Ionizing Radiation-Induced Brain Cell Aging And The Potential Underlying Molecular Mechanisms Part 4
Apr 23, 2024
3.5. Kev mob
Inflammation yog ib qho kev tiv thaiv hauv lub cev. Kev mob ntev yog txuas mus rau qhov pib thiab / lossis kev loj hlob ntawm ntau yam kab mob, xws li cov hnub nyoog ntsig txog qhov mob thiab cov kab mob neurodegenerative [177,178].
Kev mob yog lub cev lub ntuj teb los tua cov kab mob thiab kev raug mob, tab sis kev mob ntev ntev tuaj yeem cuam tshuam kev noj qab haus huv. Nws feem ntau ntseeg tias qhov mob tsuas yog cuam tshuam nrog kev mob lub cev, tab sis kev tshawb fawb tsis ntev los no tau pom tias qhov mob kuj tseem cuam tshuam rau tib neeg kev nco.
Ntau cov kev tshawb fawb tau pom tias mob o ua rau muaj kev cuam tshuam loj rau lub hlwb, ua rau cov neuron tuag, lub paj hlwb puas tsuaj, thiab cov synaptic poob. Thiab cov no yog txhua yam cuam tshuam nrog kev nco poob thiab kev paub tsis meej. Yog li ntawd, tib neeg yuav tsum tau them sai sai rau kev tswj lub cev lub cev inflammatory teb los txhim kho lawv lub cim xeeb thiab kev txawj ntse.
Kev sib raug zoo ntawm kev mob thiab kev nco tuaj yeem txheeb xyuas los ntawm ntau yam. Ua ntej, o ua rau tuag ntawm neurons, uas cuam tshuam rau kev tsim thiab khaws cia ntawm kev nco. Qhov thib ob, qhov mob tuaj yeem ua rau txo qis ntawm synapses, yog li txo qis kev muaj peev xwm kis tau thiab tau txais kev nco. Thib peb, o cuam tshuam rau neurogenesis thiab shaping txheej txheem hauv cov neeg laus, yog li cuam tshuam rau tag nrho lub hlwb kev ua haujlwm thiab kev txawj ntse.
Txhawm rau kom tsis txhob muaj qhov tshwm sim ntawm qhov mob ntev, peb tuaj yeem siv qee yam kev ntsuas zoo. Ua ntej, tswj lub neej noj qab haus huv, suav nrog kev noj zaub mov kom zoo, pw tsaug zog txaus, thiab kev tawm dag zog ib nrab. Tsis tas li ntawd, zam kev haus luam yeeb thiab haus cawv, vim tias cov tshuaj no tuaj yeem ua rau muaj kev mob tshwm sim hauv lub cev. Thaum kawg, peb tseem tuaj yeem xaiv qee yam khoom noj thiab tshuaj ntsuab uas muaj cov tshuaj tiv thaiv kab mob, xws li ntses roj, turmeric, noob hnav, thiab lwm yam, los pab peb tswj cov kab mob inflammatory.
Feem ntau, o yog ze ze rau tib neeg kev nco thiab kev txawj ntse. Peb yuav tsum paub txog cov kev phom sij ntawm qhov mob thiab ua kom muaj kev noj qab haus huv hauv lub neej kom txhim kho peb txoj kev noj qab haus huv thiab lub neej zoo. Nrog kev noj zaub mov kom raug thiab kev tswj hwm txoj kev ua neej, peb tuaj yeem txo lub cev qhov mob thiab ua kom lub cev noj qab haus huv thiab lub siab ntshiab. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco zoo vim Cistanche deserticola yog cov khoom siv tshuaj hauv Suav teb uas muaj ntau yam teebmeem, ib qho ntawm kev txhim kho kev nco. Kev ua tau zoo ntawm Cistanche deserticola los ntawm ntau yam khoom xyaw uas nws muaj, suav nrog tannic acid, polysaccharides, flavonoid glycosides, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv hauv ntau txoj hauv kev.
Nyem Paub Short-term Nco yuav ua li cas txhim kho
IR induces microglial activation thiab tso tawm inflammatory cytokines thiab chemokines. Inflamation yog ib tug yam ntxwv ntawm microglial aging thiab plays lub luag hauj lwm tseem ceeb nyob rau hauv hluav taws xob vim lub hlwb puas [179] andaging-related kab mob [55].
Raws li tau hais yav dhau los, kev raug hluav taws xob feem ntau ua rau muaj qhov tsis zoo ntawm microglial activation, ua rau cov hlwb no txuas ntxiv tsim cov cytokines neurotoxic, cov qib uas nce nrog cov koob tshuaj hluav taws xob [4]. DDR signaling kuj tuaj yeem kho los ntawm paracrine / systemic mechanisms uas ua rau lub cev ib puag ncig los ntawm kev kho cov ntaub so ntswg thiab kev tiv thaiv kab mob.
Sustained DNA puas teeb liab (telomereattrition) tuaj yeem ua rau DDR xa cov teeb liab tawm ntawm tes thiab ua rau SASPs [180–182]. Lub DDR / SASP txoj kev taw qhia txoj kev tswj hwm ntau lub bioactive pro-inflammatory mediators, xws li interleukin-chemokine kev loj hlob yam matrix-degrading enzymes thiab ROS [183]. Tsis tas li ntawd, cov pro-inflammatory transcription ntawm NF-kB thiab inflammasome yog lub hauv paus tseem ceeb uas teeb tsa. lub secretome, ntxiv qhov tseem ceeb ntawm kev ua haujlwm ntawm txoj hauv kev no hauv cov lus teb rau cov ntaub so ntswg raug mob [184–186].
NF-kB transcription ua rau muaj ntau yam kev mob ntawm SASP, xws li IL-6, IL-1, thiab TNF-, uas yog qhov tseem ceeb autonomic cellular modulators ntawm kev laus [187,188]. Tsis tas li ntawd, ib koob tshuaj ntawm 10-Gy -irradiation tuaj yeem nce qib ntawm IL-6 thiab IL-8 hauv tib neeg endothelial hlwb hauv vitro [189].
Tsis tas li ntawd, qhov nce siab hauv cov neeg kho mob inflammatory TNF- , IL-6, thiab IL-10 tau pom nrog nce cov tshuaj tiv thaiv hluav taws xob thiab hnub nyoog ntawm cov neeg muaj sia nyob ntawm cov foob pob atomic [190].Ob leeg IR thiab o muaj feem cuam tshuam rau ib qho nce ROS qib hauv cov ntaub so ntswg. Nyob rau hauv cov qauv amouse limb ischemia, mob irradiation nrog ob Gy tau pom los txhawb mast cellrecruitment thiab cov ntaub so ntswg revascularization [191].
High-dose irradiation ntawm nas plab plab ua rau neutrophil recruitment rau hauv cov ntaub so ntswg irradiated [192]. Radiation-activated microglia qhia ib qho inducible TSIS synthase thiab tsim kom muaj ntau ntawm NO, ua rau toneuronal oxidative puas. Tsis tas li ntawd, microglial hu xov tooj zoo li receptors (TLRs) tau koom nrog neuroinflamation, yog li ua rau muaj hnub nyoog ntsig txog kab mob hlwb [193].
Chronicinflammation tuaj yeem ua rau ntau tshaj ROS thiab RNS ntau lawm, ua rau DNA puas thiab kab mob. Qhov tsis tu ncua ntawm ROS thiab RNS nyob rau hauv microenvironment tuaj yeem ua rau muaj kev txhim kho ntxiv ntawm kev mob o, ua rau oxidative puas tsuaj rau DNA thiab DNA kho txoj hauv kev, ntxiv rau kev laus thiab cov kab mob uas muaj hnub nyoog.
Hauv cov qauv muaj hnub nyoog ntsig txog cov kab mob neurodegenerative, kev sim ua kom microglial TLRs tuaj yeem ua rau cov neuron degeneration, thiab pharmacological inhibition ntawm microglial activation qhia cov teebmeem neuroprotective [194].
Ntxiv nrog rau microglial activation, hluav taws xob-inducedtelomere shortening tuaj yeem ua rau mob. Luv luv telomeric xaus induceDNA kev puas tsuaj cov lus teb, ua rau zus tau tej cov NF-kB, ib tug tseem ceeb regulator ntawm inflammatory Cheebtsam xws li nod-zoo li receptor 3 inflammasomes, thiab cov secretion ntawm inflammatory cytokines nyob rau hauv lub hlwb [195].
3.6. Autophagy
IR tuaj yeem ua rau macromolecular (tsuas yog DNA) kev puas tsuaj thiab endoplasmic reticulum (ER) kev ntxhov siab induction, ob qho tib si tuaj yeem ua rau autophagy. [196]. Ntawm cov tseem ceeb moleculesactivated thaum raug hluav taws xob, cov inducible nitric oxide synthase (iNOS) gene andnitric oxide (NO) koom nyob rau hauv hluav taws xob induced autophagy thiab apoptosis [197,198].
Kev ua haujlwm ntawm iNOS tus txhawb nqa yuav ua rau muaj kev tsim tawm ntawm NO, ua rau muaj kev cuam tshuam ntawm autophagy mediated los ntawm protein nitration. Kev ua kom lub iNOS txhawb nqa muaj feem cuam tshuam rau nws muaj ntau yam kev hloov pauv hloov pauv xws li NF-κB thiab Kruppel-likefactor 6 (KLF6). [197]. Radiation-induced oxidative kev nyuaj siab tsis tsuas yog ua rau DNA puas, tab sis kuj ua rau ER kev nyuaj siab, impaired mitochondrial muaj nuj nqi, thiab protein misfolding.
Feem ntau ntawm cov xwm txheej no tau pom tias ua rau autophagy [199,200] .Radiation-induced mitochondrial dysfunction thiab biogenesis paub tias muaj feem xyuam rau mitochondrial autophagy [201].
Nyob rau hauv tej yam kev mob ntawm nws kim heev mitochondrialdamage, lub cell mus rau mitophagy tshem tawm cov puas thiab dysfunctionalmitochondria. Radiation induces ntau yam teb, nrog rau autophagy thiab senescence. Nws yog feem ntau xav tias autophagy thiab senescence yuav txhawb nqa txoj sia nyob ntawm tes.
Txawm li cas los xij, kev tshawb fawb ua ntej tau pom tias autophagy qee zaum muaj qhov cuam tshuam tsis zoo, xws li cytotoxicity lossis lwm yam tsis muaj kev tiv thaiv [202]. Pub dawb amino acids tso tawm los ntawm lysosomes thaum laus txhawb kev tsim cov inflammatory cytokinesthat synthesize SASP [203] .Autophagy regulation yog qhov tseem ceeb ntawm kev laus, kab mob hnub nyoog, thiab cov kab mob neurodegenerative.
Nyob rau hauv cov txheej txheem ntawm kev laus thiab neurodegeneration, cov kev cai ntawm autophagy yuav muaj cov kauj ruam tsis xws luag, ua rau tsub zuj zuj ntawm puas organellesand protein aggregates, cuam tshuam cov cell metabolism thiab homeostasis, li no exacerbatingautophagy-txog tsis ua hauj lwm thiab tsim ib tug vicious vajvoog, uas nws thiaj li ua rau toneuronal puas thiab cell. tuag. [204].
Kev puas tsuaj autophagy hauv cov neurons pab txhawb rau kev sib sau ntawm cov proteins lom thiab puas organelles cuam tshuam nrog cov kab mob neurodegenerative [205]. Hnub nyoog yog ib qho tseem ceeb txaus ntshai rau ntau yam kab mob neurodegenerative, xws li Alzheimer's disease, Parkinson's disease, thiab tauopathy [206].
Thaum lub sij hawm, lub hnub nyoog-dependant poob nyob rau hauv autophagy thiab cov coj poob nyob rau hauv cov protein metabolism thiab tsub zuj zuj ntawm cov protein toxicity ua ke pab rau cov kab mob kev loj hlob thiab / los yog kev loj hlob. Txij li thaum post-mitotic neurons tsis tuaj yeem tshem tawm cov protein-tshuaj lom hauv cov menyuam ntxhais thaum lub sijhawm mitosis, lawv muaj kev cuam tshuam ntau dua rau hnub nyoog txog cov protein toxicity [207].
Kev puas tsuaj autophagy hauv cov hlwb glial, uas muaj lub luag haujlwm tseem ceeb hauv homeostatic hauv nruab nrab paj hlwb, tuaj yeem cuam tshuam cov haujlwm autophagic hauv neurons [208]. Ua ke, cov xwm txheej no tuaj yeem cuam tshuam thiab txhawb kev degeneration ntawm cov neurons tshwj xeeb hauv cov kab mob neurodegenerative sib txawv, qhia tias cov kev kho mob tshwj xeeb ntawm cov neeg mob neuronal tej zaum yuav lav [204].
4. Cov lus xaus thiab cov lus qhia txog kev tshawb fawb yav tom ntej
Cov kev tshawb fawb tam sim no ntawm cov tsiaj lub hlwb qhia tias cov hluav taws xob ua rau cov laus inneural qia hlwb; paub tab thiab tsis paub qab hau neurons; glial hlwb, suav nrog astrocytes, microglia, thiab oligodendrocytes; thiab endothelial hlwb ntawm cerebral hlab ntsha.
Ntxiv mus, cov teebmeem no ua rau lub hlwb laus, ua rau muaj kev puas hlwb thiab kev loj hlob ntawm kev laus ntawm cov hlwb hauv cov tib neeg uas raug hluav taws xob, xws li cov neeg muaj sia nyob los ntawm Chornobyl nuclear fais fab nroj tsuag kev sib tsoo lossis cov neeg tau txais xov tooj cua.
Nyob rau theem theem, hluav taws xob-induced oxidative kev nyuaj siab thiab neuroinflammation yuav ua rau cov teeb liab sib txawv ntawm txoj kev, ua rau lub shortening ntawm telomeres nyob rau hauv lub hlwb, thiab thaum kawg, lub hlwb laus.
Peb txoj kev nkag siab tam sim no ntawm hluav taws xob vim lub hlwb kev laus tseem muaj tsawg heev. Nrog rau qhov nce hauv qhov kev tshawb nrhiav tob, suav nrog kev mus ncig hauv chaw, thiab kev siv IR inmedical kuaj thiab kev kho mob, cov kev tshawb fawb dav yuav tsum tau txais kev nkag siab tob npaum li cas. -dose hluav taws xob cuam tshuam rau lub hlwb laus thiab cov txheej txheem molecular uas ua rau cov txheej txheem no.
Tsis tas li ntawd, feem ntau cov kev tshawb fawb txog hluav taws xob ntsig txog kev laus ntawm lub hlwb muaj feem ntau ntawm cov hluav taws xob ntau, thiab ob peb txoj kev tshawb fawb tau tshuaj xyuas qhov rhiab heev ntawm txhua CNS celltypes thiab nws cov progenitors rau hluav taws xob thiab hluav taws xob-induced aging.Senescent hlwb raug suav hais tias yog lub hom phiaj kho mob zoo vim tias lawv khaws cia rau kev laus thiab lwm yam. cov teebmeem exogenous.
Cov tshuaj Senotherapeutics, ib chav kawm tshiab ntawm cov tshuaj, tuaj yeem xaiv tua cov hlwb (senolytics) lossis tshem tawm lawv cov kab mob uas ua rau cov phenotypes (senomorphics / senostatics). Txij li thaum xyoo 2015, ntau yam senolytics tau txheeb xyuas thiab tshuaj xyuas los ntawm kev sim tshuaj.
Cov ntaub ntawv hauv tsev kho mob qhia tau hais tias senolytics txo cov kab mob cuam tshuam hauv ntau lub cev, txhim kho lub cev ua haujlwm thiab ua kom muaj zog, thiab txo qis txhua qhov ua rau tuag, txawm tias cov neeg mob laus [209]. Tsis tas li ntawd, cov tshuaj tshiab tuaj yeem ncua tus neeg mob tus kab mob rov qab los. Kev ntsuam xyuas tseeb ntawm cov lus teb hluav taws xob tuaj yeem ua rau muaj peev xwm ua kom muaj kev nkag siab zoo ntawm cov qog nqaij hlav cancer rau kev kho hluav taws xob thaum txo kev puas tsuaj rau cov ntaub so ntswg ib txwm [202].
Ntau cov senolytics twb tau pom tias muaj txiaj ntsig zoo thaum lawv kho qhov kev ua kom lossis tsis ua haujlwm ntawm redox-sensitive hubs. Yog li ntawd, ROS-dependent txoj hauv kev uas tshwj xeeb kho cov apoptosis ntawm cov hlwb senescent tuaj yeem sawv cev rau kev tiv thaiv tshiab / kho lub hom phiaj txhawm rau txhim kho kev kho mob. Raws li cov cell faib, telomere shortening, txheej txheem txuas nrog cellular senescence tshwm sim.
Yog li ntawd, txawm tias senolytics ib ntus txo cov cellular senescence thiab nws cov teebmeem deleterious, lawv tuaj yeem ua rau muaj kev laus zuj zus ntxiv thiab cuam tshuam txog kev ua haujlwm tsis zoo [210]. Cov tshuaj tsom rau kev laus-txog mitochondrial dysfunction lossis tshwj xeeb tsom rau mitochondrial ROS kuj tseem tso cai rau kev hloov pauv hauv SASP thiab cov txiaj ntsig tsis zoo.
Txawm li cas los xij, ntxiv elucidation ntawm cov txheej txheem nyuaj los ntawm cov kev cai redox-tso cai los yog mitochondria cuam tshuam rau SASP yog yuav tsum tau. Nws yog ib qho tsim nyog yuav tsum nco ntsoov tias exacerbated antioxidation kuj tuaj yeem ua rau muaj kev phom sij loj. Tsuas yog kev tswj nruj ntawm redox homeostasis tuaj yeem tso cai rau kev kho mob xenomorphic-based [211].
Yog li ntawd, peb xav tias kev tshawb nrhiav yav tom ntej yuav tsum tsom mus rau thaj chaw hauv qab no: (1) cov nyhuv ntawm cov tshuaj IR qis rau kev laus ntawm ntau hom cell; (2) radiosensitivity ntawm txawv progenitors thiab txawv hlwb nyob rau hauv lub hlwb mus rau hluav taws xob vim aging; (3) kev kis mob ntawm lub hlwb kev laus hauv cov neeg mob uas nquag siv hluav taws xob kuaj mob thiab siv hluav taws xob kho mob rau lub hlwb tsis zoo; thiab (4) daim ntawv thov sib txawv -omics mus kom ze rau kev nkag siab txog cov txheej txheem molecular hauv qab cov tshuaj tsis tshua muaj hluav taws xob cuam tshuam lub hlwb kev laus.Cov ntaub ntawv no tuaj yeem pab tau zoo hauv kev txhim kho kev tiv thaiv thiab kho txoj hauv kev tiv thaiv hluav taws xob vim lub hlwb laus thiab lwm yam cuam tshuam txog kev puas hlwb thiab neuropsychological. .
Sau Kev Pabcuam: Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.
Cov Nyiaj Txiag: Txoj kev tshawb fawb tam sim no tau txais kev txhawb nqa los ntawm Nature Science Foundation of Hubei Province (grant no. 2017CFB786), Hubei Province Health and Family Planning Scientific Research Project (grant no. WJ2016Y10), Jingzhou Science and Technology Bureau Project (grant no. 2017-93), the Graduate innovation fund of the Health Science Center, the Yangtze University (200201), Nationalinnovation and entrepreneurship training program for College Students (grant no. 202010489017) and the National Research Foundation of Singapore to Singapore Nuclear Research thiab SafetyInitiative (TFR).
Cov Lus Qhia Muaj Cov Ntaub Ntawv: Kev sib faib cov ntaub ntawv tsis siv rau kab lus no, vim tias tsis muaj cov ntaub ntawv raug tsim lossis tshuaj ntsuam xyuas thaum kawm tam sim no.
Kev tsis sib haum xeeb ntawm kev txaus siab: Cov neeg sau ntawv tshaj tawm tsis muaj teeb meem ntawm kev txaus siab.
Cov ntaub ntawv
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