SR9011yi-REV-ERBα/βAma-Agonists, amalungu osapho lwe-nuclear receptor, afunyenwe ukulawula imetabolism yezicubu zebhayoloji.U-Huang Guodong ufumanise ukuba i-SR9011 idlala indima ebalulekileyo ekulawuleni isingqisho se-zebrafish autophagy gene.
Iiprotheni zeentsapho ze-SR9011 azinayo i-ligand ebopha i-domain kwi-C-terminal, kodwa inokuthintela ukubonakaliswa kwe-protein ye-Rev erb ngokugaya i-nuclear receptor inhibitor kunye ne-histone deacetylase 3. I-Histone deacetylase 3 yi-Rev erb agonist kunye ne-molecule encinci ye-chemical probe.Fon taine et al.okokuqala, i-Chemicalbook yabika ukuba i-SR9011 inonxibelelwano nokuvuvukala.I-SR9011 inokuthintela ukubonakaliswa kwe-Tr4, ngaloo ndlela ilawula umqondiso wokuvuvukala.Abaphengululi bamazwe angaphandle baye bafumanisa ukuba kwii-macrophages zabantu, ukwandisa i-mRNA ibonakaliso ye-SR9011 ngeendlela ze-pharmacological ngqo kukhokelela ekunciphiseni kwe-mRNA intetho ye-proinflammatory factor interleukin-6.
Isifundo se-in vitro:
I-SR9011 idosi-ixhomekeke kwi-REV-ERB-ixhomekeke kwi-repressor function ehlolwe kwiiseli ze-HEK293 ezibonisa i-chimeric Gal4 DNA Binding Domain (DBD) - REV-ERB ligand binding domain (LBD)α or β kunye ne-Gal4-responsive luciferase reporter (REV-ERBα IC 50 =790 nM, REV-ERBβ IC 50 =560 nM).I-SR9011 icinezela ngokufanelekileyo nangokusebenzayo ukukhutshelwa kuvavanyo lwe-cotransfection usebenzisa ubude obugcweleyo be-REV-ERBα kunye nentatheli ye-luciferase eqhutywa ngumgqugquzeli we-Bmal1 (SR9011 IC 50 = 620 nM).I-SR9011 icinezela intetho yeBMAL1 mRNA kwiiseli zeHepG2 kwiREV-ERBα/β -indlela exhomekeke kwi-SR9011 icinezela ukwanda kweeseli zomhlaza wamabele kungakhathaliseki isimo sabo se-ER okanye se-HER2.I-SR9011 ibonakala inqumama umjikelo weeseli zeeseli zomhlaza wamabele phambi kwesigaba se-M.I-Cyclin A (i-CCNA2) ichongiwe njengejoni elijoliswe ngqo kwi-REV-ERB ebonisa ukuba ukunyanzeliswa kwenkcazo yale cyclin nge-SR9011 kunokudibanisa ukubanjwa komjikelo weseli.Unyango nge-SR9011 luphumela ekunyukeni kweeseli kwisigaba se-G 0 / G 1 kunye nokuncipha kweeseli kwi-S kunye ne-G 2 / M isigaba esicebisa ukuba ukusebenza kwe-REV-ERB kunokubangela ukunciphisa ukuguquka ukusuka kwi-G 1 ukuya kwisigaba se-S kwaye / okanye ukusuka kwi-S ukuya kwi-G 2 /M isigaba.
Isifundo se-vivo:
SR9011 ibonisa i-plasma exposure ye-plasma enengqiqo, ngoko ke, ukubonakaliswa kwe-REV-ERB yofuzo ephendulayo ihlolwe kwisibindi seegundane eziphathwe ngeendlela ezahlukeneyo ze-SR9011 kwiintsuku ze-6. I-plasminogen activator inhibitor uhlobo lwe-1 gene (i-Serpine1) yi-REV-ERB yofuzo ekujoliswe kuyo. kwaye ibonisa ukunyanzeliswa kwe-dose exhomekeke kwi-dose ekuphenduleni i-SR9011.I-cholesterol 7α-hydroxylase (Cyp7a1) kunye ne-sterol response element binding protein (Srepf1) iigenes nazo zibonakaliswe ukuba ziphendule kwi-REV-ERB kwaye zixhomekeke kwidosi ngokunyuka. izixa ze-SR9011.Emva kweentsuku ze-12 kwi-D: D iimeko zeegundane zijojowe ngedosi enye ye-SR9011 okanye isithuthi kwi-CT6 (inkcazo ephezulu ye-Rev-erbα).Inaliti yemoto ayibangeli ukuphazamiseka kumsebenzi we-circadian locomotor.Nangona kunjalo, ukulawulwa kwedosi enye ye-SR9011 kubangela ukulahleka komsebenzi we-locomotor ngexesha lesigaba sobumnyama.Umsebenzi wesiqhelo ubuyisela umjikelo olandelayo we-circadian, ohambelana nokukhutshwa kwamachiza ngaphantsi kwe-24h.Ukuncipha kokuxhomekeka kwe-SR9011 ekuqhubeni isondo kwindlela yokuziphatha kwiimpuku phantsi kweemeko zobumnyama eziqhubekayo kuxhomekeke kwidosi kwaye i-potency (ED 50 = 56 mg / kg) ifana namandla e-SR9011-mediated gene responsive gene REV-ERB. , Srebf1 , in vivo (ED 50 = 67mg / kg).
Ixesha lokuposa: Dec-06-2022