CHIR-99021isaGSK-3α/βinhibitorwithIC₅₀of10nM/6.7nM;>500-foldselectivityforGSK-3versusitsclosesthomologsCDC2andERK2,aswellasotherproteinkinases.

IC50:10nM/6.7nM(GSK-3α/β)^[1]

CHIR99021inhibitshumanGSK-3βwithK_ivaluesof9.8nM^[1].CHIR99021isasmallorganicmoleculethatinhibitsGSK3αandGSK3βbycompetingfortheirATP-bindingsites.InvitrokinaseassaysrevealthatCHIR99021specificallyinhibitsGSK3β(IC₅₀=~5nM)andGSK3α(IC₅₀=~10nM),withlittleeffectonotherkinases^[2].InthepresenceofCHIR-99021theviABIlityoftheES-D3cellsisreducedby24.7%at2.5μM,56.3%at5μM,61.9%at7.5μMand69.2%at10μMCHIR-99021withanIC₅₀of4.9μM^[3].

InZDFrats,asingleoraldoseofCHIR99021(16mg/kgor48mg/kg)rapidlylowersplasmaglucose,withamaximalreductionofnearly150mg/dl3-4hafteradmiNISTration^[1].CHIR99021(2mg/kg)givenonce,4hbeforeirrADIation,significantlyimprovessurvivalafter14.5GyaBDominalirradiation(ABI).CHIR99021treatmentsignificantlyblockscryptapoptosisandaccumulationofp-H2AX⁺cells,andimprovescryptregenerationandvillusheight.CHIR99021treatmentincreasesLgr5⁺cellsurvivalbyblockingapoptosis,andeffectivelypreventsthereductionofOlfm4,Lgr5andCD44asearlyas4h^[4].

• [1].RingDB,etal.Selectiveglycogensynthasekinase3inhibitorspotentiateinsulinactivationofglucosetransportandutilizationinvitroandinvivo.Diabetes.2003Mar;52(3):588-95.

  [2].BennettCN,etal.RegulationofWntsignalingduringAdipogenesis.JBiolChem.2002Aug23;277(34):30998-1004.

  [3].NaujokO,etal.CytotoxicityandactivationoftheWnt/beta-cateninpathwayinmouseembryonicstemcellstreatedwithfourGSK3inhibitors.BMCResNotes.2014Apr29;7:273.

  [4].WangX,etal.Pharmacologicallyblockingp53-dependentapoptosisprotectsintestinalstemcellsandmicefromradiation.SciRep.2015Apr10;5:8566.

KinasesarepurifiedfromSF9cellsthroughuseoftheirHisorGlutag.Glu-taggedproteinsarepurified,andHis-taggedproteinsarepurified.Kinaseassaysareperformedin96-wellplateswithappropriatepeptidesubstratesina300-μLreactionbuffer(variationson50mMTris-HCl,pH7.5,10mMMgCl₂,1mMEGTA,1mMdithiothreitol,25mMβ-glycerophosphate,1mMNaF,and0.01%bovineserumalbumin).PeptideshasK_mvaluesfrom1to100μM.CHIR99021orCHIRGSKIAisaddedin3.5μLofMe₂SO,followedbyATPtoafinalconcentrationof1μM.Afterincubation,triplicate100-μLaliquotsaretransferredtoCombiplate8platescontaining100μL/wellof50μMATPand20mMEDTA.After1hour,thewellsarerinsedfivetimeswithphosphate-bufferedsaline,filledwith200μLofscintillationfluid,sealed,andcountedinascintillationcounter30minlater.Allofthestepsareatroomtemperature.Thepercentageofinhibitioniscalculatedas100×(inhibitor-noenzymecontrol)/(Me₂SOcontrol-noenzymecontrol)^[2].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

CHIR99021isdissolvedinDMSOandstored,andthendilutedwithappropriatemediabeforeuse^[3].

TheviabilityofthemouseEScellsisdeterminedafterexposuretodifferentconcentrationsofGSK3inhibitorsforthreedaysusingtheMTTassay.ThedecreaseofMTTactivityisareliablemetabolism-basedtestforquantifyingcellviability;thisdecreasecorrelateswiththelossofcellviability.2,000cellsareseededovernightongelatine-coated96-wellplatesinLIF-containingEScellmedium.OnthenextdaythemediumischangedtomediumdevoidofLIFandwithreducedserumandsupplementedwith0.1-1μMBIO,or1-10μMSB-216763,CHIR-99021orCHIR-98014.BasalmediumwithoutGSK3inhibitorsorDMSOisusedascontrol.Alltestedconditionsareanalyzedintriplicates^[3].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

CHIR99021isformulatedassolutionsin20mMcitrate-buffered15%CaptisolorasfinesUSPensionsin0.5%carboxymethylcellulose(Rat)^[1].
CHIR99021ispreparedinDMSOanddiluted(Mice)^[4].

Rat^[1]
PrimaryhepatocytesfrommaleSpragueDawleyratsthatweighed<140 g="" are="" prepared="" and="" used="" 1-3="" h="" after="" isolation.="" aliquots="" of="">⁶cellsin1mLofDMEM/F12mediumplus0.2%BSAandCHIR99021(orallyat16or48mg/kg)orcontrolsareincubatedin12-wellplatesonalow-speedshakerfor30minat37°CinaCO₂-enrichedatmosphere,collectedbycentrifugationandlysedbyfreeze/thawinbufferAplus0.01%NP40;theGSassayisagainperformed.
Mice^[4]
Mice6-10weeksoldareused.ThePUMA^+/+andPUMA^-/-littermatesonC57BL/6background(F10)andLgr5-EGFP(Lgr5-EGFP-IRES-creERT2)micearesubjectedtowholebodyirradiation(TBI),orabdominalirradiation(ABI).Miceareinjectedintraperitoneally(i.p.)with2mg/kgofCHIR990214hbeforeradiationor1mg/kgofSB41528628hand4hbeforeradiation.Micearesacrificedtocollectsmallintestinesforhistologyanalysisandwesternblotting.Allmiceareinjectedi.p.with100mg/kgofBrdUbeforesacrifice.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

• [1].RingDB,etal.Selectiveglycogensynthasekinase3inhibitorspotentiateinsulinactivationofglucosetransportandutilizationinvitroandinvivo.Diabetes.2003Mar;52(3):588-95.

  [2].BennettCN,etal.RegulationofWntsignalingduringadipogenesis.JBiolChem.2002Aug23;277(34):30998-1004.

  [3].NaujokO,etal.CytotoxicityandactivationoftheWnt/beta-cateninpathwayinmouseembryonicstemcellstreatedwithfourGSK3inhibitors.BMCResNotes.2014Apr29;7:273.

  [4].WangX,etal.Pharmacologicallyblockingp53-dependentapoptosisprotectsintestinalstemcellsandmicefromradiation.SciRep.2015Apr10;5:8566.

465.34

C₂₂H₁₈Cl₂N₈

252917-06-9

RoomtemperatureincontinentalUS;mayvaryelsewhere

DMSO:≥5.1mg/mL

*"<1 mg/ml"="" means="" slightly="" soluble="" or="" insoluble.="" "≥"="" means="" soluble,="" but="" saturation="">

Purity:99.92%

SelectBatch:HY-10182-06073HY-10182-05974HY-10182-05447

DataSheet(138KB)SDS(389KB)

COA(94KB)HNMR(2380KB)LCMS(219KB)

HandlingInstructions(1252KB)

• [1].RingDB,etal.Selectiveglycogensynthasekinase3inhibitorspotentiateinsulinactivationofglucosetransportandutilizationinvitroandinvivo.Diabetes.2003Mar;52(3):588-95.

  [2].BennettCN,etal.RegulationofWntsignalingduringadipogenesis.JBiolChem.2002Aug23;277(34):30998-1004.

  [3].NaujokO,etal.CytotoxicityandactivationoftheWnt/beta-cateninpathwayinmouseembryonicstemcellstreatedwithfourGSK3inhibitors.BMCResNotes.2014Apr29;7:273.

  [4].WangX,etal.Pharmacologicallyblockingp53-dependentapoptosisprotectsintestinalstemcellsandmicefromradiation.SciRep.2015Apr10;5:8566.

他替瑞林口服促甲状腺素释放激素他替瑞林CAS号:103300-74-9英文名称:Taltirelin英文同义词:TA0910;Taltirelin;Taltireline;Ceredist,TA-0910;TaltirelinAcetate;TA-0910,taltirelin;TaltirelininterMediate;TALTIRELININTERMEDIATES;TaltirelinAcetate,TA-0910;L-Prolinamide,(4S)-hexahydro-1-methyl-中文名称:他替瑞林中文同义词:他替瑞林;醋酸他替瑞林;1-METHYL-4,5-DIHYDROOROTYL-HIS-PRO-NH2;(4S)-N-[(2S)-1-[(2S)-2-氨基甲酰基吡咯烷-1-基]-3-(3H-咪唑-4-基)-1-氧代丙-2-基]-1-甲基-2,6-二氧代-1,3-二氮杂己环-4-甲酰胺CBNumber:CB31177191分子式:C17H23N7O5分子量:405.41MOLFile:103300-74-9.mol化学性质安全信息用途供应商86化学性质安全信息用途供应商86他替瑞林化学性质熔点:72-75°比旋光度:25D-13.6°(c=1inwater)密度:1.447±0.06g/cm3(Predicted)储存条件:Storeat+4°C酸度系数(pKa):9.32±0.40(Predicted)安全信息他替瑞林性质、用途与生产工艺口服促甲状腺素释Chemicalbook放激素他替瑞林是一种垂体激素释放兴奋药，由日本田边三菱制药株式会社研制成功，商品名Taltirelin，属于化药新药3.1类，目前临床用于改善脊髓小脑变性患者的运动失调最为有效的药物。他替瑞林（Taltirelin）是世界上第一个批准的口服促甲状腺素释放激素(TRH)，除具有内分泌作用外，还可发挥一定的中枢神经系统(CNS)作用，包括提高运动活性，拮抗利舍平诱导的体温降低，以及拮抗戊巴比妥诱导的睡眠。该品种由日本田边三菱制药株式会社开发，2000年9月首次在日本上市，用于改善脊髓小脑变性病人的共济失调。脊髓小脑共济失调(SCAs)旧称常染色体显性共济失调，是一组以共济失调、辨距不良为主要临床表现的中枢神经系统慢性变性疾病。2000年9月前，促甲状腺素释放激素（TRH）注射液是唯一用于治疗该类疾病的药物。他替瑞林是TRH的结构修饰改造药物，药理学研究显示本品经由脑TRH受体对CNS产生强而持久的多重作用。本品对CNS的兴奋作用比TRH强10～100倍，作用持续时间比TRH长约8倍。本品对TRH受体的亲和力约为TRH的1/11，因而本品的内分泌作用比TRH弱，但本品在体内比TRH稳定。另外本品对促甲状腺素(TSH)释放的作用为TRH的1/6-1/11，TSH释放是由一个包括甲状腺激素的强负反馈系统调节的，对中枢神经系统具有较强的作用，但同时其激素样作用较小，因此副作用较少。不良反应主要是消化系统反应，包括呕吐、恶心和胃不适。所有的不良反应均为轻中度，在治疗期间及(或)停药后消失。

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