Los ntawm Cocer Peptides 
1 month ago
Tag nrho cov kab lus thiab cov ntaub ntawv ntawm cov khoom lag luam muab rau ntawm lub vev xaib no tsuas yog rau cov ntaub ntawv tshaj tawm kev tshaj tawm thiab cov hom phiaj kev kawm.
Cov khoom muab rau hauv lub vev xaib no yog npaj tshwj xeeb rau kev tshawb fawb hauv vitro. Kev tshawb fawb hauv vitro (Latin: * hauv iav *, lub ntsiab lus hauv iav) yog ua los ntawm tib neeg lub cev. Cov khoom no tsis yog tshuaj, tsis tau txais kev pom zoo los ntawm US Food and Drug Administration (FDA), thiab yuav tsum tsis txhob siv los tiv thaiv, kho, lossis kho txhua yam mob, kab mob, lossis mob. Nws raug txwv nruj raws li txoj cai los qhia cov khoom no rau hauv tib neeg lossis tsiaj lub cev hauv txhua daim ntawv.
Kev laus, raws li cov txheej txheem ntuj tsim tsis tau hauv cov kab mob uas muaj sia nyob, tau ntev ua qhov tseem ceeb ntawm kev tshawb fawb tshawb fawb. Raws li cov kab mob muaj hnub nyoog, cov hlwb maj mam nkag mus rau hauv lub xeev senescent, thiab cov pob txha ntawm cov hlwb no tuaj yeem cuam tshuam tsis zoo rau kev ua haujlwm ntawm cov ntaub so ntswg thiab cov kabmob, ua rau muaj ntau yam kabmob ntsig txog hnub nyoog. FOX04 - DRI muaj txiaj ntsig zoo rau tshem tawm cov hlwb senescent.
Txheej txheem cej luam ntawm FOX04 - DRI
FOX04 - DRI yog ib qho hluavtaws peptide, nrog rau lub npe tag nrho lub taub hau lub thawv O transcription factor 4 - D - Retro - Inverso. Nws qhov kev tshawb pom tshwm sim los ntawm kev tshawb fawb tob rau hauv cov txheej txheem tswj hwm ntawm cov hlwb senescent. Thaum lub sij hawm cellular senescence, ntau yam molecular mechanisms koom nrog, thiab FOX04 transcription factor plays lub luag hauj lwm tseem ceeb hauv cov txheej txheem no. FOX04 nthuav tawm cov qauv qhia tshwj xeeb thiab kev hloov pauv hauv cov hlwb senescent. Los ntawm elucidating nws cov txheej txheem ntawm kev nqis tes ua, cov kws tshawb fawb tau tsim thiab tsim cov FOX04-DRI los tshwj xeeb rau cov hlwb senescent, aiming los daws teeb meem txog hnub nyoog.
Daim duab 1 Schematic illustration ntawm kev tshem tawm cov luam yeeb-induced senescent ntsws fibroblasts siv FOXO4 siRNA-loaded DNA nanoparticles.
Mechanism ntawm FOX04-DRI nyob rau hauv clearing senescent hlwb
Kev cuam tshuam nrog FOX04-p53 kev cuam tshuam: Hauv cov hlwb senescent, FOX04 cuam tshuam nrog cov protein p53. Cov p53 protein ua lub luag haujlwm tseem ceeb hauv cov lus teb ntawm kev ntxhov siab ntawm tes, kev tswj xyuas lub voj voog ntawm tes, thiab apoptosis. Raws li ib txwm muaj, p53 txhawb nqa apoptosis hauv cov hlwb puas lossis tsis hnov tsw los ntawm kev ua kom muaj kev nthuav qhia ntawm cov noob caj noob ces ntawm apoptosis, yog li tswj kev noj qab haus huv ntawm cov neeg ntawm tes. Nyob rau hauv senescent hlwb, FOX04 khi rau p53, inhibiting nws thauj mus rau lub cell nucleus, tiv thaiv p53 los ntawm kev ua nws pro-apoptotic muaj nuj nqi, uas ua rau muaj sia nyob thiab tsub zuj zuj ntawm senescent hlwb. FOX04-DRI tuaj yeem cuam tshuam tshwj xeeb rau qhov kev sib cuam tshuam ntawm FOX04 thiab p53, thaiv lawv txoj hlua khi, tso cai rau p53 rov nkag mus rau hauv lub cell nucleus, qhib lub apoptosis signaling txoj kev, thiab induce apoptosis nyob rau hauv lub hlwb senescent, yog li ua tiav cov clearance ntawm senescent hlwb.
Kev tswj hwm txoj hauv kev hauv lub cev: Ntxiv rau kev cuam tshuam nrog FOX04-p53 kev sib cuam tshuam, FOX04-DRI kuj tseem tuaj yeem cuam tshuam txoj hmoo ntawm cov hlwb senescent los ntawm kev tswj hwm lwm txoj hauv kev hauv lub cev. PI3K / AKT teeb liab txoj hauv kev ua lub luag haujlwm tseem ceeb hauv ntau yam ntawm kev loj hlob ntawm tes, kev loj hlob, kev ciaj sia, thiab cov metabolism. Cov kev tshawb fawb tau pom tias kev ua haujlwm ntawm PI3K / AKT signaling pathway feem ntau hloov pauv hauv cov hlwb senescent, cuam tshuam rau lawv cov haujlwm ib txwm muaj. FOX04-DRI tuaj yeem tswj hwm kev ua haujlwm ntawm PI3K / AKT teeb liab txoj hauv kev, hloov qhov sib npaug ntawm cov teeb liab hloov mus rau hauv cov hlwb senescent, yog li tsim kom muaj qhov tsis zoo ntawm qhov chaw nyob hauv lub cev rau lawv txoj sia nyob thiab ua rau apoptosis. Txoj cai ntawm txoj kev taw qhia no tseem tuaj yeem cuam tshuam cov cellular metabolic xeev, txuas ntxiv tsav cov hlwb mus rau apoptosis.
Kev cuam tshuam ntawm Senescence-Associated Secretory Phenotype (SASP): Senescent cells secrete a series of cytokines, chemokines, and proteases, forming the senescence-associated secretory phenotype (SASP). SASP tsis tsuas yog cuam tshuam tsis zoo rau ib puag ncig cov hlwb, cuam tshuam lawv cov haujlwm ib txwm muaj, tab sis kuj ua rau cov lus teb mob ntev, ntxiv rau kev ua kom cov txheej txheem laus ntawm cov ntaub so ntswg thiab lub cev. FOX04-DRI tuaj yeem txo cov teebmeem tsis zoo ntawm cov hlwb senescent ntawm ib puag ncig microenvironment los ntawm inhibiting kev qhia thiab tso tawm ntawm SASP-txog yam cuam tshuam hauv cov hlwb senescent. Hauv txoj kev tshawb no, nws tau pom tias tom qab kho cov hlwb senescent nrog FOX04-DRI, kev qhia theem ntawm SASP-txog yam xws li IL-1α, IL-1β, qog necrosis factor α (TNFα), thiab MMP2 hauv senescent hlwb tau txo qis. Qhov no qhia tau hais tias FOX04-DRI tuaj yeem tswj hwm SASP ntawm cov hlwb senescent, txhim kho cov cellular microenvironment, thiab txhawb kev tshem tawm ntawm cov hlwb senescent thiab rov qab los ntawm cov ntaub so ntswg microenvironment.
Lub luag haujlwm ntawm FOX04-DRI hauv cov nqaij sib txawv thiab kab mob
Lub luag hauj lwm nyob rau hauv Reproductive System: Txiv neej lig-pib hypogonadism yog ib qho kab mob uas muaj hnub nyoog uas nws cov txheej txheem tseem ceeb yog kev ua haujlwm tsis zoo ntawm cov hnub nyoog testicular interstitial hlwb. FOX04 yog tshwj xeeb tshaj yog qhia nyob rau hauv tib neeg testicular interstitial hlwb, thiab nyob rau hauv cov neeg laus, lub nuclear translocation ntawm FOX04 yog txuam nrog txo testosterone synthesis. Siv hydrogen peroxide-induced hnub nyoog TM3 testicular interstitial hlwb raws li ib tug qauv nyob rau hauv vitro, nws tau pom tias FOX04 tuaj yeem tswj tau qhov kev muaj peev xwm ntawm cov hnub nyoog testicular interstitial hlwb thiab inhibit lawv apoptosis. FOX04-DRI xaiv induces p53 nuclear export thiab apoptosis ntawm cov laus testicular interstitial hlwb los ntawm kev cuam tshuam FOX04-p53 kev cuam tshuam. Hauv cov qauv nas laus laus, kev tswj hwm ntawm FOX04-DRI tau txhim kho cov qog nqaij hlav microenvironment thiab txo qis hnub nyoog txog testosterone secretion deficiency. Yog li, FOX04-DRI tej zaum yuav muaj txiaj ntsig zoo rau kev kho tus txiv neej lig-pib hypogonadism.
Daim duab 2 Kev nthuav qhia ntawm FOXO4 nyob rau hauv tib neeg cov tshuaj ntsuam xyuas los ntawm immunofluorescent staining.
Lub luag haujlwm hauv kev ua pa
Pulmonary fibrosis: Pulmonary fibrosis (PF) yog ib hom kab mob ntsws interstitial. Nws qhov xwm txheej thiab kev nthuav dav nce ntxiv nrog lub hnub nyoog, thiab cellular senescence yog suav tias yog ib qho tseem ceeb ntawm kev tsav tsheb hauv nws cov kab mob. Hauv bleomycin (BLM)-induced PF nas qauv, FOX04-DRI tau pom cov teebmeem zoo ib yam li cov tshuaj pom zoo pirfenidone. Nws txo cov naj npawb ntawm cov hlwb senescent, downregulates qhov kev qhia ntawm senescence-associated secretory phenotype (SASP), thiab alleviates BLM-induced morphological hloov thiab collagen deposition nyob rau hauv lub ntsws cov ntaub so ntswg. Tsis tas li ntawd, FOX04-DRI nce qhov feem ntawm hom 2 alveolar epithelial hlwb (AEC2) thiab fibroblasts thaum txo cov myofibroblasts. Hauv vitro thwmsim pom tau tias piv rau nas thiab tib neeg lub ntsws fibroblast cell kab, FOX04-DRI tau ntau inclined mus tua transforming loj hlob factor-β (TGF-β)-induced myofibroblasts, thiab los ntawm inhibiting myofibroblasts, nws coj mus rau lub downregulation ntawm extracellular matrix (ECM) receptor kev sib cuam tshuam ntawm BLM.
Mob ntsws obstructive pulmonary disease (COPD): Lub pathogenesis thiab kev loj hlob ntawm COPD yog ze ze nrog cellular senescence. Hauv kev haus luam yeeb haus luam yeeb-tsim senescent pulmonary fibroblasts, FOX04 qhia tau siab. Txhawm rau knockdown FOX04 hauv senescent fibroblasts, nws tus kheej-assembling DNA nanotubes (siFOXO4-NT) loaded nrog ib leeg-stranded FOX04 siRNA tau tsim thiab ua ke. Cov kev tshawb fawb tau pom tias siFOXO4-NT tuaj yeem nkag mus rau tib neeg lub ntsws fibroblasts (HFL-1 hlwb) nyob rau hauv qhov concentration- thiab nyob ntawm lub sijhawm, yog li txo qis FOX04 qib hauv vitro. siFOXO4-NT xaiv tshem tawm hnub nyoog HFL-1 hlwb los ntawm kev txo qis BCLXL qhia thiab BCL2 / BAX piv hauv cov pa luam yeeb rho tawm (CSE)-induced aged HFL-1 hlwb.
Lub luag haujlwm hauv cov pob txha mos: Autologous chondrocyte implantation (ACI) yog ib txoj hauv kev kho pob txha pob txha pob txha thiab tiv thaiv kev mob osteoarthritis tom qab. Thaum lub sij hawm nyob rau hauv vitro nthuav dav ntawm chondrocytes, ib kauj ruam tsim nyog hauv ACI, senescent hlwb raug tsim, uas cuam tshuam qhov zoo thiab ntau ntawm cov pob txha mos tshiab. Cov kws tshawb fawb tau xav tias FOX04-DRI kev kho mob tuaj yeem tshem tawm cov hlwb los ntawm kev nthuav dav chondrocytes, yog li txhim kho lawv lub peev xwm los tsim cov pob txha mos zoo. Txhawm rau simulate cov txheej txheem hauv vitro nthuav dav hauv ACI, chondrocytes cais los ntawm cov neeg noj qab haus huv tau nthuav dav rau cov pej xeem ob npaug ntawm qib (PDL) 9, sawv cev rau chondrocytes npaj rau cog, thaum lub hlwb ntawm PDL3 tau txais kev tswj xyuas tsawg kawg nkaus. Cov txiaj ntsig tau pom tias FOX04-DRI kev kho mob tshem tawm ntau dua ib nrab ntawm cov hlwb ntawm PDL9 tab sis tsis muaj qhov cuam tshuam loj rau cov naj npawb ntawm PDL3 chondrocytes. Qib senescence ntawm PDL9 chondrocytes kho nrog FOX04-DRI tau txo qis. Raws li cov txiaj ntsig ntawm micro-cluster kab lis kev cai, FOX04-DRI pretreatment tsis txhim kho lub peev xwm chondrogenic ntawm PDL9 chondrocytes, tab sis cov ntaub so ntswg chondroid tau los ntawm FOX04-DRI-pretreated PDL9 hlwb nthuav tawm qis dua ntawm kev laus-koom nrog secretory yam tseem ceeb. FOX04-DRI zoo tshem tawm cov hlwb los ntawm PDL9 chondrocytes.
Lub luag hauj lwm hauv hluav taws xob-induced pulmonary fibrosis (RIPF): RIPF yog ib qho teeb meem tshwm sim thiab hnyav tom qab phais mob qog noj ntshav. C57BL / 6 nas tau muab faib ua irradiation thiab irradiation + FOX04-DRI pawg, nrog rau txoj cai hemithorax ntawm txhua pawg tau txais 17 Gy X-ray irradiation. FOX04-DRI pab pawg thiab irradiation + FOX04-DRI pab pawg nas tau tswj hwm FOX04-DRI ntawm kev txhaj tshuaj intraperitoneal ntawm lub lis piam 16 thiab 20 tom qab irradiation. Cov txiaj ntsig tau pom tias FOX04-DRI txo qis collagen deposition nyob rau hauv lub ntsws cov ntaub so ntswg ntawm RIPF nas, txo cov kev qhia ntawm col1α1 thiab α-SMA, thiab txo tus naj npawb ntawm β-galactosidase (β-gal) zoo hlwb (ib tug cim ntawm senescent hlwb) nyob rau hauv lub ntsws cov ntaub so ntswg. FOX04-DRI muaj peev xwm inhibit qhov kev qhia ntawm P21 thiab P16 ^ (Ink4a) noob thiab cov proteins nyob rau hauv lub ntsws cov ntaub so ntswg ntawm RIPF nas, nrog rau cov kev qhia ntawm SASP noob IL-1α, IL-1β, qog necrosis factor α (TNFα), thiab MMP2. FOX04-DRI kuj tseem txo qis cov pa oxygen reactive (ROS) qib hauv lub ntsws cov ntaub so ntswg ntawm RIPF nas thiab txhawb kev ua kom p-AKT thiab p-PI3K proteins. Qhov no qhia tias FOX04-DRI txo oxidative kev nyuaj siab thiab inhibits cellular senescence los ntawm activating PI3K / AKT signaling txoj kev, yog li thim rov qab RIPF.
Daim duab 3 FOXO4-DRI alleviates myofibroblast differentiation in BLM-induced PF nas.
Xaus
Nyob rau hauv cov ntsiab lus, FOX04-DRI, raws li ib tug revolutionary tshuaj muaj peev xwm ntawm tshwj xeeb tshem tawm senescent hlwb, plays ib tug tseem ceeb luag hauj lwm nyob rau hauv kev kho mob ntawm lub hnub nyoog kab mob thiab kev laus kev cuam tshuam.
Qhov chaw
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[2] Han X, Yuan T, Zhang J, et al. FOXO4 peptide tsom rau myofibroblast ameliorates bleomycin-induced pulmonary fibrosis hauv nas los ntawm ECM-receptor kev sib cuam tshuam [J]. Phau ntawv Journal of Cellular and Molecular Medicine, 2022,26(11):3269-3280.DOI:10.1111/jcm.17333.
[3] Huang Y, He Y, Makarcyzk MJ, et al. Senolytic Peptide FOXO4-DRI Selectively tshem tawm Senescent Cells Los ntawm hauv vitro Expanded Human Chondrocytes[J]. Frontiers in Bioengineering thiab Biotechnology, 2021,9:677576.DOI:10.3389/fbioe.2021.677576.
[4] Zhang C, Xie Y, Chen H, et al. FOXO4-DRI alleviates lub hnub nyoog hais txog testosterone secretion insufficiency los ntawm lub hom phiaj senescent Leydig hlwb nyob rau hauv cov laus nas [J]. Aging (Albany Ny), 2020,12(2):1272-1284.DOI:10.18632/aging.102682.
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Cov khoom muaj rau kev tshawb fawb siv nkaus xwb:
