Part 2: Tib neeg Mis nyuj Oligosaccharide 2/-Fucosyllactose Induces Neuroprotection Los Ntawm Intracerebral Hemorrhage Stroke

Hu rau: Audrey Hu Whatsapp / hp: 0086 13880143964 Email:audrey.hu@wecistanche.com

Pls nyem qhov no mus rau Part 1

3. Kev sib tham

Hauv txoj kev tshawb no, 2FL txo qis hemin-induced microglia activation thiabneurodegenerationnyob rau hauv thawj corticalneuronthiab BV2 microglia coculture. 2FL txhim kho kev ua haujlwm hauv lub tshuab ua haujlwm hauv ICH nas. Siv cov tshuaj immunohistochemical thiab qPCR tsom xam, peb tau pom tias 2FL inhibited microglia activation, CD4 (ntxiv rau) lymphocyte infilltration, thiab kev qhia ntawm inflammatory thiab ER stress markers nyob rau hauv lub hlwb ICH. Qhov tseem ceeb ntawm txoj kev tshawb no yog tias 2FL yogneuroprotectivetiv thaiv ICH raug mob.

ICH ua rau mob hnyav thiab tsis tuaj yeem ua rau lub hlwb puas. Tom qab qhov kev thuam hnyav, cov kev tshwm sim cascade tig rau, uas ua rau muaj kev cuam tshuam thib ob. Hemoglobin thiab nws cov khoom degradation yog ze rau kev raug mob thib ob. Hemin yog cytotoxic thiab ua rau lub hlwb puas, nrog rau hemorrhagic stroke [21,22]. Ntau dhau hemin catalyzes dawb-radical saw cov tshuaj tiv thaiv [23] thiab ua kom yooj yim apoptosis thiab mitochondrial fission [24]. Hemin kuj tseem muaj peev xwm ua kom microglial ua kom hnyav dua thiab ua rau muaj kev raug mob tshwm sim tom qab intracerebral hemorrhage [25,26]. Hauv txoj kev tshawb no, hemin tau siv los simulate ICH hauv aneuronthiab BV2 microglia coculture. Peb pom tias yog heminneurotoxicthiab activated microglia. Kev kho mob nrog 2FL txo qis hemin-mediated IBA1 ua kom thiab rov qab kho MAP2 immunoreactivity. Peb cov ntaub ntawv qhia tias 2FL yog tshuaj tiv thaiv kab mob thiabneuroprotectivenyob rau hauv lub cellular qauv ntawm ICH.

Yav dhau los, peb tau pom tias hauv zos collagenase infusion ua rau ICH thiab bradykinesia hauv nas [13]. Hauv txoj kev tshawb no, tus qauv tsiaj zoo sib xws tau siv los tshuaj xyuas qhov kev tiv thaiv ntawm 2FL hauv vivo. Peb tau ua pov thawj tias qhov kev siv ntawm 2FL rau 5 hnub txhim kho kev txav chaw hauv ICH nas. Raws li kev mob tshwm sim ua lub luag haujlwm tseem ceeb hauv kev loj hlob ntawm ICH [7,8,27], peb kuj pom microglia ua rau hauv ICH hlwb. 2FL txo IBA1-ir thiab ib nrab rov qab los ntawm microglia hauv cov hlab ntsha ICH hlwb. Ntxiv mus, peb pom tias 2FL upregulates qhov kev qhia ntawm M2 (anti-inflammatory) microglia/macrophage inflammatory makers nyob rau hauv lub hlwb nas ICH. Cov ntaub ntawv no qhia tias 2FL suppressed ICH-mediated microglia activation nyob rau hauv lub hlwb lesioned.

ICH txhawb kev tsiv teb tsaws ntawm peripheral lub cev tiv thaiv kab mob, xws li CD4 ntxiv thiab CD8 ntxiv rau T hlwb, mus rau lub hlwb lesioned [28,29]. Peb yav dhau los tau tshaj tawm qhov kev qhia ntawm cytotoxic T-cell cov cim hauv ICH hlwb [13]. Tsis tas li ntawd, qhov siab tshaj plaws infiltration ntawm CD4 T hlwb yog nyob nruab nrab ntawm hnub 3 thiab 4 tom qab ischemic raug mob hauv nas [30]. Hauv txoj kev tshawb no, peb tau pom tias ICH tau nce CD4 ntxiv rau lymphocyte infiltration rau hauv cov kab mob striatum hnub 5 hauv nas; CD4 cell infiltration tau txo qis los ntawm 2FL. Cov ntaub ntawv no txhawb qhov kev xav tias 2FL inhibits T-cell tsiv teb tsaws los ntawm periphery mus rau ICH hlwb.

Cistanche muaj cov nyhuv neuroprotective

Cov kev tshawb fawb yav dhau los tau qhia tias 2FL muaj kev tiv thaiv zoo nyob rau hauv ib puag ncig. Hauv tib neeg enterocytes, 2FL txo qis qhov induction ntawm CD14 [18] thiab kev qhia ntawm IL-8, IL-1b, thiab MIP-2 [31]. 2FL kuj txo qis qhov hnyav ntawm necrotizing enterocolitis nyob rau hauv nas neonatal txoj hnyuv [32]. Hauv txoj kev tshawb no, peb tau pom tias 2FL muaj kev tiv thaiv kab mob thiabneuroprotectivecov teebmeem hauv ICH lub hlwb. Lwm cov kev tshawb fawb kuj txhawb tias 2FL txhim kho kev kawm thiab hippocampal lub sijhawm ntev ntawm cov nas hauv nas [17], nrog rau kev tiv thaiv cell tuag hauv lub hlwb ischemic [19]. Cov ntaub ntawv no qhia tias 2FL muaj ntau yam txiaj ntsig zoo tiv thaiv CNS thiab peripheral o thiab degeneration.

ICH tuaj yeem ua rau theem nrabneurodegenerationlos ntawm ER kev nyuaj siab [33]. Piv txwv li, txoj hauv kev PERK tau qhib rau hauv ICH lub hlwb, raws li muaj pov thawj los ntawm kev tswj hwm ntawm p-eIF2& thiab ATF4 [34]. Qhov tshwm sim ER kev ntxhov siab ntxiv ua rauneuronalapoptosis thiab cell tuag. Peb kuj tau tshaj tawm tias qhov kev qhia ntawm PERK, IRE1, CHOP, SigmaR1, thiab caspase-3 tau txhim kho hauv ICH lub hlwb. 2FL tseem ceeb inhibited cov lus teb no. Cov txheej txheem ntxaws ntxaws hauv qab txoj cai ntawm ER kev ntxhov siab los ntawm 2FL daim ntawv pov thawj kev tshawb nrhiav.

Muaj qee qhov kev txwv rau txoj kev tshawb no. Peb tsis tau siv qhov loj ntawm hematoma los ntsuas qhov tshwm sim tom qab 2FL kho. Raws li tau hais dhau los, kev txheeb xyuas ntawm thaj chaw hematoma ntawm cov kab mob histological feem ntau yog siv zog ua haujlwm thiab qee zaum cov ntsiab lus [35]. Ib txoj hauv kev tshiab tau tsim los tsis ntev los no los tso cai ntsuas qhov tseeb thiab ua tau zoo ntawm cerebral hematoma ntim [35]. Nws yuav yog qhov txaus siab los txiav txim siab txog kev sib koom ua ke ntawm hematoma ntim nrog kev txhim kho hauv kev ua haujlwm hauv locomotor tom qab kho 2FL siv txoj hauv kev tshiab no. Peb txoj kev tshawb fawb tau ua nyob rau hauv cellular thiab tsiaj qauv ntawm ICH. Ntxiv cov kev tshawb fawb tsis yog tib neeg primate thiab cov kev sim randomized ntawm 2FL kev kho mob hauv tib neeg cov ntsiab lus yuav tsum tau ua ua ntej nws siv tshuaj kho mob.

Tib neeg cov mis nyuj yog suav tias yog qhov zoo tshaj plaws ntawm kev noj haus rau cov menyuam yug tshiab thiab tsim cov menyuam mos. Tshaj li nws cov khoom noj khoom haus, tib neeg cov mis nyuj kuj muaj cov txiaj ntsig zoo [36], xws li 2FL. Nyob rau hauv txoj kev tshawb no, peb pom tau hais tias 2FL, ib tug bioactive tivthaiv nyob rau hauv tib neeg cov mis nyuj, muaj kev tiv thaiv los ntawm ICH. 2FL tuaj yeem muaj qhov cuam tshuam rau kev kho mob ntawm ICH.

txiaj ntsig ntawm cistanche extract

4. Cov ntaub ntawv thiab cov txheej txheem

4.1. Tsiaj

Cov txiv neej laus thiab lub sijhawm cev xeeb tub Sprague-Dawley nas tau yuav los ntawm BioLASCO, Taipei, Taiwan. Kev siv tsiaj tau pom zoo los ntawm Pawg Saib Xyuas Tsiaj Tshawb Fawb ntawm National Health Research Institutes of Taiwan (NHRI-IACUC106101-A). Txhua qhov kev sim tsiaj tau ua raws li National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 8023, revised 1978).

4.2. Khoom siv

2′-Fucosyllactose yog muab los ntawm Advanced Protein Technologies Corp. (Suwon-si, Gyeonggi-do Province, Kauslim). Bovine serum albumin, chloral hydrate, fetal bovine serum, L-glutamate, paraformaldehyde, poly-D-lysine, hemin, thiab Triton X-100 tau yuav los ntawm Sigma (St. Louis, MO, USA). Alexa Fluor 488 (secondary antibody), B27 ntxiv, Dulbecco's modified Eagle's nruab nrab,NeurobasalNruab nrab, thiab trypsin tau yuav los ntawm Invitrogen (Carlsbad, CA, USA). Anti-CD4 antibody tau yuav los ntawm Proteintech (Rosemont, IL, USA). Anti-MAP2 tau yuav los ntawm Millipore (Burlington, VT, USA). Anti-IBA1 antibody tau yuav los ntawm Wako (Richmond, VA, USA).

4.3. Primary Rat Cortical Neuron (PCN) thiab Microglia Coculture

Thawj corticalneuron(PCN) kab lis kev cai tau npaj los ntawm embryonic (E14-15) cortex cov ntaub so ntswg tau los ntawm fetuses ntawm lub sij hawm cev xeeb tub Sprague-Dawley nas. Tom qab tshem tawm cov hlab ntsha thiab meninges, cov cortices pooled tau trypsinized (0.05 feem pua; Invitrogen, Carlsbad, CA, USA) rau 20 feeb ntawm chav tsev kub. Tom qab yaug tawm trypsin nrog pre-warmed Dulbecco's modificed Eagle's nruab nrab (Invitrogen, Carlsbad, CA, USA), cov hlwb raug dissociated los ntawm trituration, suav, thiab plated rau hauv 96-zoo (5.0 × 104/well) cell kab lis kev cai daim hlau precoated nrog poly-D-lysine (Sigma-Aldrich, St. Louis, MO, USA). Cov kab lis kev cai plating nruab nrab muajneurobasalnruab nrab ntxiv nrog 2 feem pua ​​​​ntawm tshav kub-inactivated FBS, 0.5 mmol/L L-glutamine, 0.025 mM L-glutamate, thiab 2 feem pua ​​B27 (Invitrogen, Carlsbad, CA, USA). Cov kab lis kev cai tau khaws cia ntawm 37 ℃ nyob rau hauv qhov chaw humidified ntawm 5 feem pua ​​​​CO2 thiab 95 feem pua ​​​​ntawm huab cua. Cov kab lis kev cai tau pub los ntawm kev sib pauv 50 feem pua ​​​​ntawm nruab nrab nrog kev noj zaub mov nruab nrab (neurobasal nruab nrab), 0.5 mmol / L L-glutamine, thiab 2 feem pua ​​​​B27 nrog cov tshuaj antioxidant ntxiv rau hnub hauv vitro ( DIVs) 3 thiab 5. BV2 microglia raug cais cais, cais los ntawm 0.05 feem pua ​​trypsin-ethylenediaminetetraacetic acid (EDTA, Invitrogen), thiab centrifuged ntawm 100 × g rau 5 min. BV2 hlwb raug tshem tawm hauv qhov nruab nrab pub mis uas muaj B27 ntxiv yam tsis muaj tshuaj tua kab mob (一AO, los ntawm Invitrogen, Carlsbad, CA, USA). Qhov ceev ntawm cov hlwb uas muaj sia nyob tau suav nrog kev sim tshuaj xiav trypan; cov hlwb tau plated ntawm PCN plated qhov dej ntawm qhov siab ntawm 3.0 × 103 / zoo ntawm DIV 7, raws li tau piav qhia yav dhau los [37]. Cov cocultures tau noj nrog 一AO nruab nrab ntawm DIVs 7 thiab 10. Ntawm DIV 10, kab lis kev cai raug kho glutamate nrog 2FL lossis tsheb. Thaum 48 teev tom qab kev kho tshuaj, cov hlwb raug kho nrog 4 feem pua ​​​​ntawm paraformaldehyde (PFA, Sigma-Aldrich, St. Louis, MO, USA) rau 1 teev ntawm chav tsev kub.

neuroprotective teebmeem ntawm cistanche: kho tus kab mob Parkinson

4.4. Immunocytochemistry

Tom qab tshem tawm 4 feem pua ​​​​PFA cov tshuaj, cov hlwb raug ntxuav nrog PBS. Cov hlwb raug kho nrog cov tshuaj thaiv thaiv (5 feem pua ​​BSA thiab 0.1 feem pua ​​Triton X-100 hauv PBS) rau 1 teev. Cov hlwb raug incubated rau 1 hnub ntawm 4 О C nrog nas monoclonal antibody tiv thaiv MAP2 (1: 500; Millipore, Billerica, MA, USA) thiab luav polyclonal antibody tiv thaiv IBA1 (1: 500; Wako, Richmond, VA, USA) , ua ntej yaug peb zaug hauv PBS. Tus thawj cov tshuaj tiv thaiv kab mob tau pom los ntawm kev siv AlexaFluor 488 tshis los tiv thaiv nas lossis AlexFluoro 568 tshis tiv thaiv kab mob ntshav qab zib theem nrab (Invitrogen, Carlsbad, CA, USA). Cov duab tau txais los ntawm kev siv lub koob yees duab DS-Qi2 (Nikon, Tokyo, Nyiv, Nyiv) txuas nrog NIKON ECLIPSE Ti2 (Nikon, Tokyo, Nyiv) inverted microscope los ntawm cov neeg saib tsis pom kev. Qhov pixel ntom ntawm MAP2-ir lossis IBA1-ir tau txheeb xyuas siv NIS Elements AR 5.11 Software (Nikon).

4.5. Kev phais

Cov nas tsuag tau nyob hauv 12 teev tsaus ntuj (7 teev tsaus ntuj txog 7 teev sawv ntxov) thiab 12 teev tsaus ntuj (7 teev sawv ntxov txog 7 teev tsaus ntuj). Tsiaj txhu tau tshuaj loog thiab muab tso rau hauv ib qho stereotaxic ncej. Hom VII collagenase (0.5 U/uL × 1.0 uL, C{{10}}, Sigma Aldrich, St. Louis, MO, USA) tau txhaj tshuaj stereotactically mus rau txoj cai striatum (coordinates: 0.0 mm rostral thiab 3.0 hli lateral rau bregma, 5.5 mm hauv qab pob txha taub hau) ntawm 0.4 uL/min Tshaj li 5 feeb ntawm hnub 0. Tom qab ntawd, 2FL (400 mg / kg / hnub × 5 hnub) lossis lub tsheb tau muab ip txij hnub 1 txog rau hnub 5. Tsiaj txhu tau muab txi rau hnub 5 rau kev soj ntsuam histological thiab PCR.

4.6. Locomotor Kev Ntsuas Tus Cwj Pwm

Locomotion tau ntsuas rau hnub 5 uas siv lub ntsuas ntsuas infrared (Accuscan, Columbus, OH, USA). Cov nas tau muab tso rau hauv ib qho 3D infrared cwj pwm chamber (42 × 42 × 21 cm) rau 120 min. Rau qhov txawv txav tau ntsuas: (i) ntsug kev ua haujlwm (VACTV, tag nrho cov nqaj cuam tshuam uas tshwm sim hauv cov ntsuas ntsug), (ii) tag nrho cov kev mus los (TOTDIST, qhov kev ncua deb, hauv centimeters, taug kev los ntawm cov tsiaj), (iii) ) ntsug txav lub sij hawm (VTIME), (iv) kab rov tav kev ua si (HACTV, tag nrho cov beam interruptions uas tshwm sim nyob rau hauv kab rov tav sensors), (v) kab rov tav txav sij hawm (MOV- TIME), thiab (vi) tus naj npawb ntawm ntsug txav (VMOVNO).

4.7. Immunohistochemistry

Tsiaj txhu tau tshuaj loog thiab perfused transcardially nrog saline ua raws li 4 feem pua ​​​​PFA hauv phosphate buffer (PB; 0.1 mol/L; pH 7.2); lawv tau tom qab kho rau 18–20 h thiab tom qab ntawd hloov mus rau 20 feem pua ​​​​sucrose hauv 0.1 M PB rau tsawg kawg 16 teev. Serial seem ntawm lub hlwb

raug txiav ntawm 30 um thickness siv lub cryostat (qauv: CM 3050 S; Leica, Heidelberg, Lub teb chaws Yelemees). Cov kab mob hlwb tau muab yaug hauv PB thiab raug thaiv nrog 4 feem pua ​​​​bovine serum albumin (Sigma-Aldrich) nrog 0.3 feem pua ​​Triton X-100 (Sigma-Aldrich) hauv 0.1 mM PB. Lub paj hlwb raug muab tso rau hauv thawj cov tshuaj tiv thaiv CD4 (polyclonal 1: 100, protein tech, Rosemont, USA) lossis IBA1 (monoclonal 1: 100, Wako, Richmond, VA, USA) ntawm 4 О C thaum hmo ntuj. Cov seem tau muab yaug hauv 0.1 mM PB thiab incubated nyob rau hauv Alexa Fluor 488 Secondary antibody tov (1:500; Molecular Probes, Eugene, OR, USA). Cov seem tswj tau incubated yam tsis muaj thawj cov tshuaj tiv thaiv. Lub paj hlwb tau mounted rau slides thiab coverlipped. Confocal tsom xam tau ua los ntawm Nikon D-ECLIPSE 80i microscope (Nikon Instruments, Inc., Tokyo, Nyiv) thiab EZ-C1 3.90 software (Nikon, Tokyo, Nyiv). Qhov optical ntom ntom ntawm IBA1 lossis CD8 immunoreactivity tau txheeb xyuas nyob rau hauv ob lub hlwb sib law liag nrog rau qhov pom kev pom sab hauv ntawm txhua tus tsiaj. Ob photomicrographs raug coj mus rau hauv cheeb tsam peri-lesioned ib lub hlwb hlais; IBA1 lossis CD4 optical ntom ntom tau soj ntsuam siv NIS Elements AR 3.2 Software (Nikon) thiab tau nruab nrab hauv txhua lub hlwb rau kev txheeb xyuas kev txheeb xyuas. Txhua qhov kev ntsuas immunohistochemical tau ua los ntawm cov neeg saib tsis pom kev.

neuroprotective teebmeem ntawm cistanche: antiparkinson tus kab mob

4.8. Quantitative Reverse Transcription PCR (RT-PCR)

Striatal cov ntaub so ntswg los ntawm cov kab mob thiab tsis-lesioned hemispheres tau sau. Tag Nrho RNAs raug rho tawm siv TRIzol Reagent (ThermoFisher, #15596-018, Waltham, MA, USA), thiab cDNAs tau tsim los ntawm 1 ug ntawm tag nrho RNA los ntawm kev siv RevertAid H Minus First-Strand cDNA Synthesis Kit (Thermo Scientific) , #K1631, Waltham, MA, USA). cDNA qib rau CD86, CD206, TGF, PERK, IRE1, CHOP, Sigmar1, BIP, ATF6, caspase3, actin, thiab GAPDH tau txiav txim siab siv cov kev sojntsuam thoob ntiaj teb cov tsev qiv ntawv primer-probe sets lossis gene-specific primers (Table 2). Cov qauv sib xyaw nrog TaqMan Fast Advanced Master Mix (Lub Neej Technologies, #4444557, Carlsbad, CA, USA) lossis SYBR (Luminaris Xim HiGreen Low ROX qPCR Master Mix; ThermoScientific, Waltham, MA, USA). Quantitative real-time PCR (qRT-PCR) tau ua los ntawm QuantStudio™ 3 Real-Time PCR System (ThermoScientific, Waltham, MA, USA). Qhov kev qhia ntawm lub hom phiaj noob tau zoo li qub txheeb ze rau cov noob siv endogenous (beta-actin thiab GAPDH qhov nruab nrab) siv qhov hloov kho delta-delta-Ct algorithm. Tag nrho cov kev sim tau ua nyob rau hauv duplicate.

4.9. Kev txheeb cais

Cov ntaub ntawv raug nthuav tawm raws li qhov nruab nrab 士 SEM. Ib qho kev sib tw t-test lossis ib-lossis ob-txoj kev ANOVA tau siv rau kev sib piv cov lej, nrog rau qib tseem ceeb ntawm p < 0.05.="" nyob="" rau="" hauv="" qhov="" kev="" tshwm="" sim="" ntawm="" ntau="" qhov="" kev="" sib="" piv,="" ib="" tug="" post="" hoc="" newman-keuls="" xeem="" tau="">

Sau Kev Pabcuam: T.-WH, sau ntawv sau, kev phais tsiaj, thiab sau thiab/lossis sib dhos ntawm cov ntaub ntawv; K.-JW, kev phais tsiaj thiab sau thiab/lossis sib dhos ntawm cov ntaub ntawv; Y.-SW, PCR, sau thiab/lossis sib dhos ntawm cov ntaub ntawv; E.-KB, kab lis kev cai ntawm tes, immunocytochemistry, thiab kev txheeb xyuas cov ntaub ntawv; YS thiab JY, 2′ -FL synthesis, cov ntaub ntawv tsom xam thiab txhais lus, thiab muab cov ntaub ntawv kawm; S.-JY, kev xav thiab tsim qauv, sau ntawv sau, kev txhawb nqa kev tswj hwm, thiab kev pom zoo kawg ntawm cov ntawv sau. Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.

Cov Nyiaj Txiag: Txoj kev kawm no tau txais kev txhawb nqa los ntawm National Health Research Institutes, Taiwan (NP-109-PP-02) thiab Ministry of Science thiab Technology, Taiwan (Feem ntau 106-2320-B{{3}) }}MY2; MOST 108-2320-B-400-023).

Institutional Review Board Statement: Txoj kev tshawb no tau ua raws li cov lus qhia ntawm Kev Tshaj Tawm ntawm Helsinki thiab pom zoo los ntawm Pawg Saib Xyuas Tsiaj Tshawb Fawb ntawm Lub Tebchaws Kev Noj Qab Haus Huv

Kev tshawb fawb lub koom haum ntawm Taiwan (NHRI-IACUC106101-A).

Cov Lus Qhia Txog Kev Pom Zoo: Tsis siv tau.

Cov Lus Qhia Txog Kev Muaj Peev Xwm: Cov ntaub ntawv uas txhawb nqa qhov kev tshawb pom ntawm qhov kev tshawb fawb no muaj los ntawm tus kws sau ntawv raws li qhov kev thov tsim nyog.

Kev lees paub: Cov kws sau ntawv ua tsaug rau Yun Wang rau nws cov lus tseem ceeb. Kev tsis sib haum xeeb ntawm kev txaus siab: YS thiab JY yog cov neeg ua haujlwm ntawm Advanced Protein Technologies.

Cov txiaj ntsig cistanche: neuroprotection

Cov ntaub ntawv

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ntawm cov neeg laus hauv Spain (2016-2018) raws li kev sib deev: Kev rov qab los, kev sib koom ua ke, kev soj ntsuam, kev xav tau zoo-muab txoj kev kawm.

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