TIAB SA 9011yog REV-ERBα/βAgonists, cov tswv cuab ntawm tsev neeg ntawm cov receptor nuclear, tau pom los tswj cov metabolism hauv cov ntaub so ntswg lom.Huang Guodong pom tias SR9011 plays lub luag haujlwm tseem ceeb hauv kev tswj lub suab ntawm zebrafish autophagy noob.
SR9011 tsev neeg cov proteins tsis muaj ligand binding domain ntawm C-terminal, tab sis muaj peev xwm inhibit qhov kev qhia ntawm Rev erb protein los ntawm recruiting nuclear receptor inhibitor thiab histone deacetylase 3. Histone deacetylase 3 yog ib tug Rev erb agonist thiab ib tug me me molecule tshuaj sojntsuam.Fontaine et al.thawj zaug, Chemicalbook qhia tias SR9011 muaj kev cuam tshuam nrog kev mob.SR9011 tuaj yeem cuam tshuam qhov kev qhia ntawm Tr4, yog li tswj cov teeb liab inflammatory.Cov kws tshawb fawb txawv teb chaws tau pom tias hauv tib neeg macrophages, nce mRNA qhia ntawm SR9011 los ntawm cov kws tshuaj ncaj qha ua rau txo qis ntawm mRNA kev qhia ntawm proinflammatory factor interleukin-6.
Kev tshawb nrhiav hauv vitro:
SR9011 koob tshuaj-raws li nce REV-ERB-dependent repressor kev ua haujlwm soj ntsuam hauv HEK293 hlwb qhia txog chimeric Gal4 DNA Binding Domain (DBD) - REV-ERB ligand binding domain (LBD)α or β thiab Gal4-responsive luciferase reporter (REV-ERBα IC 50 = 790 nM, REV-ERBβ IC 50 = 560 nM).SR9011 muaj zog thiab muaj txiaj ntsig zoo tiv thaiv kev hloov pauv hauv kev tshuaj xyuas cotransfection siv tag nrho REV-ERBα nrog rau tus neeg sau xov xwm luciferase uas tau tsav los ntawm Bmal1 txhawb nqa (SR9011 IC 50 = 620 nM).SR9011 suppresses kev qhia ntawm BMAL1 mRNA hauv HepG2 hlwb hauv REV-ERBα/β -dependent yam SR9011 suppresses proliferation ntawm lub mis mob qog noj ntshav kab tsis hais lawv ER los yog HER2 xwm txheej.SR9011 zoo li yuav ncua lub voj voog ntawm cov qog nqaij hlav cancer ntawm lub mis ua ntej M theem.Cyclin A (CCNA2) raug txheeb xyuas raws li lub hom phiaj ncaj qha ntawm REV-ERB qhia tias kev tawm tsam ntawm qhov kev qhia ntawm cov cyclin no los ntawm SR9011 tuaj yeem kho lub voj voog ntawm tes.Kev kho mob nrog SR9011 ua rau muaj kev nce hauv cov hlwb hauv G 0 / G 1 theem thiab txo qis ntawm cov hlwb hauv S thiab G 2 / M theem qhia tias kev ua kom REV-ERB tuaj yeem ua rau txo qis ntawm G 1 mus rau S theem thiab / lossis los ntawm S mus rau G 2 / M theem.
Hauv kev tshawb nrhiav vivo:
TIAB SA 9011 qhia txog qhov tsim nyog plasma raug, yog li, qhov kev qhia ntawm REV-ERB teb cov noob yog tshuaj xyuas hauv daim siab ntawm cov nas kho nrog ntau koob tshuaj SR9011 rau 6-hnub.Cov plasminogen activator inhibitor hom 1 noob ( Serpine1 ) yog REV-ERB hom phiaj gene. thiab qhia txog koob tshuaj tiv thaiv ntawm kev qhia hauv cov lus teb rau SR9011.Cov roj cholesterol 7α-hydroxylase (Cyp7a1) thiab cov tshuaj sterol teb cov ntsiab lus khi cov protein (Srepf1) cov noob kuj tau pom tias yuav teb rau REV-ERB thiab cov koob tshuaj-dependently suppressed nrog nce. SR9011 ua.Tom qab 12 hnub hauv D:D cov kab mob nas tau txhaj tshuaj ib zaug ntawm SR9011 lossis lub tsheb ntawm CT6 (nce siab qhia ntawm Rev-erbα ).Kev txhaj tshuaj tsheb ua rau tsis muaj kev cuam tshuam hauv kev ua haujlwm circadian locomotor.Txawm li cas los xij, kev tswj hwm ntawm ib koob tshuaj ntawm SR9011 ua rau poob ntawm kev ua haujlwm hauv lub cev thaum lub sijhawm tsaus ntuj.Kev ua haujlwm ib txwm rov qab mus rau lub voj voog circadian tom ntej, ua raws li kev tshem tawm cov tshuaj hauv tsawg dua 24 teev.Lub SR9011-dependant txo qis hauv log khiav tus cwj pwm hauv cov nas nyob rau hauv qhov tsaus ntuj tas li yog nyob ntawm koob tshuaj thiab tias lub zog (ED 50 = 56 mg / kg) zoo ib yam li lub zog ntawm SR9011-mediated suppression ntawm REV-ERB teb cov noob. , Srebf1 , in vivo (ED 50 = 67mg/kg).
Post lub sij hawm: Dec-06-2022