SR9011 CAS 1379686-29-9 UCWANINGO

I-SR9011iyi-REV-ERBα/βAma-Agonists, amalungu omndeni we-nuclear receptor, atholwe ukuthi alawule ukuguqulwa kwezicubu zebhayoloji.U-Huang Guodong uthole ukuthi i-SR9011 idlala indima ebalulekile ekulawuleni isigqi se-zebrafish autophagy gene.

Amaprotheni omndeni we-SR9011 awanaso isizinda esibopha i-ligand ku-C-terminal, kodwa angavimbela inkulumo ye-Rev erb protein ngokuqasha i-nuclear receptor inhibitor kanye ne-histone deacetylase 3. I-Histone deacetylase 3 iyi-Rev erb agonist kanye ne-molecule encane ye-chemical probe.Fon taine et al.okokuqala, i-Chemicalbook ibike ukuthi i-SR9011 inokuhlobana nokuvuvukala.I-SR9011 ingavimbela ukuvezwa kwe-Tr4, ngaleyo ndlela ilawule isignali yokuvuvukala.Izazi zakwamanye amazwe zithole ukuthi kuma-macrophage abantu, ukukhulisa ukubonakaliswa kwe-mRNA kwe-SR9011 ngezindlela zemithi kuholela ngokuqondile ekwehleni kwenkulumo ye-mRNA ye-proinflammatory factor interleukin-6.

Isifundo se-in vitro:

I-SR9011 incike kumthamo inyusa umsebenzi wokucindezela oncike ku-REV-ERB ohlolwe kumaseli e-HEK293 aveza isizinda esibophezelayo se-chimeric Gal4 DNA (DBD) – REV-ERB ligand binding domain (LBD)α or β kanye nentatheli ye-luciferase ephendulayo ye-Gal4 (REV-ERBα I-IC 50 =790 nM, REV-ERBβ IC 50 =560 nM).I-SR9011 icindezela ngamandla nangempumelelo ukuloba ku-cotransfection assay kusetshenziswa ubude obugcwele be-REV-ERBα kanye nentatheli ye-luciferase eqhutshwa umgqugquzeli we-Bmal1 (SR9011 IC 50 = 620 nM).I-SR9011 icindezela ukuvezwa kwe-BMAL1 mRNA kumaseli e-HepG2 ku-REV-ERBα/β -indlela encikile i-SR9011 icindezela ukwanda kwemigqa yamaseli omdlavuza webele kungakhathaliseki ukuthi i-ER noma i-HER2 injani.I-SR9011 ibonakala imisa kancane umjikelezo weseli lamaseli omdlavuza webele ngaphambi kwesigaba se-M.I-Cyclin A ( CCNA2 ) ikhonjwa njengofuzo oluqondiswe ngqo lwe-REV-ERB ephakamisa ukuthi ukucindezelwa kokuvezwa kwale cyclin nge-SR9011 kungase kulamule ukuboshwa komjikelezo weseli.Ukwelashwa nge-SR9011 kuphumela ekwandeni kwamaseli esigabeni se-G 0/G 1 kanye nokuncipha kwamaseli esigabeni se-S kanye ne-G 2/M okuphakamisa ukuthi ukusebenza kwe-REV-ERB kungase kubangele ukwehla koshintsho olusuka ku-G 1 ukuya ku-S isigaba futhi / noma ukusuka ku-S ukuya ku-G 2 /M isigaba.

Ucwaningo lwe-vivo:

I-SR9011 ibonisa ukuchayeka kwe-plasma okunengqondo, ngakho-ke, ukubonakaliswa kwezakhi zofuzo ezisabelayo ze-REV-ERB kuhlolwa esibindini samagundane aphathwa ngezilinganiso ezihlukahlukene ze-SR9011 izinsuku ezingu-6. I-plasminogen activator inhibitor uhlobo lwe-1 gene (i-Serpine1) i-REV-ERB isakhi sofuzo. futhi ibonisa ukucindezelwa kokukhuluma okuncike kumthamo ekuphenduleni i-SR9011.I-cholesterol 7α-hydroxylase (Cyp7a1) kanye nezakhi zofuzo ezibophayo ze-sterol (Srepf1) nazo ziboniswe ukuthi zisabela ku-REV-ERB futhi zicindezelwa ngokuncika kumthamo ngokukhula Intengo ye-SR9011.Ngemuva kwezinsuku eziyi-12 ezimeni ze-D:D amagundane ajovwa ngomthamo owodwa we-SR9011 noma imoto ku-CT6 (isisho esiphezulu se-Rev-erbα).Umjovo wemoto awubangeli ukuphazamiseka emsebenzini we-circadian locomotor.Kodwa-ke, ukuphathwa komthamo owodwa we-SR9011 kubangela ukulahleka komsebenzi we-locomotor phakathi nesigaba sobumnyama sesihloko.Umsebenzi ojwayelekile ubuyisela umjikelezo we-circadian olandelayo, ohambisana nokusulwa kwezidakamizwa esikhathini esingaphansi kwamahora angama-24.Ukwehla okuncike ku-SR9011 ekuziphatheni kokugijima kwamasondo kumagundane ngaphansi kwezimo ezimnyama ezihlala njalo kuncike kumthamo nokuthi amandla (ED 50 =56 mg/kg) afana namandla okucindezelwa okuphakathi kwe-SR9011 kofuzo olusabelayo lwe-REV-ERB , Srebf1 , in vivo (ED 50 =67mg/kg).