ASK1 Inhibitor NQDI-1 Txo Oxidative Stress Thiab Neuroapoptosis Ntawm ASK1/p38 Thiab JNK Signaling Pathway hauv Early Brain Injury Tom Qab Subarachnoid Hemorrhage hauv nas Part 2
Aug 03, 2023
Kev sib tham
Glycoside ntawm cistanche tuaj yeem ua rau muaj kev ua haujlwm ntawm SOD hauv plawv thiab daim siab cov ntaub so ntswg, thiab txo cov ntsiab lus ntawm lipofuscin thiab MDA hauv txhua cov ntaub so ntswg, tshem tawm ntau yam reactive oxygen radicals (OH-, H₂O₂, thiab lwm yam) thiab tiv thaiv DNA puas. los ntawm OH-radicals. Cistanche phenylethanoid glycosides muaj peev xwm tshem tawm cov dawb radicals, muaj peev xwm txo tau ntau dua li cov vitamin C, txhim kho cov haujlwm ntawm SOD hauv cov phev ncua, txo cov ntsiab lus ntawm MDA, thiab muaj qee yam kev tiv thaiv ntawm cov phev ua haujlwm. Cistanche polysaccharides tuaj yeem txhim kho kev ua haujlwm ntawm SOD thiab GSH-Px hauv erythrocytes thiab ntsws cov ntaub so ntswg ntawm cov nas senescent sim los ntawm D-galactose, nrog rau txo cov ntsiab lus ntawm MDA thiab collagen hauv lub ntsws thiab ntshav, thiab nce cov ntsiab lus ntawm elastin, muaj Cov nyhuv scavenging zoo ntawm DPPH, ncua lub sijhawm ntawm hypoxia hauv cov nas senescent, txhim kho cov haujlwm ntawm SOD hauv cov ntshav, thiab ncua lub physiological degeneration ntawm lub ntsws hauv kev sim cov nas nrog cellular morphological degeneration, kev sim tau pom tias Cistanche muaj peev xwm antioxidant zoo. thiab muaj peev xwm los ua ib qho tshuaj tiv thaiv thiab kho cov kab mob ntawm daim tawv nqaij laus. Nyob rau tib lub sijhawm, echinacoside hauv Cistanche muaj lub peev xwm tseem ceeb los tshem tawm DPPH dawb radicals thiab tuaj yeem tshem tawm cov pa oxygen reactive, tiv thaiv dawb radical-induced collagen degradation, thiab kuj muaj kev kho zoo ntawm thymine dawb radical anion puas.
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Hauv txoj kev tshawb fawb tam sim no, qib kev qhia protein ntawm ASK1 thiab p-ASK1 tau nce siab tom qab SAH. ASK1 inhibitor NQDI-1 txhim kho kev ua haujlwm luv luv thiab ntev lub paj hlwb tom qab SAH thiab txo qis oxidative stress thiab neuronal apoptosis ntawm inhibition ntawm ASK1 phosphorylation thiab ASK1 / p38 thiab JNK signaling txoj hauv EBI tom qab SAH.
ASK1 yog ib tug tswv cuab ntawm MAP3K tsev neeg thiab nws qhov kev ua haujlwm hauv kev teb rau ntau hom cellular stress mediates ntau hom cellular puas (31). Rau qee yam kab mob cuam tshuam nrog oxidative kev nyuaj siab thiab apoptosis, txo qis protein qhia ntawm ASK1 lossis inhibition ntawm nws cov phosphorylation yuav muaj txiaj ntsig zoo los ntawm kev txo qis oxidative kev nyuaj siab thiab apoptosis (32). Txawm li cas los xij, rau qhov zoo tshaj plaws ntawm peb txoj kev paub, txawm li cas los xij, lub luag haujlwm thiab lub hauv paus txheej txheem ntawm kev ua ntawm ASK1 thiab nws cov inhibitor NQDI-1 tsis tau tshaj tawm yav dhau los hauv SAH. Txoj kev tshawb fawb tam sim no tau pom tias cov protein qhia qib ntawm ASK1 thiab p-ASK1 tau nce ntxiv tom qab SAH qauv, uas qhia tias ASK1 tuaj yeem ua haujlwm hauv EBI tom qab SAH. Tsis tas li ntawd, ASK1 tau sib koom ua ke hauv cov neurons, microglia, thiab astrocytes, uas qhia txog lub luag haujlwm dav rau ASK1 hauv ntau lub hlwb neuronal tom qab SAH.
NQDI-1 yog ib qho tshwj xeeb inhibitor ntawm ASK1 thiab nws lub luag haujlwm ua haujlwm tau raug pom yav dhau los siv hauv vitro kinase kev soj ntsuam (11,33). Hauv tus qauv nas ntawm tus mob pancreatitis, NQDI-1 txo qis pancreatic follicular cell necrosis los ntawm kev txo qis ntawm ROS ntau lawm thiab receptor-interacting serine / threonine kinase 3 thiab p-mixed lineage kinase domain-zoo li pseudo ki-nase protein qhia theem (34) . Hauv ischemic lub hlwb raug mob, NQDI-1 inhibition ntawm ASK1 txo qis matrix metalloproteinase 9 kev ua haujlwm thiab tom qab neuronal apoptosis hauv hlwb endothelial hlwb (35). Hauv kev tshawb fawb tam sim no, qhov sib txawv ntawm NQDI-1 tau txhaj tshuaj intracerebroventricularly, uas tau txhim kho qhov kev hloov pauv Garcia thiab qhov sib npaug ntawm cov qhab nia xeem, uas tau qhia tias NQDI-1 tau ua rau kev txhim kho hauv lub sijhawm luv luv ntawm lub paj hlwb tom qab SAH.
Rau kev ua haujlwm ntev lub paj hlwb, ob txoj hauv kev tau siv los ntsuas kev ua haujlwm nyob rau lub sijhawm sib txawv (36). Qhov kev sim Rotarod tau siv los ntsuas qhov sib npaug ntawm qhov sib npaug ntawm qhov chaw nyob rau hnub 7, 14, thiab 21. Thaum pib ceev ntawm 5 lossis 10 rpm, lub caij nplooj zeeg latency ntawm nas nyob rau hauv pawg SAH ntxiv rau lub tsheb tau luv luv piv nrog rau hauv kev dag ntxias. pab pawg, thiab kev kho mob nrog NQDI-1 ua rau muaj kev nce ntxiv. Morris dej tshawb nrhiav tau siv los ntsuas qhov chaw nco thiab kev kawm muaj peev xwm ntawm nas nyob rau lub lim tiam plaub. Thaum lub sij hawm kev cob qhia theem ntawm hnub 1-5, SAH pab pawg nas ua luam dej rau lub sij hawm ntev thiab kev ncua ntxiv piv nrog rau pawg sham thiab NQDI-1 kev kho mob txo qhov tshwm sim no. Thaum lub sijhawm kuaj, tsis muaj qhov sib txawv tseem ceeb hauv kev ua luam dej nrawm ntawm pawg nas. Tom qab tshem tawm ntawm lub platform, lub sij hawm siv tshawb nrhiav lub hom phiaj quadrant tau pom thiab suav rau txhua pawg nas. Ua raws li SAH, cov nas tau tshawb nrhiav lub hom phiaj rau lub sijhawm luv dua, uas tau qhia tias kev ua qauv SAH ua rau muaj qhov tsis meej pem hauv cheeb tsam thiab kev nco hauv cov nas thiab ua rau lub cev tsis muaj peev xwm nco tau ntev, thaum NQDI-1 kev kho mob pom tau tias muaj kev txhim kho hauv cov txiaj ntsig no. Qhov kev sim Rotarod thiab Morris dej maze xeem tau qhia tias NQDI-1 txhim kho lub paj hlwb mus sij hawm ntev tom qab SAH.
Oxidative stress thiab neuroapoptosis yog cov kev hloov pauv tseem ceeb ntawm EBI tom qab SAH (37). Hauv cov hlwb tsis tu ncua, ROS feem ntau yog cov khoom ua pa ntawm kev ua pa uas tsim los ntawm mitochondrial electron respiratory saw thiab nruab nrab ntawm ROS kho DNA puas thiab ua haujlwm lub luag haujlwm ntawm lub cev hauv kev txhawb nqa kev muaj sia nyob ntawm tes (38). Raws li SAH, vim yog autoxidation ntawm cov ntshav nyob rau hauv subarachnoid qhov chaw, ROS catalysis los ntawm heme thiab intracellular mitochondrial dysfunction, electrons khiav mus rau hauv lub cytoplasm, thiab cov antioxidant system tsis txaus los them, uas ua rau cov tsub zuj zuj ntawm ntau ntawm ROS nyob rau hauv neuronal. hlwb (39), uas ua rau oxidative kev nyuaj siab puas. Yog li, cov tswv yim kho mob uas lub hom phiaj oxidative kev nyuaj siab thiab apoptosis yuav raug suav hais tias yog cov lus qhia kho tau zoo tom qab SAH. Nyob rau hauv txoj kev tshawb no, ROS thiab oxidative kev nyuaj siab ntawm lub hlwb cov ntaub so ntswg raug soj ntsuam siv DHE, uas yog oxidized rau hauv ethidium thiab ua ib tug liab fluorescent teeb liab (40). Qhov feem pua ntawm DHE-zoo hlwb tau nce ntxiv hauv SAH ntxiv rau pawg tsheb, qhov kev txo qis tau pom nyob rau hauv feem pua ntawm DHE-zoo hlwb hauv SAH ntxiv rau NQDI-1 pab pawg, uas qhia tias NQDI-1 txo oxidative kev nyuaj siab. Apoptosis tau soj ntsuam siv TUNEL thiab feem pua ntawm TUNEL-zoo neuronal hlwb tom qab SAH qauv tau nce ntxiv, thaum NQDI-1 txo qis feem pua ntawm TUNEL-zoo neuronal hlwb. Tej zaum nws yuav xav tias kev kho NQDI-1 txo qis oxidative kev nyuaj siab thiab apoptosis hauv EBI tom qab SAH.
Cov nyhuv ntawm NQDI-1 ntawm ASK1 thiab cov peev txheej hauv qab molecular mechanism raug soj ntsuam. Cov teebmeem ntawm NQDI-1 ntawm cov protein qhia qib ntawm ASK1 thiab p-ASK1 tau raug soj ntsuam thawj zaug. Qhov piv ntawm p-ASK1 / ASK1 tsis hloov tom qab SAH, uas qhia tias kev hloov pauv hauv phosphorylation ntawm ASK1 zoo ib yam li cov qib ASK1 protein qhia. Kev kho mob nrog NQDI-1 pom tau tias muaj kev txo qis hauv p-ASK1 protein ntau ntau tab sis pom tias tsis muaj kev cuam tshuam rau ASK1 piv nrog cov pab pawg SAH ntxiv rau lub tsheb, uas qhia tias NQDI-1 tau siv nws cov teebmeem neuroprotective feem ntau los ntawm inhibition ntawm ASK1 phosphorylation. Tom qab ntawd, qib kev qhia cov protein ntawm ob qho tib si p-ASK1 thiab ASK1 tau raug tshem tawm siv ASK1 siRNA, tom qab uas cov protein qhia qib ntawm p-p38 thiab p-JNK tau txo qis, uas qhia tias ASK1 tau ua haujlwm feem ntau ntawm phosphorylation.
Txoj kev p38, MAPK, thiab JNK tau qhia dav dav hauv cov ntaub so ntswg hlwb (41). Activated p38, MAPK, thiab JNK txhim kho qog necrosis yam tshwm sim-induced apoptosis, koom nrog Fas/FasL system, phosphorylate P53, thiab induce mitochondrial translocation ntawm BAX thiab lwm txoj hauv kev los txhawb apoptosis (42). Inhibition ntawm phosphorylation activation ntawm p38 MAPK thiab JNK txo oxidative kev nyuaj siab thiab neuronal apoptosis, alleviates EBI, thiab txhim kho cov prognosis ntawm SAH nas qauv (43). Tom qab txhaj tshuaj p38 inhibitor BMS-582949, WB cov txiaj ntsig tau pom tias nws cuam tshuam cov phosphorylation ntawm p38 thiab txo qis kev qhia txog qib ntawm oxidative kev nyuaj siab thiab apoptosis-associated proteins. Txawm li cas los xij, BMS-582949 tsis ua rau muaj qhov sib txawv loj ntawm cov protein qhia qib ntawm p-ASK1, ASK1, lossis p-JNK. Ib yam li ntawd, JNK inhibitor SP600125 cuam tshuam qhov phosphorylation ntawm JNK tab sis tsis pom muaj qhov cuam tshuam loj rau p-ASK1, ASK1, lossis p-p38 protein qhia qib. Cov txiaj ntsig no tau qhia tias p38 thiab JNK tau poob qis ntawm p-ASK1 thiab ASK1 ua rau oxidative kev nyuaj siab thiab apoptosis tom qab SAH ntawm phosphorylation-activated p38 thiab JNK.
Muaj qee qhov kev txwv cuam tshuam nrog txoj kev tshawb fawb tam sim no. Ua ntej, NQDI-1 tsuas yog siv ib zaug ntawm kev txhaj tshuaj intracerebroventricular 1 h tom qab SAH; Yog li, txoj kev tshawb fawb tam sim no tsis tsim nyog los txiav txim siab qhov zoo tshaj plaws kho qhov rai rau NQDI-1 kev kho mob thiab cov kev tshawb fawb yav tom ntej yuav tsum tau los daws qhov teeb meem no. Qhov thib ob, txoj kev tshawb fawb tam sim no yog kev tshawb fawb los soj ntsuam cov txiaj ntsig ntawm inhibition ntawm ASK1 ntawm kev ua haujlwm ntawm lub paj hlwb thiab tshawb xyuas seb NQDI-1 puas muaj txiaj ntsig kho tom qab SAH. Lub luag haujlwm ntawm ASK1 hauv astrocytes lossis microglia thiab cov tshuaj pharmacokinetics ntawm NQDI-1 xav tau kev qhia ntxiv hauv kev tshawb fawb yav tom ntej. Kev kuaj dej Morris tsuas yog ua thaum lub lim tiam thib plaub tom qab SAH; yog li ntawd, tej zaum yuav muaj kev hloov pauv ntawm lub peev xwm thaum ntxov ntawm spatial nco thiab kev kawm muaj peev xwm yuav tsis raug soj ntsuam. Thaum kawg, IF tau siv los ntsuas ASK1 co-localization; Txawm li cas los xij, tsuas yog 2 tus tsiaj / pawg sim tau raug soj ntsuam. Cov qauv me me yog qhov txwv ntawm qhov kev tshawb fawb tam sim no uas yuav ua rau cov lus xaus tsis tsim nyog thiab yuav tsum tsuas yog siv rau qhov zoo, tsis yog qhov ntau, kev ntsuas.
Hauv kev xaus, ASK1 inhibitor NQDI-1 txo qis oxidative kev nyuaj siab thiab apoptosis thiab txhim kho lub paj hlwb ua haujlwm luv luv thiab ntev tom qab SAH los ntawm inhibition ntawm ASK1 phosphorylation thiab p38 thiab JNK signaling pathways. NQDI-1 tej zaum yuav yog tus neeg sawv cev kho mob rau kev kho SAH.
Kev lees paub
Tsis siv tau.
Nyiaj txiag
Txoj kev tshawb fawb tam sim no tau txais kev txhawb nqa los ntawm National Natural Science Foundation of China (grant no. 81870944), Beijing Science thiab Technology Plan Subject: Beijing-Tianjin-Hebei Collaborative Innovation Promotion Project (grant no. Z181100009618035), National Natural Science Foundation of Tuam Tshoj (grant no. 81771233), Beijing Municipal Administration of Hospitals 'Ascent Plan (grant no. DFL20190501) thiab Kev Tshawb Fawb thiab Kev Tshaj Lij Tshaj Lij Tshaj Lij Tsim Nyog rau Kev cuam tshuam ntawm Suav Cov Neeg Muaj Mob Stroke (grant no. GN-2020R0007).
Muaj cov ntaub ntawv thiab cov ntaub ntawv
Cov ntaub ntawv siv thiab/lossis tshuaj xyuas thaum lub sijhawm kawm tam sim no muaj los ntawm tus kws sau ntawv raws li qhov kev thov tsim nyog.
Cov neeg sau ntawv pab txhawb
JD, WY, JJ, FL, thiab AL tau koom nrog kev sim tsim. JD, JJ, JW, thiab XY tau ua qhov kev sim thiab sau thiab tshuaj xyuas cov ntaub ntawv. XY, FL, thiab AL txhais cov ntaub ntawv. JD thiab WY tau sau cov ntawv sau. XY, FL, thiab AL tau kho cov ntawv sau thiab ua pov thawj cov lus. Txhua tus kws sau ntawv tau nyeem thiab pom zoo cov ntawv sau kawg. JD, JW, thiab FL lees paub qhov tseeb ntawm tag nrho cov ntaub ntawv nyoos.
Kev pom zoo ntawm kev ncaj ncees thiab kev tso cai los koom
Tag nrho cov txheej txheem kev sim tau pom zoo los ntawm Pawg Saib Xyuas Tsiaj Tsiaj thiab Siv Khoom ntawm Central South University (pom zoo. 2019sydw0104).
Tus neeg mob tso cai rau kev tshaj tawm
Tsis siv tau.
Kev nyiam sib tw
Cov kws sau ntawv tshaj tawm tias lawv tsis muaj kev sib tw nyiam.
Cov ntaub ntawv
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