SR9011iREV-ERBα/βMaAgonists, nhengo dzemhuri yenyukireya receptor, vakawanikwa vachigadzirisa metabolism yebiological tissues.Huang Guodong akawana kuti SR9011 inoita basa rakakosha mukudzora rhythm yezebrafish autophagy gene.
SR9011 mapuroteni emhuri anoshaya ligand binding domain paC-terminal, asi inogona kudzivisa kutaura kweRev erb protein nekutsvaga nuclear receptor inhibitor uye histone deacetylase 3. Histone deacetylase 3 is Rev erb agonist uye duku molecule kemikari probe.Fon taine et al.chekutanga, Chemicalbook yakashuma kuti SR9011 ine hukama nekuzvimba.SR9011 inogona kuvharidzira kutaura kweTr4, nekudaro ichidzora chiratidzo chekuzvimba.Nyanzvi dzekune dzimwe nyika dzakaona kuti mune macrophages evanhu, kuwedzera mRNA kutaura kweSR9011 nenzira dzemishonga zvinotungamirira zvakananga kukudzikira kwemRNA kutaura kweproinflammatory factor interleukin-6.
In vitro kudzidza:
SR9011 dose-inotsamira inowedzera REV-ERB-inotsamira repressor basa rakaongororwa muHEK293 masero anoratidza chimeric Gal4 DNA Binding Domain (DBD) - REV-ERB ligand binding domain (LBD)α or β uye Gal4-inopindura luciferase mutori wenhau (REV-ERBα IC 50 =790 nM, REV-ERBβ IC 50 =560 nM).SR9011 inodzvinyirira zvine simba uye zvine hunyanzvi kudzvanya kunyorwa mune cotransfection assay uchishandisa yakazara-kureba REV-ERBα pamwe chete nemutori wenhau we luciferase anotungamirirwa neBmal1 mutsigiri (SR9011 IC 50 = 620 nM).SR9011 inodzvanya kutaura kweBMAL1 mRNA mumaseru eHepG2 muREV-ERBα/β -inotsamira nzira SR9011 inodzvinyirira kuwanda kwekenza yemazamu maseru mitsara zvisinei neER kana HER2 chimiro.SR9011 inoita seinomira kutenderera kwesero rekenza yemazamu pamberi pechikamu cheM.Cyclin A (CCNA2) inoonekwa seyakananga gene yeREV-ERB inoratidza kuti kudzvinyirirwa kwekutaura kwecyclin iyi neSR9011 kunogona kuyananisira kusungwa kwesero.Kurapa neSR9011 kunoguma nekuwedzera kwemasero muG 0 / G 1 chikamu uye kuderera kwemasero muS uye G 2 / M chikamu chinoratidza kuti kushandiswa kweREV-ERB kunogona kukonzera kuderera kwekuchinja kubva kuG 1 kusvika kuS chikamu uye / kana kubva kuS kusvika kuG 2 /M chikamu.
In vivo kudzidza:
SR9011 inoratidzira kutaridzika kweplasma inonzwisisika, saka, kutaura kweREV-ERB magene anopindura anoongororwa muropa remakonzo akabatwa nemishonga yakasiyana-siyana yeSR9011 kwemazuva 6. The plasminogen activator inhibitor type 1 gene (Serpine1) inonzi REV-ERB chinangwa gene. uye inoratidza kudzvinyirirwa kwedosi-inotenderera yekutaura mukupindura SR9011.The cholesterol 7α-hydroxylase (Cyp7a1) uye sterol response element inosunga mapuroteni (Srepf1) majini akaratidzirwawo kuti anoteerera REV-ERB uye ane dose-inotsamira yakadzvinyirirwa nekuwedzera. huwandu hweSR9011.Mushure memazuva e12 muD: D mamiriro emakonzo akaiswa jekiseni rimwechete re SR9011 kana motokari paCT6 (peak expression of Rev-erbα).Jekiseni remotokari harikonzeri kukanganisa mune circadian locomotor chiitiko.Nekudaro, kutonga kweiyo imwe dosi yeSR9011 kunokonzeresa kurasikirwa kweiyo locomotor chiitiko panguva yechikamu cherima.Kuita kwakajairika kunodzosera kutenderera kunotevera kutenderera, kunoenderana nekubvumidzwa kwemishonga isingasviki 24h.Iyo SR9011-inotsamira kuderera kwekufamba kwevhiri hunhu mumakonzo pasi perima risingaperi mamiriro anoenderana nedosi uye kuti potency (ED 50 = 56 mg/kg) yakafanana neiyo potency yeSR9011-mediated kudzvinyirira yeREV-ERB inopindura gene. , Srebf1 , in vivo (ED 50 =67mg/kg).
Nguva yekutumira: Zvita-06-2022