ABSTRACT
（-）-Epigallocatechingallate（EGCG）asoneofestercatechins,whichisabioactivemolecule,hasbeenshowntopossessvarietiesofhealthfunctionssuchasantioxidant,anti-ultravioletradiationandprotectionagainstskincancer,etc.However,thestabilityofEGCGunderhumanpHenvironmentispoortocausealowbioavailability.Therefore,howtoenhancebioavailabilityofEGCGisahotissueatpresentTheethosomeisanovelcarrierforenhanceddeliveryinskin,whichhasbeenreportedtohaveproductiveadvantages,suchashighentrappingcapacityandexcellentskinpermeation.Itispotentialtoimprovestabilityandbioavailabilityofdrugs,ifdrugsareentrappedbyethosomes.
Inthepresentstudy,preparationmethodofnano~ethosomesentrappingEGCGwasinvestigatedanditsimprovedeffectonanti-ultravioletradiationwaschecked.
（1）Theconditionsofpreparingnano-EGCGethosomeswereinvestigated.Byacombinationofinjectingandultrasonicemulsificating,nano-ethosomesentrappingEGCGweresuccessfullyprepared.Theoptimumparametersforthepreparationwereobtainedbytheorthogonaltest.Theresultsshowedthat2%phospholipidsand30%ethanolforformationofethosomes,0.1%K9and1.0%Tween-80asstabilizers,and0.25%EGCGasdrugunderultrasonicprocessingfor2mincouldyieldexcellentethosomeswithmeansize62.8nm,zetapotential-42.8mVandPDI（polydisperantindex）0.097.Theentrappingefficiencyofthenanoethosomeswasmorethan90%.
（2）Skinpermeationexperimentswereconductedbycnfocallaserscanningmicroscope（CLSM）usingrodmineBasafluorescenceprobe.Theresultsshowedthatintermsofthetransdermaldepthofethosomes,theEGCGnano-ethosomescouldpermeatedeeperthantheEGCGhydroethanolicsolution,andtheEGCGtransdermalquantitybyethosomeswasobviouslygreaterthanthatofthehydroethanolicsolution.
ThetransdermaldeliveryinvitrowasstudiedbymeasuratingtheamountofEGCGinorthroughskin.FortheEGCGnano-ethosomestheEGCGamountcouldreach40.13jig?cm“2and289.8路？cm”2at8hand24htransdermalpenetrationwhilethoseoftheEGCGhydroethanolicsolutionwereonly18.26jxg?cm“2and35.67（ig?cm*2.
（3）Theanti-ultraviolet-B（UVB）irradiationwastestedbyanimalerxperimentwithnudemice.AfterthemiceweregivenUVBirradiationwithatotaldoseof625mJ/cm2,theskintissuechangewasobsveredbylightmicroscopeandTEM.TheresultsdemonslratedthatEGCGnano-ethosomescouldattenuateUVB-inducedskindamage,anditseffectwasclearlybetterthanEGCGhydroethanolicsolution.
ABSTRACT
Inthestatisticalexperiment,subjectsmayexperiencetheoutcomeofinterestmorethanonce,theeventarecalledrecurrenteventandtheobservationoftheseoutcomesarecalledrepeatedeventsdataorrecurrenteventdata.Thistypeofdataarisesinmanyfieldssuchasmedicalfield,publichealth,biology,demographyandeconomics.Toanalyzerecurrenteventdata,variousmodelsandapproacheshavebeenproposedintheliterature.Theresearchesofrecurrenteventsincludethenumberofeventsuptotheobservationtime,theeventtimesandtheinter-eventtimes（gaps）。Themodelsandapproachesforthenumberofeventsovertimeswerestudiedbymanyauthors.Generally,lowdimensionalcovariateshavebeenassumedinmodelingrecurrenteventdata,butwhichmaybeviolatedintheanalysiswhenthecovariatesarehigh-dimensional.Inrecentyears,withthedevelopmentofcomputersandotherinformationtechnology,thedataandthecovariatesaremorecomplexfromthestudiesofbiology,medicine,ecology,demography,environmentandeconomicsandotherdisciplines.Someusefulimportantinformationisoftenhiddenbehindthehigh-dimensionaldata.So,recently,thehigh-dimensionaldataregressionisverypopularinmanyareas.Duetothe”dimensioncurse“exists,manytraditionalstatisticalmethodshaveencounteredbigchallengesandunprecedenteddifficulties.Thus,inourpaper,wediscussthedimensionreductionapproachesonthejointmodelofrecurrenteventandterminaleventwithhigh-dimensionalcovariatestosolvethedimensionreductionproblemsinrecurrenteventmodel.
Inourpaper,themodelwediscussedisthejointmodelofthemultiplicativehazardratefunctionofrecurrenteventandterminationevent.Theinnovationofthispaperisthatweusethepartialsufficientdimensionreductiontheoryandmethodonthejointmodel.Wenotonlystudythedimensionreductionproblemoftherecurrenteventmodel,butalsoconsiderthedimensionreductionproblemoftheterminaleventmodel.Theapplicationofthepartialsufficientdimensionreductiontheoryandmethodonrecurrenteventmodelandthedimensionreductionproblemofterminaleventmodelareworthytostudyandnottopaymoreattentionintheliterature.Inthispaper,wemainlyfocusontwoaspects:Thefirstaspect,tosolvethedimensionreductionproblemofthemultiplicativehazardratefunctionofrecurrenteventmodel,firstanonparametricestimatorisproposedforthebaselinefunction,andthebasisofthepartialcentralsubspaceanditsstructuraldimensionareestimatedthroughthepartialsufficientdimensionreduction.Basedontheestimatedstructuraldimension,thebasisofthepartialcentralsubspaceandthebaseline,wecangettheestimatoroftheregressionfunctionbyusingthelocallinearregression.Thesecondaspect,basedonthefrailtyfactorestimatedfromthemultiplicativehazardratemodeloftherecurrentevent,wediscussthepartialdimensionreductionofthemultiplicativehazardratemodelofterminalevent.Twomethodsareproposedinthispaper,thefirstmethod:weusethepartialdimensionreductiontogettheestimatorofthepartialcentralsubspaceandthenweusethelocalpartiallikelihoodfunctiontogettheestimatorsofthebaselinefunctionandtheregressionfunction.Thesecondmethod:theefficientestimationmethodisusedtogetthecentralsubspace.Forsimplicityincalculation,weassumethebaselinefunctionisknownintheterminaleventmodel.
Asimulationisperformedtoconformandassessthetheoreticalfindings,andanexampleisalsodemonstratedonasetofchronicglaucomatousdiseasedata.
ABSTRACT
ObjectiveThroughtheestablishmentofananimalmodelofacutelunginjuryinparaquatpoisonedrats,itcanbeobservedthattheeffectsofsalidroside（SDS）onMMP-2,TIMP-1oflungtissueinlunginjuredacuteparaquat（PQ）poisonedrats,aimingtoclarifythepresenceofsalidroside'sprotectiveandanti-fibrosisfunctiononlungs.
Methods130adultmaleSDratswererandomlydividedinto:normalgroup（NSgroup,10）；PQmodelgroup（60wererandomlydividedintosixsubgroups,each10atId,3d,7d,14d,21d,28d）；SDSinterventiongroup（60wererandomlydividedintosixsubgroups,each10atId,3d,7d,14d,21d,28d）。Amongwhich,thenormalcontrolgroupisgavagedwithImLsalineonce,thePQmodelgroupandtheSDSinterventiongroupweregavagedwiththe20mg/kgPQdilutedwithImLsaline.
Aafterparaquatpoisoninglh,theSDSinterventiongroup,wasgivendailyintraperitonealinjectionoflOmg/kgSalidrosideevery12hs.AsfortheNScontrolgroupandthePQmodelgroup,theywereinjectedwithsalinewithequalvolumntotheSDSgroup,onceevery12hs.ThePQmodelgroupandtheSDSinterventiongroupweretakenspecimensfromtherightlowerlungtissueunderanesthesiaanatomical,afterparaquatpoisoningId,3ds,7ds,14ds,2Ids,28ds.Partofthespecimenswasstoredinrefrigeratorat-70.CforRT-PCRandReal-timePCRtesting,andtheotherpartwasrinsedinsaline,fixedin10%formalin,dehydrated,madetransparent,dippedintowax.Andtheparaffin-embeddedtissueblocksandthe.slices,areforHEstainingandimmunohistochemicalstaining.
ResultsComparedwiththenormalgroup,theratsinthePQmodelgroupandtheSDSinterventiongroupgottheearlysymptomsofacutelunginflammation,pulmonaryedemaandobviousbleeding.ChangesinpulmonaryfibrosiswereobservedafterexposuretoPQfor7daysanditcametotheclimaxat28thday;theSDSgroupgotthesimilarsymptoms,butwhicharerelativelymild.Incontrast,inthePQgroup,theMMP-2proteinandmRNAareobviouslyandincreasinglyexpressedinthelungtissueofratsfromonthefirstdayandtillthe7thdayitreachedapeak,thoughdeclinedslowly,stillsignificantlyhigherthanthenormalgroupatthe28thday;AndtheTIMP-1proteinexpressionalsosignificantlyenhancedfrom1std,reachingapeakatthe14thday,thenremainedhighafterwards。
Comparedwiththepreviousgroups,theSDSinterventiongroupkeptasignificantlylowerlevelatMMP-2andTIMP-1proteinandmRNAexpression（P<0.05）。
Conclusion1,20mg/kgparaquatgavagecansuccessfullymakeanimalmodelsofacutelunginjury;2,MMP-2,TIMP-1inacutelunginjuryinducedbyparaquatpoisoningandpulmonaryfibrosisplaysanimportantrole;3,Salidroside（SDS）caninhibitMMP-2,TIMP-1mRNAexpressionandproteinexpression,andrestorethebalancebetweentheprevioustwo,thusdelayingoreveninhibitingthefibroticprocess.
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