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.
Txheej txheem cej luam
Kab lus no tshawb txog cov txheej txheem los ntawm cov hlwb senescent pab rau qhov pib thiab kev loj hlob ntawm Alzheimer's disease (AD). Alzheimer's tus kab mob yog ib yam kab mob neurodegenerative feem ntau cuam tshuam rau cov neeg laus, uas tshwm sim los ntawm kev paub tsis meej thiab kev coj cwj pwm tsis zoo. Raws li cov pej xeem thoob ntiaj teb muaj hnub nyoog, qhov xwm txheej ntawm AD txuas ntxiv nce txhua xyoo, ua rau muaj kev cuam tshuam loj rau tib neeg thiab tsev neeg. Txawm hais tias muaj kev vam meej tseem ceeb hauv kev tshawb fawb AD, qhov tseeb etiology thiab pathogenesis tseem tsis meej. Raws li ib qho ntawm cov kev pheej hmoo tseem ceeb rau AD, cellular senescence tau txais kev saib xyuas ntau ntxiv nyob rau xyoo tas los no rau nws lub luag haujlwm hauv cov kab mob ntawm AD. Kev sib sau ntawm cov hlwb senescent hauv lub cev yog cuam tshuam nrog qhov pib thiab kev loj hlob ntawm ntau yam kab mob uas muaj hnub nyoog. Senescent hlwb ua lub luag haujlwm tseem ceeb hauv cov txheej txheem pathological ntawm AD, thiab qhia lawv cov txheej txheem ntawm kev ua haujlwm yog qhov tseem ceeb rau kev tsim kho tshiab rau AD.
Daim duab 1. Alzheimer's kab mob pathogenic proteins pab rau lub hlwb cell senescence. (a) Txheej txheem cej luam ntawm kev sib cuam tshuam ntawm senescent hlwb hlwb nrog amyloid plaques thiab pathogenic tau. (b-e) Cov ncauj lus kom ntxaws ntawm txhua yam xov tooj ntawm tes thiab cov yam ntxwv cuam tshuam nrog senescence tau tshaj tawm hauv cov ntaub ntawv: (b) neuron, (c) microglia, (d) oligodendrocyte / oligodendrocyte precursor cell, (e) astrocyte, thiab (f) ntshav-hlwb barrier (BBB) featuring cell, pericocytes thiab endothelytes cuam tshuam BBB kev ncaj ncees hauv AD.
Txheej txheem cej luam ntawm Senescent Cells
(1) Kev txhais thiab yam ntxwv ntawm Senescent Cells
Senescence yog hais txog qhov kev loj hlob tsis tuaj yeem raug ntes ntawm cov hlwb tom qab tau txais qee qhov kev faib tawm lossis raug cuam tshuam rau ntau yam kev ntxhov siab (xws li oxidative stress, DNA puas, telomere shortening, thiab lwm yam). Senescent hlwb nthuav tawm cov yam ntxwv phenotypic tshwj xeeb, suav nrog kev ntim ntawm tes, flattening, thiab nce β-galactosidase (β-gal) kev ua, uas yog ib qho kev siv tshuaj lom neeg los txheeb xyuas cov hlwb. Tsis tas li ntawd, senescent hlwb nthuav tawm kev tswj hwm ntawm cyclin-dependent kinase inhibitors (xws li p16INK4a thiab p21Cip1), uas inhibit cell cycle, ua rau cov hlwb raug ntes nyob rau theem G1 lossis G2 / M theem thiab yog li tiv thaiv kev faib tawm ntxiv.
Mechanisms ntawm Senescent Cell Tsim
1. Oxidative Stress thiab DNA puas: Oxidative stress yog ib qho tseem ceeb inducer ntawm cellular senescence. Raws li ib txwm muaj lub cev muaj zog, kev tsim khoom thiab tshem tawm ntawm cov pa oxygen reactive (ROS) hauv cov hlwb yog nyob rau hauv dynamic equilibrium. Txawm li cas los xij, nrog kev laus lossis nyob rau hauv qee yam kab mob pathological, nce ROS ntau lawm ua rau DNA puas. Thaum DNA kev puas tsuaj sib sau ua ke rau qee qhov thiab tsis tuaj yeem kho tau zoo, cov txheej txheem ntawm kev teeb tsa tau qhib, xws li p53-p21 thiab p16-Rb cov kev taw qhia txoj hauv kev, ua rau cov hlwb nkag mus rau hauv lub xeev senescent. Nyob rau hauv cov ntaub so ntswg ntawm lub hlwb los ntawm cov neeg mob Alzheimer's kab mob, oxidative kev nyuaj siab yog ho nce, ua rau kom DNA puas nyob rau hauv neurons thiab glial hlwb, uas nyob rau hauv lem induces cellular senescence.
2. Telomere shortening: Telomeres yog cov DNA rov ua ntu zus ntawm qhov kawg ntawm chromosomes uas maj mam luv nrog kev faib cell. Thaum telomeres luv luv mus rau ib qho ntev, lawv ua rau cov cim tsis pom kev. Nyob rau hauv neural qia hlwb, telomere shortening yog ze ze rau qhov pib ntawm senescence, uas yuav cuam tshuam tus kheej-renewal thiab txawv peev xwm ntawm neural qia hlwb, yog li cuam tshuam rau kev loj hlob thiab kev ua haujlwm ntawm lub paj hlwb.
Mechanism of Action of Senescent Cells nyob rau hauv Alzheimer's Disease
(1) Induction ntawm Neuroinflamation
1. Lub luag hauj lwm ntawm Senescence-Associated Secretory Phenotype (SASP): Senescent hlwb nthuav tawm ib qho tshwj xeeb secretory phenotype hu ua senescence-associated secretory phenotype (SASP). SASP muaj ntau yam cytokines, chemokines, kev loj hlob yam, thiab proteases, xws li interleukin-6 (IL-6), interleukin-8 (IL-8), thiab qog necrosis factor-α (TNF-α). Nyob rau hauv cov ntaub so ntswg ntawm lub hlwb ntawm cov neeg mob Alzheimer's kab mob, senescent glial hlwb thiab neurons secrete loj npaum li cas ntawm SASP yam, uas muaj peev xwm activates ib ncig ntawm lub cev tiv thaiv kab mob thiab ua rau mob inflammatory teb. IL-6 thiab TNF-α txhawb kev ua kom microglia, ua rau lawv hloov pauv los ntawm lub xeev quiescent mus rau lub xeev pro-inflammatory, tso tawm cov neeg kho mob ntau dua thiab ua rau muaj kev mob hnyav ntxiv. Qhov chaw mob ntev ntev no ua rau cov neurons puas, ua rau muaj kev ua haujlwm tsis zoo, thiab ua rau kev paub tsis meej.
2. Cov teebmeem ntawm glial hlwb: Kev laus ntawm astrocytes thiab microglia plays lub luag haujlwm tseem ceeb hauv AD neuroinflammation. Kev laus astrocytes secrete SASP yam uas txhawb kev sib sau thiab tso tawm ntawm β-amyloid (Aβ) thaum inhibiting nws clearance. Kev laus ntawm microglia txo lawv lub peev xwm rau phagocytose Aβ, tiv thaiv kev tshem tawm ntawm Aβ plaques hauv lub hlwb. Hloov chaw, lawv tso tawm ntau yam mob, tsim kom muaj lub voj voog tsis zoo uas ua rau mob ntshav qab zib ntau ntxiv thiab neurodegeneration.
Daim duab 2 Cov cim ntawm cellular senescence yog nce nyob rau hauv lub hlwb ntawm hTau nas modeling tauopathy ntawm AD.
(2) Kev txhawb nqa ntawm Neurodegeneration
1. Kev puas tsuaj ncaj qha rau cov neurons: Qee cov cytokines thiab proteases secreted los ntawm senescent hlwb tuaj yeem ua rau cov neurons ncaj qha. Matrix metalloproteinases (MMPs) yog ib qho ntawm cov khoom ntawm senescence-associated secretome (SASP), uas tuaj yeem degrade lub extracellular matrix thiab neurotransmitter-related proteins, cuam tshuam cov qauv thiab kev ua haujlwm ntawm neurons. ROS tsim los ntawm senescent hlwb kuj tuaj yeem ua rau oxidative puas tsuaj rau cov neurons, ua rau neuronal apoptosis thiab tuag. Hauv cov ntaub so ntswg ntawm cov neeg mob AD, neuronal senescence yog ze ze nrog kev tuag ntawm tes, uas tej zaum yuav yog ib qho tseem ceeb uas ua rau kev paub tsis meej.
2. Kev cuam tshuam nrog Neurotransmitter Transmitter: Lub xub ntiag ntawm cov hlwb senescent kuj tuaj yeem cuam tshuam cov synthesis, tso tawm, thiab xa cov neurotransmitters. Cov kab mob ua paug tuaj yeem cuam tshuam cov synthesis ntawm acetylcholine, neurotransmitter tseem ceeb rau kev tswj hwm kev paub txog kev ua haujlwm. Tsis tas li ntawd, qee yam tseem ceeb zais los ntawm cov hlwb senescent tuaj yeem cuam tshuam rau kev qhia thiab kev ua haujlwm ntawm neurotransmitter receptors, ua rau muaj qhov txawv txav neurotransmitter signaling, ntxiv kev cuam tshuam kev sib txuas lus thiab cov ntaub ntawv ua haujlwm ntawm neurons, thiab yog li ua rau muaj kev xav tsis zoo.
(3) Kev hloov pauv hauv kev sib txuas lus sib txuas
1. Cov Teeb Meem Tsis Zoo Paracrine: Cov hlwb senescent sib txuas lus nrog cov hlwb nyob ib puag ncig los ntawm kev qhia paracrine los ntawm kev zais SASP yam. Cov xwm txheej no tuaj yeem cuam tshuam rau kev ua haujlwm thiab txoj hmoo ntawm cov hlwb nyob sib ze, ua rau muaj kev cuam tshuam ntawm kev sib txuas lus hauv lub cev. Nyob rau hauv lub hlwb cov ntaub so ntswg ntawm cov neeg mob AD, SASP yam secreted los ntawm senescent glial hlwb tuaj yeem cuam tshuam kev loj hlob ntawm neuronal, ciaj sia taus, thiab sib txawv, thaum tseem cuam tshuam rau microenvironment ntawm neural qia hlwb, inhibiting lawv proliferation thiab sib txawv, yog li cuam tshuam rau neural regeneration thiab kho cov txheej txheem.
2.Kev cuam tshuam ntawm kev sib txuas ntawm intercellular: Cov hlwb senescent kuj tuaj yeem cuam tshuam cov qauv kev sib txuas ntawm cov cell, xws li cov junctions nruj thiab qhov sib txawv. Nyob rau hauv cov ntshav-hlwb barrier, senescence ntawm endothelial hlwb ua rau txo cov kev qhia ntawm nruj junction proteins, ua rau cov permeability ntawm cov ntshav-hlwb barrier thiab tso cai rau cov teeb meem tshuaj mus rau hauv lub hlwb yooj yim dua, exacerbating neuroinflammation thiab neurodegeneration. Gap junctions ntawm neurons yog qhov tseem ceeb rau kev xa xov hluav taws xob thiab kev sib koom ua ke ntawm cov neurons. Cov ntsiab lus zais cia los ntawm cov hlwb senescent tuaj yeem cuam tshuam kev ua haujlwm ntawm qhov sib txawv ntawm qhov sib txawv, cuam tshuam rau kev ua haujlwm synchronized thiab cov ntaub ntawv xa mus ntawm cov neurons.
(4) Kev cuam tshuam rau microenvironment ntawm neural qia hlwb
1. Inhibition of neural stem cell proliferation and differentiation: Neural stem cells muaj nyob rau hauv lub hlwb ntawm cov tsiaj nyeg laus thiab muaj peev xwm ua rau nws tus kheej tshiab thiab sib txawv rau hauv cov neurons, astrocytes, thiab oligodendrocytes. SASP yam secreted los ntawm senescent hlwb yuav hloov lub microenvironment ntawm neural qia hlwb, inhibiting lawv proliferation thiab sib txawv. Qee cov cytokines hauv SASP tuaj yeem txhim kho qhov kev qhia ntawm cyclin-dependent kinase inhibitors, ua rau cov kab mob neural qia hlwb raug ntes ntawm qee theem ntawm lub voj voog ntawm tes thiab tsis tuaj yeem ua raws li kev faib thiab sib txawv. Inflammatory yam secreted los ntawm senescent hlwb kuj yuav cuam tshuam qhov sib txawv ntawm cov neural qia hlwb, ua rau lawv sib txawv ntau rau hauv glial hlwb es tsis yog neurons, yog li cuam tshuam rau neural regeneration thiab kho.
2. Kev cuam tshuam rau neural stem cell migration: Neural stem cell migration yog ib qho tseem ceeb rau lawv qhov chaw zoo thiab kev ua haujlwm hauv lub hlwb. Qee yam uas zais los ntawm cov hlwb senescent tuaj yeem cuam tshuam nrog neural qia cell tsiv teb tsaws, tiv thaiv lawv los ntawm kev tsiv mus rau thaj chaw uas yuav tsum tau kho. Kev qhia txawv txav ntawm chemokines tuaj yeem hloov pauv kev tsiv teb tsaws ntawm neural qia hlwb, tiv thaiv lawv los ntawm kev mus txog qhov chaw ntawm kev raug mob rau kev kho, yog li ua rau lub paj hlwb tsis muaj peev xwm kho tus kheej.
Cov tswv yim kho mob Alzheimer's cov tswv yim tsom rau cov hlwb senescent
(1) Senolytics
1. Mechanism ntawm kev txiav txim: Senolytics yog ib chav kawm ntawm cov tebchaw uas tuaj yeem xaiv tshem tawm cov hlwb senescent. Lawv cov txheej txheem ntawm kev ua haujlwm feem ntau suav nrog inducing senescent cell apoptosis thiab inhibiting senescent cell anti-apoptotic signaling pathways. Dasatinib thiab quercetin tam sim no yog cov kev tshawb fawb tshaj plaws ntawm kev sib txuas ntawm senolytics. Dasatinib tuaj yeem cuam tshuam lub overactivated kinase signaling txoj hauv kev hauv cov hlwb senescent, thaum quercetin txhim kho cov teebmeem ntawm dasatinib. Thaum siv ua ke, lawv tuaj yeem xaiv ua kom apoptosis hauv cov hlwb senescent thiab txo lawv cov tsub zuj zuj hauv lub cev.
2.Kev nce qib hauv kev sim tsiaj thiab kev tshawb fawb soj ntsuam: Hauv kev sim tsiaj, kev kho mob ntawm AD qauv nas nrog cov tshuaj tua kab mob senescent cell clearance txo tus naj npawb ntawm cov hlwb hauv lub hlwb, txo qis neuroinflammation theem, thiab txhim kho kev txawj ntse. Cov kev tshawb fawb pom tias tom qab siv dasatinib thiab quercetin kev sib xyaw ua ke rau AD qauv nas, tus nqi ntawm Aβ plaques hauv lub hlwb tau txo qis, kev puas tsuaj ntawm neuronal raug txo, thiab kev kawm spatial thiab kev nco muaj peev xwm txhim kho.
Daim duab 3 Cellular senescence ua ib feem ntawm kev noj qab haus huv kev laus thiab AD.
(2) Senescence-associated secretory phenotype modulators (Senomorphic)
1. Mechanism of action: Senomorphis aims tswj lub secretion ntawm SASP yam los ntawm senescent hlwb, txo lawv cov teeb meem tshwm sim nyob ib ncig ntawm lub hlwb. Qee cov tshuaj tiv thaiv kab mob tuaj yeem cuam tshuam qhov kev qhia thiab tso tawm ntawm cov kab mob inflammatory hauv SASP, alleviating neuroinflammation. Qee qhov me me-molecule tebchaw tuaj yeem tswj cov txheej txheem metabolic ntawm cov hlwb senescent, hloov cov SASP kom tsis muaj zog rau nws cov kev puas tsuaj rau cov hlwb nyob ib puag ncig.
2.Potential Application Prospects: Qhov kom zoo dua ntawm senescence-associated secretory phenotype modulators nyob rau hauv lawv lub peev xwm los txhim kho cov ntaub so ntswg microenvironment los ntawm regulating lub secretory muaj nuj nqi ntawm senescent hlwb es tsis ncaj qha tshem tawm lawv. Qhov no yuav zam tau qee qhov kev pheej hmoo cuam tshuam nrog cov tshuaj tua kab mob senescent cell clearance, xws li tsis muaj kev puas tsuaj rau cov hlwb ib txwm. Yog li ntawd, senescence-associated secretory phenotype modulators tuav dav daim ntawv thov kev cia siab thiab tej zaum yuav tshwm sim raws li ib tug tshiab kho tswv yim rau AD.
Xaus
Senescent hlwb ua si ntau lub luag haujlwm hauv qhov pib thiab kev loj hlob ntawm Alzheimer's disease. Los ntawm cov txheej txheem xws li inducing neuroinflammation, txhawb neurodegeneration, hloov intercellular kev sib txuas lus, thiab influencing microenvironment ntawm neural qia hlwb, senescent hlwb exacerbate cov txheej txheem pathological ntawm AD. Cov tswv yim kho mob tsom rau cov hlwb senescent, xws li kev txhim kho senescent cell clearance agents thiab senescence-associated secretory phenotype modulators, muab cov kev xaiv tshiab rau kev kho mob ntawm AD.
Qhov chaw
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