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Antioxidative and Anti-Inflammatory Properties of Cannabidiol

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Cannabidiol (CBD) is one of the main pharmacologically active phytocannabinoids of Cannabis sativa L. CBD is non-psychoactive but exerts a number of beneficial pharmacological effects, including anti-inflammatory and antioxidant properties. The chemistry and pharmacology of CBD, as well as various molecular targets, including cannabinoid receptors and other components of the endocannabinoid system with which it interacts, have been extensively studied. In addition, preclinical and clinical studies have contributed to our understanding of the therapeutic potential of CBD for many diseases, including diseases associated with oxidative stress. Here, we review the main biological effects of CBD, and its synthetic derivatives, focusing on the cellular, antioxidant, and anti-inflammatory properties of CBD.
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Antioxidants2020,9,21;doi:10.3390/antiox9010021www.mdpi.com/journal/antioxidants
Review
AntioxidativeandAntiInflammatoryProperties
ofCannabidiol
SinemyizAtalay,IwonaJarockaKarpowiczandElzbietaSkrzydlewska*
DepartmentofAnalyticalChemistry,MedicalUniversityofBiałystok,15089Białystok,Poland;
sinemyiz.atalay@umb.edu.pl(S.A.);iwona.jarockakarpowicz@umb.edu.pl(I.J.K.)
*Correspondence:elzbieta.skrzydlewska@umb.edu.pl;Tel.:+48857485882
Received:19November2019;Accepted:23December2019;Published:25December2019
Abstract:Cannabidiol(CBD)isoneofthemainpharmacologicallyactivephytocannabinoidsof
CannabissativaL.CBDisnonpsychoactivebutexertsanumberofbeneficialpharmacologicaleffects,
includingantiinflammatoryandantioxidantproperties.ThechemistryandpharmacologyofCBD,
aswellasvariousmoleculartargets,includingcannabinoidreceptorsandothercomponentsofthe
endocannabinoidsystemwithwhichitinteracts,havebeenextensivelystudied.Inaddition,
preclinicalandclinicalstudieshavecontributedtoourunderstandingofthetherapeuticpotentialof
CBDformanydiseases,includingdiseasesassociatedwithoxidativestress.Here,wereviewthe
mainbiologicaleffectsofCBD,anditssyntheticderivatives,focusingonthecellular,antioxidant,
andantiinflammatorypropertiesofCBD.
Keywords:cannabidiol;cannabidiolsyntheticderivatives;endocannabinoids;oxidativestress;lipid
peroxidation;inflammation;membranereceptors;
1.Introduction
Theendocannabinoidsystemisanimportantmolecularsystemresponsibleforcontrolling
homeostasisandisbecominganincreasinglypopulartargetofpharmacotherapy.Endocannabinoids
areester,ether,andamidederivativesoflongchainpolyunsaturatedfattyacids(PUFAs),suchas
arachidonicacid,andtheyactmainlyascannabinoidreceptorligands[1].Endocannabinoidsbelong
toalargegroupofcompoundswithasimilarstructureandbiologicalactivitycalledcannabinoids.
Cannabinoidsarechemicalderivativesofdibenzopyreneormonoterpenoid,andtodateoverfour
hundredhavebeenidentified.ThemostimportantoftheseareΔ
9
tetrahydrocannabinol(Δ
9
THC),
Δ
8
tetrahydrocannabinol(Δ
8
THC),cannabinol(CBN),andcannabidiol(CBD),andtheyaremembers
ofalargegroupofbiologicallyactivecompoundsfoundinCannabissativaL.[2].Themedicaluseof
cannabinoids,inparticularphytocannabinoids,hasbeenoneofthemostinterestingapproachesto
pharmacotherapyinrecentyears.
CBDisoneofthemainpharmacologicallyactivephytocannabinoids[3].Itisnonpsychoactive,
buthasmanybeneficialpharmacologicaleffects,includingantiinflammatoryandantioxidanteffects.
[4].Inaddition,itbelongstoagroupofcompoundswithanxiolytic,antidepressant,antipsychotic,
andanticonvulsantproperties,amongothers[5].Thebiologicaleffectsofcannabidiol,includingthe
variousmoleculartargets,suchascannabinoidreceptorsandothercomponentsofthe
endocannabinoidsystem,withwhichitinteracts,havebeenextensivelystudied.Thetherapeutic
potentialofCBDhasbeenevaluatedincardiovascular,neurodegenerative,cancer,andmetabolic
diseases,whichareusuallyaccompaniedbyoxidativestressandinflammation[6].Oneofthebest
studiedusesofCBDisfortherapeuticeffectindiabetesanditscomplicationsinanimalandhuman
studies[7].CBD,byactivatingthecannabinoidreceptor,CB2,hasbeenshowntoinduce
vasodilatationintype2diabeticrats[8,9],andbyactivating5HT
1A
receptors,CBDshoweda
therapeuticeffectindiabeticneuropathy[10].Moreover,thisphytocannabinoidacceleratedwound
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healinginadiabeticratmodelbyprotectingtheendothelialgrowthfactor(VEGF)[11].Inaddition,
bypreventingtheformationofoxidativestressintheretinaneuronsofdiabeticanimals,CBD
counteractedtyrosinenitration,whichcanleadtoglutamateaccumulationandneuronalcelldeath
[12].
ThisreviewsummarizesthechemicalandbiologicaleffectsofCBDanditsnaturalandsynthetic
derivatives.ParticularattentionwaspaidtotheantioxidantandantiinflammatoryeffectsofCBDand
itsderivatives,bearinginmindthepossibilitiesofusingthisphytocannabinoidtoprotectagainst
oxidativestressandtheconsequencesassociatedwithoxidativemodificationsofproteinsandlipids.
AlthoughCBDdemonstratessafetyandagoodsideeffectprofileinmanyclinicaltrials[4],allofthe
therapeuticoptionsforCBDdiscussedinthisreviewarelimitedinaconcentrationdependent
manner.
2.MolecularStructureofCBD
CBDisaterpenophenolcompoundcontainingtwentyonecarbonatoms,withtheformula
C21H30O2andamolecularweightof314.464g/mol(Figure1).Thechemicalstructureofcannabidiol,
2[1R3methyl6R(1methylethenyl)2cyclohexen1yl]5pentyl1,3benzenediol,wasdeterminedin
1963[13].ThecurrentIUPACpreferredterminologyis
2[(1R,6R)3methyl6prop1en2ylcyclohex2en1yl]5pentylbenzene1,3diol.Naturally
occurringCBDhasa()CBDstructure[14].TheCBDmoleculecontainsacyclohexenering(A),a
phenolicring(B)andapentylsidechain.Inaddition,theterpenicring(A)andthearomaticring(B)
arelocatedinplanesthatarealmostperpendiculartoeachother[15].TherearefourknownCBDside
chainhomologs,whicharemethyl,npropyl,nbutyl,andnpentyl[16].AllknownCBDforms(Table
1)haveabsolutetransconfigurationinpositions1Rand6R[16].
Figure1.Chemicalstructureofcannabidiol(CBD)[16].
TheCBDchemicalactivityismainlyduetothelocationandsurroundingsofthehydroxyl
groupsinthephenolicringattheC1’andC5’positions(B),aswellasthemethylgroupattheC1
positionofthecyclohexenering(A)andthepentylchainattheC3′ofthephenolicring(B).However,
theopenCBDringintheC4positionisinactive.Duetothehydroxylgroups(C1’andC5’intheB
ring),CBDcanalsobindtoaminoacidssuchasthreonine,tyrosine,glutamicacid,orglutamineby
meansofahydrogenbond[17].
Table1.Cannabidiolderivatives[16].
CompoundR1R2R3
cannabidiolicacid(CBDAC5)COOHnC5H11H
(–)cannabidiol(CBDC5)HnC5H11H
cannabidiolmonomethylether(CBDMC5)HnC5H11Me
CannabidiolC4(CBDC4)HnC4H9H
cannabidivarinicacid(CBDVAC3)COOHnC3H7H
(–)cannabidivarin(CBDVC3)HnC3H7H
cannabidiorcol(CBDC1)HCH3H
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CBDhaspotentialantioxidantpropertiesbecauseitsfreecationicradicalsexhibitseveral
resonancestructuresinwhichunpairedelectronsaredistributedmainlyonetherandalkylmoieties,
aswellasonthebenzenering[18].
3.BiologicalActivityofCBD
CBDhasawidespectrumofbiologicalactivity,includingantioxidantandantiinflammatory
activity,whichiswhyitsactivityinthepreventionandtreatmentofdiseaseswhosedevelopmentis
associatedwithredoximbalanceandinflammationhasbeentested[4,19,20].Basedonthecurrent
researchresults,thepossibilityofusingCBDforthetreatmentofdiabetes,diabetesrelated
cardiomyopathy,cardiovasculardiseases(includingstroke,arrhythmia,atherosclerosis,and
hypertension),cancer,arthritis,anxiety,psychosis,epilepsy,neurodegenerativedisease(i.e.,
Alzheimer’s)andskindiseaseisbeingconsidered[20–22].AnalysisofCBDantioxidantactivity
showedthatitcanregulatethestateofredoxdirectlybyaffectingthecomponentsoftheredoxsystem
andindirectlybyinteractingwithothermoleculartargetsassociatedwithredoxsystemcomponents.
3.1.DirectAntioxidantEffectsofCBD
CBDhasbeenshowntoaffectredoxbalancebymodifyingthelevelandactivityofbothoxidants
andantioxidants(Figures2and3).CBD,likeotherantioxidants,interruptsfreeradicalchain
reactions,capturingfreeradicalsortransformingthemintolessactiveforms.Thefreeradicals
producedinthesereactionsarecharacterizedbymanyresonancestructuresinwhichunpaired
electronsaremainlyfoundonthephenolicstructure,suggestingthatthehydroxylgroupsofthe
phenolringaremainlyresponsibleforCBDantioxidantactivity[18].
CBDreducesoxidativeconditionsbypreventingtheformationofsuperoxideradicals,whichare
mainlygeneratedbyxanthineoxidase(XO)andNADPHoxidase(NOX1andNOX4).Thisactivity
wasshownintherenalnephropathymodelusingcisplatintreatedmice(C57BL/6J)[23]andinhuman
coronaryendothelialcells(HCAEC)[24].Inaddition,CBDpromotedareductioninNOlevelsinthe
liverofdoxorubicintreatedmice[25]andinthepawtissueofWistarratsinachronicinflammation
model[26].
Figure2.DirectantioxidanteffectsofCBD(closedarrowsindicatereducingeffects;openedarrows
indicateinducingaction).
CBDalsoreducesreactiveoxygenspecies(ROS)productionbychelatingtransitionmetalions
involvedintheFentonreactiontoformextremelyreactivehydroxylradicals[27].Itwasshownthat
CBD,actingsimilarlytotheclassicantioxidantbutylatedhydroxytoluene(BHT),prevents
dihydrorodamineoxidationintheFentonreaction[28].Inaddition,CBDhasbeenfoundtodecrease
β‐amyloidformationinneuronsbyreducingtheconcentrationoftransitionmetalions[29].
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Inadditiontothedirectreductionofoxidantlevels,CBDalsomodifiestheredoxbalanceby
changingthelevelandactivityofantioxidants[19,26].CBDantioxidantactivitybeginsatthelevelof
proteintranscriptionbyactivatingtheredoxsensitivetranscriptionfactorreferredtoasthenuclear
erythroid2relatedfactor(Nrf2)[30],whichisresponsibleforthetranscriptionofcytoprotective
genes,includingantioxidantgenes[31].CBDwasfoundtoincreasethemRNAlevelofsuperoxide
dismutase(SOD)andtheenzymaticactivityofCu,Zn‐andMnSOD,whichareresponsibleforthe
metabolismofsuperoxideradicalsinthemousemodelofdiabeticcardiomyopathytypeIandin
humancardiomyocytestreatedwith3nitropropionicacidorstreptozotocin[32].Repeateddosesof
CBDininflammatoryconditionswerefoundtoincreasetheactivityofglutathioneperoxidaseand
reductase,resultinginadecreaseinmalonaldehyde(MDA)levels,whichweresixtimeshigherin
untreatedcontrols[26].Glutathioneperoxidaseactivity(GSHPx)andglutathionelevel(GSH)were
similarlychangedafterusingCBDtotreatUVBirradiatedhumankeratinocytes.Thehighaffinityof
CBDforthecysteineandselenocysteineresiduesoftheseproteinsisapossibleexplanationforthis
observation[33].Itisknownthatunderoxidativeconditions,alterationsinenzymaticactivitymaybe
causedbyoxidativemodificationsofproteins,mainlyaromaticandsulfuraminoacids[34].Ithasalso
beensuggestedthatthereactiveCBDmetabolitecannabidiolhydroxyquinonereactscovalentlywith
cysteine,formingadductswith,forexample,glutathioneandcytochromeP4503A11,andthereby
inhibitingtheirbiologicalactivity[35].Inaddition,CBDhasbeenfoundtoinhibittryptophan
degradationbyreducingindoleamine2,3dioxygenaseactivity[36].CBDalsosupportstheactionof
antioxidantenzymesbypreventingareductioninthelevelsofmicroelements(e.g.,ZnorSn),which
areusuallyloweredinpathologicalconditions.Theseelementsarenecessaryforthebiological
activityofsomeproteins,especiallyenzymessuchassuperoxidedismutaseorglutathioneperoxidase
[25].
ByloweringROSlevels,CBDalsoprotectsnonenzymaticantioxidants,preventingtheir
oxidation,asinthecaseofGSHinthemyocardialtissueofC57BL/6Jmicewithdiabetic
cardiomyopathy[32]anddoxorubicintreatedrats[25].AnincreaseinGSHlevelsafterCBD
treatmentwasalsoobservedinmousemicrogliacells[37]andintheliverofcadmiumpoisonedmice
[25].ThisisofgreatpracticalimportancebecauseGSHcooperateswithotherlowmolecularweight
compoundsinantioxidantaction,mainlywithvitaminssuchasA,E,andC[38].CBDexhibitsmuch
moreantioxidantactivity(30–50%)thanα‐tocopherolorvitaminC[4].
3.2.TheConsequencesofDirectAntioxidantActionofCBD
Theresultofanimbalancebetweenoxidantsandantioxidantsisoxidativestress,the
consequencesofwhichareoxidativemodificationsoflipids,nucleicacids,andproteins.Thisresults
inchangesinthestructureoftheabovemoleculesand,asaresult,disruptstheirmolecular
interactionsandsignaltransductionpathways[39].Oxidativemodificationsplayanimportantrole
inthefunctioningofredoxsensitivetranscriptionfactors(includingNrf2andthenuclearfactor
kappaB(NFκB).Asaconsequence,oxidativemodificationsplayaroleintheregulationof
pathologicalconditionscharacterizedbyredoximbalancesandinflammation,suchascancer,
inflammatorydiseases,andneurodegenerativediseases[40,41].
Inthissituation,oneofthemostimportantprocessesislipidperoxidation,whichresultsinthe
oxidationofpolyunsaturatedfattyacids(PUFA),suchasarachidonic,linoleic,linolenic,
eicosapentaenoic,anddocosahexaenoicacids[42].AsaresultoftheROSreactionwithPUFAs,lipid
hydroperoxidesareformed,andasaresultofoxidativefragmentation,unsaturatedaldehydesare
generated,including4hydroxynenenal(4HNE),malonodialdehyde(MDA)oracrolein[43].In
addition,thepropagationofoxidationchainreactions,especiallywithregardtodocosahexaenoic
acid,canleadtooxidativecyclization,resultinginproductionofisoprostanesorneuroprostanes[44].
Theformationoflipidperoxidationproductsdirectlyaffectsthephysicalpropertiesandfunctioning
ofthecellmembranesinwhichtheyareformed[42].Duetotheirstructure(thepresenceofa
carbonylgroupsandcarboncarbondoublebonds)andelectrophiliccharacter,generated
unsaturatedaldehydesarechemicallyreactivemoleculesthatcaneasilyformadductswiththe
majorityofthecell’snucleophiliccomponents,includingDNA,lipids,proteins,andGSH[45].For
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example,4hydroxynonenal(4HNE)hasbeenidentifiedasastimulatorofthecytoprotective
transcriptionfactorNrf2,aninhibitorofantioxidantenzymes(e.g.,catalaseandthioredoxin
reductase)andaproinflammatoryfactoractingthroughtheNFκBpathway[46].Thesereactions
reducethelevelofreactivelipidperoxidationproducts,whileincreasingtheformationofadducts
withproteinsthatpromotecellsignalingdisorders,thusstimulatingmetabolicmodificationsthat
canleadtocellulardysfunctionandapoptosis[47,48].
Inadditiontolipidperoxidation,oxidativeconditionsalsofavortheoxidativemodificationof
proteinsbyROS.Thearomaticandsulfhydrylaminoacidresiduesareparticularlysusceptibleto
modifications,andcanresultinproductionoflevodopa(LDOPA)fromtyrosine,orthotyrosine
fromphenylalanine,sulfoxidesanddisulfidesfromcysteine,andkynureninefromtryptophan,
amongothers[49].Theresultingchangesintheproteinstructurescausedisruptionoftheirbiological
propertiesand,asinthecaseoflipidmodification,affectcellmetabolism,includingsignal
transduction[46,50].
OneofthemostnoticeableCBDantioxidanteffectsisthereductioninlipidandprotein
modifications[25,51].CBDsupplementationhasbeenfoundtoreducelipidperoxidation,as
measuredbyMDAlevels,inmousehippocampal(HT22)neuronalcellsdepletedofoxygenand
glucoseunderreperfusionconditions[51].AreductioninlipidperoxidationfollowingCBD
supplementationhasalsobeenshowninC57BL/6Jmouseliverhomogenates,assessedby4HNE
levels[52].CBDalsoprotectedthebrainagainstoxidativeproteindamagecausedby
Damphetamineinaratmodelofmania[53].Ontheotherhand,CBDinducedubiquitinationofthe
amyloidprecursorprotein(APP),anindicatorofcellularchangesinthebrainofpeoplewith
Alzheimer’sdisease,whenevaluatedinhumanneuroblastomacells(SHSY5YAPP+)[54].Inaddition,
CBDtreatmenthasrecentlybeenshowntoexhibitanunusualprotectiveeffectbytransporting
proteinsincludingmultidrug1resistanceproteinandcytosoltransferases,suchasSglutathioneM1
transferase,priortomodificationbylipidperoxidationproducts.Thispreventselevationof4HNE
andMDAadductlevelsinfibroblastcellculture[55].Itwasalsoshownthatthisphytocannabinoid
reducedthelevelofsmallmolecularαβunsaturatedaldehydesinthemyocardialtissueof
SpragueDawleyratsandmicewithdiabeticcardiomyopathy,andintheliverofmicefromtheacute
alcoholintoxicationmodel[21,25,32].Additionally,CBDcausedareductioninthelevelofPUFA
cyclizationproducts,suchasisoprostanes,inthecortexoftransgenicmice(APPswe/PS1ΔE9)with
Alzheimer’sdisease[56].Thus,CBDprotectslipidsandproteinsagainstoxidativedamageby
modulatingthelevelofoxidativestress,whichparticipatesincellsignalingpathways.
3.3.IndirectAntioxidantEffectsofCBD
Variouscellmetabolicsystems,includingtheendocannabinoidsystem,areinvolvedinthe
regulationofredoxbalance.Thus,theactionofCBDasaphytocannabinoidmaysupportthe
biologicalactivityoftheendocannabinoidsystem.CBDhasrecentlybeenshowntomodulatethe
endocannabinoidsystemactivitybyincreasinganandamide(AEA)levels[5],whichcanaffect
cannabinoidssignaling,includingtheirinteractiononcannabinoidreceptors[57].However,itis
knownthattheperoxisomeproliferatoractivatedreceptoralpha(PPAR‐α),forexample,activatedby
endocannabinoids,directlyregulatestheexpressionofantioxidantenzymessuchassuperoxide
dismutasebyinteractingwiththeirpromoterregions[58].Therefore,itisbelievedthatthemost
importantantioxidantactivityofCBD,likeendocannabinoids,isassociatedwithitseffecton
receptors.CBD,dependingontheconcentration,canactivate,antagonizeorinhibitcannabinoid
receptors(CB1andCB2),aswellasionotropic(TRP)andnuclear(PPAR)receptors(Figure4)
[52,59,60].
3.4.CannabinoidReceptors
CBDhasbeenshowntobeaweakagonistofthehuman,mouse,andratCB1receptor[61].The
activationoftheCB1receptorincreasesROSproductionandaproinflammatoryresponse,including
thedownstreamsynthesisoftumornecrosisfactorα(TNF‐α)[62].Inaddition,itwasshownthatCBD
isanegativeallostericmodulatoroftheCB1receptor[63].RegardlessoftheeffectontheCB1
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receptor,CBDisaweakagonistoftheCB2receptor[64],butithasalsobeensuggestedthatitmay
demonstrateinverseagonismoftheCB2receptor[65].Importantly,CB2activationleadstoadecrease
inROSandTNF‐αlevels,whichreducesoxidativestressandinflammation[62].Therefore,ithasbeen
suggestedthatCBDmayindirectlyimproveantiinflammatoryeffects.Clinicalstudieshave
confirmedthatCBDreducesthelevelsofproinflammatorycytokines,inhibitsTcellproliferation,
inducesTcellapoptosisandreducesmigrationandadhesionofimmunecells[66].Inaddition,CBD
antiinflammatoryactivityhasbeenshowntobeantagonizedbybothaselectiveCB2antagonistand
AEA,anendogenousCB2receptoragonist[67].
CB1andCB2arereceptorswithstrongexpressioninthecentralnervoussystemandtheimmune
systemprimarily,butalsooccurinothertissues.CBD,actingontheabovereceptors,inhibitsthe
activityofadenylylcyclaseandvoltagegatedcalciumchannels,activatespotassiumchannelsand
activatesmitogenactivatedproteinkinase(MAPK),3phosphoinositolkinase(PI3K)/AKT,andthe
mammaliantargetofrapamycin(mTOR)signalingpathways[68].ThePI3K/AKT/mTORpathwayis
oneofthebasicpathwaysnecessaryforphysiologicalproteinsynthesisandinductionofother
intracellularpathways,suchastheMAPKpathway,whichplaysanimportantroleinregulatingcell
survival,proliferation,andapoptosis[69].CBDwasfoundtoinduceapoptosisinleukemiacellsby
reducingp38MAPKlevels[70].However,CBDwasalsoshowntoinhibitapoptosisinhumanbreast
cancercelllines(T47DandMDAMB231)byinhibitingexpressionofoncogenicandprosurvival
cyclinD1andmTOR,andbyincreasingPPARγreceptorexpression[71].
Figure3.IndirectantioxidantandantiinflammatoryeffectsofCBD(closedarrowsindicateinhibition;
openedarrowsindicateactivation.
3.5.TRPReceptors
IthasbeenshownthatCBDcanalsoaffectredoxbalanceandinflammationbymodulating
mammaliantransientreceptorpotential(TRP)channels[72,73].CBDactivatesvanilloidreceptors
(TRPV),directlyorindirectly,byincreasingthelevelofendogenousAEA,whichisoneofthe
endogenousTRPV1agonists[64].CBD,asaTRPV1receptoragonist,bindstoitandcauses
desensitization,leadingto“paradoxicalanalgesicactivity”similartothatofcapsaicin[26].Ithasbeen
suggestedthatthereisarelationshipbetweenmolecularsignalingofTRPV1andoxidativestress[74]
becauseROSandlipidperoxidationproductscanregulatethephysiologicalactivityofTRPV1by
oxidizingitsthiolgroups[75].Consequently,CBDnotonlyactivatesTRPthroughadirect
agonistreceptorinteraction,butalsobyloweringthelevelofoxidativestress.Inaddition,CBD
activatesothervanilloidreceptorssuchasTRPV2andthepotentialankarinprotein1receptor
subtype(TRPA1),whileantagonizingtheTRP8receptor(TRPM8)[72].CBDhasalsobeenshownto
stimulatecalciumionsintransfectedHEK293cellsviaTRPV3[76]andregulatecalciumion
homeostasisinimmuneandinflammatorycellsmainlyviaTRPchannels,whichisimportantfor
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proliferationandproinflammatoryrelatedcytokinesecretion[77].Inaddition,Ca2+ionscontrolthe
activationofseveraltranscriptionfactors(e.g.,NFAT)thatregulatetheexpressionofvarious
cytokines,suchasIL2,IL4andIFNγ,whichaffectcellularinflammatoryresponses[78].
RegardlessofthedirecteffectofCBDonTRPreceptors,increasingthelevelofAEA,asafull
TRPV1agonist,alsoaffectstheactivationofTRPreceptorsandnegativelyregulatesthe
2arachidonoylglycerol(2AG)metabolism[79].IthasbeenshownthatbothAEAand2AGcanbe
synthesizedintheplasmamembrane.However,thedegradationofphosphatidylinositolby
phospholipaseCresultsintheformationofadiacylglycerolprecursor,whosehydrolysis(through
diacylglycerollipaseactivity,DAGL)allowstheformationof2AG[80].However,activationof
DAGLαandDAGLβrequiresGSH.Additionally,theseenzymesaresensitivetoCa2+ions[81].TRPV1
agonists,suchascapsaicinandAEA,havebeenshowntoinhibit2AGsynthesisinstriatalneuronsof
C57BL/6micebyglutathionedependentpathways,sinceDAGLisstimulatedbyGSH[82].In
addition,theinteractionbetweenAEAand2AGhasbeenshowntodisappearafterinactivationof
TRPV1channels.ThissuggeststhatthenegativeeffectofAEAon2AGmetabolismcanbemimicked
bystimulationofTRPV1channels.Therefore,AEAand2AGinteractionsrequireredoxbalance,due
totheparticipationofGSHin2AGsynthesis.Insummary,CBDmodifiesTRPV1receptoractivation
throughreducingoxidativestressaswellasbiosynthesisof2AG.
3.6.PPARγReceptor
CBDisanagonistofthePPARγreceptor,whichisamemberofthenuclearreceptorsuperfamily
ofligandinducibletranscriptionfactors[52].PPARγ,anubiquitinE3ligase,hasbeenshownto
interactdirectlywithNFκB.TheinteractionoccursbetweentheligandbindingdomainofPPARγand
theRelhomologydomainregionofthep65subunitofNFκB.Lys48linkedpolyubiquitinofthe
ligandbindingdomainofPPARγisresponsibleforproteosomaldegradationofp65[83].Inthisway,
PPARγ participatesinthemodulationofinflammationbyinducingubiquitinationproteosomal
degradationofp65,whichcausesinhibitionofproinflammatorygeneexpression,suchas
cyclooxygenase(COX2)andsomeproinflammatorymediatorssuchasTNF‐α,IL1β,andIL6,as
wellasinhibitionofNFκBmediatedinflammatorysignaling[84].Forthisreason,PPARγagonists
canplayanantiinflammatoryrolebyinhibitingtheNFκBmediatedtranscriptionofdownstream
genes[84].Thismolecularmechanismismediatedbyβ‐cateninandglycogensynthasekinase3beta
(GSK3β).βcateninattenuatestranscriptionofproinflammatorygenesbyinhibitingNFκB[85,86].
Ontheotherhand,GSK3βisdecreasedbyPPARγstimulation[87].
PPARγcooperatesalsowithanothertranscriptionfactor,Nrf2,whichcontrolstheexpressionof
genesencodingcytoprotectiveproteins,particularlyantioxidantproteins[28,88].PPARγmaybindto
specificelementsinthepromoterregionofgenesitregulates,includingNrf2,catalase(CAT),
glutathioneStransferase(GST),hemeoxygenase1(HO1),andmanganesedependentsuperoxide
dismutase(MnSOD).Incontrast,Nrf2canregulatePPARγ expressionbybindingtothePPARγ
promoterinthesequenceofantioxidantresponseelements(ARE)thatarelocatedinthe‐784/764and
916regionsofthePPARγpromoter[89,90].ThereductioninPPARγ expressioninNrf2knockout
miceprovidesconfirmationofthisregulation[91].
ActingthroughthePPARγ receptor,CBDdemonstratesantiinflammatoryandantioxidant
properties.Inaddition,directCBDactivityisenhancedbytheactionofAEAand2AG,whichare
alsoPPARγagonistsandwhoselevelsareelevatedbyCBD[92].Ithasbeenfoundthatstimulationof
PPARαandreductionofoxidativestressbyCBDpreventsamyloidβinducedneuronaldeathby
increasingthelevelsofWnt/β‐catenin[84].However,therearenodataontheinteractionbetween
CBDandotherPPARsubtypes(PPARα,β,δ).ItisknownthattheendocannabinoidsAEA(whose
biosynthesisisstimulatedbyCBD)and2AGcanactivatePPARγ[92].AEAactivatesPPARα,while
the2AGderivative15hydroxyyeicosatetraenoicacidglycerylesterincreasesthetranscriptional
activityofPPARα[92].Insummary,CBDdemonstratesantiinflammatoryactivityandantioxidant
effectsbyactivatingPPARs,eitherdirectlyorindirectly.
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3.7.GPRReceptors
GPR55,whichisstronglyexpressedinthenervousandimmunesystemsaswellasinother
tissues,isaGproteincoupledreceptor[93].ActivationofGPR55increasestheintracellularlevelof
calciumions[94].CBDisaGPR55antagonistandcanmodulateneuronalCa2+levelsdependingon
theexcitabilityofcells[95].CBDantagonismismanifestedasananticonvulsanteffect[96].Because
CBDincreasesendocannabinoidexpression,itcanalsoindirectlyaffectinflammationandredox
balanceviathesemolecules[58].Inaddition,GPR55knockoutmicehavebeenshowntohavehigh
levelsofantiinflammatoryinterleukins(IL4,IL10,andIFN‐γ)[97],whilehighexpressionofGPR55
reducesROSproduction[98].Therefore,theorganism’sresponsetoCBDdependsonwhetherdirect
orindirecteffectsdominate.
CBDhasalsobeenshowntobeaninverseagonistofotherGPRreceptors,includingGPR3,GPR6
andGPR12.Itreducesβ‐arestinin2levelsandcAMPaccumulationinamyloidplaqueformationin
thedevelopmentofAlzheimer’sdisease,inaconcentrationdependentmanner[98].Inaddition,one
oftheneuropharmacologicaleffectsofCBDisitsreducingeffectonhippocampalsynaptosomes
mediatedbyitsinteractionwithGPR3[99].IthasalsobeensuggestedthattheeffectofCBDonthese
orphanreceptorsrepresentsanewtherapeuticapproachindiseasessuchasAlzheimer’sdisease,
Parkinson’sdisease,cancer,andinfertility[100].
3.8.5HT1AReceptor
CBDhasdirectaffinityforthehuman5HT1A(serotonin)receptor[101].Inaddition,CBDcan
inducethe5HT1AreceptorindirectlybyincreasingthelevelofAEA[102].However,theactivated
5HT1AreceptorcanactasamembraneantioxidantbycapturingROS[103].Therefore,through
activationof5HT1A,CBDcancounteractperoxidationofphospholipidsandthusparticipateinthe
protectionofbiomembranesagainstoxidativemodifications.Inaddition,studiesinWistarratshave
shownthatCBD,byactivating5HT1Areceptors,canreducephysiologicalandbehavioralresponses
torestrictivestress[104].CBDhasalsobeensuggestedasatherapeuticcompoundforthetreatmentof
painfuldiabeticneuropathyduetoitsabilitytoactivate5HT1Areceptors[10].
3.9.AdenosineA2AReceptors
CBDisalsoanagonistofadenosineA2Areceptors[61],whichareGproteincoupledreceptors.
Theyareexpressedinvariouscelltypes,participateinnumerousphysiologicalandpathological
processesandalsoregulateinflammatoryprocesses[105].Adenosineanditsagonistsexhibit
antiinflammatoryactivityinvivo[106].Therefore,adenosinereleaseisoneofthemechanismsof
immunosuppressionduringinflammation[107],andadenosinereceptoragonistsreduceTNF‐α
levels[108,109].IthasbeenshownthatCBDbyactivatingA2Aadenosinereceptorscanreducethe
levelofvascularcelladhesionmolecule(VCAM1)inendothelialcellsinSJL/Jmice,whichmay
provideanewmechanismtocontrolneuroinflammatorydiseasessuchasmultiplesclerosis(MS)
[110].
Inaddition,ithasbeenfoundthatA2Aactivationcanpreventreperfusionconsequencesand
alleviateoxidativestressinmitochondria[111].ThissuggeststhatCBDpreventsoxidativestressby
activatingA2Areceptors.ItwasalsoshownthatA2AreceptorscanformheteromerswithCB1receptors
inCA1neuronsandinthehippocampusofC57BL/6Jmice[112].Therefore,CBDcanmodifythe
functioningoftheentireheteromer,andthusmodulatetheactivationoftwogroupsofreceptors
involvedintheregulationofredoxbalanceandinflammation.
Antioxidants2020,9,219of21
Figure4.MajoreffectsofCBDonseveralmembranereceptors(AEA,anandamide;2AG,
2arachidonoylglycerol;FAAH,fattyacidamidehydrolase;AMT,AEAmembranetransporter;ROS,
reactiveoxygenspecies;Ub,ubiquitin;p65,transcriptionfactorNF‐κB;Nrf2,nuclearfactorerythroid
2relatedfactor2;ARE,antioxidantresponseelements.Bluearrowsindicateagonistactivity;red
arrowsindicateantagonistactivity;dashedbluearrowsindicateweaklyagonisticactivity;green
arrowsindicateendocannabinoidagonistactivity;greyarrowsindicatechemicalandbiological
effects).
4.EffectsofNaturalDerivativesofCBDonReceptors
DuetotherangeofCBDmetaboliceffectsknowntodate,interestinthepossibilityofusingthis
phytocannabinoidisconstantlygrowing.ConsideringthefactthatmodificationstotheCBDstructure
mayresultinanimprovedtherapeuticprofileandbiologicalactivity,naturalCBDderivativesare
soughtandtheirtherapeuticutilityisbeingevaluated.Therefore,knownorpotentialeffectsof
naturallyoccurringCBDderivativesarepresented.Theiractivitythroughmembranereceptorsis
emphasized,whicharedescribedinthisreviewasthosewhichundertheinfluenceofCBDshow
antioxidantand/orantiinflammatoryactivities.
4.1.CB1/CB2Receptors
Cannabidiolicacid(CBDA),beingaC3’carboxylderivativeofCBD(2,4dihydroxy3[(1R,
6R)3methyl6prop1en2ylcyclohex2en1[alpha]6pentylbenzoicacid),actsasaselectiveCOX2
andprostaglandinendoperoxidesynthaseinhibitorandexhibitsantiinflammatorypropertiesin
humanbreastcancercells[113].Ithasbeensuggestedthatitsactionmaybeduetoaweakaffinityfor
CB1andCB2receptors(Table2)[114].Similarly,otherCBDderivatives,suchascannabidivarin
(CBDV),whichisaCBDanalogueofC4’propyl(2[(1R,
6R)3methyl6prop1en2)ylcyclohex2en1yl]5propylbenzene1,3diol),7hydroxyCBD
(7OHCBD)andthehydroxylatedCBDderivativeof7carboxylicacid(7COOHCBD)havepoor
affinitiesforCB1andCB2(Table2)[2].Thereisnopublisheddataexaminingtheirimpactonthe
redoxbalance.
Antioxidants2020,9,2110of21
4.2.GPR55andTRPV1Receptors
CBDVhasbeenfoundtohaveantagonisticeffectsonGPR55(Table2),whichprobablyleadsto
anticonvulsanteffects[115].Therefore,thiscompoundissuggestedforusewhentherapeutic
antiepilepticactivitiesareneeded.Ontheotherhand,CBDAhasbeensuggestedtobeaneffective
compoundinanalgesiaandcancerthroughitsagonisticactiononTRPA1andTRPV1receptors(Table
2)andantagonisticactiononTRPM8,similartoCBD[76,116].
Anothernaturalphytocannabinoidiscannabimovone(1[(1R,2R,3R,
4R)3(2,6dihydroxy4pentylphenyl)2hydroxy4prop1en2ylcyclopentyl]ethanone),whichhas
lowaffinityfortheCB1andCB2receptors,butsignificantaffinityforTRPV1(Table2)[117].
Incontrast,cannabigivarin(acannabigerolropylanalogue)hasbeenshowntostimulateand
desensitizehumanTRPV1(Table2)[72].ItisalsoknownthatTRPV1receptoractivityisdeeply
involvedinoxidativestressandinflammation[114].Basedontheunderstandingoftherelationship
betweenTRPV1andoxidativestressdescribedinsection3.5,allofthesederivativesmayprovide
differenttherapeuticapproachesinthecaseofinflammationandoxidativestress.
4.3.5HT1AandPPARγReceptors
IthasbeenshownthatanotherCBDderivative,cannabigerol(CBG;
(2[(2E)3,7dimethylocta2,6dienyl]5pentylbenzene1,3diol]),anaturallyopenanalogueof
cyclohexenylCBD,activatesTRPV1aswellas5HT1A(Table2)andhasantidepressantand
antiinflammatoryeffectsinintestinaldiseases[2,72,118].CBGmayalsobindtoPPARγ(Table2)and
increaseitstranscriptionalactivity[92].StudiesontheHEK293celllinehaveshownthatCBG,by
activatingPPARγ,significantlyreducesthesecretionofinflammatorymediatorssuchasIL6and
TNF‐α[119].
5.EffectsofSyntheticDerivativesofCBDonReceptors
GiventhelimitationsinthebiologicalactivityofCBDitselfanditsnaturalderivativesandthe
factthatthebiologicalpropertiesofCBDderivativesdependontheirstructure,syntheticderivatives
areproducedthathavebeendesignedsothattheirstructureallowsdirectinteractionwith
componentsoftheredoxsystemorindirectlywithmoleculartargetsinteractingwiththese
components,includingthecannabinoidreceptors(Table2).Thederivativeswithpotential
antioxidantandantiinflammatoryeffectsinclude,butarenotlimitedto,(+)CBDderivatives,
dihydrocannabidiolandtetrahydrocannabidiolderivatives,and(+)dihydro7hydroxyCBD[2].
Promisingsyntheticderivativesthatcanmodulateredoxbalanceand/orinflammationarepresented
below.
5.1.CB1/CB2Receptors
Ithasbeenshownthatboththenaturallyoccurring()CBDenantiomeranditssynthetic
derivatives[()7hydroxy5’dimethylheptylCBD,and()1COOH5’dimethylheptylCBD]have
weakaffinityfortheCB1andCB2cannabinoidreceptors(Table2).However,(+)CBDandits
derivatives[(+)5’dimethylheptylCBDand(+)7hydroxy5’dimethylheptylCBD]havehighCB1
receptoraffinity,slightlyloweraffinityfortheCB2receptorandinhibitAEAcellularuptake[120].
Similarly,()7hydroxydimethylheptylCBDcaninhibitbothAEAuptakeanddegradationthrough
fattyacidamidehydrolase(FAAH)activity[121].Recently,()dimethylheptylCBDhasbeenshown
tobeaCB1receptoragonist(Table2)inHEK293Acells[122].Inaddition,byreducingtheexpression
ofproinflammatorygenes(IL1b,IL6,andTNF‐α),itexhibitsadosedependentantiinflammatory
effectonmicrogliaBV2cells[30].
Furthermore,hydrogenatedCBDderivativessuchas(+)dihydrocannabidioland
(+)tetrahydrocannabidiolhaveCB1receptoraffinity(Table2)andshowantiinflammatoryeffectson
theperitonealcellsofC57BL/6miceandamacrophagecellline.Thisbehaviormaysuggestthatthe
activationofproinflammatorymediatorsisnotdirectlythroughtheCB1cannabinoidreceptor[123].
Similarly,the(+)8,9dihydro7hydroxyCBDderivative(HU465),whichhasantiinflammatory
Antioxidants2020,9,2111of21
activity,especiallyathigherconcentrations,bindstobothCB1andCB2receptors,whileits()
enantiomer,()8,9dihydro7hydroxyCBD(HU446)hasnegligibleaffinityforbothCB1andCB2
receptors(Table2).However,bothHU465andHU446havebeenfoundtoexhibitantiinflammatory
activitybyinhibitingthereleaseofIL17inmouseencephalitogenicTcells(TMOG)[124].
Inaddition,thepinenedimethoxydimethylheptylCBDderivativeHU308[(3R,4S,
6S)2[2,6dimethoxy4(2methyloctan2yl)phenyl]7,7dimethyl4bicyclo[3.1.1]hept3enyl]methan
ol]anditsenantiomerHU433[(3S,4R,
6R)2[2,6dimethoxy4(2methyloctan2yl)phenyl]7,7dimethyl4bicyclo[3.1.1]hept3enyl]methan
ol]wereshowntohavespecificagonisticactivityfortheCB2receptor(Table2),andconsequently,
antiinflammatoryactivityinculturedcalvarialosteoblastsfromC57BL/6Jmice[125].However,ithas
beenfoundthatHU433exhibitsgreaterantiinflammatoryactivitywithpoorerCB2receptorbinding
affinity(Table2)[125].Incontrast,HU308,aCB2agonist,wasfoundtodecreaseTNF‐α‐induced
expressionofICAM1andVCAM1insinusoidalendothelialcellsofhumanlivertissue[24].Another
CB2receptoragonist,HU910
((1S,4R)2[2,6dimethoxy4(2methyloctan2yl)phenyl]7,7dimethyl1bicyclo[2.2.1]hept2enyl]met
hanol)),significantlyinhibitstheeffectsofLPSthatleadtoincreasedinflammation(assessedby
increasedTNF‐αexpression)andincreasedoxidativestress(assessedbyincreasedlevelsof4HNE
andproteincarbonylgroups)inmouseKupffercells[126].Thissuggeststhattheseeffectsare
associatedwithCB2receptoractivation(Table2).
5.2.GPRReceptors
AbnormalCBD
(4[(1R,6R)3methyl6prop1en2ylcyclohex2en1yl]5pentylbenzene1,3diol),namedO1602,is
asyntheticCBDregioisomerandaselectiveGPR55receptoragonist(Table2),butnotaCB1/CB2
receptoragonist.Itcausesvasodilationindependentofthereceptorsaswell[2,127].Therefore,ithas
beensuggestedthatO1602canbeusedtoregulateROS/RNSlevelsandmodifytheeffectofoxidative
stressoncellularmetabolismbymodulatingGPR55receptoractivation[58].Inaddition,O1602,asa
GPR18agonist,mediatesthereductionofcyclicadenosinemonophosphate(cAMP)andtheactivation
ofthePI3K/AKTandERK1/2pathwaysinvitro[128].ASpragueDawleyratstudyshowedthat
GPR18receptoractivationviaO1602leadstoreductionofROSlevels,howeverinhibitionofGPR18
receptoractivationincreasesoxidativestressbyincreasingROSproduction[129].
5.3.PPARγReceptor
RecentlyithasalsobeenfoundthatthesyntheticquinolinederivativesofCBG,VCE003
[(2[(2E)3,7dimethylocta2,6dienyl]3hydroxy5pentylcyclohexa2,5dien1,4dione)]andHU331
[(3hydroxy2[(1R,6R)3methyl6prop1en2ylcyclohex2en1yl]5pentylcyclohexa2,5dien1,4
dione],activatethePPARγreceptorasCBGdoes(Table2)[130].HU311wasshowntointerferewith
mitochondrialtransmembranepotentialandinduceROSgeneration,aswellasactivatetheNrf2
pathway[130].However,anotherCBDderivative,VCE003,inducesPPARγ‐mediatedantioxidant
andantiinflammatoryactivitythatpreventsneuronaldamagecausedbyinflammationinthe
Parkinson’smousemodel(intravascularLPSinjection).Thesameeffectwasseenintheinvitro
cellularmodelofneurologicalinflammation(BV2cellsexposedtoLPSandM213cellstreatedwith
mediapreparedfromBV2cellsexposedtoLPS)[131].
5.4.TRPV1,5HT1AandAdenosineA2AReceptors
DespiteextensiveresearchintothebiologicaleffectsofsyntheticCBDderivatives,theyhavenot
beenevaluatedfortheirinteractionwithTRPV1,5HT1AandadenosineA2Areceptorsinthecontextof
antiinflammatoryandantioxidantactivity.
Antioxidants2020,9,2112of21
Table2.InfluenceofnaturalandsyntheticCBDderivativesonreceptoractivation(X:agonistactivationorY:antagonistactivationbyrelatedCBDderivative;*
weakaffinity;#:fullnameisinchapter4.1)[2,24,72,76,114–116,120,122–127,130].
CBDDerivativesMembraneReceptors
NaturalCB1CB2Gpr55Gpr18TRPV1TRPA1TRPM85HT1APPARγ
cannabigerol(CBG)XX
cannabigivarin(CBGV)X
cannabidiolicacid(CBDA)X*X*  XXY 
cannabidivarin(CBDV)X*X*Y 
cannabimovoneX*X*  X   
7OHCBDX*X* 
7COOHCBDX*X* 
SyntheticCB1CB2Gpr55Gpr18TRPV1TRPA1TRPM85HT1APPARγ
()dimethylheptylCBD(DMHCBD)X 
()7hydroxy5′‐dimethylheptylCBDX*X* 
()1COOH5′‐dimethylheptylCBDX*X* 
(+)5′‐dimethylheptylCBDXX* 
(+)7hydroxy5′‐dimethylheptylCBDXX* 
(+)dihydrocannabidiol(H2CBD)X 
(+)tetrahydrocannabidiol(H4CBD)X 
()8,9dihydro7hydroxyCBD(HU446)X*X* 
(+)8,9dihydro7hydroxyCBD(HU465)XX 
pinenedimethoxydimethylheptylCBDderivative(HU433) X* 
pinenedimethoxydimethylheptylCBDderivative(HU308) X 
HU910#X 
4’fluorocannabidiol(HUF101/4’FCBD)XX 
quinolderivativeVCE003X
quinolderivativeHU331X
abnormalCBDXX    
Antioxidants2020,9,2113of21
6.Conclusions
OxidativestressresultingfromoverproductionofROSisakeyelementoftheimmunesystem’s
responsetocombatpathogensandinitiatestissuerepair.However,metabolicmodificationsresulting
fromoverproductionofROSalsohavemanynegativeaspectsandleadtothedevelopmentand/or
exacerbationofmanydiseases.Itisbelievedthattheendocannabinoidsystem,whichincludes
Gproteincoupledreceptorsandtheirendogenouslipidligands,mayberesponsibleforthe
therapeuticmodulationofoxidativestressinvariousdiseases.Inthiscontext,thephytocannabinoid
cannabidiol,whichwasidentifiedseveraldecadesagoandmayinteractwiththecannabinoidsystem,
isapromisingmoleculeforpharmacotherapy.
Relativelyrecently,multidirectionalbiologicaleffectshavebeendemonstratedinvarious
preclinicalmodels,includingtheantioxidantandantiinflammatoryeffectsofcannabidiol[14.73].In
thecontextoftheabovedata,CBDseemstobemorepreferredthanothercompoundsfromthe
phytocannabinoidgroup.RegardlessofthebeneficialpharmacologicaleffectsofCBDitself,ifthis
compoundispresentintheΔ
9THCenvironment,theundesirableeffectsof99THCarereduced,
whichimprovesitssafetyprofile[132].
ImportantinCBDtherapeuticapplicationsisthelackofpsychotropiceffects.Furthermore,this
phytocannabinoidisnotteratogenicormutagenic[133].Untilrecently,CBDwasthoughttohaveonly
lowtoxicitytohumansandotherspecies[134],butrecentstudiesindicateanincreaseinALTand
ASTlevelsafterCBDtreatment,whichdisqualifiesitasthedrugofchoice[135,136].Inaddition,ithas
beenfoundthatCBDmayinterferewiththehepaticmetabolismofsomedrugsbyinactivating
cytochromeP4503AandP4502C[137].Suchinteractionsshouldbeconsideredwhen
coadministeringCBDwithotherdrugsmetabolizedbyaboveenzymes.
InordertofindcompoundswithagreatertherapeuticprofileandactivitythanCBD,without
anyadverseeffects,thebiologicalpropertiesofbothnaturalandsyntheticCBDderivativeswere
checked,withthehopeoffindingtheperfectderivativethatprovidesaclosetoidealtherapeutic
effect.
AuthorContributions:conceptualization,E.S.;writing—originaldraftpreparation,S.A.andI.J.K.;
writing—reviewandediting,E.S.;visualization,S.A.;supervision,E.S.Allauthorshavereadandagreedtothe
publishedversionofthemanuscript.
Funding:S.A.:coauthorofthework,wassupportedbytheprojectwhichhasreceivedfundingfromthe
EuropeanUnion’sHorizon2020researchandinnovationprogrammeundertheMarieSkłodowskaCuriegrant
agreementNo754432andthePolishMinistryofScienceandHigherEducation,fromfinancialresourcesfor
sciencein20182023grantedfortheimplementationofaninternationalcofinancedproject.
ConflictsofInterest:Theauthorsdeclarenoconflictofinterest.
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