsafterexposuretoahighdoseofGLPP(CaoandLin2006).

Celladhesion,invasion,andmigrationarethekeyfactorsindeterminingtheaggressivenessofcancerhence,controlofcellmotilityiseffectiveinavoidingcancermetastasis.ApolysaccharideextractofG.lucidummyceliainhibitedtheformationofoncogenicrasinducedtransformedfociinanR6embryofibroblastcellline(Hsiaoetal.2004).SporesandthefruitingbodyofG.lucidumwereshowntoinhibittheregulatoryproteinsphosphatidylinositolandNFBinhighlyinvasivebreastandprostatecancercells(Slivaetal.2002).Celladhesion,invasion,andcolonyformationofbreastcancercellsweresignificantlyinhibitedonexposuretoG.lucidumextracts(Sliva2004).Inaddition,Luetal.(2004)demonstratedthatwaterandethanolextractsofG.lucidummodulatedtheF/Gactinratio,which,inturn,reducedtheformationofstressfiberandfocaladhesioncomplexesofbladdercancercells,suggestingtheactinremodelingwasassociatedwiththeinhibitionofcarcinogeninducedcellmigration.InhibitionofmitogeninducedinvasionofHepG2cellswasdemonstratedinastudybyusingMatrigelcoatedfilterinsertsassay(Wengetal.2009).

9.6.1.3.AnimalStudies

RodentstudiesofpossibleantitumorigeniceffectsofG.lucidumcanbetracedbacktotheearly1980s.Tendaysofintraperitoneal(i.p.)injectionsofapolysaccharidefraction(GL1)fromthefruitbodywasreportedtoinhibit(by9598%)thegrowthoftransplantedsarcoma180tumorcellsinmice(MiyazakiandNishijima1981).AcomplexofpolysaccharidesandproteinfromthemushroomwasalsofoundtoshowsignificantantitumoractivityinasimilarstudyconductedbyKimetal.(1980).Aninhibitionrateof88%wasreported,andtherewascompleteregressionoftumorinathirdofthetestanimals.InastudyconductedbyHyun,Choi,andKim(1990),whichusedasimilarprotocolbutusedvariousextractedpolysaccharides,inhibitionratesof5281%werefound.Ahotwaterextract(2mg/mouse)giveni.p.for3daysresultedinanaverage74%inhibitionoftumorgrowthinmice,with3outof10animalsshowingcompleteregression,andanoraladministration(dailyfor5weeks)showed4563%inhibition(Ohnoetal.1998).Similarinhibitoryeffectswereshownwithimplantedsarcoma180cellsafterpolysaccharidewasgivenorallytomice(ZhangandLin1999).Apure(13)glucanwastestedinparallelwithcrudeG.lucidumextracts,whichresultedin90%inhibitionoftumorgrowth(Ohnoetal.1998).AdrypowderpreparationoftheantleredformofG.lucidum(knownasdeerhornlingzhiduetoitsappearance)wasshowntoinhibittumorgrowthandelongatethelifespaninbothallogeneicsarcoma180bearingddYmiceandsynergenicMM46mammarytumorbearingC3H/Hemice(Nonakaetal.2006).

G.lucidumisamajorcomponentofmanytraditionalbotanicalformulations,suchasTBS101,whichwasdemonstratedtoinhibittumorgrowthandinvasioninPC3implantedmice(Evansetal.2009).Yun(1999)reportedthat9weeksoforaladministrationofmycelialextractsignificantlyinhibitedlungadenomaformationinmice.Oraladministrationoftriterpenoidfractionsfor18consecutivedaysinhibitedMartigelinducedangiogenesis,whichsignificantlyreducedtumorweightandthenumberoftumorcellcoloniesthathadmetastasizedtotheliverinfemaleC57BL/6JstrainmicewithintrasplenicimplantationofLewislungcancercells(Kimura,Taniguchi,andBaba2002Wangetal.2007).InmaleICRnu/nunudemiceinjectedwithhepatomaHepG2cells,dailyoraladministrationoflucidenicacidrichextractfor68days(800mg/kgdosage)decreasedboththenumberandsizeoftumorsbyupto99%,andalsothenumberofmetastatictumorsoccurringinliverandlung(Wengetal.2009).Anaqueousextract(administeredi.p.at10,20,and40mg/mouse)ofthefruitbodysignificantlyincreasedthelifespanofmiceimplantedwithLewislungcarcinomacells.However,nodoseresponseeffectwasseen(Furusawaetal.1992).AnadditiveeffectwasseenwhenG.lucidumwasgivenincombinationwithcytotoxicantineoplasticdrugs,andtherewasasuggestionofapossiblesynergisticeffectwith

cisplatin(Furusawaetal.1992).Inanotherstudy,G.lucidumwasfoundtoalsoprolongthelifespanoftumortransplantedmicebyinhibitingmetastasistothelung(Leeetal.1995).Whengiven1weekpriortotheadministrationofacarcinogenicagent,ahotwaterextractofthemycelium/growthmediumcomplexdecreasedthedevelopmentofaberrantcryptfoci(ACF)andprecancerouslesionsinthecolon(Luetal.2001Luetal.2003).Notoxicityorsideeffectswereseenintheratswhentheextractwasadministeredfor3months.Whentestedwithmousecolontumorimplantedchambers,apolysaccharidemixturecontainingisoflavoneaglyconsfromculturedG.lucidummyceliawasfoundtoinhibitangiogenesisinvivo(Miuraetal.2002).

ThechemopreventiveactivitiesofthemushroomonprostatecancerweredemonstratedbyatriterpenoidrichextractofG.lucidumthatsuppressedtheventralprostategrowthinducedbytestosterone(Liuetal.2007a).GanoderolBwasidentifiedastheactiveprinciplethatwasabletobindtoanandrogenreceptorandinhibit5reductase,suppressingandrogeninducedLNCaPcellgrowthanddownregulatingtheprostatespecificantigen(Liuetal.2007b).

9.6.1.4.HumanStudies

Inhumans,whethertheantitumoreffectoflingzhiisadirectoneorismediatedviaeffectsontheimmunesystemisakeyquestiontoaddress.G.lucidumisoneoftheeightcomponentsofanherbalmixturecalledprostatecancerhope(knownasPCSEPS),whichhasbeenusedasanalternativeinthetreatmentofandrogendependentandindependentprostatecancer(GaoandZhou2009).However,onlyafewclinicaltrialshaveusedG.lucidumasasingleagentoncancerpatients(Gao,Zhouetal.2002Gao,Zhouetal.2003Gao,Saietal.2003).Tworandomized,controlledtrialshavebeenconductedusingaGLPSrichextract(apatentedoverthecounterproduct,GanopolyGaoetal.2003GaoandSaietal.2003).Gao,Zhouetal.(2003)recruited134patientswithadvancedcancersofdifferentsitesandsupplementedthemwithG.lucidumcapsulesatadosageof1800mg/dayfor12weeks.Cellularimmunityin80%ofthesepatientswassignificantlyenhancedintermsofelevatedplasmainterleukin(IL)2,IL6,andinterferon(IFN)levelsandnaturalkiller(NK)cellactivity.Inanotherstudy,thesameprotocolwasfollowedwith68lungcancerpatients(Gao,Saietal.2003)inwhomimmuneparametersincludingtotalTcells,NKcells,andCD4/CD8ratioweresignificantlyenhancedintheG.lucidumtreatedgroup.Inaddition,qualityoflifeintermsofKarnofskyscorewasimprovedinabout65%ofthesepatients(Gao,Saietal.2003).GanopolywasalsodemonstratedtoenhancemitogenicactivityandNKcellsinpatientswithadvancedcancerinabeforeandaftercomparisonstudy(Gao,Minetal.2002).TheseresultsprovidesomeevidencethattheantitumoreffectsofG.lucidumaremediatedviaeffectsontheimmunesystem.However,itmustbenotedthatallstudieswereconductedbythesameresearchgroupandthatotherdirectantitumoreffectsofG.lucidumhavenotyetbeenstudiedonhumansinvivo.

9.6.2.IMMUNOMODULATION

Agentsthatenhancethefunctioningofthehostimmunesystemcouldbeexpectedtoenhancehealthintermsofimprovedresistanceand,thus,removalofmalignantorpremalignantcells.ManyG.lucidumproductsonthemarketarelabeledorpromotedasimmunomodulatingagents.

ThereisconsiderableevidencetosupporttheimmunostimulatingactivitiesofG.lucidumviainductionofcytokinesandenhancementofimmunologicaleffector(Wangetal.1997ZhuandLin2006).DifferentcomponentsfromG.lucidumwereprovedtoenhancetheproliferationandmaturationofTandBlymphocytes,splenicmononuclearcells,NKcells,anddendriticcellsincultureinvitroandinanimalstudiesinvivo(Baoetal.2001CaoandLin2002Zhu,Chen,andLin2007Maetal.2008).InnormalBALB/cmice,apolysacchariderichextractofG.lucidumpromotedtheproliferationofsplenocytesandenhancedtheactivitiesofmacrophagesandNKcells,whichresultedintheincreaseofIL6andIFN(Changetal.2009).AlthoughacommercialG.lucidumextractdidnotstimulateproliferationoflymphocytes,itactivatedthegeneexpressionofIL1,IL6,IL10,andtumornecrosisfactor(TNF)(Maoetal.1999).Apolysaccharidefraction(F3)wasshowntoenhancebothadaptiveandinnateimmunitiesbytriggeringtheproductionofcytokinesIL1,IL6,IL12,IFN,TNF,andcolonystimulatingfactors(CSFs)frommousesplenocytes(Chenetal.2004).ItwasreportedalsothatTNFandIL6productionwerestimulatedinhumanandmurinemacrophagesbyG.lucidummycelia(Kuoetal.2006).Thiseffectmightbeduetoincreasedsynthesisofnitricoxide(NO)inducedbyDglucan(Ohnoetal.1998).Thesepolysaccharideswerealsofoundtobehighlysuppressivetotumorcellproliferationinvivowhileenhancingthehostsimmuneresponse(OoiandLiu2000).

Wangetal.(1997)foundthatapolysaccharideenrichedfractionfromG.lucidumactivatedculturedmacrophagesandTlymphocytesinvitro,whichledtoanincreaseofIL1,TNF,andIL6intheculturemedium.Inanotherstudy

(ZhangandLin1999),incubationofmacrophagesandTlymphocyteswithapolysaccharideresultedinanincreaseinTNFandINFlevelsintheculturemedium.Thisconditionedculturemediumwasfoundtoinhibitcellgrowthandinduceapoptosisinsarcoma180andHL60cells(ZhangandLin1999).Furthermore,serumincorporatedtreatmentwithapolysaccharidepeptidefractionfromG.lucidummarkedlyinhibitedtheproliferationofhumanlungcarcinoma(PG)cells,whereasthepurefractionbyitselfdidnotinducesimilareffects(CaoandLin2004).Inadditiontopolysaccharides,alanostanetriterpenoid,ganodericacidMe,inhibitedtumorgrowthandmetastasisofLewislungcarcinomainThelper1responderC57BL/6micebyenhancingimmunefunctionintermsofIL2andIFNexpressionandNKcellactivity(Wangetal.2007).ZhuandLin(2006)usedcytokineinducedkiller(CIK)cellstoinvestigatetheinteractionbetweenGLPSsandcytokines,whichmediatedcellproliferationandantitumoractivity.ThecytotoxicityofCIKcellswascorrelatedwellwiththeexpressionofperforinandgranzymeBinducedbyIL2andantiCD3.ResultsindicatedthatGLPSsenhanceIL2andTNFproductionaswellasproteinandmessengerribonucleicacid(mRNA)expressionofgranzymeBandperforininCIKcellsculture,andthusdecreasethedosesofIL2andantiCD3withoutaffectingthekillingeffectsonNKresistantmouseP815mastocytomacellsandNKsensitivemouseYAC1lymphomacells(ZhuandLin2006).

9.6.3.LINGZHIASANANTIOXIDANT

Consumptionofantioxidantrichplantsmayhelppreventcancerandotherchronicdiseases(Collins2005BenzieandWachtelGalor2009).Antioxidantsprotectcellularcomponentsfromoxidativedamage,whichislikelytodecreaseriskofmutationsandcarcinogenesisandalsoprotectimmunecells,allowingthemtomaintainimmunesurveillanceandresponse.VariouscomponentsofG.lucidum,inparticularpolysaccharidesandtriterpenoids,showantioxidantactivityinvitro(Leeetal.2001Mau,Lin,andChen2002Shietal.2002WachtelGalor,Choi,andBenzie2005YuenandGohel2008Saltarellietal.2009WuandWang2009).AsshowninFigure9.4,antioxidantsfromlingzhiwerefoundtobeabsorbedquicklyafteringestion,resultinginanincreaseintheplasmatotalantioxidantactivityofhumansubjects(Figure9.4WachtelGalor,Szetoetal.2004).

OoiandLiu(2000)reportedthatproteinboundpolysaccharide(PBP)andpolysaccharidepeptidewereabletomimictheendogenousantioxidantsuperoxidedismutase(SOD)incancerbearinganimalsinvivo.Thesepolysaccharideswerealsoreportedtoprotecttheimmunecellsfromoxidativedamage(OoiandLui2000).TheprotectiveeffectsofG.lucidumonDNAstrandscissioninducedbyametalcatalyzedFentonreaction,ultravioletirradiation,andhydroxylradicalattackwereshowninagarosegelelectrophoresisinvitro(Leeetal.2001).HotwaterextractsofG.lucidumsignificantlyprotectedRajicellsfromhydrogenperoxide(H O )inducedDNAdamage(Shietal.2002).HotwaterextractsprotectedhumanlymphocyteDNAonlyatlow(.01%w/v)(WachtelGalor,Choi,andBenzie2005).TwoantioxidantenrichedextractsfromG.lucidumactedoppositelyinpremalignantHUCPCcellsundercarcinogenicattack(YuenandGohel2008).TheaqueousextractprotectedcellularDNAfromoxidativedamage,whereastheethanolicextractdamagedcellularDNA,withincreasedH O productionandsignificantcellkillingeffectsobserved.TheresultssuggestedthatdifferenteffectsofG.lucidumcouldbeexhibitedbydifferentextractablecomponentsinbladderchemoprevention.MethanolextractsofG.lucidumwerereportedtopreventkidneydamage(inducedbytheanticancerdrugcisplatin)throughrestorationoftherenalantioxidantdefensesystem(Sheena,Ajith,andJanardhanan2003).Incontrast,afractionofganodermatriterpenes(GTS)wasfoundtoenhancetheintracellularreactiveoxygenspecies(ROS)producingeffectofdoxorubicin(DOX)inHelacells,leadingtomoreDNAdamageandapoptosis,whereassuchsynergismwasinhibitedbyaROSscavenger(Yueetal.2008).Inananimalstudy(diabeticrats),nonenzymicandenzymicantioxidantslevelsincreasedandlipidperoxidationlevelsdecreasedwithG.lucidumtreatment(Jiaetal.2009).However,adirectlinkhasnotbeenestablishedbetweentheantioxidantpropertiesofG.lucidumanditsimmunomodulatoryandanticancereffects,andwhetherlingzhiactsasanantioxidantorprooxidantmaydependonconcentrationandenvironment.

9.6.4.VIRALANDBACTERIALINFECTIONS

Thegoalofresearchinthetreatmentofviralandbacterialinfectionsisthediscoveryofagentsthatspecificallyinhibitviralandbacterialmultiplicationwithoutaffectingnormalcells.Theundesiredsideeffectsofantibioticsandantiviralsandtheappearanceofresistantandmutantstrainsmakethedevelopmentofnewagentsanurgentrequirement.Thishasledresearcherstoinvestigatetheantibacterialandantiviralactivityofmedicinalplantsandfungi(WasserandWeis1999ZhongandXiao2009).Isolationofvariouswaterandmethanolsoluble,highmolecularweightPBPsfromG.

2 2

2 2

2 2

lucidumshowedinhibitoryeffectsonherpessimplexvirustype1(HSV1),herpessimplexvirustype2(HSV2),andvesicularstomatitisvirus(VSV)NewJerseystraininatissueculturesystem.Usingtheplaquereductionmethod,asignificantinhibitoryeffectwasseenatdosesthatshowednocytotoxicity(Eoetal.1999Ohetal.2000).Inaddition,therewasamarkedsynergisticeffectwhenPBPfromG.lucidumwasusedintissuecultureinconjunctionwithantiherpeticagents,acyclovirorvidarabine,andwithIFN(Kimetal.2000Ohetal.2000).SimilarresultswereshowninHSV1andHSV2withaGLPGisolatedfromthemyceliaofG.lucidum(Liuetal.2004Li,Liu,andZhao2005).Thecellsweretreatedbefore,during,andafterinfection,andviraltiterinthesupernatantofcellculture48hourspostinfectionwasdetermined.TheantiviraleffectsoftheGLPGweremoreremarkablebeforeviraltreatmentthanaftertreatment.Althoughthemechanismwasnotdefined,theauthorsconcludedthatGLPGinhibitsviralreplicationbyinterferingwithearlyeventsofviraladsorption(Li,Liu,andZhao2005).

SometriterpenesfromG.lucidumhavealsobeenreportedtohaveaninhibitoryeffectagainsthumanimmunodeficiencyvirus(HIV)1proteaseactivity,withIC valuesrangingfrom20tomorethan1000Mhowever,notalloftheexaminedtriterpenesshowedantiHIVactivity(ElMekkawyetal.1998Minetal.1998).Inanotherstudy,aganodericacidisolatedfromG.lucidumshowedinhibitoryeffectsonthereplicationofhepatitisBvirus(HBV)inHepG2215cells(HepG2HBVproducingcellline)over8days.ProductionofHBVsurfaceantigen(HBsAg)andHBVeantigen(HBeAg)were,respectively,20%and44%ofcontrolswithoutganodericacidtreatment(LiandWang2006).

Somesmallstudiesinhumanpatientshavealsoreportedbeneficialeffectsoflingzhiintake.AdriedhotwaterextractofG.lucidumtakenorally(equivalentto36or72gofdriedmushroomperday)wasusedasthesoletreatmentforpostherpetic(varicellazostervirus)neuralgiain4elderlypatients.Thistreatmentwasreportedtodramaticallydecreasepainandpromotethehealingoflesions,withoutanytoxicityevenatveryhighdoses(HijikataandYamada1998).Inanotherstudy,amixtureofG.lucidumwithotherherbsimprovedrecoverytimeinpatientswithherpesgenitalis(n=15)andherpeslabiallis(n=13Hijikata,Yamada,andYasuhara2007).

Forevaluatingtheantibacterialeffectsofthemushroom,severalinvitroandinvivoanimalstudiesusingG.lucidumwereperformed.MiceinjectedwithG.lucidumextract(2mg/mouse)1daypriortoinjectionwithEscherichiacolishowedmarkedlyimprovedsurvivalrates(>80%comparedto33%incontrolsOhnoetal.1998).Inaninvitrostudythatusedthediskassay(Keypouretal.2008),achloroformextractofG.lucidumwasinvestigatedforitsantibacterialeffectongrampositivebacteria(Bacillussubtilis,Staphylococcusaureus,Enterococcusfaecalis)andgramnegativebacteria(E.coli,Pseudomonasaeruginosa).Resultsshowedthattheextracthadgrowthinhibitoryeffectsontwoofthegrampositivebacteriawithaminimalinhibitoryconcentration(MIC)of8mg/mLforS.aureusandB.subtilis.Inanotherinvitrostudy,thedirectantimicrobialeffectofaG.lucidumwaterextractwasexaminedagainst15speciesofbacteriaaloneandincombinationwith4kindsofantibiotics(Yoonetal.1994).G.lucidumwasfoundtobemoreeffectivethanantibioticsagainstE.coli,Micrococcusluteus,S.aureus,B.cereus,Proteusvulgaris,andSalmonellatyphi,butlesseffectiveagainstotherspeciestested.TheantimicrobialcombinationofG.lucidumwithfourcommonlyusedantibiotics(Yoonetal.1994)resultedinanadditiveorsynergisticeffectinmost,butnotall,instances,withapparentantagonismagainstcefazolinandampicillineffectsonP.vulgaris.

Todate,theantimicrobialcomponentsofthetestedcrudeextractshavenotbeenidentified,althoughantimicrobialpolysaccharideshavebeenidentifiedinotherfungiandplantterpeneshavebeenreportedtohaveantimicrobialactivity(WasserandWeis1999ZhongandXiao2009).Inaddition,thebioavailabilityofputativeantimicrobialcomponentsofG.lucidumhasnotbeenestablished.Nonetheless,G.lucidumoffersapotentiallyeffectivetherapy.Thereisalsotheimplicationthatcombinationtherapymaybemoresafeandcosteffective,asloweramountsofcytotoxicantiviralandantibacterialdrugscouldbeusedwithaconcomitantdecreaseintheriskofsideeffects.However,thisneedsfurtherinvestigationintermsofinvitrostudiesandwelldesignedclinicaltrials.

9.6.5.DIABETESMELLITUS

ComponentsofG.lucidumhavebeenprovedtohaveahypoglycemiceffectinanimals.TheadministrationofganoderansAandB(doseof100mg/kg),twopolysaccharidesisolatedfromfruitbodywaterextracts,byi.p.injectiontonormalandalloxaninduceddiabeticmicesignificantlydecreased(byupto50%)theplasmaglucoseconcentrations,andthehypoglycemiceffectwasstillevidentafter24hours(Hikinoetal.1985).Usingamousemodel,ganoderanBwasalsoreportedtoincreaseplasmainsulin,decreasehepaticglycogencontent,andmodulatetheactivityofglucosemetabolizingenzymesintheliver(Hikinoetal.1989).Thesamegroupreportedthatathirdpolysaccharide(ganoderan

50

C)isolatedfromG.lucidumalsoshowedsignificanthypoglycemiceffectsinmice,andthatganoderanBincreasedplasmainsulinlevelsinbothnormalandglucoseloadedmice(Hikinoetal.1989Tomodaetal.1986).

Inamorerecentstudy,oraladministrationofG.lucidumhotwaterextract(0.03and0.3g/kgBW)for4weekswasfoundtolowertheserumglucoselevelsinobese/diabetic(+db/+db)mice,witheffectsseenafterthefirstweekoftreatment(Setoetal.2009).However,theglucoselevelswerestillhigherintheseanimalsthaninthecontrolanimals,andinsulinlevelswerenotaltered.Theextractmarkedlyreducedlevelsofphosphoenolpyruvatecarboxykinase(PEPCK),whichareusuallyhighinobese/diabeticmice.Thesuggestedmechanism,accordingtotheauthors,isthatofloweringtheserumglucoselevelsthroughsuppressionofthehepaticPEPCKgeneexpression.Inanotherstudy(Jiaetal.2009),apolysaccharidesrichextractshowedbeneficialeffectsinstreptozotocininduceddiabeticrats.ThediabeticratsweretreatedwithG.lucidumfor30days.Followingthetreatment,seruminsulinlevelsincreased(comparedwiththenontreateddiabeticgroup)andglucoselevelsdecreasedinadosedependentway.Treatmentwithstreptozotocinalsoelevatedlevelsoflipidperoxidationmarkers(thiobarbituricacidreactivesubstances[TBARS]),lipidhydroperoxides,andconjugateddienes)decreasedlevelsofnonenzymicantioxidants(vitaminC,reducedglutathione[GSH]vitaminE)anddecreasedactivitiesoftheantioxidantenzymes,SOD,catalase,andglutathioneperoxidase(Gpx).FollowingtreatmentwithGLPSs,levelsofnonenzymicandenzymicantioxidantsincreasedandlipidperoxidationlevelsdecreased.Therefore,inadditiontoitsglycemicmodulation,treatmentwithG.lucidumhelpedtodecreaseoxidativestress(Jiaetal.2009).

Inonestudyreportedintheliterature,71adultpatientswithconfirmedtype2diabetesmellitus(DM)weresupplementedwithGanopoly(polysaccharidefractionsextractedfromG.lucidum).ThepatientsreceivedeitherGanopolyorplaceboorallyat1800mg,threetimesdailyfor12weeks.Glycosylatedhemoglobin(HbA1 )andplasmaglucosedecreasedsignificantlyafter12weeks,indicatingahypoglycemiceffectoftheextract(Gao,Lanetal.2004).Overall,thedatafromdifferentstudiessuggestthatG.lucidumintakehelpsinmodulatingbloodglucoselevels.However,thestudieswereperformedmostlyinanimals.Moresupportfromwellplannedhumanclinicalstudiesisneededwithandwithoutcombinationwithconventionalmedicines.

9.6.6.LIVERANDGASTRICINJURY

HotwaterandwateretherextractsofthefruitbodyofG.lucidumwerefoundtohaveapotenthepatoprotectiveeffectonliverinjuryinducedbycarbontetrachloride(CCl )givenorallyandintraperitoneallytorats(Linetal.1995Kimetal.1999).Themeasuredmarkersforliverinjuryincludedaspartateandalaninetransaminases(ASTandALT)andlactatedehydrogenase(LDH).OneactivecompoundoftheextractwasseparatedandidentifiedasganoderenicacidA.Thiswasfoundtohaveapotentinhibitoryeffectonglucuronidase,andtheauthorssuggestthatthisinhibitoryeffectmayhavemediatedthehepatoprotectionseenwhenthisisolatedcompoundwasgiven(Kimetal.1999).ProtectionwasalsoreportedinastudyinwhichahotwaterextractofG.lucidumwasgivenorallytomice30minutesbeforeadministrationofethanol.Theextractwasfoundtohaveaninhibitoryeffectagainsttheformationofmalondialdehyde(MDA),adegradationproductoflipidperoxides,inmouseliverandrenalhomogenate,withevidenceofadoseresponseseen(Shiehetal.2001).TheMDAeffectwasalsoreportedbyShietal.(2008)whentheextractwasgivenorallytomice(at60,120,and180mg/kg/day)for2weekspriortotreatmentwithDgalactosamine,whichinducedhepaticinjury.Inaddition,pretreatmentwithG.lucidummaintainednormalvaluesofAST,ALT,SOD,andGSH(Shietal.2008).AlcoholandCCl toxicityisassociatedwithincreasedoxidativestressandfreeradicalassociatedinjury.Therefore,hepatoprotectionmayalsobemediatedbytheradicalscavengingpropertiesofG.lucidum.Linetal.(1995)reportedthathotwaterextractsofG.lucidumshowedsignificantradicalscavengingactivityagainstbothsuperoxideandhydroxylradicals.

Further,G.lucidummethanolicextractwasreportedtoshowhepaticprotection.Theextractwasgivenorallytorats(500mg/kg/day)for30daysbeforehepaticdamagewascausedbybenzo(a)pyrene(Lakshmietal.2006).TheextractpreventedtheincreaseofserumAST,ALT,andalkalinephosphatase(ALP)activitiesthatresultfrombenzo(a)pyrenechallenge,andenhancedthelevelsofGSH,SOD,GpX,CAT,andglutathioneStransferase(GST).ProtectionofliverinjuryinducedbyCCl wasalsoobservedinmicetreatedwithganodericacid(fromG.lucidum)at10mgand30mg/kg/daygivenbyintravenousinjectionfor7days(LiandWang2006).ThemediuminwhichG.lucidumwasgrownwasalsoprovedtohaveliverprotectiveeffectsinananimalstudyofCCl inducedliverdamage(Liuetal.1998).OraladministrationofthemediuminwhichG.lucidummyceliaweregrown(butnotthemyceliaalone)hadmarkedbeneficialeffects,asassessedbylowerserumASTandALTactivitiesat96hourspostinjury.Nodecreasewasseenin

C

4

4

4

4

theactualdamagecaused,astransaminaseactivitiesat24hourswerenotdifferentfromlevelsincontrolanimals,implyingthatthemyceliummediummayhavepromotedrecoveryinsomeway.ThereleaseofahepatoprotectivecomponentfromG.lucidummyceliumwasalsoreportedbySongetal.(1998).Inthisstudy,anextracellularpeptidoglycan(apolysaccharide/aminoacidcomplexnamedWK003)producedduringmyceliumfermentationwasadministeredorallytoratsfor4dayspriortoCCl intoxication.TheincreaseinserumALTlevelswassignificantlydecreased(by70%P

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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,andS.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.Withpermission.)

FIGURE9.4

Mean+SEM(standarderrorsofthemean)changeinplasmatotalantioxidantpower(astheferricreducingabilityofplasma[FRAP]value)at90minutespostingestionofplacebo(verticallines),1.1gofG.lucidumextract(horizontallines),and3.3gofG.lucidumextract(diagonallines)inahumaninterventiontrial(n=10).Asignificant(*p

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.

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