SR9011ke REV-ERBα/βLi-Agonists, litho tsa lelapa la li-nuclear receptor, li fumanoe li laola metabolism ea lisele tsa baeloji.Huang Guodong o fumane hore SR9011 e na le karolo ea bohlokoa ho laoleng morethetho oa mofuta oa liqoaha autophagy.
Liprotheine tsa lelapa tsa SR9011 ha li na sebaka se tlamang sa ligand sebakeng sa C-terminal, empa se ka thibela polelo ea Rev erb protein ka ho hira nuclear receptor inhibitor le histone deacetylase 3. Histone deacetylase 3 ke Rev erb agonist le molek'hule e nyenyane ea lik'hemik'hale.Fon taine et al.pele, Chemicalbook e tlaleha hore SR9011 e na le kamano le ho ruruha.SR9011 e ka thibela polelo ea Tr4, ka hona e laola lets'oao la ho ruruha.Litsebi tsa linaha tse ling li fumane hore ho macrophages ea batho, ho eketsa polelo ea mRNA ea SR9011 ka mekhoa ea phekolo ea meriana ka ho toba ho lebisa ho fokotseha ha polelo ea mRNA ea proinflammatory factor interleukin-6.
Thuto ea in vitro:
SR9011 ho itšetlehile ka tekanyo e eketsa ts'ebetso ea khatello e itšetlehileng ka REV-ERB e hlahlobiloeng liseleng tsa HEK293 tse hlahisang chimeric Gal4 DNA Binding Domain (DBD) - REV-ERB ligand binding domain (LBD)α or β le moqolotsi oa litaba oa luciferase ea Gal4 (REV-ERBα IC 50 =790 nM, REV-ERBβ IC 50 =560 nM).SR9011 e hatella mongolo ka mokhoa o hlakileng le ka katleho tekong ea cotransfection e sebelisa REV-ERB ea bolelele bo felletseng.α hammoho le moqolotsi oa litaba oa luciferase ea khannoang ke motlatsi oa Bmal1 (SR9011 IC 50 = 620 nM).SR9011 e hatella polelo ea BMAL1 mRNA liseleng tsa HepG2 ho REV-ERBα/β -e itšetlehileng ka mokhoa oa SR9011 o hatella ho ata ha lisele tsa kankere ea matsoele ho sa tsotellehe boemo ba bona ba ER kapa HER2.SR9011 e bonahala e emisa potoloho ea lisele tsa mofetše oa matsoele pele ho karolo ea M.Cyclin A (CCNA2) e khetholloa e le mofuta o tobileng oa REV-ERB e fanang ka maikutlo a hore ho hatelloa ha polelo ea cyclin ena ka SR9011 ho ka 'na ha e-ba mokena-lipakeng oa ho tšoaroa ha lisele.Kalafo ka SR9011 e fella ka keketseho ea lisele karolong ea G 0 / G 1 le ho fokotseha ha lisele karolong ea S le G 2 / M e bontšang hore ts'ebetso ea REV-ERB e ka 'na ea fella ka ho fokotseha ha phetoho ho tloha G 1 ho ea ho S le / kapa ho tloha ho S ho ea ho G 2 /M mohato.
Thuto ea in vivo:
SR9011 e bonts'a ts'oaetso ea plasma e utloahalang, kahoo, polelo ea liphatsa tsa lefutso tse arabelang tsa REV-ERB e hlahlojoa sebeteng sa litoeba tse tšoaroang ka mefuta e sa tšoaneng ea SR9011 bakeng sa matsatsi a 6. The plasminogen activator inhibitor type 1 gene (Serpine1) ke REV-ERB target gene 'me e bonts'a khatello ea maikutlo e itšetlehileng ka lethal dose ho arabela SR9011.The cholesterol 7α-hydroxylase (Cyp7a1) le sterol reaction element e tlamang protheine (Srepf1) liphatsa tsa lefutso le tsona li bontšitsoe hore li arabela ho REV-ERB 'me li hatelloa ho itšetlehile ka tekanyo ea ho eketseha. litšenyehelo SR9011.Ka mor'a matsatsi a 12 maemong a D: D litoeba li kenngoa ka tekanyo e le 'ngoe ea SR9011 kapa koloi ho CT6 (peak expression of Rev-erbα).Ente ea koloi ha e bake tšitiso ts'ebetsong ea circadian locomotor.Leha ho le joalo, tsamaiso ea tekanyo e le 'ngoe ea SR9011 e fella ka tahlehelo ea mosebetsi oa locomotor nakong ea karolo e lefifi ea sehlooho.Ts'ebetso e tloaelehileng e khutlisa potoloho e latelang ea circadian, e tsamaellanang le ho tlosoa ha lithethefatsi ka nako e ka tlase ho lihora tse 24.Ho fokotseha ho itšetlehileng ka SR9011 ea boitšoaro ba mabili ho litoeba tlas'a maemo a lefifi a sa khaotseng ho itšetlehile ka tekanyo le hore potency (ED 50 = 56 mg / kg) e tšoana le matla a khatello ea SR9011-mediated ea REV-ERB gene e arabelang. , Srebf1 , in vivo (ED 50 = 67mg/kg).
Nako ea poso: Dec-06-2022