Uphando olunzulu kwiindlela ze-cell senescence lukhokelele kuphuhliso lwe-FOXO4-DRI., ikhompawundi ye-senolytic eyaziwa ngokuba yi-IT-Inhibitor peptide. Le peptide ye-bioactive ibonisa iipropathi ezithembisayo zokuchasa ukuguga.
Kwiiseli zeseli, njengokuba, I-FOXO4 ibophelela kwi p53, ukwenza i-complex eyaziwa ngokuba yi-FOXO4-p53 aggregates. Olu bunzima lusebenza njenge-inhibitor ye i-apoptosis ulwaluko. Ngenxa yoko, olu nxibelelwano lwandisa ubomi be ukuvela kweselula kwaye ikhokelela ekuqokeleleni kwabo ngokuhamba kwexesha.
Ngokucacileyo, I-FOXO4-DRI ayijoli ngqo kwi-FOXO1, IFOXO3, okanye p53 iiproteni. Kunoko, isebenzisana ngokuthe ngqo ne-FOXO4 indawo yokubopha ngaphakathi kwendawo ye-FOXO4-p53. Olu nxibelelwano lukhuthaza ukuhlukana kobunzima, ikhutshwa p53, kwaye ngokwenza njalo ivule kwakhona i-apoptosis eyenziwe yi-p53, lonke ngelixa ugcina iiseli eziqhelekileyo kwiziphumo ebezingalindelekanga.
Iingxelo ezininzi zibonisa ukusebenza okunamandla kwe-FOXO4-DRI ekukhetheni ukubulala iiseli zenyama.. Ngaphaya koko, Uphononongo lubonisa ukuba i-FOXO4-DRI ibuyisela umva ukuhla komzimba okunxulumene nobudala: kwandisa ukunyamezela komzimba kunye nokusebenza kweemoto, ibuyisela ukusebenza kwezintso kunye nokukhula kweenwele, kwaye ngaloo ndlela ithoba isantya sokubola kwezicubu ezinxulumene neminyaka. Umzekelo, imifuziselo yempuku endala ibonisa ngokucacileyo ezi zibonelelo. Ukongeza, I-FOXO4-DRI iyancipha ukudumba okungapheliyo kunye nomonakalo wezicubu kwi-post-chemotherapy microenvironment, ngaloo ndlela kuphuculwe umgangatho wobomi kunye nokukhuthaza impilo yexesha elide kwizigulane ezinomhlaza.
Ulandelelwano
H-D-Leu-D-Thr-D-Leu-D-Arg-D-Lys-D-Glu-D-Pro-D-Ala-D-Ser-D-Glu-D-Ile-D- Ala-D-Gln-D-Ser-D-Ile-D-Leu-D-Glu-D-Ala-D-Tyr-D-Ser-D-Gln-D-Asn-D-Gly- D-Trp-D-Ala-D-Asn-D-Arg-D-Arg-D-Ser-D-Gly-D-Gly-D-Lys-D-Arg-D-Pro-D-Pr o-D-Pro-D-Arg-D-Arg-D-Arg-D-Gln-D-Arg-D-Arg-D-Lys-D-Lys-D-Arg-D-Gly-OH
Inombolo yeCAS
2460055-10-9
Ifomula yeemolekyuli
C228H388N86O64
Ubunzima beMolekyuli
5358.05
UPhando lweeNzuzo zeFoxo4-dri
1.Ukungeniswa okuKhethekileyo kwe Senescent Cell Apoptosis
Eyona ndlela iphambili ye-FOXO4-DRI ibandakanya uvuselelo oluthile lokufa kweeseli ezicwangcisiweyo kwiiseli zeseli.. Apha, I-p53 isebenza njenge-trans-activating factor for pro-apoptotic genenes, ukukhuthaza i-apoptosis. Nangona kunjalo, phantsi kweemeko eziqhelekileyo zomzimba, i-FOXO4-p53 i-complex icinezela lo msebenzi we-apoptotic.
Ngokukhuphisana ngokubophelela kwe-p53, I-FOXO4-DRI iphazamisa ukusebenzisana kwe-FOXO4-p53. Oku kuphazamiseka kuqalisa indlela ye-apoptosis yangaphakathi ngokukodwa kwiiseli ze-senescent.
Kwiimpuku ezindala, unyango nge-FOXO4-DRI ikhokelele ekukhuleni kwakhona kweenwele ngokuthelekiswa neempuku ezibudala buphakathi kunye nokusebenza kakuhle kweemoto.
2.Umgangatho woBomi kwiZigulana zoMhlaza
Abaphandi baphonononga i-FOXO4-DRI njengechiza elinokubakho le-adjuvant ukuphucula umgangatho wobomi bezigulane ezinomhlaza emva ichemotherapy. Ngelixa uninzi lweearhente ezichasene nomhlaza zichaphazela iiseli ithumba, nazo zibangela ukwenzakala okungangqalanga kwiiseli eziqhelekileyo, ukwandisa umthwalo wokuthomalalisa okubangelwa kunyango(I-TIS).
Uphononongo olubanzi luqinisekisa ukuba i-FOXO4-DRI inokuphelisa ngokufanelekileyo zombini iiseli zeseli ezizenzekelayo kunye nonyango., ukuvuselela ichemotherapy-induced frailty syndrome. Njengokuba, Uphononongo kwiSeli lubonise ukuchacha okuphuculweyo kunye nokuphila kwiimpuku ezinyangwe ngechemotherapy. Ezi ziphumo zibonisa amandla anamandla onyango lwe-adjuvant ye-FOXO4-DRI kwi-oncology..
3.Ukuphucula i-Pathology yeSifo sesibindi
Kwi NASH(I-steatohepatitis engeyiyo utywala) izigulane, iiseli zeseli ziqokelele esibindini kwaye zikhuphe iimolekyuli zepro-ukudumba kunye ne-pro-fibrotic ngokusebenzisa i-senescence-enxulumene ne-secretory phenotype (SASP), ukuqhuba ukuqhubela phambili kwesifo. Uphononongo olusebenzisa imodeli ye-NASH yemouse yafumanisa ukuba i-FOXO4-DRI yazicima ezi seli ze-hepatic senescent, ukucinezela imveliso ye-SASP kumthombo wayo.
4.Unyango lweempuku ngeBleomycin-Induced I-Pulmonary Fibrosis
I-FOXO4-DRI ibangela ukuba i-p53 ikhethe ukukhutshwa kwenyukliya kunye nokuchithwa kwe-FOXO4-p53 complex.. Kwiimodeli zempuku ezenziwe nge-bleomycin, unyango kunye FOXO4-DRI amanqanaba ehla Collagen, uhlobo I, alpha 1 (Kol1a1) kunye ne-α-SMA kwizicubu zemiphunga. Oku kuncitshiswa kuphakamisa ukwehla kwemveliso ye-matrix ye-extracellular kunye nokuthintela i-myofibroblast ukusebenza.
Nangona uphononongo aluzange lucacise ngokupheleleyo indlela echanekileyo yokusebenzisana kwe-FOXO4-DRI kunye ne-p53., ibonise ngokucacileyo inhibition esebenzayo ye-fibrosis, ukuqaqambisa isicwangciso sonyango esinokubakho kwi idiopathic pulmonary fibrosis (IPF).
5.Ukunciphisa Okunxulumene nobudala Hypogonadism (Ukunqongophala kweTestosterone)
I-hypogonadism yasemva kwexesha yamadoda kukungasebenzi kakuhle okunxulumene nokwaluphala okwenzakalisa iiseli zeLeydig ezisele zikhulile.. Ukucoca ezi seli zesescent kunokuvuselela umsebenzi wezicubu. Uphononongo lubonisa ukuba i-FOXO4-DRI isebenza ngokukodwa kwi-testicular yomntu Iiseli zeLeydig. Ukuyilawula kwiimpuku ezindala kwaphucula i-testicular microenvironment, ukuthintela ukunqongophala kwe testosterone yobudala. A 2021 Uphononongo luchaze ukonyuka okukhulu kumanqanaba e-serum testosterone kwiimpuku eziphathwayo.
Indlela ecetywayo ibandakanya ukucinezelwa okuthe ngqo kwe-p53 yendawo yenyukliya kunye nokuchithwa kwe-FOXO4-p53 complex., okukhokelela kwi-senescent-cell apoptosis. Ezi ziphumo zibonisa indlela yonyango enokubakho yokunyanga ukunciphisa i-testosterone ehambelana neminyaka.
I-COA
HPLC
NKSK
