PioglitazonehydrochlorideisapotentandselectivePPARγagonistwithhighaffinitybindingtothePPARγligand-bindingdomainwithEC₅₀of0.93and0.99μMforhumanandmousePPARγ,respectively.

EC50:0.93μM(humanPPARγ),0.99μM(mousePPARγ)^[1]

AGEs-inducedbetacellnecrosisiscompletelyabrogatedbyaddingPioglitazonetotheAGEsculturemedium.FurThermorePioglitazonecompletelypreventedanyAGEs-inducedincrementincaspase-3activation,therebyrestoringcaspase-3activitytothesamelevelsasthecontrolcells.AsexpectedAGisabletocounteractAGEs-inducedimpairedviABIlity^[2].

Theserum-freefattyacidandtriglyceridelevelsaswellasADIpocytesizesinob/obandadipo^-/-ob/obmiceareunchangedafter10mg/kgPioglitazonebutaresignificantlyreducedtoasimilardegreeafter30mg/kgPioglitazone.Moreover,theexpressionsofTNFαandresistininadiposetissuesofob/obandadipo^-/-ob/obmiceareunchangedafter10mg/kgPioglitazonebutaredecreasedafter30mg/kgPioglitazone.Thus,Pioglitazone-inducedameliorationofinsulinresistanceanddiabetesmayoccuradiponectindependentlyintheliverandadiponectinindependentlyinskeletalmuscle^[3].Pioglitazone(10mg/kgperd)treatmentsignificantlyattenuatesthelossofbodyweight(BW)andcardiachypertrophy.Pioglitazonetreatmentsignificantlyreducestheelevatedserumglucoselevelsandmarkedlyimprovedtheassociateddyslipidemia.Furthermore,thereisaslightbutsignificantincreaseinserumcreatininelevelinDratsovertheirNcontrols(P<0.05). however,="" a="" marked="" renal="" dysfunction="" is="" observed="" in="" diabetic="" nephropathic="" (dn)="" group=""><0.05). moreover,="" dn="" rats="" exhibits="" the="" highest="" serum="" activity="" of="" ck-mb,="" relative="" to="" both="" n="" and="" d="" rats=""><0.05). pioglitazone="" is="" able="" to="" decrease="" the="" elevated="" serum="" levels="" of="" both="" creatinine="" and="" creatine="" kinase-mb="">^[4].

• [1].KuwabaraK,etal.Anovelselectiveperoxisomeproliferator-activatedreceptoralphaagonist,2-methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylicacid(NS-220),potentlydecreasesplasmatriglycerideandglucoseleve

  [2].PudduA,etal.Pioglitazoneattenuatesthedetrimentaleffectsofadvancedglycationend-productsinthepancreaticbetacelllineHIT-T15.RegulPept.2012Aug20;177(1-3):79-84.

  [3].KubotaN,etal.Pioglitazoneamelioratesinsulinresistanceanddiabetesbybothadiponectin-dependentand-independentpathways.JBiolChem.2006Mar31;281(13):8748-55.

  [4].ElrashidyRA,etal.Pioglitazoneattenuatescardiacfibrosisandhypertrophyinaratmodelofdiabeticnephropathy.JCardiovascPharmacolTher.2012Sep;17(3):324-33.

Inordertoevaluatecellproliferation,HIT-T15cellsareseededon96-wellplates(3×10⁴cells/well)andculturedfor5daysasdescribed.ViablecellsaredeterminedusingtheCellTiter96AqueousOneSolutionCellProliferationAssay.Toevaluatecellapoptosisandcellnecrosis,HIT-T15cellsareplatedon6-welldishes(7×10⁵cells/well)for5daysinstandardconditions(CTR)orinthepresenceofAGEs(AGEs)withorwithoutPioglitazone(0.5or1μM)orAG(1mM).Theyarethenprocessedtomeasureboththeactivityofcaspase-3andtheactivityoflactatedehydrogenase(LDH)(astablecytosolicenzymethatisaMarkerofcellmembranedamageandcelldeathduetonecrosis)usingCytotox96NonRadioactiveCytotoxicityAssay^[2].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

Pioglitazone(AD4833)hydrochlorideispreparedin0.25%carboxymethylcellulose(Mice)^[3].
PioglitazonehydrochlorideissUSPendedin0.5%carboxymethylcellulose(Rat)^[4].

Mice^[3]
10mg/kgPioglitazoneHClorvehicle(0.25%carboxymethylcellulose)isadnimisteredtoob/obandadipo^-/-ob/obmicebyoralgavageoncedailyfor14consecutivedays.30mg/kgPioglitazoneorvehicleisalsoadnimisteredtoob/obandadipo^-/-ob/obmicebyoralgavageoncedailyfor14consecutivedays.
Rat^[4]
MaleWistaralbinorats(weighing250±20g)areued.Ratsthatachievedserumglucoselevel≥250mg/dLandserumcreatininelevel≥1.5mg/dLaredividedinto2groups(n=10pereachgroup):diabeticnephropathic(DN)groupinwhichratsreceivedanequalamountofvehicle(0.5%carboxymethylcellulose)andPioglitazone-treated(DN+Pio)groupinwhichratstreatedwithPioglitazone.Pioglitazone(10mg/kgBW)isgivenorallybygastricgavage,oncedaily,for4weeks.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

• [1].KuwabaraK,etal.Anovelselectiveperoxisomeproliferator-activatedreceptoralphaagonist,2-methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylicacid(NS-220),potentlydecreasesplasmatriglycerideandglucoseleve

  [2].PudduA,etal.Pioglitazoneattenuatesthedetrimentaleffectsofadvancedglycationend-productsinthepancreaticbetacelllineHIT-T15.RegulPept.2012Aug20;177(1-3):79-84.

  [3].KubotaN,etal.Pioglitazoneamelioratesinsulinresistanceanddiabetesbybothadiponectin-dependentand-independentpathways.JBiolChem.2006Mar31;281(13):8748-55.

  [4].ElrashidyRA,etal.Pioglitazoneattenuatescardiacfibrosisandhypertrophyinaratmodelofdiabeticnephropathy.JCardiovascPharmacolTher.2012Sep;17(3):324-33.

392.9

C₁₉H₂₁ClN₂O₃S

112529-15-4

RoomtemperatureincontinentalUS;mayvaryelsewhere

10mMinDMSO

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