SR9011waa REV-ERBα/βAgonists, xubno ka tirsan qoyska reseptor nukliyeerka, ayaa la ogaaday inay nidaamiyaan dheef-shiid kiimikaadka unugyada noolaha.Huang Guodong waxa uu ogaaday in SR9011 ay door muhiim ah ka ciyaarto nidaaminta laxanka hidda-wadaha zebrafish autophagy.
SR9011 borotiinada qoyska ayaa ka maqan domain xidhidhiyaha ee C-terminal, laakiin waxay joojin karaan muujinta borotiinka Rev erb iyadoo la qorayo xannibaadaha nukliyeerka iyo histone deacetylase 3. Histone deacetylase 3 waa agonist Rev erb iyo kiimiko yar oo kiimiko ah.Fon taine et al.Marka hore, Kitaabkii Kiimikada ayaa sheegay in SR9011 ay xiriir la leedahay caabuqa.SR9011 waxay joojin kartaa muujinta Tr4, sidaas darteed xakamaynta calaamadda bararka.Culimada ajnabiga ah waxay ogaadeen in macrophages bini'aadamka, kordhinta muujinta mRNA ee SR9011 ee hababka dawooyinka ayaa si toos ah u horseedaya hoos u dhaca muujinta mRNA ee proinflammatory factor interleukin-6.
Barashada vitro:
Qiyaasta SR9011-ku-tiirsanaanta waxay kordhisaa waxqabadka cadaadiska ku-tiirsanaanta REV-ERB ee lagu qiimeeyay unugyada HEK293 oo muujinaya chimeric Gal4 DNA Binding Domain (DBD) - REV-ERB ligand binding domain (LBD)α or β iyo wariyaha Luciferase ee Gal4-ka jawaaba (REV-ERBα IC 50 = 790 nM, REV-ERBβ IC 50 = 560 nM).SR9011 waxay si xoog leh oo wax ku ool ah u xakamaysaa qoraalka ku jira qiimaynta isku-gudbinta iyadoo la isticmaalayo REV-ERB oo dhererkeedu dhan yahayα oo ay la socdaan wariye luciferase ah oo uu wado horumariyaha Bmal1 (SR9011 IC 50 = 620 nM).SR9011 waxay xakameysaa muujinta BMAL1 mRNA ee unugyada HepG2 ee REV-ERBα/β Habka-ku-tiirsanaanta SR9011 waxay xakameysaa fidinta khadadka unugyada kansarka naasaha iyada oo aan loo eegin xaaladooda ER ama HER2.SR9011 waxay u muuqataa inay hakisay wareegga unugyada unugyada kansarka naasaha ka hor marxaladda M.Cyclin A (CCNA2) waxaa loo aqoonsaday hidde-sidaha tooska ah ee REV-ERB oo soo jeedinaya in xakamaynta muujinta wareeggan ee SR9011 ay dhexdhexaadin karto xiritaanka wareegga unugyada.Daaweynta SR9011 waxay keenaysaa kororka unugyada G 0 / G 1 iyo hoos u dhaca unugyada S iyo G 2 / M marxaladda soo jeedinta in firfircoonida REV-ERB ay keeni karto hoos u dhac ku yimaada marxaladda G 1 ilaa S iyo /ama laga bilaabo S ilaa G 2/M marxaladda.
In vivo waxbarashada:
SR9011 waxay soo bandhigaysaa soo-gaadhista balaasmaha macquulka ah, sidaas awgeed, muujinta hiddo-wadaha jawaab-celinta REV-ERB waxaa lagu baaraa beerka jiirarka oo lagu daaweeyaa qiyaaso kala duwan oo SR9011 ah maalmaha 6. Qalabka plasminogen activator inhibitor nooca 1 hidda (Serpine1) waa hidda-socodka REV-ERB waxayna muujisaa xakamaynta qiyaasta ku-tiirsanaanta muujinta jawaabta SR9011. Kolestaroolka 7a-hydroxylase (Cyp7a1) iyo borotiinka jawaab-celinta sterol-ka ee borotiinka (Srepf1) ayaa sidoo kale lagu muujiyay inay ka jawaabayaan REV-ERB waxayna ku tiirsan yihiin qiyaasta si loo xakameeyo iyadoo la kordhinayo Qiimaha SR9011.Ka dib 12 maalmood gudaha D: D xaaladaha jiirarka ayaa lagu duraa hal qiyaas SR9011 ama baabuur at CT6 (muujinta ugu sarreysa ee Rev-erbα).Cirridka baabuurtu wax carqalad ah kuma keenayso dhaqdhaqaaqa wareegga wareegga.Si kastaba ha ahaatee, maamulka hal dose oo ah SR9011 waxay keenaysaa luminta dhaqdhaqaaqa lugaha inta lagu jiro marxaladda mugdiga ah.Dhaqdhaqaaqa caadiga ah wuxuu soo celiyaa wareegga xiga ee wareegga, si waafaqsan nadiifinta daawooyinka wax ka yar 24 saacadood.Hoos-u-dhaca SR9011-ku-tiirsanaanta ee dabeecadda orodka taayirrada ee jiirarka hoos yimaada xaaladaha mugdiga joogtada ah waxay ku xiran tahay qiyaasta iyo in awoodda (ED 50 = 56 mg/kg) ay la mid tahay awoodda SR9011-dhexdhexaadin ee xakamaynta hiddo-wadaha REV-ERB , Srebf1, in vivo (ED 50 = 67mg/kg).
Waqtiga post: Dec-06-2022