Ukuqonda i-Nrf2 kunye neMpembelelo yayo kwii-Neurodegenerative Diseases

Izifo ezingenayo i-neurodeergenerative, ezifana nesifo se-Alzheimer kunye nesifo sika-Parkinson, sichaphazela izigidi zabantu emhlabeni jikelele. Izinyango ezahlukeneyo zonyango ziyafumaneka ukuphatha iimpawu zamagciwane amaninzi athileyo ngaphandle kokuba iziphumo zihlala ziphela. Iziphumo zophando ziye zafumanisa ukuba uxinzelelo lweengcinezelo olubangelwa zizinto zangaphakathi nangaphandle zingabangela ukuphuhliswa kwezifo ezingenayo i-neurodeergenerative. I i-factual factor, i-Nrf2, uye wazimisela ukusebenza njengendlela enkulu yokukhusela ukuxinzezeleka kwengcinezelo. Injongo yecandelo elingezantsi kukubonisa imiphumo I-Nrf2 kwizifo ezingenayo i-neurodeergenerative.

Ukumodareyitha kweProteostasis nge-Transcription factor NRF2

Izifo ze-neurodeergenerative zidibene nokuqokelelwa kweeprotheyini ezithile ezidibeneyo, ezibonisa uxhulumaniso olusondeleyo phakathi kwengqondo eyenzakeleyo kunye nokulahlekelwa kweproteostasis. I-Proteostasis ibhekisela kuzo zonke iinkqubo apho iiseli zilawula ubuninzi kunye nokugotywa kweproteome ngokubonga kuthungelwano olubanzi oludibanisa ukulawulwa kweendlela zokubonisa, ukubonakaliswa kofuzo kunye neenkqubo zokuthotywa kweprotheni. Olu hlaziyo luzama ukushwankathela ezona ziphumo zichaphazelekayo malunga ne-transcriptal modulation ye-proteostasis eyenziwa yi-transcription factor NRF2 (i-nuclear factor (i-erythroid-derived 2) -njenge-2). I-NRF2 iye yaqwalaselwa ngokweklasi njengomlawuli oyintloko wempendulo yeseli ye-antioxidant, nangona ngoku ivela njengenxalenye ephambili yomatshini wokutshintshela ukugcina i-proteostasis. Njengoko siza kuxubusha, i-NRF2 inokubonwa njenge-hub ehlanganisa iimpawu eziphuthumayo ezivela kwi-protein eqokelelweyo ephosakeleyo ukuze kwakhiwe impendulo edibeneyo kunye neyokunyamezelayo yokubhala. Oku kuphunyezwa ngemisebenzi ye-NRF2 enxulumene nokulawulwa kweejene ezibandakanyekayo ekugcinweni kwe-endoplasmic reticulum physiology, i-proteasome kunye ne-autophagy.

Internet: Izifo ezingenayo i-neurodeergenerative, impendulo yeprotheni ebonakalayo, iProteasome, i-Ubiquitin, i-Autophagy, uxinzelelo lwe-oxidative

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Sciencedirect.com/science/article/pii/S2213231716304050

intshayelelo

Isixhobo seNyukliya (i-2-derivedroid-derived 2) -fana ne-2 (NRF250) yiprotheni ye-base-leucine-zipper ethathwa njengamhlanje njengomlawuli we-homeostasis weselula. Ilawula ukusetyenziswa kwe-basal kunye nokunyanzeliswa kwengcinezelo kweengqikithi ze-1 ezabelana ngokufanayo kwintsebenziswano ye-cis-ebizwa ngokuba yi-antioxidant element element (ARE) [2], [3], [4], [5], [6]. Ezi zityalo zithatha inxaxheba kwi-phase I, II kunye ne-III, i-glutathione kunye ne-peroxiredoxin / thioredoxin metabolism, ukuveliswa kwe-NADPH nge-pentose phosphate indlela kunye ne-enzyme ye-malic, i-fatty acid oxidation, i-metabolism yensimbi kunye ne-proteostasis [2]. Ngenxa yokuba le mi sebenzi ebanzi ye-cytoprotective, kungenzeka ukuba enye i-NMF2 ifakwe kwi-NRF7 inganciphisa impembelelo yezigulana ezingapheliyo, kuquka ukuxinzelelwa kwe-oxidative, inflammatory kunye ne-proteotoxic. Indima ye-NRFXNUMX kwimodyuli ye-antioxidant defense and resolution of inflammation iye yaqwalaselwa kwizifundo ezininzi (ihlaziywe kwi- [XNUMX]). Apha, siza kujolisa indima yayo kwiproteostasis, oko kukuthi, ukulawula i-homeostatic yeprotein ye-protein, ukulandelwa, ukurhweba kunye nokuhlaziywa. Imizekelo iya kunikwa kwimiqathango yezifo ezingenayo i-neurodeergenerative.

Ukulahlekelwa kwe-Proteostasis Iimpembelelo ze-NRF2 Umsebenzi kwii-Neurodegenerative Diseases

Uphawu oluqhelekileyo lwezifo ze-neurodeergenerative sisiganeko sokudityaniswa kweeproteni ezithile. Ke, ukungqinwa kweeprotheyini ezihlanganisiweyo ze-? -Synuclein (? -SYN) zifunyenwe kwisifo sikaParkinson's (PD),? -Amyloid (A?) Amacwecwe kunye ne-hyper-phosphorylated TAU neurofibrillary tangles kwisifo se-Alzheimer's (AD), Huntingtin (Htt) in Isifo sikaHuntington (i-HD), i-superoxide dismutase 1 (SOD1) kunye ne-TAR DNA ebopha iproteni 43 (TDP-43) kwi-amyotrophic lateral sclerosis (ALS), iprotein prion (PrP) kwi-encephalopathies ye-spongiform, njl.njl. Iindlela zeselula, ezinokuthi zichaphazele amanqanaba e-NRF2 kunye nomsebenzi.

Uluhlu oluhlukeneyo lweMimiselo Ulawulo lwe-NRF2

Ngaphansi kweemeko zomzimba, iiseli zibonisa amanqanaba eeprotheni aphantsi aphantsi kwe-NRF2 ngenxa yokuthengiswa kwayo ngokukhawuleza. Ekuphenduleni kwimimiselo ehlukeneyo, iprotheni ye-NRF2 iqokelelwe, ingena kwinucleus kwaye ikhulise ukubhalwa kwezinto eziphilayo zeGEN. Ngoko ke, ukulawulwa kwamanqanaba eeprotheyini ze-NRF2 yingongoma ephambili ekufuneka idibanise iimpawu zengeniso ezilungileyo nezimbi. Njengoko siza kuxubusha ngokuqhubekayo, i-NRF2 isebenze ngeendlela ezahlukeneyo zokuqhawula ukulungiselela ukuphendula ngokukhawuleza nangokukhawuleza kodwa ngakwelinye icala i-NRF2 ingavinjelwa, mhlawumbi kwisigaba sesibini, ukuze ishintshe impendulo yayo.

Ukusuka kwindawo yokujonga yeklasikhi, ukwenziwa kwe-NRF2 kuthathelwe ingqalelo njengesiphumo sempendulo yeselula kwii-oxidant okanye i-electrophilic compounds. Kule meko, i-ubiquitin E3 ligase adaptha ye-Kelch-efana ne-ECH enxulumene neprotein 1 (KEAP1) idlala indima ebalulekileyo. Iinkcukacha zemolekyuli ziya kuqwalaselwa ngakumbi kwiCandelo 4.1. Ngamafutshane, i-KEAP1 isebenza njenge-redox sensor ngenxa yeentsalela ezibalulekileyo ze-cysteine ​​ezikhokelela kwi-NRF2 ubiquitination kunye ne-proteasomal degradation. Ukongeza kolu tshintsho lweklasikhi, i-NRF2 ilawulwa ngokunzulu ngokusayina imicimbi. Ewe kunjalo, ii-kinase ezahlukeneyo zibonisiwe kwi-phosphorylate kwaye zilawula i-NRF2. Umzekelo, i-NRF2 inokuthi iphosphorylated yi-mitogen activated protein kinases (MAPKs), nangona igalelo layo kwimisebenzi ye-NRF2 ihlala ingacacanga [8], [9], [10], [11]. I-PKA kinase kunye nezinye ze-PKC isozymes [12], CK2 [13] okanye iFyn [14] phosphorylate NRF2 eguqula uzinzo lwayo. Umsebenzi wangaphambili kwiqela lethu uxele ukuba i-glycogen synthase kinse-3? (GSK-3?) Inhibit NRF2 ngokukhutshelwa ngaphandle kwenyukliya kunye nokuthotywa kweproteasomal [15], [25], [26], [27], [28], [29], [30]. Iinkcukacha zeemolekyuli ziya kuxutyushwa kwiCandelo 4.1. Ngapha koko, i-NRF2 ingeniswa kwezinye iintlobo zommiselo. Umzekelo, i-NRF2 acetylation yi-CBP / p300 yonyusa umsebenzi wayo [17], ngelixa ithintelwe yi-miR153, miR27a, miR142-5p, kunye ne-miR144 [16], okanye nge-methylation yeziqithi ze-cytosine-guanine (CG) ngaphakathi kwesikhuthazi se-NRF2 [18].

Impembelelo yeziNyunithi zeProteyini kwiindlela zeNRF2 zokuLawula

Kule candelo siza kugxininisa indlela ukuqokelela kwiprotheyini ephangaleleyo kungachaphazela ngayo umsebenzi we-NRF2 onika ezinye zeendlela ezikhankanywe ngasentla njengemizekelo engumzekelo. Okokuqala, kufuneka sicinge ukuba ukuqokelela kweprotein kuye kwaxinwa ngokuqinileyo kunye nomonakalo ochaphazelekayo. Enyanisweni, ukugqithiswa kweeprotheyini kunye nokuhlanganiswa kwenza ukuba i-oksijeni ye-oksijini (ROS) iphumelele kwi-mitochondria kunye nezinye izinto [19]. Njengoko kukhankanywe ngentla, i-ROS iya kutshintsha ama-cysteines anesifo esibucayi se-KEAP1 ekhokelela ekukhululweni, ukuzinza kunye nendawo ye-NRF2.

Ngokumalunga neproteinopathies, umzekelo weziganeko zokubonisa ukungalawulwa kakuhle ezinokuchaphazela i-NRF2 ibonelelwa yi-hyperactivation ye-GSK-3? kwi-AD. I-GSK-3?, Ekwabizwa ngokuba yi-TAU kinase, ithatha inxaxheba kwi-phosphorylation yale protein inxulumene ne-microtubule, ekhokelela kukudityaniswa kwayo, ukuyilwa kweetangles ze-neurofibrillary kunye nokuphazamiseka kwezothutho lwe-axonal (kuhlolwe kwi [20]). Kwelinye icala, i-GSK-3? kunciphisa ngokumangalisayo amanqanaba e-NRF2 kunye nomsebenzi njengoko kuchaziwe apha ngasentla. Nangona ingamkelwa ngokubanzi, i-amyloid cascade iphakamisa ukuba le tyhefu A? ii-oligomers zonyusa i-GSK-3? umsebenzi kunye ne-TAU hyper-phosphorylation kunye ne-neuron ukufa [21], [22]. Kukho iimodeli ezahlukeneyo zokuchaza indlela A? uthanda i-GSK3-? umsebenzi. Umzekelo, A? ibophelela kwi-insulin receptor kwaye inqanda i-PI3K kunye ne-AKT indlela yokubonisa, ebaluleke kakhulu ukugcina i-GSK-3? ayenziwanga yenziwe yi-phosphorylation kwindawo yayo eseleyo ye-N-terminal Ser9 [23]. Kwelinye icala, ngaphandle kwangaphandle A? idibana ne-Frizzled receptors, ibhloka ukusayinwa kwe-WNT [24] kwaye iphinde ikhokelele ekukhululweni kwe-GSK-3 esebenzayo ?. Isishwankathelo, A? Ukuqokelelwa kukhokelela ku-hyperactivation engaqhelekanga ye-GSK-3?, ke oko kuyonakalisa impendulo efanelekileyo ye-NRF2.

Njengoko kuxoxwe kwinqanaba elilandelayo, iiprotheni ezigqithisileyo zikhokelela ekusebenziseni i-PERK kunye nee-MAPK, eziya phezulu-lawula i-NRF2 [31], [8], [9], [10], [11]. Ngaphezu koko, umsebenzi owenziwe i-CBP / p300 uye waxelwa kwiiproteopathies eziliqela [32] kunye nokuncipha kwehlabathi kwi-DNA methylation kwi-A brains yaboniswa kwakhona [33], ngoko ke kunika ithuba lokuphonononga ukubaluleka kwezi ziphumo kumgaqo we-NRF2.

Thina nabanye siye sabona kwiinkalo ze-PD kunye ne-AD izigulane ukwanda kwamazinga eeprotheni ze-NRF2 kunye nezinye iinjongo zayo, njenge-heme oxygenase 1 (HMOX1), i-NADPH i-quinone oxidase i-1 (NQO1), i-p62, njl. nge-immunohistochemistry [34], [35], [36], [37], [38], [39]. I--R-up-regulation ye-NRF2 kwezi zifo isichazwa njengomzamo ongaphumeleli wengqondo egule ukubuyisela ixabiso le-homeostatic. Nangona kunjalo, olunye uphando lubonise ukuba i-NRF2 yindawo ehlala kuyo kwi-cytoplasm ye-AD ye-hippocampal neurons, ebonisa ukuba kuncitshiswe umsebenzi we-NRF2 kwintliziyo yengqondo [40]. Kucingeka ukuba ukungafani kwezi mboniso kuhambelana nezinguqu kwizinto ezilawula i-NRF2 kunye neendlela eziqhubela phambili ze-neurodegeneration.

Iinkqubo ezinkulu ezintathu zifaka isandla kwiproteostasis, okuyi-response protein response (UPR), inkqubo ye-ubiquitin proteasome (UPS) kunye nokuzimela. Emva koko, sibonisa ubungqina bokujonga i-NRF2 njengethabhu edibanisa izibonakaliso eziphuthumayo eziqaliswe ngamanyathelo eeprotheyini kunye noomatshini bokuvelisa amaprotheni.

I-NRF2 ithatha inxaxheba kwi-Protein Response Response (UPR)

Ukuqaliswa kwe-NRF2 ekuphenduleni i-UPR

Ukusongelwa kweprotein ye-oxidative kwi-ER kuqhutywa ziindlela ezahlukeneyo, eyona ilondoloziweyo ibandakanya iprotheyini disulfide-isomerase (PDI) kunye ne-sulfhydryl oxidase endoplasmic oxidoreductin 1 (ERO1? Kunye ne-ERO1? Kwizilwanyana ezincancisayo) njenge-disulfide donor. Ngokufutshane, i-PDI ikhuthaza ukwenziwa kunye nokuqhekeka kwe-disulfide bond phakathi kweentsalela ze-cysteine ​​ngaphakathi kweeproteni, njengoko zisonga, ngenxa yokuncitshiswa kunye ne-oxidation ye-cysteine ​​aminoacids. I-PDI iphinde iphinde isetyenziswe sisenzo se-enzyme yokugcina indlu i-ERO1, ephinda ivelise iibhondi ze-disulfide kwi-PDI [41]. Imolekyuli yeoksijini sisixhobo esamkelayo se-electron se-ERO1, esenza isixa se-stoichiometric se-hydrogen peroxide kuyo yonke ibhondi ye-disulfide evelisiweyo [42]. I-Peroxidases (PRX4) kunye ne-glutathione peroxidases (GPX7 kunye ne-GPX8) zii-enzyme eziphambili zokunciphisa i-hydrogen peroxide kwi-ER. Xa le nkqubo yokunciphisa i-oxido ingasebenzi kakuhle, ukuqokelelwa okungaqhelekanga kweeprotheyini ezingafakwanga kakuhle kwenzeka kwi-ER kunye neseti yemiqondiso ebizwa ngokuba yimpendulo yeprotein engafakwanga (UPR) idluliselwa kwi-cytoplasm kunye ne-nucleus yokuphinda ibuyise i-ER homeostasis [43]. Iiproteni ezintathu ezinxulumene nembumba zichongiwe ukuba zithathe uxinzelelo lwe-ER kwii-eukaryotes: ukwenza into ekhutshelweyo ye-6 (ATF6), i-pancreatic ER eIF2? i-kinase (i-PERK, kunye ne-protein ye-kinase-efana ne-ER kinase), kunye ne-inositol-efuna kinase1 (IRE1). Idomain yesikhanyisi yoluvo ngalunye ibotshelelwe kwi-78 kDa chaperone ebizwa ngokuba yiprotein elawulwa siswekile (GRP78 / BIP). I-BIP iyazahlula kuxinzelelo lwe-ER ukubopha iiprotein ezingagqitywanga, okukhokelela ekusebenzeni kwezi zivamvo zintathu [44].

I-NRF2 kunye ne-homologue yayo ye-NRF1, nayo ihambelana nokuphendula okuxhatshazwayo, ithatha inxaxheba ekutshintsheni kwe-UPR kwi-nucleus. Kwimeko ye-NRF1, le protoyini ifumaneka kwi-ER membrane kwaye ihambisa i-nyukliya kwi-deglycosylation okanye i-cleavage. Emva koko, usebenziso lwe-UPR lukhokelela ekuqhutyweni kwe-NRF1 kunye nokuqokelela kwenyukliya yeqhekeza elikhuphayo kwinqanaba lekliya. Nangona kunjalo, amandla okuguqula iiGEN ezineengqungquthela ze-NRF1 fragment isengxoxwa [45].

I-Glover-Cutter kunye nabasebenzi abambisene nabo babonisa ukusebenza kwe-NRF2 umbhali weC elegans, SKN-1, kunye noxinzelelo lwe-ER ezahlukeneyo. Ukunyuka kwe-SKN-1 ibonakaliso kuxhomekeke kumlamli ohlukeneyo we-UPR, kuquka i-IRE1 okanye i-PERK iimbumba zezilwanyana [46]. Kwiiseli ezingenayo i-PERK, iprotheni engaphiliyo yokuqala iququzelela i-peroxide engapheliyo kunye ne-apoptosis elandelayo [47]. Umqhubi osetyenziswa yi-PERK ukukhusela i-ER kulezi zi-peroxide inokuba yi-NRF2, kuba kuye kwaxelwa ukuba i-PERK phosphorylates i-NRF2 kwi-Ser40, ngaloo ndlela ikhusela ukuthotywa kwayo ngu-KEAP1 [31]. Ukuqulunqwa kwe-ASK1 kunokwenzeka nokuba kudlala indima kule ndlela nge-TRAF2-mediated action kinase ye-IRE1 [48]. Nangona indima ye-MAPKs kwimimiselo ye-NRF2 isaphikisana, ivanje iphakanyiswe ukuba i-IRE1-TRAF2-ASK1-JNK indlela ingasebenzisa i-NRF2 [49] (Umfanekiso we1). Ngokuthakazelisayo, kwi-C. elegans kunye neeseli zomntu, ubungqina obutsha bubonisa ukuba i-cysteine ​​sulfenylation ye-IRE1 kinase ekusebenzeni kwayo i-activated loop inhibits u-IRE1-i-UPR ephakathi kwaye iqala impendulo ye-p38 antioxidant eqhutywa yi-NRF2. Idatha ibonisa ukuba i-IRE1 inomsebenzi wasendulo njenge-sentinel ye-cytoplasm evula i-p38 kunye ne-NRF2 [50].

Izifundo ezininzi zokungeniswa kwe-UPR zenziwe nge-inhibitor yeprotein glycosylation tunicamycin. I-NRF2 ibonakala ibalulekile ekuthinteleni i-tunicamycin-induction apoptotic cell death [31] kunye nokusebenza kwayo phantsi kwezi meko kuqhutywa kukuthotywa kwe-KEAP1 [51] okuzenzekelayo. Ngokuhambelana, i-shRNA-Mediated silencing ye-NRF2 expression in? I-TC-6 iiseli, i-murine insulinoma? -Cell line, eyonyuse kakhulu i-tunicamycin-indased cytotoxicity kwaye ikhokelele ekwandeni kwinkcazo ye-pro-apoptotic ER yoxinzelelo lwe-CHOP10. Kwelinye icala, ukwenziwa kwe-NRF2 yi-1,2-dithiole-3-thione (D3T) kunciphise i-tunicamycin cytotoxicity kwaye kwanciphisa ukubonakaliswa kwe-CHOP10 kunye ne-PERK [52]. Into enomdla kukuba, ii-olfactory neurons ezingeniswe kwinkqubo yenkqubo ye-tunicamycin inyuse i-NRF2 ngokuhambelana namanye amalungu e-UPR anje nge-CHOP, BIP, XBP1 [53]. Ezi ziphumo ziye zandiswa zaya kwizifundo ze-vivo, njengokufakwa kwe-tunicamycin emacaleni kwiigundane ezibonisa ukubonakaliswa kwe-PERK kunye ne-NRF2 kwi-hippocampus ehamba kunye nokusilela okubonakalayo, ukonyuka kwe-phosphorylation ye-TAU kunye ne-A? 42 idipozithi [54].

I-NRF2 iphezulu-Ilawula iGenesis eyiNtloko yokuLondolozwa kwe-ER Physiology

I-lumen ye-ER ifuna ubonelelo oluninzi lwe-GSH kwi-cytosol ukwenzela ukugcina i-disulfide chemistry. I-NRF2 imodareyitha ii-enzymes ezibalulekileyo ze-GSH metabolism kwingqondo, njenge-cystine / glutamate zothutho,? -Glutamate cysteine ​​synthetase (? -GS), glutamate-cysteine ​​ligase catalytic kunye ne-modulator subunits (GCLC kunye ne-GCLM), glutathione reductase (GR) kunye glutathione peroxidase (GPX) (iphononongwe kwi [55]). Ukubaluleka kwe-NRF2 kulondolozo lwe-GSH kwi-ER kuxhaswe kukufumanisa ukuba ukwenziwa kwamayeza okanye ukwenziwa kwemfuza kweziphumo ze-NRF2 kwiziphumo zokwanda kwe-GSH ngokudlula kwi-GCLC / GCLM, ngelixa kuthintela ukubonakaliswa kwezi enzymes yi-NRF2-knockdown ibangele ingqokelela yokonakala Iiproteni ngaphakathi kwe-ER ekhokelela ekusebenzeni kwe-UPR [56].

Ku-C. Elegans amacandelo aliqela e-UPR ejolise kuhlobo olulawulwa yi-SKN-1, kubandakanya u-Ire1, Xbp1 kunye no-Atf6. Nangona i-NRF2 inyusa ukubonakaliswa kwe-peroxidase eliqela (PRX) kunye ne-glutathione peroxidase (GPX) yemfuza kwizilwanyana ezincancisayo (ezihlaziyiweyo kwi [57]), yi-GPX8 kuphela eyi-enzyme eyenzelwe i-ER, egcina umqondiso wokubuyisa i-KDEL [58]. Ukuphulukana ne-GPX8 kubangela ukwenziwa kwe-UPR, ukuvuza kwe-ERO1? -I-hydrogen peroxide eyenziweyo kwi-cytosol kunye nokufa kweseli. Ihydro peroxide ephuma kwi-ERO1? Umsebenzi awunakusasazeka ukusuka kwi-ER uye kwi-cytosol ngenxa yesenzo esimanyeneyo se-GPX8 kunye ne-PRX4 [59]. Kule meko, uhlalutyo lokhuselo lwe-antioxidant yendlela-ye-gene expression expression esebenzisa i-RNA evela kuhlobo lwasendle kunye ne-NRF2-null iimpuku izicubu, ityhile ukuba ukubonakaliswa kwe-GPX8 kwakuphantsi-kulawulwa kungabikho kwe-NRF2 [60]. Ngokuhambelana noku, uhlalutyo olukhutshelweyo olusuka kwiisampulu zesigulana esineengxaki ze-myeloproliferative neoplasms, polycythemia okanye myelofibrosis, izifo zikwanxulumana noxinzelelo lwe-oxidative kunye neqondo eliphantsi lokudumba okungapheliyo, bonisa amanqanaba asezantsi okuchaza zombini i-NRF2 kunye ne-GPX8 xa kuthelekiswa nezifundo zolawulo [61]. Azikabikho izifundo ezibandakanya ngokukodwa i-GPX8 kukhuseleko lobuchopho bomntu kodwa uhlalutyo olukhutshelweyo kwiimpuku lubonisa ukunyuka okunyanzelekileyo kwe-GPX8 ekuphenduleni ityhefu yeParkinsonian MPTP [62].

Impembelelo ye-NRF2 kwi-UPR Dysregulation kwi-Neurodegenerative Diseases

Ukungasebenzi kwee-enzyme zePDI kunye nokusebenza okungahleliyo kwe-UPR kungase kuqaliswe okanye kuphuthumise ukwenziwa kwe-neurodegeneneration. Izifo ezithintekayo ngeengxaki, izifo zezilwanyana zesifo esinjenge-neurodeergenerative kunye nezicubu zomntu eziza emva kokufa ezibonakalisiweyo-ukulawulwa kwamanqaku angaphantsi kwe-UPR kwiintlobo ezininzi zeengxaki. Ukuguqulwa kwendlela ye-PDI / UPR kwizifo ezingenayo i-neurodeergenerative izihlolisiswe kakuhle kwi- [63] kodwa ezi ziphumo ezilandelayo ezivela kwiisampuli ze-post-mortem zengqondo kufuneka ziqwalaselwe. Amanqanaba e-PDI anyuselwa kwi-neurons enezikhwebu kunye nee-Lewy Bodies ze-AD ne-PD, ngokulandelanayo [64], [65]. I-PDI ne-ERP57 zilawulwa phezulu kwi-CSF kwizigulane ze-ALS nakwiibongo ezivela kwizifundo ze-CJD [66], [67], [68]. BIP, PERK, IRE1 kunye ne-ATF6 ziphakanyisiwe kwiisampuli kwizigulane ezine-AD, i-PD okanye i-ALS [69], [70], [71], [67]. I-BIP, i-CHOP kunye ne-XBP1 ziphakanyisiwe kwiisampuli ze-post-mortem ze-HD [72], [73]. Ukongezelela, ukulawulwa kwe-ERP57, i-GRP94 kunye ne-BIP itholakala kwiiscupu ze-cortex ezivela kwizigulane ze-CJD [74]. Konke, obu bungqina bubonakalisa ukuba ukuqokelela kweeprotheni ezigqithisiweyo kwi-brain parenchyma kukhokelela ekusebenziseni okungekho nto kunye nokungapheliyo kwe-UPR. Kuyathakazelisa, kukho uphando olutshanje oluxhuma ukusebenza kwe-NRF2 nge-PERK ekuqaleni kwe-AD. Kule sifundo, abalobi bahlalutya ukuba ingxaki yokuxininisa ingxubevange kwi-NRF2 kunye ne-UPR ingabangela iziganeko zakuqala kwi-AD pathogenesis ngokusebenzisa i-cell peripheral cell cells kunye ne-AD yesimo se-mouse esingaqhelekanga kwizigaba ezahlukeneyo zesifo. Ukunyuka kwengcinezelo ye-oxidative kunye nokwandiswa kwe-pSer40-NRF2 kuboniswe kwigazi lomntu wegazi lomzimba wecala lonyukliya olwahlukeneyo nabantu abanokukhubazeka okucokisekileyo. Ukongezelela koko, baxela ukukhubazeka kwe-ER calcium homeostasis kunye ne-ER-pressure markers markers kule maseli avela kubantu abanokukhubazeka okucokisekileyo kunye no-AD [75].

Ulawulo oludibeneyo lwe-NRF2 kunye ne-Ubiquitin Proteasome�System (UPS)

I-UPS ihamba neNRF2 Amanqanaba eProtheni

I-UPS ithatha inxaxheba ekuthotyisweni kweeprotheni ezonakaliswe okanye ezilawulwayo kwaye zilawula amanqanaba amakhemikhali alawulayo kwi-cytosol kunye nucleus. Ingundoqo yinkqubo yi-enzyme enkulu ye-multisubunit ene-proteolytic esebenzayo enegama elingu-20S. I-20S yengundoqo yeproteasome ihlaziye iiprotheni ezibonakalayo, kodwa ukubophelela kwiiprotheni eziyinkqubo ezahlukeneyo zitshintsha utshintsho lwayo lwe-substrate kunye nomsebenzi. Ngokomzekelo, ukongezwa kweyunithi enye okanye ezimbini ze-19S zokulawula kwi-20S ingundoqo i-proteasome ye-26S kwaye iguqula inkcazo yayo kwiiprotheni ezihlanjulweyo [76], [77]. Ukuchithwa kwe-Proteasomal kudinga ukubophelela ngokukhawuleza kwe-ubiquitin. Ukuqhawulwa kwe-ubiquitin kuqhubeka ngeendlela ezintathu zokunyathelisa. Okokuqala, i-enequitin-activating enzyme I-E1 isebenzela u-ubiquitin kwi-ATP-efuna ukuphendula. Emva koko, enye ye-enzyme ye-E2 (i-ubiquitin-protein protein okanye i-ubiquitin-conjugating enzyme) idlulisela i-ubiquitin esebenzayo esuka kwi-E1 ukuya kwicandelwana elibophelelwe ngokukhethekileyo ilungu lentsapho ye-ubiquitin-protein ligase, egama lingu-E3. Nangona isithuba esiza ku-propati-protein sinokuxhomekeka kwimeko ye-ubiquitin chain, le nkqubo inokubangela ukuthotywa kwe-26S proteasome [78].

I-E3-ligase KEAP1 yiyona inhibitor eyaziwayo kakhulu ye-NRF2. Indlela yokwenza umgaqo we-KEAP1 ichaza ngokucacileyo indlela ama-NRF2 aguqula ngayo ukuguquguquka kwezinto ezixhamlayo. Phantsi kweemeko carcinoma, esandula kuhlelwe NRF2 ke wambamba yi homodimer KEAP1, lona lubopha omnye NRF2 molecule kwi ulandelelwano ezimbini acid acid kunye ephantsi (aspartate, leucine, glycine; DLG) kunye ophezulu (glutamate, threonine, glycine, glutamate; ETGE) ngobuhlobo. Ukusebenzisana ne-KEAP1 zixhobo zokubonelela i-NRF2 kwiprotheni eyinkimbinkimbi ye-CULLIN3 / RBX1, okubangele ukutyunjwa kwayo kunye nokuthotywa kweproteasomal. Nangona kunjalo, ukuguqulwa kwe-redox ye-KEAP1 kukuvimbela ukunikezwa kwe-NRF2 kwi-UPS ebelwe ngu-CULLIN3 / RBX1. Ngenxa yoko, i-NRF2 esanda kuhlanganiswa iphunyukileyo iphuma kwi-KEAP1-i-degradation exhomekeke kuyo, iqokelela kwi-nucleus iphinde isebenze i-GNI ene-gene [79], [80], [81], [82].

I-adaptha ye-E3-ligase? -TrCP ikwayi-homodimer ethatha inxaxheba kwimisitho yokubonisa enxulumene ne-phosphorylation ye-NRF2 yi-GSK-3?. Le kinase phosphorylates intsalela ethile ye-serine ye-NRF2 (i-aspartate, i-serine, i-glycine, i-isoleucine serine; i-DSGIS) ukwenza idomain yokuthotywa eyamkelweyo yi--TrCP kwaye iphawulwe ukuthotywa kweproteasome yi-CULLIN1 / RBX1 complex. Ukuchongwa kwee-amino acid ezithile eziPhosphorylated yi-GSK-3? kule degron yenziwa ngokudityaniswa kwesiza esijolise ngqo kwisiza se-Neh6, i-2D-gel electrophoresis [15], [26] kunye ne-mass spectroscopy [83]. Ngenxa yoko, inhibition ye-GSK-3? ngeziyobisi ezikhethwe kakhulu okanye ii-siRNAs ngokuchasene ne-GSK-3 isoforms zikhokelele ekunyukeni kwamanqanaba eproteni e-NRF2. Iziphumo ezifanayo zafunyanwa nge-siRNAs ngokuchasene? -TrCP isoforms 1 kunye 2. Ukuzinziswa kwe-NRF2 kulandela i-GSK-3? Inhibition yenzeke kwi-KEAP1-deficit mouse embryo fibroblasts nakwi-ectopically echazwe i-NRF2 ukususwa kwe-mutant engenazo iintsalela eziphambili ze-ETGE zokubopha kakhulu kwi-KEAP1, eqhubeka nokubonisa umgaqo ozimeleyo we-KEAP1.

Kwimeko yezifo ze-neurodeergenerative, sinokujonga ukumodareyitha kwe-NRF2 yi-UPS ngeendlela ezimbini ezahlukeneyo. Kwelinye icala, inkqubo ye-KEAP1 iyakuqonda ukungalingani kwe-redox evela kukuqokelelwa kweeprotheyini, ngelixa i-GSK-3 /? - I-axis ye-TrCP iya kuthatha inxaxheba ekuthatheni inxaxheba ekutshintsheni ukuhanjiswa kuguqulwe yilahleko yeproteostasis (Ikhiwane. 2).

I-NRF2 ikhulisa umsebenzi we-UPS ngokulawulwa kweTranscription of Subunits

I-NRF2 up-ilawula ukubonakaliswa kweqela leeproteasome subunits, ngaloo ndlela ikhusela iseli ekuqokeleleni iiproteni ezinobuthi. Imfuza engamashumi amabini yeeproteasome- kunye ne-ubiquitination ezinxulumene nokubonakala ngathi ilawulwa yi-NRF2, ngokokuphononongwa okubanzi kwe-microarray ukusuka kwisibindi se-RNA eyamiselwa nge-NRF2 inducer D3T [84]. Kwisifundo esingasemva, ababhali abafanayo babonakalisile ukuba ukubonakaliswa kweyona mininzi ye-26S proteasome yonyuswe yaya kufikelela kathathu kwizibindi ezivela kwiimpuku eziphathwe nge-D3T. Amanqanaba okuhambisa iiprotein kunye nomsebenzi weproteasome wonyuswe ngokulandelelana. Nangona kunjalo, akukho kungeniswa kubonwe kwiimpuku apho into ekhutshelweyo ye-NRF2 yaphazamiseka. Umsebenzi wokukhuthaza wePSMB5 (20S) proteinasun subunit inyuke nge-NRF2 overexpression okanye unyango ngabaphembeleli kwimouse embryonic fibroblasts, kwaye ii-AREs zichongiwe kwi-proximal promoter yePSMB5 [85]. Ukusebenza kwe-Pharmacological ye-NRF2 kukhokelela kumanqanaba aphakamileyo okubonisa ama-subunits abamele i-proteasome (i-PSMA3, i-PSMA6, i-PSMB1 kunye ne-PSMB5) kuphela kwii-fibroblast ezingabonakaliyo ze-fibroblast zabantu eziqukethe i-NRF2 [86] esebenzayo. Ukusebenza kwe-NRF2 ngexesha lokuziqhelanisa neziphumo zoxinzelelo lwe-oxidative kwizibonakaliso eziphezulu ze-PSMB1 (20S) kunye ne-PA28? iisununithi (okanye i-S11, umlawuli weproteasome) [87]. Ngapha koko, iziphumo ezivela kwi-embryonic stem cells zityhile ukuba i-NRF2 ilawula ukubonakaliswa kweproteasome maturity protein (POMP), iproteasome chaperone, ethi yona iphinde ilungelelanise ukwanda kokuzihlaziya kweeseli zemibungu yabantu, ukwahlulahlula iintsholongwane ezintathu kunye nophinda wenze inkqubo yeselfowuni [ 88]. Lilonke, ezi zifundo zibonisa ukuba i-NRF2 inyusa ukubonakaliswa kwezinto eziphambili ze-UPS kwaye ke ngoko inegalelo ekucocweni kweeproteni ezinokuthi zibe yityhefu.

I-NRF2-UPS Axis kwii-Neurodegenerative Diseases

Indima ye-UPS kwizifo ezingenayo i-neurodeergenerative yintsimi yeengxoxo enzulu. Izifundo zokuqala zabikwa ziyancipha umsebenzi weproteasome kwiziganeko zabantu ezigulane ezichaphazelekayo kwiintlobo ezininzi zezifo ezingenayo i-neurodeergenerative. Nangona kunjalo, ezinye izifundo ezisebenzisayo kwi-in vitro kunye neendlela ezisetyenziswayo zifunyanwe zingatshintshi okanye zonyuka umsebenzi weproteasome (uhlaziywe kwi- [89]). Enye inkcazo enokwenzeka malunga nale ngxaki kukuba amanqanaba e-UPS angashintsha ngexesha lokunyuka kwesifo nakwiindawo ezahlukeneyo zeengqondo njengoko kuphakanyiswe iinjongo ze-NRF2.

Nangona le ngxabano, kufuneka kuphawulwe ukuba ukulawulwa kwe-ARE eziqulethe i-proteasome ziza kugxininisa i-UPS ngokunyusa ukukhutshwa kweeprotheni ezinobuthi kwindawo yengqondo. Enyanisweni, ukususwa kwe-NRF1, kunye ne-modulator impendulo ye-antioxidant, kwiiseli ze-neuronal zikhokelela kwimisebenzi ye-proteasome engafanelekanga kunye ne-neurodegeneneration. Uvavanyo lwe-Chromatin immunoprecipitation kunye nohlalutyo olubhalweyo lubonisa ukuba i-PSMB6 ilawulwa yi-NRF1. Ukongezelela, ukuchazwa kwemfuza yomzimba kubangele ukuchongwa kwe-NRF1 njengomlawuli oyintloko oyigqirha yamagciwane e-proteasome kwi-neurons, ebonisa ukuba ukuphazamiseka kwi-NRF1 kunokufaka isandla kwi-pathogenesis yezifo ezingenayo i-neurodeergenerative [90]. Okuthakazelisayo, i-NRF1 kunye ne-isoform yayo ende ebizwa ngokuba yi-TCF11 iboniswe ukuphakanyiswa kwe-GET ene-genetic proteasome kwi-proteasome inhibition kwi-loop feedback ukuze ihlawulise umsebenzi ophantsi weproteolytic [91], [92].

Ngokubhekiselele ku-NRF2, kukho ukulungiswa phakathi kokunciphisa kwe-NRF2, i-RPT6 (i-19 S) kunye ne-PSMB5 (i-20 S) kumgangatho we-DJ-1-iphiji ephosakeleyo ephathwe nge-neurotoxin paraquat [93]. Ukongezelela, i-sulforaphane (i-SFN) eyenziwa ngokwemvelo inika umfanekiso onamandla ngakumbi we-NRF2 njengomodareli obalulekileyo we-UPS. Ukuhlolwa kwe-in vitro kunye ne-nerine neuroblastoma I-Neuro2A iiseli zibonakalise ukubonakaliswa okuphuculweyo kwee-subunits zokuncedisa iproteasome, kwakunye nemisebenzi yayo ye-peptidase ekuphenduleni i-SFN. Le nkunkuma ikhusele iseli kwi-cytotoxicity kunye neprotheni oxidation ngendlela exhomekeke kumsebenzi weproteasome [94]. Ukongezelela, uLiu kunye nabasebenzi abaqeshwe baqeshwe umgca wegulana ukubeka iliso umsebenzi we-UPS ngokuphendula i-SFN kwingqondo. Ezi iisondlo zibonisa ngokucacileyo iprotheni ye-fluorescence eluhlaza (GFP) ifakwe kwisigxina sokuthotywa komonakalo okhuthaza ukuthotywa kwayo ngokukhawuleza yi-UPS (GFPu). Kwi-cortex ye-cerebral, i-SFN yanciphisa izinga le-GFPu ngokunyuka okufana nokufana ne-chymotrypsin (PSMB5), i-caspase-like (PSMB2), kunye ne-trypsin-like (PSMB1) imisebenzi yeprotasome ye-20 S. Ukongezelela, unyango lwama-cell-derived cells olwenziwa yi-Huntington kunye ne-SFN luveze ukuba ukusetyenziswa kwe-NRF2 kwandiswe ukuhlaziywa kwamanzi kunye nokunciphisa i-cytotoxicity [95]. Inkqubo enkulu ye-SFN isenzo ngokuqulunqwa kwe-NRF2 [96]. Igalelo elithile le-NRF2 kufuneka libhekiswe kwi-NRF2-null iinkqubo kwizifundo ezongezelelweyo.

Uxhumano olusebenzayo Phakathi kwe-NRF2 kunye ne-Macroautophagy

Amanqanaba eeprotheyini ze-NRF2 ziModyuli yiProtheni ye-Adapter iP62

I-autophagy ibhekisela kuhlazo lwezinto ze-cytosolic ngaphakathi kwe-lysosomes. Le nqubo isetyenziselwa ukukhutshwa kweeprotheni ezide kunye nezidalwa eziphangaleleyo kunye neenjello ezinobungozi. Ikhonkco ngqo phakathi kwe-NRF2 kunye ne-autophagy yabonwa kuqala ngokuphathelele kwiprotheni ye-adapter p62, ebizwa ngokuba yi-SQSTM1 [97], [98], [99], [100], [101]. Ezi protein shuttles ezi-proteins ezi-ubiquitated kwi-proteasomal kunye ne-lysosomal degradation machineries kunye nama-proteins abonakalisiweyo abonakele kwi-aggregates phambi kokuthotywa kwabo. I-P62 inika i-ubiquitin-associated (UBA) domain, ngokubophezela kwiiprotheni ezingabonakaliyo, kunye nommandla we-LC3-interactive (LIR) wokudibanisa kunye nomlenze we-autophagosomal nge-recepor autophagy LC3.

Nangona i-p62-Mediated induction ye-NRF2 kunye neithagethi zayo ekujoliswe kuzo zaxelwa okokuqala kwi-2007 [102], indlela yeemolekyuli ayizange iqondwe ngokupheleleyo de kufunyanwe ukuhlangana kwayo ne-KEAP1 [103], [98], [99], [100 ], [101]. I-Komatsu kunye nabo basebenza nabo bachonge indawo ye-KEAP1 yokunxibelelana (KIR) kwi-p62 ebopha i-KEAP1 kwipokotho efanayo engaphezulu njenge-NRF2 kunye nobumbano olubophayo olufana ne-ETGE motif kwi-NRF2, iphakamisa ukhuphiswano phakathi kwe-p62 kunye ne-NRF2. I-phosphorylation ye-Ser351 kwi-KIR motif kwi-p62 (349-DPSTGE-354) yaboniswa ukuba inyuse ubumbano lwayo kwi-KEAP1, ikhuphisana ne-NRF2 iyabopha kwaye ivumela ukuqokelelwa kwayo kunye nokukhutshelwa kokukhutshelwa kohlobo lwayo ekujolise kuyo [98], [99]. Ngapha koko, i-p62 overexpression ikhokelele ekunciphiseni i-NRF2 ubiquitination kunye nokuzinza okulandelayo kunye nokungeniswa kohlobo lwento ekujolise kuyo [104]. Ezinye ii-kinase zicetyisiwe ukuba zithathe inxaxheba kwi-p62 phosphorylation. Ujoliso lwe-mammalian lwe-rapamycin complex 1 (mTORC1) lunokunyanzeliswa, njengoko unyango nge-mTOR inhibitor rapamycin icinezele i-phosphorylation ye-p62 kunye nolawulo olusezantsi lwe-KEAP1 kunyango lwe-arsenite. Kutshanje, kubonisiwe ukuba i-TGF-? - isebenze kinase 1 (TAK1) nayo iphosphorylate p62, ukuphucula ukonakaliswa kwe-KEAP1 kunye nommiselo we-NRF2. Ababhali beli phononongo bacebisa ukuba le yindlela yokulawula i-redoxtasis yeselula phantsi kweemeko zikarhulumente, njengoko i-TAK1-defence-up-regulates ROS ngokungabikho kwayo nayiphi na i-oxidant exogenous in tissue mouse ezahlukeneyo ngokuhambelana nokunciphisa amanqanaba eeprotheyini ze-NRF2 [105 ].

I-p62 eyakhayo engenakho idilesi ye-UBA yayisakwazi ukubopha i-KEAP1, ebonisa ukuba ukusebenzisana akuxhomekeke kwi-KEAP1 [101]. Nangona kunjalo, i-p62 isigxina kwi-Drosophila melanogaster, egama linguRef (2), aliqukethe i-KIR motif kwaye ayinxibelelwano ngqo ne-DmKEAP1, nangona iyakwazi ukubopha kwi-DmKEAP1 kwi-domain ye-UBA. Ngaphezu koko, i-DmKEAP1 inokusebenzisana ngqo ne-Atg8 (i-homologue kumamalia aseLC3). Ukungasebenzi kwe-KEAP1 kuphumela kwi-Atg8 kunye nokuzenzekela nge-autophagy kuxhomekeke kwi-NRF2 ye-orthologue CncC kwaye zimele kwi-TFEB / MITF [106]. Ulwalamano phakathi kwe-NRF2 kunye ne-autophagy lubonakala lugcinwa, kodwa lugqamisa ukusebenza kwalo.

Ukuqulunqwa kwe-NRF2 nge-p62 yiphumo lobambiswano ukhuphiswano lwe-KEAP1 kunye nokuchithwa kwe-KEAP1 kwi-lysosome. Ukuxiliswa kwe-p62 nge-siRNA kabini i-KEAP1 yobomi bemizuzu efana nokuhla kwe-NRF2 kunye neengcambu zayo zegciwane [101]. Ngokwesivumelwano, ukuchithwa kwe-p62 ibonakaliso kubonisa ukuba kunyuke amazinga e-KEAP1 xa kuthelekiswa namagundane asendle. Efanelekileyo kakhulu, ukunyuka kwamazinga e-KEAP1 akuchaswanga ngama-proteasome inhibitors kodwa kuncitshiswa phantsi kwe-star--ducing autophagy [107]. Enyanisweni, i-KEAP1 ikhona kwiiseli zamammalian ezithandwayo zemihlobiso ehlotshiswe nge-p62 kunye ne-LC3 [99], [100], [103]. Yonke le nkcazelo ibonisa ukuba i-KEAP1 yinkqutyana yamashishini ase-macroautophagy, kodwa le ngxaki iya kuhlaziywa ngolwazi olungakumbi ngenxa yokuba kukho iziphumo eziphikisanayo. Amanqanaba e-KEAP1 anyukisiwe kwi-Atg7-null amagundane, umphambili we-macroautophagy [107], kodwa ukuchithwa kwemithi ye-macroautophagy nge-torin1, i-E64 / pepstatin okanye i-filomycin ayiphumelelanga i-KEAP1 [107], [100]. Ngokubanzi, ezi ziphumo zibonisa ukuba ukwandiswa kwamanqanaba e-P62 kwinqanaba le-KEAP1 kwi-vacuoles ngokuzenzekelayo kwaye mhlawumbi le miphumo kwi-KEAP1 ukuchithwa kokuzenzekelayo ukuvumela ukusebenza kwe-NRF2 (umzobo 3). Izifundo ezimbini ezahlukileyo zichaze ukuba i-sulfinic acid iyanciphisa i-SESTRIN indima ebalulekileyo kulo mongo. I-SESTRIN 2 inxibelelana ne-p62, i-KEAP1 kunye ne-RBX1 kwaye iququzelela ukuthotywa kwe-P62 ekuxhaseni kwe-KEAP1 kunye ne-NRF2 ukusetyenziswa kweengqikembe zengqondo (108]. Olunye uphando lubonise ukuba i-SESTRIN 2 ihlangene no-ULK1 kunye ne-p62, ukukhuthaza i-phosphorylation ye-p62 kwi-Ser403 eyenza ukuba kuphuculwe iiprotheni ze-cargo eziquka i-KEAP1 [109].

Ukumodareyithwa kwe-Macroautophagy Genes by NRF2

I-NRF2 ilawula i-geni echaphazelekayo ye-macroautophagy kunye nokwenzayo kwi-UPR kunye ne-UPS. Ubungqina bokuqala buvela kwizifundo apho ibinzana le-p62 liboniswa ukuba linyanzeliswe xa lichazwa kwi-electrophiles, iROS kunye ne-nitric oxide [110], [111], [112]. Inkqubo yokuqulunqwa ichazwe kwiminyaka emva emva kokufumanisa ukuba i-p62 iqulethe i-ARE esebenzayo kumgqugquzeli wezofuzo [99]. Kuhlolisiso lwakutshanje, ii-ARE ezisebenzayo zifunyenwe kwaye ziqinisekisiwe emva kokuhlaziywa kwe-bioinformatics kunye nokuhlolwa kwe-ChIP. Ngaphezu koko, i-fibroblast ye-embryonic kunye ne-neurons ye-coral evela kwi-Nrf2-khonkco-kondlo ibonise ukunciphisa ibinzana le-p62, elingasindiswa nge-NRF2-ebonisa i-lentivirus. Ngokufanayo, ukulahleka kwe-NRF2 kuncitshiswe amanqanaba e-P62 kwi-neurons elimazi kwi-hippocampus i-hippocampus [36]. Ngoko ke, kucetyiswa ukuba ukusebenza kwe-NRF2 kwandise amazinga e-P62, okubangelwa ukuchithwa kwe-KEAP1 nokuthanda ukuqhubeka nokuqiniswa kwe-NRF2 kwi-loop feedback feedback. Le ndlela engabonakaliyo ye-canonical ye-NRF2 ukutyunjwa idinga utshintsho kwigama lomzimba kwaye ingaba yimpendulo efanelekileyo kwixinzelelo lomlingo olude.

Iprotein ye-REP52 ebonakalayo yokuthengiswa kwempahla yaboniswa ukuba ilawulwe ngokubhalwe ngu-NRF2. I-NDP52 isebenza ngendlela efana ne-p62, ikwazi ukufumana iiprotheni ezinobuninzi kunye nokusebenzisana ne-LC3 nge-domain ye-LIR, ukwenzela ukuba imithwalo yempahla ihlaziywe kwii-lysosomes. Iifayile ezi-5 zokubeka i-ARE zifumaneka kwi-NDp52 umgqugquzeli we-DNA ngokulandelelana. Abathathu kubo bachongwa ngezakhiwo ezahlukeneyo ze-mutant kunye ne-AIP zokuhlola njenge-indispensable NRF2-mediated Ndp52 transcription [113]. Ingqalelo, amazinga e-Ndp52 mRNA ayancitshiswa kwi-hippocampus ye-Nrf2-knockout pice. Enye yezi zilandelelwanisiweyo zaqinisekiswa kwakhona kwisifundo esizimeleyo njenge-NRF2-elawulwa yi-ARE [36].

Nangona kunjalo, indima ye-NRF2 kwindlela yokumodareyitha ye-autophagy ayikhawulelwanga ekufakweni kwezi zixhobo ezimbini zokufumana iiprotheni. Ukuze ufumane ingqiqo ejulile kwendima ye-NRF2 kwindlela yokumodareyitha ye-gene ehlobene ne-autophagy, iqela lethu lihlolisise i-chromatin immunoprecipitation database ENCODE kwiiprotheyini ezimbini, i-MAFK ne-BACH1, ebopha ii-ARE ezilawulwa yi-NRF2. Ukusebenzisa isicatshulwa esenziwe kwi-JASPAR yesivumelwaniso, siqaphele ii-AREIT ezininzi kwiijethi ezininzi ze-autophagy. Ezilishumi elinambini kwezi zilandelelwano zaqinisekiswa njengoko i-NRF2 ilawulwa iI-ARE kwii-gene ze-autophagy ezi-9, ezazithengiswa ngamazwi kwi-embroblast ye-mouse ye-Nrf2-knockout pice kodwa ingabuyiselwa yi-NRF2-ebonisa i-lentivirus. Ucwaningo lwethu lubonise ukuba i-NRF2 isebenzise ukubonakalisa ezinye izakhi zofuzo ezibandakanyekayo kumanyathelo ahlukeneyo enkqubo yokuzimela, kuquka ukuqaliswa kwe-autophagy (ULK1), ukuqaphela imithwalo (i-P62 kunye ne-NDP52), ukwakheka kwe-autophagosome (ATG4D, ATG7 kunye ne-GABARAPL1), ububanzi (ATG2B kunye ne-ATG5 ), kunye ne-autolysosome imvume (ATG4D). Ngenxa yoko, ukuzenzekela nge-autophagy flux ekuphenduleni i-hydrogen peroxide yayinamandla xa i-NRF2 engekho [36].

Ukubaluleka kwe-NRF2-Mediated Macroautophagy Genealog Expression kwi-Neurodegenerative Disorders

I-autophagy ephosakeleyo iboniswe ukuba idlale indima ebalulekileyo kwiintlobo ezininzi zezifo ezingenayo i-neurodeergenerative [114] kunye nokuphulukiswa kwe-autophagy kukhokelela ekuhambeni kwemvelo kwiinkonzo [115], [116]. I-Atg7-knockout pice yabonisa ukuba ukulahleka kwe-autophagy kubangela ukuqokelela kwe-p62 kwimibutho yokufaka i-ubiquitin-positive. I-KEAP1 yayisetyenziselwa ezi ziko, ezikhokelela kwi-NRF2 ukuzinza nokuqulunqwa kwezityalo zegciwane (103]. Okubaluleke kakhulu, ukuqokelela ngokweqile kwe-p62 kunye neeprotheni ezinobuninzi kuye kwafunyaniswa kwizifo ezingenayo i-neurodeergenerative, kuquka i-AD, i-PD kunye ne-ALS [117]. Enyanisweni, i-neurons ebonisa amanqanaba aphakamileyo ye-APP okanye i-TAU yezigulane ze-AD nayo ibonise i-p62 kunye neNuclear nyuzi-NRF2, ebonisa ukuba izame zabo zokunciphisa ama-intraneuronal aggregates ngokuzimela kwe-autophagy [36].

Ukusilela kwe-NRF2 kukonyusa ukuhlanganiswa kweprotein kwimeko ye-AD. Ngapha koko, amanqanaba anyukayo e-phosphorylated kunye ne-sarkosyl-insoluble TAU afunyanwa kwiimpuku ze-Nrf2-knockout, nangona kungekho mahluko kwimisebenzi ye-kinase okanye ye-phosphatase enokufunyanwa xa kuthelekiswa nemvelaphi yohlobo lwasendle [113]. Ngokubalulekileyo, i-NDP52 ibonakalisiwe ukuba isebenzisane ne-TAU kwii-murine neurons kunye nokunxibelelana ngokuthe ngqo phakathi kwe-phospho-TAU kunye ne-NDP52 kuboniswe ngovavanyo lwe-co-immunoprecipitation kuzo zombini iimpuku nakwiisampulu ze-AD, zikhomba kwindima yayo ekonakaleni kwe-TAU. Into enomdla kukuba, ukuthulisa i-NDP52, i-p62 okanye i-NRF2 kwii-neurons kukhokelele ekwandeni kwe-phospho-TAU [113], [118]. Ngaphaya koko, ukwanda kokudityaniswa kwe-APP ye-intraneuronal kwafunyanwa kwi-hippocampus ye-APP / PS1? Iimpuku ze-E9 xa i-NRF2 yayingekho. Oku kunxulunyaniswa nokutshintsha kweempawu zokuzimisela, kubandakanya ukwanda kwe-phospho-mTOR / mTOR kunye ne-phospho-p70S6k / p70S6k ratios (ebonisa ukuthintela i-autophagy), amanqanaba ongezelelweyo e-pre-cathepsin D kunye nenani elikhulu lemizimba ye-multivesicular [119]. Kwiimpuku ezibonisa ukusebenzisana kwabantu kwi-APP (V717I) kunye ne-TAU (P301L), ukusilela kwe-NRF2 kukhokelele kumanqanaba anyukayo e-phospho-TAU kwisiqwengana esinganyibilikiyo kunye nokunyuka kwamanani e-intraneuronal ye-APP, kunye namanqanaba ancitshisiweyo e-neuronal ye-p62, NDP52, ULK1, ATG5 kunye neGABARAPL1. Ukudityaniswa kwendawo phakathi kweprotein ye-adaptha p62 kunye ne-APP okanye i-TAU yancitshiswa xa kungekho-NRF2 [36]. Ngokubanzi, ezi ziphumo zibonisa ukubaluleka kwe-NRF2 kwi-neuronal autophagy.

UMthetho woBucala beeTranscription ezahlukeneyo ngokuthe ngqo kwi-Modulate Proteostasis

Ngaphantsi kweemeko zeemeko zeemeko, i-proteostasis ilawulwa nge-protein-protein interactions kunye nokuguqulwa kwithuba emva kokuguqulela ukufumana impendulo ngokukhawuleza. Nangona kunjalo, ukulungelelaniswa kwamaselula kudinga umgaqo-myalelo we-UPR, i-UPS kunye ne-autophagy gene. Ukuqwalasela ukuba iiseli zesisongela ziqhubeka zithunyelwa kwiincwadana ezinobungozi obuncinane, kubandakanywa uxinzelelo lwe-oxidative kunye neproteotoxic, ukuqiniswa kweproteostasis eyenziwa ngokuchithwa kwe-transcription kunganceda ukukhusela ingqondo.

Kwimeko ye-UPR, ukuphunyezwa kweengalo ezintathu kuya kubangelwa ekuqulunqweni kwimiqulu ethile yemfuza (ihlaziywe kwi- [43]). Ngokomzekelo, isiqephu se-ATF6-derived (ATF6f) sibophezela kwi-ER-stress response elements (ERSE) kwaye sinciphisa ukuthetha kweendiza eziliqela, kuquka i-XBPI, i-BIP ne-CHOP. Ukongeza, ukubonakaliswa kwe-PERK kukhokelela ekusebenziseni kwe-transcription factor ATF4, elawula ukubonakaliswa kweengqimba ezininzi ezihlobene ne-UPR kunye nezinye ezibandakanya i-NRF2 izakhi zegciwane Hmox1 kunye ne-p62. Ekugqibeleni, iziphumo ze-IRE1 zenza uveliso lwe-transcription factor, lucacisa i-XBP1 (XBP1s), elawula ukubhalwa kweejeni ezifakela iiprotheyini ezibandakanyeka kwiprotheni yokunyathela.

Ngakolunye uhlangothi, i-NRF1 iboniswe ukuba iyimfuneko kwi-expression ye-proteasomal gene kwi-brain, njengoko i-Nrf1-knockout pice ibonise ukunciphisa ukubonakalisa iigeni ezifakela iinqununu ezahlukeneyo ze-20S, kunye ne-19S yokulawula kunye kunye ne-proteasomal functional incomplete [90 ]. Zombini i-NRF1 kunye ne-NRF2 zibophelela kwi-ARE ngokulandelelanisa kwimimandla yazo ekujoliswe kuyo, ebonisa ukuba banemisebenzi ebhaliweyo yokubhaliweyo, nangona bahluke kwiindlela zabo zokulawula kunye nokwakhiwa kwamaselula [120].

Iziganeko zeTranscription ze-Forkhead kwibhokisi ye-O (FOXO) yolawulo lwentsapho lilawula ukubonakaliswa kweengqikithi ezininzi ze-autophagy. Ngokufanayo nento eyenzeka nge-NRF2, kukho iindlela ezininzi zokulawula umsebenzi wee-FOXO amalungu, onokubangela ukunyanzeliswa kokutya okanye ukuxinzezeleka komzimba (121]. Ekugqibeleni, i-TFEB ye-transcription factor, ebonwa njengomlawuli we-lysosomal biogenesis, idlala indima ebalulekileyo ekulawuleni ukuzenzekela ngokwemimiselo phantsi kweemeko zokuxinwa kwesondlo. Ngaloo ndlela, ukuvinjelwa kwe-MTORC1 kukhokelela ekutheni i-TFEB ishintshelwe i-nyukliya kunye nokutyalwa kwegama lokuzimela kwegazi (122].

Ngokubanzi, ubukho bezolawulo ezahlukeneyo zale mishini zibonisa ukuba kukho iindlela ezinokuthi ziqinisekise iproteostasis phantsi kweemeko ezahlukeneyo. Ngako oko, i-NRF2 inokuba nenxaxheba ebalulekileyo kwiiscuksi ezixhasa amanqanaba aphezulu okuxinzezeleka kwengcinezelo. Ngokomzekelo, i-NRF2 eyenza uxinzelelo lwe-oxidative ingasebenza phantsi kweemeko ezizityebi ezinokondlo ngokubhalwe ngokusemthethweni-ukulawula ukuzenzekelayo, okufana noko kufunyenwe kwi-TFEB phantsi kwezimo zendlala. Ngaphezu koko, iinjongo zengqondo ziphantsi kweemeko ezicebileyo ezondlobisayo, zibeka i-NRF2 njengendlela efanelekileyo yokwenza umzenzelo we-autophagy kwi-neurons.

Ukuthembisa�Amandla okuNyanga kwi-NRF2 kwiiProteinopathies

Kwiminyaka embalwa edlulileyo, kuye kwenziwa inkqubela phambili enkulu kulwazi lweendima zokulawula i-UPR, i-UPS kunye ne-autophagy kumsebenzi we-NRF2, kunye nokubhalwa kwe-NRF2-mediated-reciprocal of components of these three systems. Ke ngoko, amathuba amatsha onyango anokuvela ngokusekwe ekusetyenzisweni kwe-NRF2 njengolawulo olubalulekileyo lweprotein clearance kwizifo ze-neurodeergenerative.

Nangona kunjalo, umbuzo obalulekileyo oseleyo kukuba ngaba kuya kuba luncedo okanye ukucima ukunyusa amanqanaba e-NRF2 engqondweni. Uhlalutyo lwedatha ye-epidemiological inokubonelela ngempendulo engaphelelanga, njengoko ibonisa ukuba i-NFE2L2 gene i-polymorphic kakhulu kwaye enye i-polymorphisms ye-nucleotide enye efunyenwe kwindawo yokulawula umgqugquzeli wayo inokubonelela ngoluhlu lokuhlukahluka kwe-physiological kwi-gene expression kwinqanaba labantu kunye nezinye ii-haplotypes. zidibene nokunciphisa umngcipheko kunye / okanye ukulibaziseka kwe-AD, PD okanye i-ALS [123]. Ngaphezu koko, njengoko kuxoxwe nguHayes kunye noogxa [124], umphumo we-NRF2 unokuba nempendulo efana ne-U, oku kuthetha ukuba amanqanaba aphantsi kakhulu e-NRF2 angabangela ukulahlekelwa kwe-cytoprotection kunye nokunyuka kwe-stressors, ngelixa i-NRF2 eninzi inokuphazamisa ibhalansi ye-homeostatic ngokubhekiselele. imeko yokunciphisa (uxinzelelo oluncitshisiweyo), oluya kuthanda iprotein engalunganga kunye nokudibanisa. Amanqanaba aphantsi e-NRF2 ebuchosheni axhasa ingcamango yokuba umgaqo-nkqubo omncinci unokwanela ukufezekisa inzuzo phantsi kweemeko ze-pathological. Enyanisweni, indima yokukhusela ye-pharmacological NRF2-mediated activation of protein clearance iboniswe kwiinkcubeko ezahlukeneyo ze-neurodegeneration cell kunye ne-vivo models.

I-SFN yi-activator ye-NRF2 ye-pharmacological ebonakaliswe ukuba ibangele i-proteasomal kunye ne-autophagy expression expression [95], [36]. Into enomdla kukuba, uJo noogxa bakhe babonisa ukuba i-SFN inciphise amanqanaba e-TAU ye-phosphorylated kwaye yonyusa i-Beclin-1 kunye ne-LC3-II, ukucebisa ukuba i-NRF2 isebenze inokuthi iququzelele ukuthotywa kwale protein inetyhefu ngokusebenzisa i-autophagy [113]. Ngaphezu koko, ukuthotywa kwe-mHtt kwandiswa nge-SFN, kwaye oku kwabuyiselwa ekusebenziseni i-MG132, ebonisa ukuthotywa kweproteasomal kwale protein inetyhefu [95]. Ukonakaliswa okuphakathi kwe-Autophagy kwe-phospho- kunye ne-insoluble-TAU kwaxelwa nge-organic flavonoid fisetin. Eli ziko likwazile ukubangela ukuzenzekelayo ngokunyusa ngaxeshanye ukwenziwa kwezinto kunye nokudluliselwa kwenyukliya kuzo zombini i-TFEB kunye ne-NRF2, kunye nezinye izinto ekujolise kuzo. Le mpendulo ithintelwe yi-TFEB okanye i-NRF2 ithule [125]. I-Bott kunye noogxa baxela iziphumo eziluncedo ze-NRF2, i-NRF1 kunye ne-HSF1 activator kwiprotein yetyhefu kwi-spinal kunye ne-bulbar muscular atrophy, isifo se-neurodegenerative esibangelwa kukwandiswa kwe-polyglutamine-encoding CAG ephindayo apho iiprotein aggregates zikhona [126]. Ukubakho kokusebenza kwe-NRF2 kunyango lweengxaki ze-neurodegenerative kubonisiwe ngemvume ye-BG-12, ukwenziwa ngomlomo kwe-NRF2 inducer dimethyl fumarate (DMF), kunyango lwe-multiple sclerosis [127], [128]. Impumelelo ye-DMF ngezifo ezisebenza gwenxa ezinento yokuvuvukala iphakamisa ukuba izifo ze-neurodeergenerative zinokuxhamla ekubekeni kwakhona eli chiza. Kuphononongo lwakutshanje lwe-PD?, Imodeli ye-PD, i-DMF ibonakaliswe njenge-neuroprotective ngenxa, ngokuyinxenye, ekungenisweni kwayo kwe-autophagy [129]. Izifundo zokuxela iziphumo eziluncedo ze-NRF2 kwi-neurodegeneration kodwa ingagxili kwimpembelelo yayo ekucoceni iiprotein zininzi ngakumbi (ukuphononongwa ngokubanzi, jonga [7]). Oku kufanelekile, njengoko kugxininisa iinkqubo ezininzi ezonakalisayo ezinokuthi zijolise kwangaxeshanye kwi-NRF2, kubandakanya uxinzelelo lwe-oxidative, neuroinfigueation okanye ukungasebenzi kakuhle kwe-mitochondrial. Nangona kunjalo, umsebenzi wexesha elizayo uya kufuneka ngokuqinisekileyo ukumisela ukuba ukwenziwa kwe-pharmacological ye-NRF2 inokuba sisicwangciso esisebenzayo sokuququzelela ukonakaliswa kweeproteni ezinetyhefu kwingqondo.

Njengoko bekuchaziwe ngaphambili, iyanda i-GSK-3? Umsebenzi uxeliwe kwizifo ze-neurodeergenerative kwaye kuye kwaqikelelwa ukuba isiphumo sokuncitshiswa kwe-NRF2 sinokuba noxanduva lwesiphumo esibi. Ngaphantsi kwezi meko ze-pathological, i-GSK-3 inhibitors nayo inokusebenzisana ukwandisa amanqanaba e-NRF2 kunye neproteostasis. Iziphumo eziluncedo ze-GSK-3 inhibitors zixeliwe kwiimodeli ezahlukeneyo ze-neurodegeneration kwaye, okunomdla ngakumbi, ingcinezelo ye-GSK-3 yaboniswa ukunciphisa amanqanaba eeproteni ezinetyhefu [130], [131], [132], [133]. Nangona kungekho makhonkco ngokuthe ngqo phakathi kwe-GSK-3 inhibition kunye ne-NRF2-transcriptional regulation of genes ekukhuthazeni i-proteostasis esele yaqwalaselwa okwangoku, kusengqiqweni ukuqikelela ukuba ezantsi-ukumiselwa kwemisebenzi ye-GSK-3 kungakhokelela ekwandeni kwamanqanaba e-NRF2, eya kuthi ekugqibeleni ikhokelele ekuqiniseni. Iproteostasis.

Umsebenzi okhutshelweyo we-NRF2 kunye nomthamo weselfowuni wokugcina ukuhla kweproteostasis kunye nobudala, eyona nto iphambili yomngcipheko kuphuhliso lwezifo ze-neurodeergenerative. Kusengqiqweni ukucinga ukuba ukuqiniswa kwe-NRF2 kwaye, ngenxa yoko, iprostostasis, ubuncinci, iya kulibazisa ukuqokelelwa kweeprotegregates kunye ne-neurodegeneration. Ewe kunjalo, unyango lwe-fibroblast ye-senescent yabantu ene-18? -Glycyrrhetinic acid (18? -GA) triterpenoid ikhuthaze ukwenziwa kwe-NRF2, ekhokelela ekungenisweni kweproteasome kunye nexesha lokuphucula ubomi. Olu pho nonongo lubonisa ukuba ukusebenza kwe-pharmacological ye-NRF2 kunokwenzeka nakwixesha elidlulileyo [86]. Ngaphezu koko, uphando lwamva kamva lubonise ukuba eli khompawundi lilungelelanise i-SKN-1 kunye nokusebenza kweproteasome ku-C.elegans ezineziphumo eziqinisekileyo ekuqhubekeni kwe-AD kwiimodeli ezifanelekileyo zematode [134].

Zonke izinto zicatshangelwe, ukufakelwa kwe-NRF2-mediation of genetic-related related genes kubonakala kunenzuzo kwiiprotheniopathies ezahlukeneyo.

I-Sulforaphane kunye neZiphumo zayo kuMhlaza, ukusweleka, ukuGuga, uBongo kunye nokuziphatha, isifo sentliziyo kunye nokunye

I-Isothiocyanates zizinye zezona zibalulekileyo zityalo zezityalo onokuzifumana kwisondlo sakho. Kule vidiyo ndiyenzela iimeko ezinzulu kunazo zonke eziye zenziwa. Ukufutshane okufutshane? Dlulela kwisihloko ozithandayo ngokuchofoza enye yeengongoma zangezantsi. Umgca wexesha eliphantsi.

Amacandelo aphambili:

• 00: 01: 14 - I-cancer kunye nokufa
• 00: 19: 04 - Ukuguga
• 00: 26: 30 - Ubunono nokuziphatha
• I-00: I-38: 06 - I-recap yokugqibela
• 00: 40: 27 - Dose

Umgca wexesha elipheleleyo

• 00: 00: 34 - Ukuqaliswa kwe-sulforaphane, ingqwalasela ephambili yevidiyo.
• I-00: I-01: 14 - Ukusetyenziswa kwemifuno yeCruciferous kunye nokunciphisa kuzo zonke izizathu zokufa.
• I-00: 02: 12 - Umngcipheko womhlaza we-prostate.
• I-00: 02: 23 - Ingozi yomhlaza wesibeletho.
• I-00: 02: 34 - Umdlavuza womlenze kwingozi yokubhema.
• 00: 02: 48 - Ingozi yomhlaza wesifuba.
• I-00: 03: 13 - I-Hypothetical: kuthekani ukuba unomdlavuza? (ukungenelela)
• I-00: I-03: 35 - Indlela engabonakaliyo yokuqhuba umhlaza kunye nokufa kwedatha yokudibanisa.
• 00: 04: 38 - Sulforfane nomhlaza.
• I-00: 05: 32 - Ubungqina benkomo obonakalisa impembelelo enamandla ye-broccoli inhluma ehluthwayo ekuphuculweni kwe-tumor kwi-rats.
• I-00: I-06: 06 - Impembelelo yokuxhaswa ngokuthe ngqo kwe-sulforaphane kwizigulane zomhlaza wesibeletho.
• I-00: I-07: 09 - Ukuqokelela i-isothiocyanate i-metabolites kwimizimba yesisu.
• I-00: 08: 32 - Ukuvinjelwa kweeseli zomhlaza zesisu.
• 00: 08: 53 - Isifundo somlando: i-brassicas yasungulwa njengezakhiwo zezempilo nakwiRoma lasendulo.
• I-00: 09: 16 - I-Sulforfane ikhono lokuphucula ukwanda kwe-carcinogen (benzene, acrolein).
• I-00: 09: 51 - NRF2 njengenguqu yokuguqula izakhi nge-antioxidant response elements.
• I-00: 10: 10 - Indlela eyenziwa ngayo i-NRF2 isebenzise ukwanda kwe-carcinogen nge-glutathione-S-conjugates.
• I-00: I-10: I-34 - i-Brussels ihluma iyakhuphula i-glutathione-S-transferase kwaye iyanciphisa umonakalo we-DNA.
• I-00: 11: I-20 - i-Broccoli ihluma isiselo iphakamisa ibhenene ngaphandle kwe-61%.
• I-00: I-13: I-31 - I-Broccoli ihluma i-homogenate ikwandisa i-enzymes e-antioxidant ephezulu.
• I-00: I-15: 45 - Ukusetyenziswa kwemifuno yeCruciferous kunye nokufa kwesifo senhliziyo.
• I-00: I-16: I-55 - i-Broccoli ihluma i-powder iphucula i-lipids yegazi kunye nesifo sengqondo senhliziyo yesifo se-2.
• 00: 19: 04 - Ukuqala kwecandelo lokuguga.
• I-00: I-19: I-21 - I-Sulforaphane-ukutya okunomsoco kwandisa ubomi be-beetles ukusuka kwi-15 ukuya ku-30% (kwiimeko ezithile).
• I-00: 20: 34 - Ukubaluleka kokuvuvuka okuphantsi kwexesha elide.
• I-00: I-22: I-05 - Imifuno e-Cruciferous kunye ne-broccoli ihlumela i-powder ibonakala iyanciphisa iindidi ezahlukahlukeneyo zokumangalisa abantu.
• I-00: 23: 40 - Ukuhlaziywa kwe-mid-video: umdlavuza, izigulane eziguga
• I-00: I-24: I-14 - Iziphumo zemouse zibonisa ukuba i-sulfurephane inokuphucula ukusebenza kwe-immune ngexesha lokuguga.
• I-00: I-25: I-18 -Sulforaphane ithuthukise ukunyuka kweenwele kwimodeli ye-mouse yokukhangela. Umfanekiso kwi-00: 26: 10.
• 00: 26: 30 - Ukuqala kwecandelo lobuchopho kunye nokuziphatha.
• I-00: 27: 18 - Impembelelo ye-broccoli ihluma i-autism.
• 00: 27: 48 - Umphumo we-glucoraphanin kwi-schizophrenia.
• I-00: I-28: 17 - Ukuqala kwengxoxo yokudandatheka (iindlela kunye nezifundo).
• I-00: 31: 21 - Uvavanyo lweMouse usebenzisa i-10 imizekelo eyahlukeneyo yokuxinezeleka okubangelwa uxinzelelo kubonisa ukuba i-sulforaphane efana neyofana ne-fluoxetine (prozac).
• I-00: I-32: I-00 - Ukufundiswa kubonisa ukungena ngokuthe ngqo kwe-glucoraphanin kwiimicebe kusebenza ngokufanayo ekukhuseleni ukudandatheka kwindlela yokuxhatshazwa kwentlalo.
• I-00: I-33: 01 - Ukuqala kwecandelo lokuvelisa i-neurodegeneneration.
• 00: 33: 30 - Sulforaphane kunye nesifo se-Alzheimer.
• 00: 33: 44 - Sulforaphane kunye nesifo sikaParkinson.
• 00: 33: 51 - iSulforaphane nesifo sikaHongtington.
• I-00: 34: I-13 - I-Sulforfane iphakamisa ama-proteins.
• 00: 34: 43 - Ukuqala kwecandelo lokulimala kwengqondo elibuhlungu.
• I-00: I-35: I-01 - I-Sulforaphane injected ngokukhawuleza emva kwe-TBI iphucula imemori (isifundo se mouse).
• I-00: 35: 55 - iSulforaphane kunye ne-plastic neuronal.
• I-00: I-36: I-32 - I-Sulforfane iphucula ukufunda kwi-type II yesifo sikashukela kwiimiceba.
• I-00: 37: 19 - iSulforaphane kunye ne-duchenne i-dystrophy muscular.
• I-00: 37: 44 - I-Myostatin inhibition kwiiseli ze-satellite ze-muscle (in vitro).
• I-00: 38: 06 - Ukuhlaziywa kwexesha elide: i-mortality kunye nomhlaza, umonakalo we-DNA, uxinzelelo lwe-oxidative kunye nokuvuvukala, i-benzene excretion, isifo se-cardiovascular, uhlobo lwesi-2 seswekile, iimpembelelo kwingqondo (ukudandatheka, autism, schizophrenia, neurodegeneration), indlela ye-NRF2.
• I-00: I-40: 27 - Iingcamango zokuqikelela umthamo wamahlumela e-broccoli okanye i-sulforfane.
• I-00: I-41: I-01 - i-Anecdotes xa ihluma ekhaya.
• I-00: 43: 14 - Ekuphekeni kwamaqondo okushisa kunye nomsebenzi we-sulforaphane.
• I-00: 43: 45 - Gut bacteria ukuguqulwa kwe-sulforaphane kwi-glucoraphanin.
• I-00: I-44: I-24 - I-Supplements isebenza ngcono xa idibene ne-myrosinase esebenzayo kwimifuno.
• I-00: I-44: I-56 - Amasu okupheka kunye nemifuno e-cruciferous.
• 00: 46: 06 - Isothiocyanates njenge-goitrogens.

I-nuclear-derived 2 (NF-E2) -yinto ehambelana ne-2, enye eyaziwa ngokuba ngu-Nrf2, yinto engumyalezo wokubhala olawula iindidi ze-antioxidant kunye ne-detoxifying enzymes. Uphando lwezophando luye lwabonisa indima yalo ekulawuleni uxinzelelo lwe-oxidative. Izifo ezininzi ezinokuphefumula, ezifana nesifo se-Alzheimer kunye nesifo sika-Parkinson, sichazwa ngxinzelelo lwe-oxidative kunye nokuvutha okungapheliyo, iithagethi eziqhelekileyo Ukunyanga kwe-Nrf2. UDkt Alex Jimenez DC, i-CCST Insight

Ukuphetha

I-transcription factor NRF2 iququzelela impendulo yeproteostatic ngokubona kunye nokuguqula utshintsho kwi-UPR, i-UPS kunye ne-autophagy (umzobo 4). Ngenxa yoko, ukungabikho kwe-NRF2 kuye kwaboniswa ukwandisa iproteinopathy, ebonisa ukuba i-NRF2 iyimfuneko kwi-protein clearance. Sonke, sinokucinga ukuba i-NRF2 ingaba yinjongo yonyango enomdla kwiproteinopathies.

Imibulelo

Sciencedirect.com/science/article/pii/S2213231716304050

Ngokubhekiselele kwinqaku elingentla, ngelixa iimpawu zezifo ezingenazo izifo zingaphathwa ngeendlela ezahlukeneyo zonyango, uphando luye lwabonisa ukuba ukusetyenziswa kwe-Nrf2 ingaba yindlela yokwenza unyango. Ngenxa yokuba I-activators yeNrf2 ijolise iindlela ezibanzi zezifo, zonke izifo ze-neurodeergenerative zinokuzuza ngokusetyenziswa kwe-Nrf2 transcription factor. Iziphumo ze-Nrf2 ziye zaluguqula unyango lwezifo ze-neurodeergenerative. Ubungakanani bolwazi lwethu lukhawulelwe kwi-chiropractic kunye nemiba yempilo yomgogodla. Ukuxoxa ngalo mbandela, nceda uzive ukhululekile ukubuza uGqr. Jimenez okanye uqhagamshelane nathi apha915-850-0900 .

Ikhutshwe nguDkt. Alex Jimenez

Isingqinisiso sivela kwi: Sciencedirect.com

Ingongoma eyongezelelweyo Ingxoxo: Ukuxoxisa ubuhlungu be-Knee Pain ngaphandle kokuPhenywa

Intlungu yedolo luphawu olwaziwayo olunokuthi lwenzeke ngenxa yeengozi zamadolo kunye / okanye iimeko, kubandakanya ukulimala kwezemidlalo. Idolo lelinye lawona malungu anzima kakhulu emzimbeni womntu njengoko lenziwe kwi-intersection yamathambo amane, iigaments ezine, ii-tendon ezahlukeneyo, i-menisci ezimbini kunye ne-cartilage. Ngokutsho kwe-American Academy of Family Physicians, eyona nto ibangela ukuba iintlungu zedolo ziquka i-patellar subluxation, i-patellar tendinitis okanye i-jumper's knee, kunye nesifo se-Osgood-Schlatter. Nangona iintlungu zamadolo zinokwenzeka ukuba zenzeke kubantu abangaphezu kweminyaka engama-60 ubudala, iintlungu zamadolo zingenzeka nakubantwana nakwishumi elivisayo. Ubuhlungu bedolo bunokuphathwa ekhaya ngokulandela iindlela ze-RICE, nangona kunjalo, ukulimala kwamadolo okunzima kunokufuna unyango olukhawulezileyo, kubandakanywa nokunakekelwa kwe-chiropractic. �

I-EXTRA EXTRA | ISIHLOKO ESIBALULEKILEYO: Kunconywe i-El Paso, TX I-Chiropractor

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