Neuroprotection Ntawm N-benzyl Eicosapentaenamide hauv Neonatal nas Tom qab Hypoxic-Ischemic Brain raug mob

Hu rau:joanna.jia@wecistanche.com/ WhatsApp: 008618081934791

Abstract:

Maca(Lepidium meyenii) tau tshwm sim los ua cov khoom noj cog qoob loo nrov vim nws cov khoom siv tshuaj thiab khoom noj muaj txiaj ntsig.Macamides, raws li cov khoom xyaw tshwj xeeb uas muaj nyob hauvmaca, yog ib tug tshwj xeeb series ntawm tsis-polar, ntev-chain fatty acid N-benzyl amides nrog ntau yam bioactivities xws li antifatigue yam ntxwv thiab kev txhim kho kev loj hlob ntawm cov me nyuam. Nyob rau hauv txoj kev tshawb no, ib yam tshiab ntawm maximize, N-benzyl eicosapentaenamide (NB-EPA), tau txheeb xyuas los ntawmmaca. Peb txuas ntxiv tshawb nrhiav nws lub luag haujlwm neuroprotective hauv hypoxic-ischemic hlwb raug mob. Peb qhov kev tshawb pom tau qhia tias kev kho mob nrog biosynthesized NB-EPA tseem ceeb txo qhov loj ntawm lub paj hlwb infarction thiab txhim kho cov kab mob neurobehavioral tom qab hypoxic-ischemic hlwb puas hauv cov nas me me. NB-EPA inhibited apoptosis ntawm cov hlwb neuronal tom qab kev sib tw ischemic. NB-EPA txhim kho neuronal cell ciaj sia thiab kev loj hlob los ntawm kev ua kom muaj phosphorylated AKT signaling. Nco ntsoov, cov cuab yeej tiv thaiv ntawm NB-EPA tiv thaiv ischemic neuronal kev puas tsuaj yog nyob ntawm kev tawm tsam ntawm p53-PUMA txoj hauv kev. Ua ke, cov kev tshawb pom no qhia tias NB-EPA tuaj yeem sawv cev rau cov tshuaj tiv thaiv kab mob tshiab rau cov menyuam yug tshiab nrog hypoxic-ischemic encephalopathy.

Ntsiab lus:maca; N-benzyl eicosapentaenamide; neonatal hypoxic-ischemic encephalopathy; neuroprotection; PUMA

1 Kev Taw Qhia

Neonatal hypoxic-ischemic encephalopathy (HIE) yog ib qho ua rau lub hlwb raug mob vim yog oxygen deprivation thiab ntshav txaus [1,2]. HIE yog qhov tsis txaus ntseeg rau kev loj hlob ntawm lub hlwb, uas yog qhov tseem ceeb ua rau cov paj hlwb tsis ua haujlwm hauv cov menyuam yaus [3]. Qhov feem ntau tshwm sim ntawm HIE muaj xws li mob hlwb palsy, kev puas hlwb loj heev, thiab lub cev muaj zog thiab kev coj cwj pwm tsis zoo, ua rau ntau lab tus menyuam mos tuag los yog xiam oob qhab mus sij hawm ntev txhua xyoo [4]. Therapeutic hypothermia yog qhov kev kho mob ntau tshaj plaws rau cov neeg mob HIE neonatal thiab tau pom tias yuav txhim kho cov txiaj ntsig neurologic hauv cov neeg muaj sia nyob [5]. Txawm li cas los xij, tsuas yog siv kev kho mob hypothermia tsis txaus los txo cov neeg tuag los yog zam cov kab mob neurodevelopmental loj heev hauv HIE [6]. Txawm hais tias muaj kev txhim kho tseem ceeb hauv cov cuab yeej kho mob niaj hnub no, tsis muaj kev kho mob zoo rau cov hlab ntsha puas tsuaj los ntawm HIE [7]. Neuroprotective therapy yog qhov tseem ceeb heev rau kev rov ua haujlwm ntev ntawm lub hlwb [8]. Yog li ntawd, nws yog ib qho tsim nyog los tsim kom muaj kev nyab xeeb thiab siv tau zoo neuroprotective therapeutics.

Kuv tuaj yeem yuav cistanche bark qhov twg

Maca(Lepidium meyenii) yog cov tshuaj ntsuab txhua xyoo lossis ob xyoos ntawm South American cruciferous tsev neeg, uas tau muab cais ua cov khoom noj tshiab hauv xyoo 2011 [9,10]. Ntau yam khoom siv nrog cov tshuaj pharmacological thiab kev noj haus tau raug txheeb xyuas hauv maca, uas suav nrog polysaccharides, phytosterols, alkaloids, glucosinolates, macaenes, thiabmacamides[11,12]. Ntawm cov khoom xyaw bioactive, macamides, ib pawg ntawm cov tsis-polar, ntev-chain fatty acid N-benzyl amide tebchaw, tau lees paub tias yog cov yam ntxwv ntawm cov khoom siv thaum pab txhawb rau cov txiaj ntsig tseem ceeb hauv maca xws li tshuaj tiv thaiv kab mob, tiv thaiv osteoporosis, thiab txhim kho fertility [13 — 15]. Macamides thiab lawv cov analogues hluavtaws tsis ntev los no tau tshaj tawm los qhia txog qhov sib txawv fatty acid amide hydrolase (FAAH) inhibitory kev ua, uas txhais tau hais tias cov tshuaj no muaj peev xwm tiv thaiv kab mob thiab tiv thaiv kev ua haujlwm [16,17].

cistanche tubulosa

Nyob rau hauv txoj kev tshawb no, ib yam tshiab ntawm maximize N-benzyl eicosapentaenamide (NB EPA) tau raug txheeb xyuas los ntawmmaca. Peb txuas ntxiv tshawb nrhiav nws cov haujlwm lom neeg ntawm kev puas hlwb hypoxic-ischemic. Peb qhov kev tshawb pom tau pom tias NB-EPA tseem ceeb ua rau HI-mediated neonatal hlwb raug mob los ntawm kev txhim kho ntawm lub hlwb infarction thiab kev coj cwj pwm tsis zoo. Qhov tseem ceeb, cov nyhuv neuroprotective ntawm NB-EPA ntawm ischemic neuron ciaj sia taus yog nyob ntawm kev tawm tsam ntawm p53-PUMA teeb liab txoj hauv kev.

2. Cov txiaj ntsig

2.1. Kev txheeb xyuas thiab Synthesis ntawm N-benzyl Eicosapentaenamide

Macamidesyog ib chav kawm ntawm amide alkaloids tsim los ntawm benzylamine thiab fatty acid moiety, uas yog suav hais tias yog cov yam ntxwv cim kev sib txuas ntawmmaca. Ntawm no, peb tau txheeb xyuas qhov ua tau zoo tshiab, NB-EPA (molecular formula C27H37NO), los ntawm maca. Raws li pom nyob rau hauv daim duab 1A, high-performance kua chromatography nrog electrospray ionization huab hwm coj spectrometry (HPLC-ESI-MS/MS) tso tawm ob lub ncov uas tau kaw nyob rau hauv tag nrho cov ion chromatogram ntawm m/z 392.3 nrog tuav lub sij hawm ntawm 7.{{1 0}} min thiab 9.0 feeb, raws li. MS/MS spectrum qhia tau hais tias cov ntaub ntawv tawg ntawm lub ncov nrog lub sijhawm khaws cia ntawm 7.0 min tau ua raws li kev xav tau ntawm NB-EPA (Daim duab 1B). Lub ntsiab fragment ion ncov pom los ntawm cov macamide tshiab no yog m/z 91.1, sib xws rau benzyl [C7H7] ntxiv. MS / MS fragment ion peaks ntawm fatty acid sab tau ua raws li cov ntaub ntawv MS / MS qhia ntawm eicosapentaenoic acid hauv National Institute of Standards and Technology (NIST) Chemistry WebBook (SRD 69).

Vim cov ntsiab lus qis ntawm NB-EPA hauvmaca, peb mam li muab cov NB-EPA siv txoj kev carbodiimide condensation. Cov khoom sib xyaw ua ke tau ua kom huv los ntawm ib qho kev npaj HPLC ib nrab. Cov feem nrog khaws cia lub sij hawm los ntawm 23.5 mus rau 25.5 min tau sau, thiab purity ntawm cov seem sau tau mus txog 98.2 feem pua ​​(Daim duab 1C, D). Kev tshuaj xyuas HPLC-MS/MS tau pom tias biosynthesized NB-EPA thiab ntuj NB-EPA muaj cov yam ntxwv sib txawv ntawm chromatographic sib cais thiab cov ntaub ntawv xov xwm thib ob loj spectrometry fragment (Daim duab 1E-G). Ua ke, cov ntaub ntawv no qhia tias ib qho tshiabmacamideNB-EPA tau txheeb xyuas los ntawmmacathiab ntse synthesized.

2.2. NB-EPA txo qis Infarct Volumes thiab Neurobehavioral Deficits hauv Neonatal HI Brain Injury

Tom qab ntawd peb tshawb xyuas bioactivity ntawm NB-EPA hauv cov nas me me tom qab hypoxic-ischemic (HI) lub hlwb raug mob. Cov duab ntawm lub hlwb pom tau tias cov ntaub so ntswg ischemic tau ua dawb thiab o nyob rau hauv lub tsheb pab pawg hnub 1, 3, 7, thiab 14 tom qab HI (Daim duab 2A). Los ntawm qhov sib txawv, kev tswj hwm ntawm NB-EPA ntawm ib koob ntawm 250 µg / hnub rau 3 d txo qis lub hlwb o thiab cov dej hauv lub hlwb (Daim duab 2A, B). Staining nrog 2,3,5-triphenyl tetrazolium chloride (TTC) tau pom tias kev kho NB-EPA (11.13 ± 2.58 feem pua) kom meej meej txo qhov loj ntawm cerebral infarction 3 d post-HI piv nrog lub tsheb (37.01 ± 4.68%) ) (Daim duab 2C). Kev ntsuam xyuas Neurobehavioral pom tau hais tias cov nas nyob hauv pab pawg tsheb tau pom cov kab mob neurobehavioral tseem ceeb ntawm 1, 3, thiab 7 d post-HI (Daim duab 2D–F). Ntawm qhov tsis sib xws, kev kho NB-EPA kom meej meej txhim kho cov kev puas siab puas ntsws (Daim duab 2D-F). Yog li, cov ntaub ntawv no qhia tau hais tias NB-EPA tiv thaiv kab mob ischemic thiab neurobehavioral deficits nyob rau hauv neonatal nas tom qab HI hlwb raug mob.

Daim duab 1. Chromatograms thiab MS/MS spectra ntawm ntuj NB-EPA thiab hluavtaws NB-EPA.(A) Cov neeg sawv cev tag nrho ion tam sim no (TIC)chromatogram tau txais hauv kev xaiv zoo ion saib xyuas (SIM) hom rau cov qauv maca extract. (B) MS/MS spectra of m/z3923([NB-EPA plus H]*) rau maca extract sample.(C) Semi-preparation HPLCchromatogram of synthetic NB-EPA material. (D)HPLC chromatogram ntawm NB-EPA feem (23.5-25.5 min) sau los ntawm HPLC qhov kev npaj ib nrab. (E) Tus neeg sawv cev TIC chromatogram tau txais hauv hom SIM zoo rau cov qauv NB-EPA hluavtaws. (F) MS/MS spectra ntawm m/z 392.3 rau biosynthetic NB-EPA qauv (G) Cov qauv tshuaj ntawm NB-EPA.

2.3. NB-EPA Txo HI-Induced Brain Damage los ntawm Kev Tiv Thaiv ntawm Neuronal Apoptosis

Tom ntej no, peb tshawb xyuas seb qhov kev tiv thaiv ntawm NB-EPA hauv HI lub hlwb raug mob puas cuam tshuam rau kev hloov pauv ntawm neuronal tuag. Hematoxylin-eosin (HE) staining qhia tau hais tias neuron kev npaj nyob rau hauv lub cortex, hippocampus dentate gyrus (DG), Cornu's ammonia (CA) 1, thiab CA3 cheeb tsam tau teeb meem. thiab cov hlab ntsha fibers tau loosened thiab vacuolated hauv ischemic hlwb tom qab HI raug mob. Txawm li cas los xij, kev kho mob nrog NB-EPA kom meej meej abrogated neuronal cell puas (Daim duab 3A). Western blot tau lees paub tias NB-EPA tau txo qis qhov kev qhia ntawm pro-apoptotic proteins xws li p53, PUMA, thiab Bax hauv cov ntaub so ntswg ischemic (Daim duab 3B, C). Tsis tas li ntawd, neuronal nuclei antigen (NeuN) thiab TUNEL ob chav staining pom tau tias qhov txo qis ntawm TUNEL ntxiv rau NeuN ntxiv cov hlwb 7 d post-HI hauv NB-EPA-kho nas (5.80 ± 1.35 feem pua) piv nrog cov tsheb (14.39 ± 2.55 feem pua). (Daim duab 3D). Ua ke, cov ntaub ntawv no qhia tau hais tias cov txiaj ntsig zoo ntawm NB-EPA hauv HI lub hlwb insults koom nrog inhibition ntawm neuronal cell apoptosis.

Daim duab 2. NB-EPA kev tswj hwm txo qis paj hlwb infarction thiab kev coj cwj pwm tsis zoo hauv cov nas me me tom qab HI lub hlwb raug mob. (A) Cov duab sawv cev ntawm lub hlwb tshwm sim ntawm 1,3,7 thiab 14 hnub tom qab-HI.(B) Kev txheeb xyuas cov dej hauv hlwb los ntawm txhua pawg nas ntawm 3 hnub tom qab Hl. (C) Cov duab sawv cev ntawm TTC-stained coronal hlwb seem los ntawm txhua pab pawg nas ntawm 3 hnub tom qab HI thiab kev soj ntsuam ntau ntawm cov ntim infarct. (DF)Neurobehavioral tshwm sim ntawm geotaxis reflex (D), pob tsuas zam kev tawm tsam (E), thiab tuav tes (F) ntawm 1,3, thiab 7 hnub tom qab-HI.Data yog ± tus qauv kev ua yuam kev ntawm qhov nruab nrab (SEM) ( n=8 ib pab).*p<0.05 compared="" to="">

2.4. NB-EPA Txo HI-Induced Brain Damage los ntawm Kev Tiv Thaiv ntawm Neuronal Apoptosis

Nissl staining qhia tau hais tias ntau tus neurons tau nthuav tawm atrophy, o, thiab nuclear pyknosis, thiab txawm tuag nrog kev ploj ntawm Nissl lub cev hauv lub hlwb ischemic. Los ntawm qhov sib txawv, NB-EPA pom tau tias txhim kho neuronal ciaj sia taus thiab kho neuron tom qab HI raug mob (Daim duab 4A, B). Western blot pom tau hais tias NB-EPA nce qib ntawm phosphorylated AKT (p-AKT), ua raws li kev muaj sia nyob, hauv ischemic hlwb cov ntaub so ntswg 7 d tom qab HI kev sib tw (Daim duab 4C, D). Doublecortin (DCX) yog ib qho cim rau cov neuronal precursors thiab cov tub ntxhais hluas migrating neurons [18], thiab Ki-67 yog cov cim ntawm cell proliferation [19]. NB-EPA kev kho mob (19.83 ± 1.25 hlwb / mm3 ) zoo kawg nkaus nce tus naj npawb ntawm Ki-67 ntxiv rau DCX ntxiv cov hlwb 7 d post-HI piv nrog lub tsheb (11.83 ± 1.08 cell/mm3) (Daim duab 4E). Yog li, cov ntaub ntawv no qhia tau hais tias NB-EPA pab txhawb kev muaj sia nyob thiab kev loj hlob ntawm cov nas me me tom qab HI lub hlwb raug mob.

Daim duab 3. NB-EPA inhibits neuronal tuag nyob rau hauv neonatal nas tom qab HI hlwb raug mob. (A) Cov duab sawv cev ntawm HE staining nyob rau hauv cortex, hippocampus DG, CA1, thiab CA3 cheeb tsam los ntawm txhua pawg nas ntawm 7 hnub tom qab-HI (Scale bar, 75 μm). thiab Bax los ntawm txhua pawg nas ntawm 7 hnub tom qab HI. HI(sab laug, Scale bar, 25 um) nyob rau hauv lub paj hlwb cortex; Quantification ntawm NeuN thiab TUNEL dual-labeled hlwb ntawm 7 hnub tom qab-HI(Right). *p<005 compared="" to="">

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2.5. NB-EPA Txo HI-Induced Brain Damage los ntawm Kev Tiv Thaiv ntawm Neuronal Apoptosis

Raws li cov kev tiv thaiv saum toj no ntawm NB-EPA hauv neonatal HI lub hlwb puas tsuaj, peb tau soj ntsuam ntxiv qhov cuam tshuam ncaj qha ntawm NB-EPA ntawm neuronal ciaj sia nyob hauv vitro. Primary cortical neurons cultured rau 7 hnub nyob rau hauv vitro yog puag ncig thiab me me, nrog kev nplua nuj synapses thiab kev sib txuas sib txuas (Daim duab 5A). Lub purity ntawm neurons tau txiav txim siab los ntawm kev ntws cytometry, thiab tus nqi zoo tshaj 95 feem pua ​​(Daim duab 5B). NeuN* neurons kuj tau txheeb xyuas los ntawm immunofluorescence (Daim duab 5C). Cov txiaj ntsig no qhia tau tias thawj cortical neurons tau ua tiav kev coj noj coj ua.

Daim duab 4. NB-EPA txhim kho neuronal survival thiab proliferation hauv neonatal nas tom qab HI hlwb raug mob. (A) Cov duab sawv cev ntawm Nissl staining nyob rau hauv cortex, hippocampus DG, CAl, thiab CA3 cheeb tsam los ntawm txhua pab pawg nas ntawm 7 hnub tom qab-HI (Scale bar, 75 μm). (B) Kev txheeb xyuas txheeb cais ntawm tus naj npawb ntawm cov neurons tau qhia hauv (A). (C) Cov neeg sawv cev Western blot duab ntawm p-AKT thiab AKT los ntawm txhua pawg nas ntawm 7 hnub tom qab H. (D) Densitometric tsom xam ntawm cov ntaub ntawv tau qhia hauv (C). (E) Cov duab sawv cev ntawm DCX(ntsuab) thiab Ki-67 (liab) los ntawm txhua pawg nas ntawm 7 hnub tom qab HI (sab laug, Scale bar, 25 um) hauv cheeb tsam hippocampus DG; quantification ntawm DCXand Ki-67 dual-labeled cell ntawm 7 hnub tom qab-HI (txoj cai).Data yog txhais tau tias ±SEM (n=8 ib pab pawg).*p<0.05 compared="" to="">

Tom qab ntawd, cov neurons tau raug rau 3 h oxygen-glucose deprivation (OGD) thiab kho nrog ntau qhov sib txawv ntawm NB-EPA. Hypoxic neurons tshwm sim nrog atrophy thiab nuclear pyknosis hauv tsheb PBS-kho kab lis kev cai. Hauv qhov sib piv, NB-EPA kev kho mob tau txhim kho neuronal ciaj sia tom qab OGD (Daim duab 5D). Neuron ciaj sia tau ntsuas 24 teev tom qab siv cov khoom siv ntawm tes suav -8(CCK-8) kev tshuaj xyuas. Raws li pom nyob rau hauv daim duab 5E, NB-EPA kev kho mob pom tau tias cawm txoj sia nyob ntawm cov neurons tom qab OGD iniury. Qhov kev ua tau zoo tshaj plaws ntawm NB-EPA tau ua tiav ntawm 1 μM, uas tau siv rau txhua qhov kev sim hauv vitro. Flow cytometry tsom xam tau lees paub tias tus naj npawb ntawm annexin-zoo neurons nyob rau hauv NB-EPA-kho kab lis kev cai tau txo qis dua piv nrog lub tsheb PBS-kho kab lis kev cai (Daim duab 5F). Lub caij no, kev kho NB-EPA kuj tseem ua rau muaj kev cuam tshuam qhov kev qhia ntawm apoptosis-txog cov proteins, suav nrog p53, PUMA, thiab Bax hauv OGD-conditioned neurons (Daim duab 5G, H). Yog li ntawd, cov ntaub ntawv no txhais tau hais tias NB-EPA txo qis kev puas tsuaj ntawm neuronal los ntawm kev txhim kho ntawm kev muaj sia nyob hauv lub hlwb thaum inhibiting neuronal apoptosis.

Daim duab 5. NB-EPA txo cov ischemic neuronal raug mob tom qab OGDchallenge. (A) Cov duab sawv cev ntawm thawj cortical neurons kab lis kev cai ntawm 1,3 thiab 7 hnub (Scale bar, 25 μm). (B) Qhov feem pua ​​​​ntawm NeuN ntxiv cov hlwb los ntawm thawj cortical neurons kab lis kev cai rau 7 hnub hauv vitro.(C) Cov duab sawv cev ntawm NeuN(ntsuab) thiab 4',6-diamidino-2-phenylindole (DAPI) ( xiav) los ntawm thawj cortical neurons kab lis kev cai rau 7 hnub hauv vitro (Scale bar, 10 um). (D) Cov duab sawv cev ntawm thawj cortical neurons los ntawm txhua pawg ntawm 24 hof kab lis kev cai tom qab 3 h OGD (Scale bar, 25 μm). (E)CCK-8 assay nyob rau hauv neutron-enriched kab lis kev cai raug rau 3 h OGDor tswj tej yam kev mob raws li kev kho mob nrog ib tug ntau ntawm cov concentrations ntawm NB-EPA rau lwm 24 h.(F) Qhov feem pua ​​ntawm annexing neurons ntawm 24 teev ntawm kab lis kev cai tom qab 3 h OGD. (G) Cov neeg sawv cev Western blot duab ntawm p53, PUMA, thiab Bax los ntawm txhua pab pawg ntawm 24 h ntawm kab lis kev cai tom qab 3 h OGD.(H) Densitometric tsom xam ntawm cov ntaub ntawv qhia hauv (G). Cov ntaub ntawv txhais tau tias ±SEM (n =3 hauv txhua pab pawg).* p<0.05 compared="" to="">

2.6. NB-EPA Tiv Thaiv Neurons los ntawm Apoptosis los ntawm Kev Tiv Thaiv ntawm p53-PUMA

Kev taw qhia Txoj hauv kev p53-PUMA paub tias koom nrog ischemia / reperfusion-induced cerebral neuronal cell apoptosis [20]. Peb tau tshawb xyuas ntawm no seb qhov kev tiv thaiv ntawm NB-EPA tiv thaiv kev tuag neuronal puas cuam tshuam rau inhibition ntawm p53-PUMA txoj hauv kev. Raws li pom nyob rau hauv daim duab 6A, NB-EPA abrogated OGD-conditioned cell apoptosis tab sis tsis muaj kev cuam tshuam rau cov qauv pretreated nrog Pififithrin- (PFT), p53 inhibitor. Lub caij no, kev kho mob NB-EPA tau ua rau muaj kev cuam tshuam qhov kev qhia ntawm pro-apoptotic protein Bax hauv OGD-conditioned neurons tab sis tsis muaj kev cuam tshuam rau cov pretreated nrog PFT (Daim duab 6B). PUMA qhia tau pom zoo hauv cov neurons tom qab qhov kev sib tw OGD, thaum PUMA mRNA thiab cov lus qhia protein tsis hloov pauv hauv PFT -pretreated neurons, qhia tias PUMA induction hauv neurons yog p53- nyob ntawm (Daim duab 6C). NB-EPA kev kho mob inhibited OGD-induced PUMA qhia hauv neurons tab sis tsis muaj kev cuam tshuam rau PFT-pretreated neurons (Daim duab 6C). Cerebral neurons nrog tshwj xeeb PUMA silencing pom qhov qis dua ntawm cov hlwb apoptotic (Daim duab 6D) thiab txo qis ntawm Bax protein (Daim duab 6E) ntawm 24 teev tom qab OGD kev sib tw piv rau PUMA-expressing neurons. Yog li, cov ntaub ntawv no qhia tau hais tias NB-EPA-mediated inhibition ntawm OGD-induced neuron apoptosis yog feem ntau nyob ntawm kev tsuj ntawm p53-PUMA txoj kev.

Daim duab 6. NB-EPA txo cov neuron apoptosis los ntawm inhibition ntawm p53-PUMA txoj kev. (A) Qhov feem pua ​​​​ntawm annexin ntxiv rau cov neurons nrog lossis tsis muaj p53 inhibition ntawm 24 h ntawm kab lis kev cai nrog lossis tsis muaj NB-EPA thiab tom qab 3 h OGD. (B) Tus neeg sawv cev Western blot duab ntawm Bax nrog lossis tsis muaj p53 inhibition ntawm 24 h ntawm kab lis kev cai nrog lossis tsis muaj NB-EPA thiab tom qab 3 h OGD (sab laug); densitometric tsom xam ntawm Bax protein qhia (txoj cai). (C) PUMA mRNA qhia hauv neurons ntawm 12h ntawm kab lis kev cai nrog lossis tsis muaj NB-EPA thiab tom qab 3 h OGD (sab laug); txhais tau tias feem pua ​​​​ntawm PUMA protein qhia hauv cov neurons ntawm 24 teev ntawm kab lis kev cai nrog lossis tsis muaj NB-EPA thiab tom qab 3 h OGD (txoj cai). (D) Qhov feem pua ​​​​ntawm cov annexin neurons nrog lossis tsis muaj PUMA knockdown ntawm 24 teev ntawm kab lis kev cai nrog lossis tsis muaj NB-EPA thiab tom qab 3 h OD.(E) Tus Neeg Sawv Cev Western blot duab ntawm Bax nrog lossis tsis muaj PUMA knockdown ntawm 24 teev ntawm kab lis kev cai nrog lossis tsis muaj NB-EPA thiab tom qab 3 h OGD (sab laug); densitometric tsom xam ntawm Bax protein qhia (txoj cai).Cov ntaub ntawv txhais tau tias ± SEM (n=3 ib pawg).*p< 0.05="" compared="" to="" vehicle.="" n.s.="" not="">

3. Kev sib tham

Neonatal hypoxic-ischemic kev puas tsuaj los ntawm perinatal asphyxia yog ib qho ntawm cov kab mob ntau tshaj plaws nyob rau hauv lub sij hawm neonatal. Muaj qhov tsis muaj txiaj ntsig ntawm kev kho tshuaj kho mob uas txo cov kev raug mob hauv hlwb lossis txhim kho cov hlab ntsha hauv cov menyuam mos [21]. Hauv txoj kev tshawb fawb tam sim no, peb pom tias kev kho mob nrog cov macamide tshiab NB-EPA tau txo qhov kev raug mob ntawm lub hlwb hypoxic-ischemic hauv cov nas me me. Kev tiv thaiv neuroprotection ntawm NB-EPA tau cuam tshuam nrog kev tswj hwm ntawm kev muaj sia nyob ntawm neuronal thaum inhibiting neuronal tuag. Qhov tshwj xeeb, NB-EPA-mediated antiapoptotic mechanism yog nyob ntawm kev tawm tsam ntawm p53-PUMA signaling. Macamides, lub npe hu ua tus yam ntxwv cim cov khoom sib txuas ntawm maca, muaj benzylamine thiab cov saw ntev fatty acid moiety nrog qhov sib txawv ntawm qhov tsis txaus ntseeg [22].

Nees nkaum-peb hom macamides tau tshaj tawm nyob rau hauv maca extract, ntawm cov uas N-benzylhexadecanamide yog cov ntau tshaj plaws nyob rau hauv maca los ntawm Peru, thaum N-benzyl-9Z,12Z-octadecadienamide yog cov nplua nuj nyob rau hauv lub Yunnan maca. [23]. Hauv txoj kev tshawb no, peb tau txheeb xyuas qhov tshiab macamide NB-EPA hauv maca los ntawm Yunnan. Cov macamide NB-EPA yog tsim los ntawm benzylamine thiab eicosapentaenoic acid (EPA; 20:5, n{11}}), ib qho ntawm cov khoom tseem ceeb ntawm omega-3 polyunsaturated fatty acid (n-3 PUFA) ). n-3 PUFAs thiab lawv cov metabolites tau tshaj tawm tias muaj nyob rau hauv lub hauv paus paj hlwb thiab ua lub luag haujlwm tseem ceeb hauv kev ua haujlwm ntawm lub hlwb thiab kab mob, xws li neurotransmission, neurogenesis, thiab neuroinflammation [24]. Nco ntsoov, qee qhov kev tshawb fawb tau qhia tias EPA, es tsis yog n-3 PUFAs thiab docosahexaenoic acid (DHA; 22:6, n{19}}), muaj feem xyuam rau kev pheej hmoo tsawg dua ntawm feem ntau hom ischemic stroke [25 ]. Raws li kev pom zoo nrog cov kev tshawb pom no, peb tau pom tias qhov tshiab no macamide NB-EPA tsis tsuas yog txo qis kev raug mob ntawm lub hlwb, tab sis kuj tseem txhim kho cov kev coj cwj pwm tsis zoo tom qab HI raug mob. Neurons yog cov txheej txheem yooj yim tshaj plaws thiab kev ua haujlwm ntawm lub paj hlwb, uas muaj lub luag haujlwm ntawm kev sib txuas thiab sib txuas cov ntaub ntawv tawm tswv yim thiab xa tawm cov ntaub ntawv. Thaum lub paj hlwb raug mob, tshwm sim los ntawm hypoxia thiab ischemia, ntau cov neurons raug puas ntsoog, uas, dhau los, ua rau lub paj hlwb tsis ua haujlwm. p53, tus tswj hwm tseem ceeb ntawm cov lus teb ntawm cov xov tooj ntawm tes, tuaj yeem qhib rau hauv thaj chaw ischemic tom qab raug mob hlwb [26]. Nws tuaj yeem txhawb nqa neuronal apoptosis, thiab p53 tsis txaus lossis daim ntawv thov ntawm p53 inhibitors tuaj yeem ua rau lub hlwb puas tsuaj hauv ntau hom mob stroke [27]. p53-mediated apoptosis tshwm sim los ntawm ntau yam molecular mechanisms, ntawm cov uas PUMA, ap53- thiab upregulated modulator ntawm apoptosis, yog ib tug muaj zog proapoptotic noob downstream ntawm p53 [28]. Cov kev tshawb fawb tau pom tias txoj kev p53-PUMA tau koom nrog hauv mitochondrial inhibitor-induced apoptosis ntawm striatum neurons hauv nas [29].

mob raum thiab kab mobcistanche propiedades

Inhibition ntawm p53-PUMA tawm tswv yim voj kev ua kom los ntawm p53 inhibitors thiab PUMA siRNA tuaj yeem txo cov neuronal apoptosis thiab mob tshwm sim los ntawm ischemia-reperfusion [30]. Ntawm no, peb qhov kev tshawb pom zoo ib yam nrog cov kev tshawb fawb no qhia tias PUMA yog tus thawj coj muaj zog ntawm p53- kho apoptosis hauv cov neurons tom qab HI lub hlwb raug mob. NB-EPA kev kho mob inhibits HI-induced elevation ntawm PUMA hauv neurons. Tsis tas li ntawd, kev tiv thaiv los ntawm NB-EPA ntawm kev muaj sia nyob neuronal yog nyob ntawm kev tsim txom ntawm PUMA signaling. Incremental pov thawj qhia tau hais tias n-3 PUFAs pab txhawb rau neuron ciaj sia taus thiab neurogenesis tom qab ischemic cerebral puas [31,32]. Lawv tuaj yeem txhim kho kev mob stroke thiab txwv kev puas tsuaj ntxiv rau neuron [33]. Txawm hais tias ischemic stroke induces proliferation thiab sib txawv ntawm neural progenitor hlwb nyob rau hauv subventricular cheeb tsam (SVZ), feem ntau ntawm cov tshiab generated neurons tuag sai tom qab mob stroke [34]. n-3 PUFAs tau raug tshaj tawm tsis yog los txhim kho kev ciaj sia ntawm cov neurons tsis paub tab tab sis kuj pab txhawb lawv txoj kev loj hlob hauv cortical parenchyma tom qab mob stroke puas tsuaj [35]. Tsis ntev los no, ntau qhov kev tshawb fawb kuj tau qhia txog cov txiaj ntsig zoo ntawm macamides hauv kev ua kom zoo dua ntawm kev puas hlwb neuronal, uas cuam tshuam rau kev txhim kho ntawm mitochondrial ua pa ua haujlwm [36,37].

AKT teeb liab kev hloov pauv txoj hauv kev ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv apoptosis mechanism. Thaum lub paj hlwb raug mob, txoj kev AKT tau qhib, thiab lub cev pib tiv thaiv tus kheej thiab kho kev raug mob, ua rau muaj kev nce ntxiv ntawm p-AKT [38–41]. Nyob rau hauv txoj kab nrog cov kev tshawb pom no, peb pom tias kev kho mob nrog NB-EPA tiv thaiv neuronal ciaj sia tawm tsam HI-mediated hlwb raug mob los ntawm kev ua kom muaj sia nyob AKT teeb liab thaum inhibiting txoj kev pro-apoptotic.

Tau ntev, neurobiologists ntseeg tias neural stem cells (NSCs) ploj mus sai sai ua ntej lossis tom qab yug me nyuam, thiab neurogenesis tau nres thaum lub sijhawm ntawd. Qhov kev xav tias tsis muaj cov neurons tshiab hauv lub hlwb paub tab pib hloov pauv hauv 1960s. Nrog rau kev txhim kho ntawm kev tshawb fawb, nws tau pom tias cov neeg laus NSCs feem ntau muaj nyob hauv SVZ thiab subgranular zone (SGZ) ntawm hippocampal dentate gyrus [42–44]. Tsis tas li ntawd, tom qab ntawd nws tau lees paub tias NSCs kuj muaj nyob rau hauv lwm qhov chaw dav dav ntawm lub hauv paus paj hlwb (CNS) [45]. Cov kev tshawb fawb tsis ntev los no tau pom tias endogenous NSCs nyob rau hauv lub cortex tuaj yeem qhib tau tom qab lub hlwb raug mob los pab txhawb kev kho mob ntawm hypoxic-ischemic lub hlwb raug mob los ntawm kev rov ua dua tshiab, kev loj hlob, thiab tiam tshiab ntawm cov neurons, astrocytes, thiab oligodendrocytes [46,47] . DCX pab txhawb kev kho neuronal los ntawm kev ruaj khov microtubules hauv cov hlwb neuronal thiab sawv cev rau cov cim rau kev taug qab kev tsiv teb tsaws ntawm cov neurons tshiab rau hauv qhov chaw raug mob ntawm lub hlwb [48]. Hypoxic-ischemic lub hlwb raug mob thiab mob hlwb raug mob hnyav ua rau muaj kev tsim cov striatum neurons tshiab uas qhia DCX [49]. Ki-67 yog cov tshuaj tiv thaiv nuclear cuam tshuam nrog cov cell proliferating, npog txhua lub voj voog loj hlob uas tsis yog G0 theem. Hauv txoj kev tshawb no, NB-EPA kev tswj hwm pom tau tias txhawb nqa neurogenesis, uas cuam tshuam nrog kev txhim kho ntawm Ki-67 ntxiv rau DCX ntxiv cov hlwb tom qab HI lub hlwb raug mob. Txawm li cas los xij, txawm tias qhov nce ntawm Ki-67 ntxiv rau DCX ntxiv rau cov hlwb muaj feem cuam tshuam nrog kev loj hlob thiab kev sib txawv ntawm cov kab mob neural qia hlwb raug ntxias los ntawm NB-EPA tseem yuav tsum tau kawm ntxiv.

Cov ntaub ntawv

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