Oxidants waxaa guud ahaan loo soo saaraa hab la xakameeyey si loo habeeyo hababka lagama maarmaanka ah ee jidhka bini'aadamka, oo ay ku jiraan kala qaybinta unugyada, caabuqa, shaqada difaaca, autophagy, iyo jawaab celinta cadaadiska. Si kastaba ha noqotee, wax soo saarka aan la xakameynin ee oksaydhiyeyaashan ayaa wax ku biirin kara cadaadiska qiiqa, taas oo saameyn karta shaqada gacanta, taasoo keenta horumarinta sunta, cudurrada daba-dheeraada iyo kansarka. Hababka antioxidant-ka difaaca jirka bini'aadamka waxaa nidaamiya waddooyin muhiim ah oo taxane ah kuwaas oo xakameynaya jawaabta unugga ee oksaydhiyeyaasha. Qodobka nukliyeerka ee erythroid 2- la xidhiidha, haddii kale loo yaqaan Nrf2, waa nidaamiye soo baxaya oo ah caabbinta gacanta ee oksidants. Ujeedada maqaalka hoose waa in laga wada hadlo oo muujiyo doorka soo baxaya ee Nrf2 ee shaqada mitochondrial.
aan la taaban karin
Qodobka qoraalka NF-E2 p45 ee la xidhiidha 2 (Nrf2; magaca hidda-wadaha NFE2L2) ayaa u oggolaanaya la qabsiga iyo badbaadada xaaladaha walaaca iyadoo la xakameynayo muujinta hidda-wadaha ee shabakadaha kala duwan ee borotiinnada cytoprotective, oo ay ku jiraan antioxidant, anti-bararka, iyo enzymes detoxification sidoo kale sida borotiinada caawiya hagaajinta ama ka saarista makromolecules dhaawacmay. Nrf2 waxay leedahay door muhiim ah oo ku saabsan dayactirka redox homeostasis-ka gacanta iyadoo la xakameynayo biosynthesis, ka faa'iidaysiga, iyo dib-u-soo-nooleynta glutathione, thioredoxin, iyo NADPH iyo iyada oo la xakameynayo soosaarka noocyada oksijiinta firfircoon ee mitochondria iyo NADPH oxidase. Marka la eego xaaladaha homeostatic, Nrf2 waxay saamaysaa awoodda xuubka mitochondrial, oxidation fatty acid, helitaanka substrates (NADH iyo FADH2 / succinate) ee neefsiga, iyo isku-dhafka ATP. Marka la eego xaaladaha walaaca ama kicinta koritaanka, firfircoonida Nrf2 waxay ka hortagtaa soosaarka noocyada oksijiinta firfircoon ee mitochondria iyada oo loo marayo hagaajinta qoraalka ee borotiinka 3 iyo saameyn ku yeelashada mitochondrial biogenesis iyada oo la ilaalinayo heerarka nukliyeerka nukliyeerka factor 1 iyo peroxisome proliferator-activated receptor ? coactivator 1?, iyo sidoo kale kor u qaadida purine nucleotide biosynthesis. Dhaqdhaqaaqayaasha Pharmacological Nrf2, sida isothiocyanate sulforaphane ee si dabiici ah u dhacda, waxay joojisaa furitaanka oksaydhka-dhexdhexaadinta ee daloolka kala-guurka ee mitochondrial permeability iyo bararka mitochondrial. Si cajiib leh, isku-dhafka 1,4-diphenyl-1,2,3-triazole synthetic, oo asal ahaan loogu talagalay sidii Nrf2 activator, ayaa lagu helay inuu kor u qaado mitophagy, taas oo ka qayb qaadanaysa guud ahaan mitochondrial homeostasis. Sidaa darteed, Nrf2 waa ciyaaryahan caan ah oo taageeraya qaab dhismeedka iyo sharafta shaqada ee mitochondria, doorkanina wuxuu si gaar ah muhiim ugu yahay xaaladaha walaaca.
Keywords:Bioenergetics, Cytoprotection, Keap1, Mitochondria, Nrf2, Xagga xorta ah
Tilmaamaha
Nrf2 waxay door muhiim ah ku leedahay ilaalinta redox homeostasis-ka gacanta.
Nrf2 waxay saamaysaa awoodda xuubka mitochondrial iyo isku-dhafka ATP.
Nrf2 waxay taageertaa qaab-dhismeed iyo daacadnimo shaqayneed ee mitochondria.
Dhaqdhaqaaqayaasha Nrf2 waxay leeyihiin saameyn faa'iido leh marka shaqada mitochondrial la wiiqo.
Hordhac
Qodobka qoraalka NF-E2 p45 ee la xidhiidha 2 (Nrf2; magaca hidda-wadaha NFE2L2) ayaa nidaamiya muujinta shabakadaha hiddo-wadaha oo ku dhejinaya borotiinno leh hawlo kala duwan oo cytoprotective ah. Nrf2 lafteeda ayaa lagu xakameynayaa ugu horreynta heerka xasilloonida borotiinka. Marka la eego xaaladaha aasaasiga ah, Nrf2 waa borotiin muddo gaaban ah oo lagu sakhiray meel-ka-bax joogto ah iyo nabaad-guurka borotiinka. Waxaa jira saddex nidaam oo loo yaqaan ubiquitin ligase kuwaas oo gacan ka geysta hoos u dhaca Nrf2. Taariikh ahaan, nidaamiyaha xun ee ugu horreeya ee Nrf2 ee la ogaaday wuxuu ahaa Kelch-sida ECH-ku xiran borotiinka 1 (Keap1) [1], borotiinka adabtarada substrate ee Cullin 3 (Cul3) / Rbx1 ubiquitin ligase [2], [3], 4]. Keap1 waxay isticmaashaa hannaan wareeg ah oo wax ku ool ah si ay u beegsato Nrf2 si ay u baabi'iso meel kasta iyo proteasomal, inta lagu jiro taas oo Keap1 si joogto ah loo cusbooneysiiyo, taas oo u oggolaanaysa wareegga inuu sii socdo (Jaantus. 1A) [5]. Nrf2 ayaa sidoo kale hoos u dhigtay hoos u dhigista dhexdhexaadinta glycogen synthase kinase (GSK) 3 /?-TrCP-ku-tiirsanaanta Cul1-ku salaysan ubiquitin ligase [6], [7]. Dhawaanahan, waxaa la soo wariyay in, inta lagu jiro xaaladaha diiqada endoplasmic reticulum stress, Nrf2 waa la baabi'iyay oo hoos u dhigay habka dhexdhexaadinta E3 ubiquitin ligase Hrd1 [8].
Jaantuska 1 Qaabka xidhidhiyaha isku xigxiga iyo dib u soo kicinta ee Keap1-dhexdhexaadinta xaalufinta Nrf2. (A) Nrf2 waxay si isdaba joog ah ugu xidhan tahay Keap1 dimer bilaash ah: marka hore iyada oo loo marayo xidhiidhkeeda sare ee ETGE (ulaha cas) xidhidhiyaha ka dibna iyada oo loo marayo DLG (ulaha madow) xidhidhiyaha hoose. Is-waafajinta isku-dhafka borotiinka, Nrf2 waxay maraysaa meel-ka-baxsan waxaana loogu talagalay hoos u dhaca borotiinka. Keap1 lacag la'aana waa dib loo soo nooleeyay oo awood u leh inay ku xidho Nrf2 cusub oo la turjumay, wareegguna wuxuu bilaabmayaa mar labaad. Keap1 bilaasha ah dib looma soo kicin, oo Nrf1-ka cusub ee la soo saaray ayaa urura oo u beddelaa xudunta.
Marka lagu daro u adeegida sida borotiinka substrate substrate-ka, Keap1 sidoo kale waa dareemayaasha noocyo badan oo ka mid ah firfircoonayaasha molecule-yar ee Nrf2 (oo loo yaqaan 'inducers') [9]. Soo-saarayaashu waxay xannibaan wareegga Keap1-dhexdhexaadinta hoos u dhaca Nrf2 iyagoo kiimiko wax ka beddelaya hadhaaga cysteine ee gaarka ah ee Keap1 [10], [11] ama iyagoo si toos ah u carqaladeynaya Keap1: Nrf2 isku-xirnaanta isku-xirnaanta [12], [13]. Sidaa darteed, Nrf2 ma hoos u dhacdo, oo qodobka qoraalka ayaa urura oo u beddela xudunta (Jaantus. 1B), halkaas oo ay ka sameyso heterodimer leh borotiinka Maf yar; waxay ku xidhan tahay walxaha jawaab-celinta-antioxidant, gobollada sharciyeynta sare ee hiddo-wadaha bartilmaameedka ah; oo bilaabay qoraal [14], [15], [16]. Batariyada bartilmaameedyada Nrf2 waxay ka kooban yihiin borotiinno leh hawlo kala duwan oo cytoprotective ah, oo ay ku jiraan enzymes ee dheef-shiid kiimikaad xenobiotic, borotiinno leh antioxidant iyo hawlaha ka-hortagga bararka, iyo borotiinada borotiinka, iyo sidoo kale borotiinnada xakameynaya redox homeostasis gacanta oo ka qaybqaata dheef-shiid kiimikaad dhexdhexaad ah.
Nrf2: Maamule Master of Cellular Redox Homeostasis
Shaqada Nrf2 sida maamulaha sare ee redox homeostasis gacanta ayaa si weyn loo aqoonsaday. Muujinta hidda-wadaha labada qaybood ee catalytic iyo xeer-hoosaadka ee ?-glutamyl cysteine ligase, enzyme kicinta heerka xaddidaadda xaddidan ee biosynthesis ee hoos u dhaca glutathione (GSH), ayaa si toos ah u nidaaminaya Nrf2 [17]. Qaybta xCT ee nidaamka xc-, kaas oo keena cystineka unugyada, sidoo kale waa bartilmaameed toos ah oo qoraal ah oo Nrf2 [18]. Unugga dhexdiisa, cystine wuxuu u beddelaa cysteine, horudhac u ah biosynthesis ee GSH. Marka lagu daro doorka ay ku leedahay GSH biosynthesis, Nrf2 waxay bixisaa habka loogu talagalay dayactirka glutathione ee xaaladdeeda la dhimay iyada oo loo marayo nidaaminta isku-dhafka ah ee glutathione reductase 1 [19], [20]. . NADPH-ga loo baahan yahay waxaa bixiya afar enzymes oo soo saara NADPH, malic enzyme 1 (ME1), isocitrate dehydrogenase 1 (IDH1), glucose-6-phosphate dehydrogenase (G6PD), iyo 6-phosphogluconate dehydrogenase (PGD), kuwaas oo dhammaantood ah si qoraal ahaan loo habeeyey qayb ahaan Nrf2 (Jaantus 2) [21], [22], [23], [24]. Si cajiib leh, Nrf2 ayaa sidoo kale nidaamisa muujinta hidda-wadaha aan la dabooli karin ee cytosolic, microsomal, iyo foomamka mitochondrial ee aldehyde dehydrogenase [25], kuwaas oo u isticmaala NAD (P) + sidii cofactor, taasoo keenaysa NAD (P) H. Runtii, heerarka NADPH iyo saamiga NADPH / NADP + way ka hooseeyaan fibroblast embriyaha ee ka go'ay jiirka Nrf2-knockout (Nrf2-KO) marka la barbar dhigo unugyada dhigooda nooca duurjoogta ah (WT), iyo heerarka NADPH waxay hoos u dhacaan marka Nrf2 garaacdo. Khadadka unugyada kansarka oo leh Nrf2 [26]. Sida la filayo, heerarka GSH waxay ku hooseeyaan unugyada Nrf2 la carqaladeeyey; Taa bedelkeeda, Nrf2 firfircoonida hidaha ama farmashiistaha waxay keenaysaa kor u qaadista GSH [27], [28], [29]. Muhiimad ahaan, Nrf2 waxay sidoo kale nidaamisaa muujinta hidda-wadaha thioredoxin [30], [31], [32], thioredoxin reductase 1 [28], [29], [32], [33], iyo sulfiredoxin [34], kuwaas oo lagama maarmaan u ah. si loo yareeyo thiols borotiinka oksaydhka.
Jaantuska 2 Doorka Nrf2 ee dheef-shiid kiimikaadka unugyada degdega ah. Nrf2 waa nidaamiye togan oo hiddo-wadaha ku dhejinaya enzymes ee labadaba cududda oksaydhka [ie, glucose-6-phosphate dehydrogenase (G6PD) iyo 6-phosphogluconate dehydrogenase (PGD)] iyo cududda nonoxidative [ie, transaldolase 1 (TALDO1) iyo transketolase TKT)] ee dariiqa fosfooraska pentose. G6PD iyo PGD waxay dhaliyaan NADPH. Nrf2 waxay sidoo kale xakameysaa muujinta hidda-wadaha ee labada kale ee NADPH-abuurka enzymes, malic enzyme 1 (ME1) iyo isocitrate dehydrogenase 1 (IDH1). Muujinta hidda-wadaha fosforbosyl pyrophosphate amidotransferase (PPAT), kaas oo kicinaya gelitaanka jidka de novo purine biosynthetic, sidoo kale si togan u habeeya Nrf2, sida muujinta methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), enzyme mitochondrial oo door muhiim ah ku leh bixinta halbeeg kaarboon ah oo loogu talagalay biosynthesis de novo purine. Pyruvate kinase (PK) waxaa si xun u habeeya Nrf2 waxaana la filayaa in ay door bido dhisidda dhexdhexaadiyeyaasha glycolytic iyo, oo ay weheliso G6PD, dheef-shiid kiimikaadka iyada oo loo marayo waddada fosfatka pentose iyo isku-darka acids nucleic, acids amino, iyo fosfolipids. Nrf2 waxay si xun u xakameysaa muujinta hiddaha ee ATP-citrate lyase (CL), taas oo kordhin karta helitaanka citrate ee isticmaalka mitochondrial ama (iyada oo loo marayo isocitrate) ee IDH1. Casaan iyo buluug ayaa tilmaamaya xeerar togan iyo taban, siday u kala horreeyaan. Mitochondion waxaa lagu muujiyey cawl. Soo gaabinta dheef-shiid kiimikaadka: G-6-P, glucose 6-phosphate; F-6-P, fructose 6-fosfate; F-1,6-BP, fructose 1,6-bisphosphate; GA-3-P, glyceraldehyde 3-phosphate; 3-PG, 3-phosphoglycerate; PEP, phosphoenolpyruvate; 6-P-Gl, 6-phosphogluconolactone; 6-PG, 6-phosphogluconate; R-5-P, ribulose 5-phosphate; PRPP, 5-phosphoribosyl-?-1-pyrophosphate; THF, tetrahydrofolate; IMP, monophosphate inosine; AMP, adenosine monophosphate; GMP, guanosin monophosphate.
Marka la eego doorka muhiimka ah ee Nrf2 oo ah maamulaha sare ee redox homeostasis, maahan wax la yaab leh, marka la barbardhigo unugyada WT, heerarka noocyada oksijiinta falcelinta (ROS) ayaa ka sarreeya unugyada Nrf2 la carqaladeeyey (Nrf2-KO) [35] Kala duwanaanshiyahani wuxuu si gaar ah u taabanayaa marka lala tartamo wakiilada keena cadaadiska oksaydhka. Waxaa intaa dheer, unugyada ku yar Nrf2 waxay aad ugu nugul yihiin sunta oksijiinta ee noocyada kala duwan oo aan lagu ilaalin karin Nrf2 inducers, kuwaas oo, isla shuruudo la mid ah, ay bixiyaan ilaalin hufan oo joogto ah unugyada WT [29], [36] , [37]. Marka lagu daro guud ahaan redox homeostasis-ka gacanta, Nrf2 ayaa sidoo kale muhiim u ah dayactirka homeostasis mitochondrial redox. Markaa, marka la barbar dhigo WT, wadarta guud ee mitochondrial NADH barkadda ayaa si weyn u kordhay Keap1-KO oo si weyn hoos ugu dhacay unugyada Nrf2-KO [35].
Isticmaalka sawirka unugyada nool, waxaan dhawaan la soconay heerarka wax soo saarka ROS ee cocultures glioneuronal aasaasiga ah iyo jeexjeexyada unugyada maskaxda ee ka go'ay WT, Nrf2-KO, ama Keap1-knockdown (Keap1-KD) jiirarka [38]. Sida la filayo, heerka wax soo saarka ROS wuxuu ahaa mid degdeg ah unugyada Nrf2-KO iyo unugyada marka la barbardhigo dhiggooda WT. Si kastaba ha noqotee, waxaan samaynay indho-indheyn lama filaan ah, marka loo eego WT, unugyada Keap1-KD waxay sidoo kale leeyihiin heerar sare oo wax soo saar ah ROS, in kasta oo baaxadda farqiga u dhexeeya WT iyo genotypes Keap1-KD uu ka yaraa midka u dhexeeya WT iyo Nrf2-KO . Ka dib waxaan falanqeynnay heerarka mRNA ee NOX2 iyo NOX4, qayb-hoosaadyada catalytic ee labada NADPH oxidase (NOX) isoforms ee lagu lug yeeshay pathology maskaxda, waxaana ogaanay in NOX2 ay si weyn u korodhay xaaladaha Nrf2 yaraanta, halka NOX4 la hagaajiyay marka Nrf2 si dastuuri ah ayaa loo hawlgeliyay, in kasta oo ilaa xad yar. Tiro ahaan, xajmiga kor u kaca ee unugyada iyo unugyada ka yimaada jiirarka mutant waxay barbar socdaan korodhka u dhigma ee wax soo saarka ROS [38]. Waxa xiiso leh, ma aha oo kaliya Nrf2 waxay xakameysaa NADPH oxidase, laakiin ROS ay soo saartay NADPH oxidase waxay dhaqaajin kartaa Nrf2, sida lagu muujiyay unugyada epithelial sambabada iyo cardiomyocytes [39], [40]. Intaa waxaa dheer, daraasad dhowaan la sameeyay ayaa muujisay in NADPH oxidase-ku-tiirsanaanta Nrf2 ay ka dhigan tahay hab muhiim ah oo muhiim ah oo loogu talagalay ka hortagga dhaawaca mitochondrial iyo dhimashada unugyada wadnaha inta lagu jiro cadaadiska joogtada ah [41].
Marka lagu daro dhaqdhaqaaqa firfircoon ee NADPH oxidase, neefsashada mitochondrial waa il kale oo weyn oo gudaha gudaha ah ee ROS. Isticmaalka baaritaanka mitochondria-gaar ah ee MitoSOX, waxaan baarnay wax ku biirinta ROS ee asalka mitochondrial ee soosaarka guud ee ROS ee cocultures glioneuronal ee go'doonsan. laga bilaabo WT, Nrf2-KO, ama jiirarka Keap1-KD [38]. Sida la filayo, unugyada Nrf2-KO waxay lahaayeen heerar sare oo wax soo saarka mitochondrial ROS marka loo eego WT. Iyadoo la raacayo natiijooyinka guud ahaan wax soo saarka ROS, heerarka wax soo saarka mitochondrial ROS ee Keap1-KD ayaa sidoo kale ka sarreeyay unugyada WT. Muhiimad ahaan, xannibaadda isku-dhafka I ee leh rotenone waxay sababtay koror aad u weyn oo ku yimid soosaarka mitochondrial ROS ee labadaba unugyada WT iyo Keap1-KD, laakiin wax saameyn ah kuma yeelan unugyada Nrf2-KO. Marka la barbardhigo kororka la filayo ee mitochondrial ROS ee unugyada WT ka dib marka lagu daro pyruvate (si kor loogu qaado helitaanka NADH, kordhinta awoodda xuubka mitochondrial, iyo caadi ahaan neefsashada), wax soo saarka ROS ayaa hoos u dhacay unugyada Nrf2-KO. Si wada jir ah, natiijooyinkani waxay si xoog leh u soo jeedinayaan, maqnaanshaha Nrf2: (i) waxqabadka qalafsanaanta I waa daciif, (ii) waxqabadka daciifka ah ee kakan I waxay sabab u tahay xaddidaadda substrates, iyo (iii) waxqabadka daciifka ah ee kakan Anigu waa mid ka mid ah sababaha ugu waaweyn ee kororka wax soo saarka mitochondrial ROS, laga yaabo inay sabab u tahay inay ka noqoto socodka elektarooniga ah ee kakan II.
Awoodda xuubka mitochondrial (??m) waa tilmaame caalami ah oo ku saabsan caafimaadka mitochondrial iyo xaaladda dheef-shiid kiimikaad ee unugga. Unug caafimaad qaba, ??m waxaa ilaaliya silsiladda neefsiga ee mitochondrial. Waxa xiisaha lihi leh, calaamadaynta isotopic ee xasilloon oo leh asiidhyada amino acids ee daraasadda borotiinka ku salaysan dhaqanka ee estrogen receptor-negative nontumorigenic bini aadamka naasaha epithelial MCF10A khadka unugyada ayaa muujiyay in qaybta silsiladda gaadiidka ee mitochondrial ee NDUFA4 lagu hagaajiyay firfircoonida farmashiyaha (by sulforaphane) ee Nrf2, halka kor u qaadista hidda-wadaha ee Nrf2 (by Keap1 garaacid) ay keento hoos u dhigista cytochrome c oxidase-hoosaadka COX2 iyo COX4I1 [42]. Daraasad ku saabsan proteome beerka iyadoo la adeegsanayo laba-cabbir jel electrophoresis iyo matrix-caawin laser desorption / ionization mass spectrometry ayaa lagu ogaaday in Nrf2 ay nidaamiso muujinta ATP synthase subunit? [43] Intaa waxaa dheer, borotiinka mitochondrial DJ-1, kaas oo door ka ciyaara dayactirka dhaqdhaqaaqa adag ee I [44], ayaa lagu soo warramey inuu dejiyo Nrf2 [45], [46], in kasta oo saameynta neuroprotective ee firfircoonida dawooyinka ama hiddaha. ee Nrf2 waa ka madax banaan DJ-1 [47]. Si kastaba ha ahaatee, cawaaqibka indha-indhayntan ee shaqada mitirka lama baarin.
Iyada oo la raacayo waxqabadka daciifka ah ee kakan I ee xaaladaha Nrf2 yaraanta, basal ??m ayaa ka hooseeya Nrf2-KO mouse fibroblasts embriyaha (MEFs) iyo unugyada glioneuronal aasaasiga ah marka la barbardhigo dhiggooda WT (Jaantus. 3, inset) [35] Taas bedelkeeda, basal ??m wuu sarreeyaa marka Nrf2 si hidde ahaan loo habeeyay ( garaacid ama garaaca Keap1). Kala duwanaanshahan ??m ee ka mid ah genotypes waxay muujinayaan in neefsashadu ay saamayso hawsha Nrf2. Runtii, qiimeynta isticmaalka oksijiinta ee gobolka basal ayaa shaaca ka qaaday in, marka la barbardhigo WT, isticmaalka oksijiinta ayaa ka hooseeya Nrf2-KO iyo Keap1-KO MEFs, by ~ 50 iyo ~ 35%, siday u kala horreeyaan.
Jaantuska 3 Habka la soo jeediyay ee loogu talagalay shaqada mitochondrial ee la dhimay ee hoos timaada shuruudaha Nrf2 yaraanta. (1) Heerarka hoos u dhaca ee ME1, IDH1, G6PD, iyo PGD waxay keenayaan heerarka NADPH hoose. (2) Heerarka GSH sidoo kale waa hooseeyaan. (3) Dhaqdhaqaaqa hooseeya ee ME1 wuxuu yareyn karaa barkada pyruvate ee galaya mitochondria. (4) Jiilka NADH wuu gaabiyaa, taasoo horseedaysa hoos u dhac ku yimaada dhaqdhaqaaqa kakan I iyo kor u kaca wax soo saarka mitochondrial ROS. (5) Hoos u dhigista FAD ilaa FADH2 ee borotiinnada mitochondrial sidoo kale waa la dhimay, hoos u dhigista socodka elektaroonigga ah ee FADH2 ilaa UbQ iyo isku dhafan III. (6) Samaynta gaabis ah ee UbQH2 waxay hoos u dhigi kartaa dhaqdhaqaaqa enzym ee dehydrogenase succinate. (7) Heerarka kordhay ee ROS waxa laga yaabaa inay sii hakiyaan dhaqdhaqaaqa kakan II. (8) Waxtarka hoose ee oksaydhdheynta aashitada dufanku waxay gacan ka geysataa helitaanka substrate hoos u dhaca ee neefsashada mitirka. (9) Glycolysis waxaa loo xoojiyey sidii habka magdhowga ah ee hoos u dhaca wax soo saarka ATP ee fosforyaalka oksaydhka. (10) ATP synthase waxay u shaqeysaa gadaal si ay u ilaaliso ??m. Casaan iyo buluug ayaa tilmaamaya kor u kaca iyo hoos u dhigista, siday u kala horreeyaan. Sanduuqyadu waxay muujinayaan helitaanka caddayn tijaabo ah. Gelitaanka wuxuu muujinayaa sawirada mitochondria ee WT iyo Nrf2-KO kortikal astrocytes oo lagu sawiray shaybaarka fluorescent potentiometric tetramethylrhodamine methyl ester (TMRM; 25 nM). Bar miisaan, 20 �m.
Kala duwanaanshahan ??m iyo neefsiga ka dhex jira genotypes waxaa ka muuqda heerka ka faa'iidaysiga substrates ee neefsiga mitochondrial. Codsiga substrates ee wareegga tricarboxylic acid (TCA) (malate/pyruvate, taas oo iyana kordhisa wax soo saarka kakan I substrate NADH) ama methyl succinate, substrate kakan II, waxay sababtaa koror tartiib tartiib ah ??m labadaba WT iyo Keap1-KD neurons, laakiin heerka korodhku wuu ka sarreeyaa unugyada Keap1-KD. Tan ka sii muhiimsan, qaababka jawaab celinta wareegyada wareegga TCA waxay ku kala duwan yihiin labada genotypes, taas oo kor u kaca degdegga ah ee ??m ee unugyada Keap1-KD marka lagu daro substrate-ka waxaa ku xiga hoos u dhac degdeg ah halkii ay ka ahaan lahayd taagga, taasoo soo jeedinaysa si aan caadi ahayn. isticmaalka substrate degdeg ah. Natiijooyinkani waxay si dhow ula socdaan heerarka aadka u hooseeya (50�70%) ee malate, pyruvate, iyo succinate kuwaas oo la arkay ka dib garaaca garaaca 1-h ee [U-13C6]glucose ee Keap1-KO marka la barbar dhigo WT MEF unugyo [24]. Nrf2-KO neurons, kaliya pyruvate ayaa awood u leh inay kordhiso ??m, halka malate iyo methyl succinate ay sababaan depolarization khafiif ah. Saamaynta Nrf2 ee wax-soo-saarka substrate-ka mitochondrial waxay u muuqataa inay tahay habka ugu muhiimsan ee Nrf2 ay saameynayso shaqada mitochondrial. Mitochondrial NADH redox index (isku dheelitirka u dhexeeya isticmaalka NADH ee kakan I iyo wax soo saarka NADPH ee wareegga TCA) ayaa si aad ah uga hooseeya unugyada Nrf2-KO marka la barbardhigo dhiggooda WT, iyo sidoo kale, heerarka dib u soo celinta barkadaha barkadaha NADH iyo FADH2 ka dib joojinta kakan IV (isticmaalka NaCN) waxay ku gaabiyaan unugyada mutant.
Mitochondria ka go'doonsan maskaxda iyo beerka, kabidda substrates ee kakan I ama kakan II waxay kordhisaa heerka isticmaalka oksijiinta si xoog leh marka Nrf2 la hawlgeliyo oo si aan waxtar lahayn marka Nrf2 la carqaladeeyo [35]. Sidaa darteed, malate waxay kicisaa heerka sare ee isticmaalka oksijiinta ee Keap1-KD marka la barbar dhigo WT, laakiin saameynteedu way daciif tahay Nrf2-KO mitochondria. Sidoo kale, joogitaanka rotenone (marka adag ee la xakameeyo), succinate waxay u kicisaa isticmaalka oksijiinta ilaa xad ka badan Keap1-KD marka la barbardhigo WT, halka jawaabta Nrf2-KO mitochondria ay hoos u dhacdo. Intaa waxaa dheer, Nrf2-KO dhaqamada asaasiga ah ee neerfaha iyo jiirarka ayaa aad ugu nugul sunta kakan II inhibitors 3-nitropropionic acid iyo malonate, halka ku-tallaalidda intrastriatal ee Nrf2-overexpressing astrocytes ay ilaalinayso [48], [49]. Sidoo kale, jiirarka Nrf2-KO ayaa aad ugu nugul, halka firfircoonida hidda-socodka ama farmasiga ee Nrf2 ay leedahay saameyn difaac ah oo ka dhan ah, neurotoxicity oo ay sababtay isku-dhafka I inhibitor 1-methyl-4-phenylpyridinium ion ee 1-methyl-4-phenyl-1,2,3,6, 49-tetrahydropyridine nooca xayawaanka ee cudurka Parkinson? [50], [51], [52], [53].
Saamiga xakameynta neefsashada (RCR), saamiga Gobolka 3 (ADP-kicin) ee Neefsashada Gobolka 4 (ma jiro ADP), waa la dhimay maqnaanshaha Nrf2, laakiin RCR waxay la mid tahay inta u dhaxaysa Keap1-KD iyo WT mitochondria [35] ]. Maaddaama RCR ay tahay calaamad muujinaysa heerka isku-xidhka dhaqdhaqaaqa silsiladda neefsiga ee mitochondrial ee fosforyaalka oksaydhka, natiijadani waxay muujinaysaa in heerka sare ee neefsiga ee Keap1-KD mitochondria aysan sabab u ahayn isku-dhafka fosforyaalka oksaydhka. Waxay kaloo soo jeedinaysaa in fosforyaalka oksaydhisku uu waxtar badan yahay marka Nrf2 la hawlgeliyo. Heerarka sare ee neefsashada ee Keap1-KD mitochondria waxay la socotaa heerarka sare ee wax soo saarka mitochondrial ROS [38] maadaama heerarka neefsashada sare ay horseedi karto kororka korontadu. Si kastaba ha noqotee, xaaladaha walaaca oksaydhka, kororka wax soo saarka ROS wuxuu ka hortagayaa Nrf2-ku-tiirsanaanta qoraalka ku-tiirsanaanta borotiinka 3 (UCP3), taas oo kordhisa socodka proton ee xuubka gudaha ee mitochondrial oo sidaas awgeed hoos u dhigaya wax soo saarka superoxide [62]. Dhawaan, waxaa la muujiyay in sheyga peroxidation lipid 4-hydroxy-2-nonenal uu dhexdhexaadiyo Nrf2-ku-tiirsanaanta ku-tiirsanaanta UCP3 ee wadnaha wadnaha; Tani waxay si gaar ah muhiim ugu tahay ilaalinta xaaladaha walaaca oksaydhka sida kuwa inta lagu jiro ischemia�reperfusion [63].
Nrf2 waxay saamaysaa waxtarka Fosforyaalka Oxidative iyo Isku-dhafka ATP
Iyada oo la raacayo saamaynta Nrf2 ee neefsiga, maskaxda iyo beerka mitochondria, yaraanta Nrf2 waxay keentaa hoos u dhaca waxtarka fosforyaalka oksida (sida lagu qiyaaso saamiga ADP ee oksijiinta, kaas oo loo isticmaalo isku-darka ATP), halka Nrf2 firfircoonida (Keap1) -KD) waxay leedahay saamayn lid ku ah [35]. Marka la barbardhigo WT, heerarka ATP ayaa si aad ah ugu sarreeya unugyada leh kor u kaca Nrf2 iyo hoose marka Nrf2 la garaaco [64] ama la carqaladeeyo [35]. Intaa waxaa dheer, isticmaalka ka hortagga fosfooraska oxidative (oligomycin) ama glycolysis (iodoacetic acid) ayaa shaaca ka qaaday in Nrf2 ay beddesho habka ay unugyadu u soo saaraan ATP. Markaa, WT neurons, oligomycin waxay sababtaa hoos u dhac dhammaystiran oo ATP ah iyo iodoacetic acid ma laha saameyn dheeraad ah. Si cajiib ah, unugyada Nrf2-KO, oligomycin waxay kordhisaa heerarka ATP, ka dibna si tartiib ah, laakiin gebi ahaanba, oo ay baabi'isay iodoacetic acid, taas oo muujinaysa in maqnaanshaha Nrf2, glycolysis, oo aan ahayn fosforyaal oksidative, waa isha ugu weyn ee wax soo saarka ATP. Waxa xiiso leh, in kasta oo ay korodhay waxtarka fosfooraska oksaydhka ee unugyada Keap1-KD, ku darida oligomycin waxay keenaysaa ~ 80% hoos u dhac ku yimaada heerarka ATP, iyo iodoacetic acid waxay keentaa ~ 20% dheeraad ah. Sidaa darteed, mid ka mid ah yaraanta Nrf2 ama firfircoonideeda ka kooban waxay yaraynaysaa waxtarka fosforyaalka oksaydhka waxayna kordhisaa waxtarka glycolysis ee ku wajahan isku-dhafka ATP. Saamayntan ayaa si gaar ah loogu dhawaaqaa marka Nrf2 maqan tahay oo ay la socoto ku-tiirsanaanta ??m ee joogitaanka gulukooska ee dhexdhexaadka ah [35] iyo heerarka korodhka ah ee dhexdhexaadiyeyaasha glycolytic (G-6-P, F-6-P) , dihydroxyacetone phosphate, pyruvate, iyo lactate) ka dib markii la garaacay Nrf2 [24].
Korodhka heerarka ATP ka dib joojinta F1F0-ATPase ee oligomycin waxay muujinaysaa in maqnaanshaha Nrf2, F1F0-ATPase u shaqeeyo sida ATPase oo aan ahayn ATP synthase, ie, waxay u shaqeysaa si kale. Dib-u-celinta noocan oo kale ah ee dhaqdhaqaaqa waxay u badan tahay inay ka tarjumayso baahida loo qabo in lagu shubo protons gudaha xuubka mitochondrial gudaha iyada oo la isku dayayo in la ilaaliyo ??m, taas oo muhiim u ah daacadnimada shaqeynta xubintan. Dib u noqoshada shaqada F1F0-ATPase ayaa sidoo kale caddaynaysa hoos u dhigista mitochondrial ee maamulka oligomycin ee unugyada Nrf2-KO, taas oo si weyn uga soo horjeeda hyperpolarization ka dhacaya WT ama dhiggooda Keap1-deficient [35]. Guud ahaan, waxay u muuqataa in xaaladaha Nrf2 yaraanta ATP lagu soo saaro ugu horrayn glycolysis, iyo ATP-kan ayaa markaa qayb ahaan loo isticmaalaa F1F0-ATPase si loo ilaaliyo ??m.
Saamaynta Nrf2 yaraanta 'm' ayaa si gaar ah loogu dhawaaqaa marka unugyada lagu dhexjiro dhexdhexaad ah oo aan lahayn glucose, iyo ??m waa ~ 50% hoose ee Nrf2-KO marka la barbardhigo unugyada WT [35]. Marka la eego xaaladaha gulukoosta-yarida, oksaydhka mitochondrial fatty acid (FAO) waa bixiyaha ugu weyn ee substrates ee neefsiga iyo fosforyaalka oksaydhka, taasoo soo jeedinaysa in Nrf2 ay saameyn karto FAO. Runtii, waxtarka FAO ee labada silsilad-dheer (C16: 0) palmitic acid dufan buuxa leh iyo silsiladda gaaban (C6: 0) hexanoic acid waxay ku sarreysaa Keap1-KO MEFs iyo wadnaha iyo beerka mitochondria ee go'doonsan marka loo eego WT dhigooda, halka ay ku yar tahay unugyada Nrf2-KO iyo mitochondria [65]. Saamayntan ayaa sidoo kale aad ugu habboon bini'aadamka: runtii, isbeddellada dheef-shiid kiimikaadka oo tilmaamaya is-dhexgalka wanaagsan ee FAO iyo waxqabadka wareegga TCA ayaa lagu soo warramey inay ku dhacaan daraasadaha faragelinta bini'aadamka ee cuntooyinka hodanka ku ah glucoraphanin, horudhaca Nrf2 activator sulforaphane. 66].
Inta lagu jiro talaabada ugu horeysa ee mitochondrial FAO, pro-R hydrogen ee ?-carbon waxay ka baxdaa sidii hydride taas oo yaraynaysa isku-xidhka FAD ilaa FADH2, taas oo markaa u wareejisa electrons ubiquinone (UbQ) ee silsiladda neefsiga, ugu dambeyntii wax ku biirinta wax soo saarka ATP . Halka kicinta FAO ee palmitoylcarnitine ee maqnaanshaha gulukooska ay keento korodhka la filayo ee heerarka ATP ee unugyada WT iyo Keap1-KO, iyada oo kor u kaca ATP uu si dhakhso ah ugu jiro unugyada Keap1-KO, daaweynta isku midka ah ma soo saarto isbeddel ATP ah ee Nrf2-KO MEFs [65]. Tijaabadani waxay muujinaysaa in, maqnaanshaha Nrf2, FAO la xakameynayo, iyo sidoo kale, waxay ku lug leedahay xakamaynta FAO mid ka mid ah sababaha heerarka hoose ee ATP ee xaaladaha Nrf2 yaraanta [35], [64].
Gaar ahaan, unugyada 293 T ee bini'aadamka ee Nrf2 lagu aamusay waxay leeyihiin muujin hoose oo CPT1 iyo CPT2 [67], laba isoforms of carnitine palmitoyltransferase (CPT), enzyme-ka xaddidaya heerka mitochondrial FAO. Heshiiska, heerarka mRNA ee Cpt1 ayaa ku hooseeya beerka Nrf2-KO marka loo eego jiirarka WT [68]. CPT waxay kicisaa wareejinta kooxda acyl ee silsiladda dheer ee dufanka leh ee acyl-CoA laga bilaabo coenzyme A una gudubta l-carnitine sidaas darteed waxay ogolaataa soo dejinta acylcarnitine ka cytoplasm ee mitochondria. Inkasta oo tan aan la baarin ilaa maanta, waxaa suurtogal ah in marka lagu daro saameynta qoraalka ee CPT1, Nrf2 waxay sidoo kale saameyn kartaa shaqada enzyme this iyada oo la xakameynayo heerarka allasteric inhibitor, malonyl-CoA. Tani waa sababta oo ah, habka aan hadda caddayn, Nrf2 waxay si xun u xakameysaa muujinta stearoyl CoA desaturase (SCD) [69] iyo citrate lyase (CL) [69], [70]. Si cajiib leh, garaacid ama joojinta SCD waxay keentaa fosforyaal kordhinta iyo kicinta AMP-activated protein kinase (AMPK) [71], [72], [73], waxaana la qiyaasi karaa in, maqnaanshaha Nrf2, heerarka SCD wuu kordhi doonaa, taas oo hoos u dhigaysa dhaqdhaqaaqa AMPK. Tan waxaa lagu sii kordhin karaa heerarka borotiinka ee AMPK ee la dhimay ee lagu arkay beerka jiirarka Nrf2-KO [68], natiijadaas oo si dhow ula socota heerarka AMPK ee kordhay, kuwaas oo laga soo sheegay beerka Keap1-KD jiirarka [74]. Mid ka mid ah cawaaqibka hoos u dhaca dhaqdhaqaaqa AMPK waa gargaarka fosforyaalka xannibaadda (at Ser79) ee acetyl-CoA carboxylase (ACC) [75], taas oo si dheeraad ah loo hagaajin karo maqnaanshaha Nrf2 sababtoo ah waxaa hoos u dhigaya Nrf2 firfircoonida [70] ]. Dhaqdhaqaaqa sare ee ACC, oo ay weheliso muujinta CL ee kor loo qaaday ee kordhin doonta wax soo saarka acetyl-CoA, substrate-ka ACC, ayaa ugu dambeyntii kordhin kara heerarka alaabta ACC, malonyl-CoA. Heerarka sare ee malonyl-CoA waxay hor istaagi doontaa CPT, taas oo hoos u dhigaysa qaadista asiidhka dufanka leh ee mitochondria. Ugu dambeyntii, Nrf2 waxay si togan u xakameysaa muujinta CD36 [76], oo ah translocase kaas oo keena asiidh dufan ah oo ku yaal balaasmaha iyo xuubabka mitochondrial. Sidaa daraadeed, hal hab oo Nrf2 ay saameyn karto waxtarka mitochondrial FAO waa iyada oo la xakameynayo soo dejinta dufanka silsiladda dheer ee mitochondria.
Marka lagu daro qawaaniinta tooska ah ee qoraalka, Nrf2 waxa kale oo laga yaabaa inay wax ka beddesho waxtarka mitochondrial FAO saameynteeda dheef-shiid kiimikaadka redox-ka gacanta. Tani waxay si gaar ah u khusayn kartaa marka dhaqdhaqaaqa Nrf2 uu hooseeyo ama maqan yahay, xaaladaha u beddelaya heerka redox-ka gacanta ee gobolka oksaydhka. Runtii, dhowr enzymes oo FAO ah ayaa loo aqoonsaday inay xasaasi u yihiin isbedelada dib u habaynta. Mid ka mid ah enzymka noocan oo kale ah waa silsilad aad u dheer oo loo yaqaan 'acyl-CoA dehydrogenase' (VLCAD), kaas oo wax ka badan 80% ku biiriya dhaqdhaqaaqa fuuq-baxa ee palmitoyl-CoA ee unugyada aadanaha [77]. Waxa xiiso leh, Hurd et al. [78] waxay muujiyeen in VLCAD ay ka kooban tahay haraaga cysteine-ka oo si weyn u beddelaya xaaladdooda dib-u-dhiska marka ay soo bandhigaan mitochondria wadnaha go'doonsan ee H2O2. Intaa waxaa dheer, S-nitrosylation of murine hepatic hepatic VLCAD at Cys238 waxay hagaajinaysaa waxtarka catalytic ee enzyme [79], waxayna u badan tahay in oksaydhka isla cysteine-ka uu yeelan karo saameyn lid ku ah, ugu dambeyntii hoos u dhigista waxtarka mitochondrial FAO. Sidaa darteed waa suurtogal in, inkasta oo heerarka muujinta VLCAD aysan si weyn uga duwanayn WT, Nrf2-KO, ama Keap1-KO MEFs [65], waxqabadka enzyme ee VLCAD wuxuu hoos u dhigi karaa maqnaanshaha Nrf2 sababtoo ah heerarka sare. ee ROS.
Iyada oo ku saleysan dhammaan natiijooyinkaan, waxaa la soo jeedin karaa in (Jaantus. 3): Maqnaanshaha Nrf2, heerarka NADPH waa hooseeyaa sababtoo ah muujinta ME1, IDH1, G6PD, iyo PGD. Heerarka glutathione ee la dhimay ayaa sidoo kale hooseeya sababtoo ah hoos u dhaca muujinta enzymes ee ka qaybqaata biosynthesis iyo dib u soo kabashada iyo heerarka hoose ee NADPH ee looga baahan yahay beddelka oksaydhka qaabka hoos u dhaca ee glutathione. Muujinta hoose ee ME1 waxay hoos u dhigi doontaa barkada pyruvate ee soo galaya mitochondria, iyadoo glycolysis ay noqoto isha ugu weyn ee pyruvate. Jiilka NADH wuu gaabiyaa, taasoo horseedaysa hoos u dhac ku yimaada dhaqdhaqaaqa kakan I iyo korodhka wax soo saarka mitochondrial ROS. Hoos u dhigista FAD ilaa FADH2 ayaa sidoo kale ah mid gaabis ah, ugu yaraan qayb ahaan iyada oo ay ugu wacan tahay oksaydhka aashitada dufanka leh ee waxtarka yar, taas oo wax u dhimaysa socodka elektaroonigga ah ee FADH2 ilaa UbQ iyo isku-dhafka III. Maaddaama UbQH2 ay tahay firfircoone dehydrogenase succinate [80], hoos u dhigidda dhismaheeda waxay hoos u dhigi kartaa waxqabadka enzyme ee succinate dehydrogenase. Heerarka korodhka ah ee superoxide iyo hydrogen peroxide waxay hor istaagi karaan waxqabadka II ee kakan [81]. Waxtarka hoose ee oksaydheynta aashitada dufanka leh waxay gacan ka geysataa hoos u dhaca helitaanka substrate ee neefsashada mitochondrial iyo wax soo saarka ATP ee fosforyaalka oksaydhka. Habka magdhow ahaan, glycolysis waa la wanaajiyey. ATP synthase waxay u shaqeysaa gadaal, sida ATPase, isku day lagu ilaalinayo ??m.
Nrf2 iyo Mitochondrial Biogenesis
Waxaa la soo wariyay in, marka la barbardhigo WT, beerka jiirarka Nrf2-KO waxay leeyihiin maaddo mitochondrial hoose ah (sida lagu go'aamiyo saamiga mitochondrial iyo DNA nukliyeerka); tan waxaa sii yaraanaya 24-saac oo degdeg ah labadaba jiirarka WT iyo Nrf2-KO; Taas bedelkeeda, in kasta oo aan ka duwanayn WT ee xaaladaha quudinta caadiga ah, maadada mitochondrial ee jiirarka leh dhaqdhaqaaqa sare ee Nrf2 ma saameynayso soonka [82]. Waxa xiiso leh, kabidda Nrf2 activator (R) -?-lipoic acid [83], [84], [85] waxay kor u qaadaa biogenesis mitochondrial ee 3T3-L1 adipocytes [86]. Laba qaybood oo ka mid ah xeeriyeyaasha qoraalka nukliyeerka ayaa door muhiim ah ka ciyaara biogenesis-mitochondrial. Fasalka koowaad waa qodobbo qoraal ah, sida qodobbada neefsashada nukliyeerka11 iyo 2, kuwaas oo xakameynaya muujinta hiddo-wadaha codeeya qaybo ka mid ah shanta qaybood ee neefsashada, qaybaha tarjumaadda mitochondrial, iyo enzymes heme biosynthetic kuwaas oo ku yaal matrixka mitochondrial [88]. Piantadosi iyo al. [89] waxay muujiyeen in Nrf2-ku-tiirsanaanta transcriptional-ku-tiirsanaanta nukliyeerka nukliyeerka nukliyeerka 1 uu kor u qaado biogenesis mitochondrial wuxuuna ka ilaaliyaa cytotoxicity ee wakiilka kimoterapeutic anthracycline ee doxorubicin. Taas bedelkeeda, Zhang et al. [82] ayaa soo sheegay in firfircoonida hidda-socodka ee Nrf2 aysan saameyn ku yeelanaynin muujinta mRNA-ga asalka ah ee nukliyeerka nukliyeerka 1 ee beerka murineka.
Heerka labaad ee xakameynaya nuqullada nukliyeerka ee leh hawlaha muhiimka ah ee mitochondrial biogenesis waa isku-xireyaasha transcriptional, sida soo-dhoweeyaha proliferator-activated peroxisome? isku xirayaasha (PGC)1? iyo 1?, kuwaas oo la falgala qodobbada qoraalka, mashiinnada qoraalka asalka ah iyo RNA-kala-baxa, iyo enzymes-beddelka histone [88], [90], [91]. Muujinta qoyska PGC1 ee coaktivators waxaa saameeya calaamado badan oo deegaanka ah. Daawaynta fibroblasts bini'aadamka leh Nrf2 activator sulforaphane waxay sababtaa kororka miisaanka mitochondrial iyo kicinta PGC1? iyo PGC1? [92], inkasta oo ku tiirsanaanta suurtagalka ah ee Nrf2 aan lagu baarin daraasaddan. Si kastaba ha ahaatee, jiirarka sokorowga kaas oo Nrf2 ama ay ka shaqeyso Keap1 hidda-wadaha hypomorphic garaaca (db/db:Keap1flox/?:Nrf2+/+) ama khalkhal galiyay (db/db:Keap1flox/?:Nrf2?/?) waxay leeyihiin PGC1 cagaarshowga hoose? Heerarka muujinta marka loo eego xayawaanka kantaroolka (db/db:Keap1flox/+: Nrf2+/+) [93]. Ma jiraan farqi u dhexeeya heerarka mRNA ee PGC1? waxaa lagu arkaa beerka jiirarka aan macaanka lahayn ee WT ama Nrf2-KO, halka heerarkani ay ka hooseeyaan Nrf2-overexpressing (Keap1-KD iyo Keap1-KO) xayawaanka [82]. Waxaa xusid mudan, soonka 24-saac wuxuu kordhiyaa heerarka PGC1? mRNA ee beerka jiirarka dhammaan genotypes, laakiin kororka ayaa si weyn uga weyn beerka Nrf2-KO marka la barbar dhigo WT ama Nrf2-jiirarka xad dhaafka ah. Marka la barbardhigo WT, jiirarka Nrf2-KO ee la kulma caabuqa septic ama dhaawaca sambabada ba'an ee caabuqa ayaa muujinaya kor u qaadida qoraalka qoraalka ee qodobka neefsashada nukliyeerka 1 iyo PGC1? [94], [95]. Si wada jir ah, indho-indhayntani waxay soo jeedinayaan in doorka Nrf2 ee ilaalinta heerarka labadaba nukliyeerka factor factor 1 iyo PGC1? waa kakan oo waxa uu noqdaa mid caan ka ah xaaladaha walaaca.
Marka lagu daro muujinta hiddo-wadaha soo koobaya borotiinnada mitochondrial, biogenesis mitochondrial wuxuu u baahan yahay isku-darka nucleotide. Dhaqdhaqaaqa hidaha ee Nrf2 waxay kor u qaadaysaa biosynthesis purine iyadoo kor u qaadeysa dariiqa phosphate pentose iyo dheef-shiid kiimikaadka folate iyo glutamine, gaar ahaan unugyada si degdeg ah u koraya (Jaantus 2) [24]. Falanqaynta transcriptome of mutant Drosophila deficient ee serine mitochondrial / threonine protein kinase PTEN-induced putative kinase 1 (PINK1) ayaa muujisay in cilladda mitochondrial ay keento kor u kaca transcriptional ee hiddo saameeya dheef-shiid kiimikaad nucleotide [96]. waxay u taagan tahay hab ka hortag ah cawaaqibka neurotoxic ee yaraanta PINK1. Nrf2 waxay xakameysaa muujinta phosphoribosyl pyrophosphate amidotransferase (PPAT), kaas oo kicinaya gelitaanka de novo purine nucleotide biosynthetic pathway, iyo mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) (Jaantus 2). Midda dambe waa enzyme bifunctional leh dehydrogenase iyo hawlaha cyclohydrolase kuwaas oo muhiim u ah bixinta glycine iyo formate labadaba sida ilaha halbeeg kaarboon ah oo loogu talagalay biosynthesis purine ee unugyada degdega ah u koraya [97]. Sidaa darteed waxay u badan tahay in firfircoonida Nrf2 laga yaabo inay noqoto mid difaac ah oo laga yaabo inay beddesho cilladda mitochondrial ee yaraanta PINK1. Runtii, firfircoonida dawooyinka ee Nrf2 ee sulforaphane, ama triterpenoid RTA-408, waxay dib u soo celisaa ??m waxayna ka ilaalisaa unugyada PINK1-yarida sunta dopamine [98]. Inkasta oo hababka hoose ay u muuqdaan kuwo adag, wada jir, natiijooyinkani waxay muujinayaan in dhaqdhaqaaqa Nrf2 uu saameyn ku yeelan karo biogenesis-ka mitochondrial isagoo saameynaya heerarka muujinta ee qodobbada qoraalka muhiimka ah iyo isku-xireyaasha, iyo sidoo kale kor u qaadista biosynthesis nucleotide.
Nrf2 iyo daacadnimada Mitochondrial
Inkasta oo caddaynta tooska ah aan had iyo jeer la heli karin, waxaa jira calaamado xooggan oo muujinaya in Nrf2 ay muhiim u tahay daacadnimada mitochondrial, gaar ahaan xaaladaha cadaadiska oksaydhka. Mitochondria oo ka go'doonsan maskaxda iyo beerka jiirka ee la maamulay hal dose oo ah Nrf2 activator sulforaphane ayaa u adkeysanaya furitaanka dabada kala-guurka ee mitochondrial permeability (mPTP) oo ay sababtay oxidant tert-butylhydroperoxide [99], [100]. mPTP, kakan oo u oggolaanaya xuubabka gudaha mitochondrial si ay u noqdaan kuwo la daadin karo molecules leh tiro dhan 1500 Da, ayaa dhawaan la aqoonsaday in laga sameeyay dimers ee F0F1-ATP synthase [101]. Caabbinta sulforaphane-dhexdhexaadinta ee furitaanka mPTP waxay la xiriirtaa difaacayaasha antioxidant-ka ee kordhay, iyo heerarka mitochondrial GSH, glutathione peroxidase 1, malic enzyme 3, iyo thioredoxin 2 ayaa dhamaantood lagu hagaajiyay jajabyada mitochondrial ee ka soocaya xayawaanka sulforaphane-daaweeyay [100].
Burburinta borotiinka Mitochondrial iyo daciifnimada neefsiga ee ay keento sheyga elektrofilic lipid peroxidation 4-hydroxy-2-nonenal ayaa lagu yareeyay mitochondria oo ka go'doonsan kiliyaha maskaxda ee jiirka sulforaphane-la daweeyay [102]. Unugyada epithelial kelyaha ee jiirka iyo kelyaha, sulforaphane waxay ka ilaalinayaan sunta cisplatin-iyo gentamicin-ku keeno iyo luminta ??m[103], [104]. Ka-hortagga guddi oksaydhiyeyaasha ah (superoxide, hydrogen peroxide, peroxynitrite) iyo electrophiles (4-hydroxy-2-nonenal iyo acrolein) iyo korodhka difaacayaasha antioxidant-ka ee mitochondrial ayaa sidoo kale lagu arkay daaweynta unugyada muruqyada siman ee jiirka ee leh sulforaphane [105] ]. Qaabka dhaawaca kelyaha ee ba'an ee isbarbar-dhigga, horudhaca ischaemic ischemic ee addinka ayaa dhawaan la muujiyay inuu leeyahay saameyn difaac, oo ay ku jiraan xannibaadda furitaanka mPTP iyo bararka mitochondrial, iyada oo la kicinayo Nrf2 taasoo ka dhalatay joojinta GSK3? [106].
Mitophagy, habka ay mitochondria aan shaqaynayn ayaa si xushmad leh loo xushay autophagosomes oo loo geeyaa lysosomes si loo yareeyo oo dib loo warshadeeyo unugga, ayaa lagama maarmaan u ah mitochondrial homeostasis [107], [108]. Halka aanay jirin xidhiidh sababa oo u dhexeeya Nrf2 iyo mitophagy, waxa jira caddayn ah in qodobka qoraalka ahi uu muhiim u yahay xakamaynta tayada mitirka iyadoo door ka ciyaaraysa mitophagy. Tani waxay si gaar ah ugu caan noqon kartaa xaaladaha diiqada oksaydhka. Sidaa darteed, qaabka sepsis-ka, korodhka heerarka calaamadaha autophagosome MAP1 silsilad iftiin 3-II (LC3-II) iyo borotiinka xamuulka p62 ee 24 h ee caabuqa ka dib ayaa lagu xakameynayaa Nrf2-KO marka la barbardhigo jiirarka WT [109] . Inducer yar-molecule ee mitophagy (oo loo yaqaan p62-mediated mitophagy inducer, PMI) ayaa dhawaan la helay; Xaruntan 1,4-diphenyl-1,2,3-triazole waxaa markii hore loogu talagalay sidii Nrf2 activator kaas oo carqaladeeya isdhexgalka qodobka qoraalka ee Keap1 [110]. Si la mid ah unugyada Nrf2 lagu hagaajiyay hidde ahaan (Keap1-KD ama Keap1-KO), unugyada soo gaadhay PMI waxay leeyihiin nasasho sare ??m. Muhiimad ahaan, kororka degellada mitochondrial LC3 ee la arkay ka dib daaweynta PMI ee unugyada WT kuma dhacaan unugyada Nrf2-KO, oo soo jeedinaya ku lug lahaanshaha Nrf2.
Ugu dambeyntii, falanqaynta ultrastructural ee qaybaha beerka ayaa shaaca ka qaaday joogitaanka mitochondria barar leh oo leh crista oo yaraaday iyo xuubabka khalkhalka leh ee hepatocytes ee Nrf2-KO, laakiin maaha WT, jiirarka oo la quudiyay cunto dufan badan leh toddobaadyada 24; gaar ahaan, beerkaani waxay muujinayaan caddayn cad oo ku saabsan cadaadiska oksaydhka iyo bararka [68]. Waxaa lagu soo gabagabeyn karaa in Nrf2 ay door muhiim ah ku leedahay ilaalinta sharafta mitochondrial ee xaaladaha oksaydhka iyo cadaadiska bararka.
Sulforaphane iyo Saameyntiisa Kansarka, Dhimashada, Gabowga, Maskaxda iyo Dhaqanka, Cudurrada Wadnaha & in ka badan
Isothiocyanates waa qaar ka mid ah xeryahooda dhirta ee ugu muhiimsan ee aad ka heli karto cuntadaada. Fiidiyowgaan waxaan u sameynayaa kiiskii ugu badnaa ee abid la sameeyo. Fiiro gaar ah oo gaaban? U gudub mawduuca aad jeceshahay adiga oo gujinaya mid ka mid ah dhibcaha wakhtiga hoose. Jadwalka wakhtiga oo buuxa hoos
Qaybaha muhiimka ah:
00:01:14 - Kansarka iyo dhimashada
00:19:04 - gabowga
00:26:30 - Maskaxda iyo dhaqanka
00:38:06 - Dib u soo koobid kama dambays ah
00:40:27 - Qiyaasta
Waqtiga buuxa:
00:00:34 - Horudhaca sulforaphane, diiradda weyn ee fiidiyowga.
00: 31: 21 - Daraasada jiirka iyadoo la adeegsanayo 10 nooc oo kala duwan oo niyad-jabka ah ayaa muujinaya sulforaphane si la mid ah waxtarka sida fluoxetine (prozac).
00: 32: 00 - Daraasadu waxay muujineysaa in si toos ah loo nuugo glucoraphanin ee jiirarka ay si la mid ah waxtar ugu leedahay ka hortagga niyad-jabka ee ka timaadda qaabka cadaadiska bulshada.
Nrf2 waa arrin qoraal ah oo door muhiim ah ka ciyaara nidaamka difaaca antioxidant-ka gacanta ee jirka bini'aadamka. Cunsurka ka jawaaba antioxidant-ka, ama ARE, waa hab nidaaminta hiddo-wadaha. Daraasado badan oo cilmi baaris ah ayaa muujiyay in Nrf2, ama NF-E2 ee la xiriirta 2, ay maamusho noocyo kala duwan oo hiddo-wadaha ARE-ga ah ee dhammaan noocyada unugyada. Nrf2 ayaa sidoo kale lagu ogaaday in ay door muhiim ah ka ciyaarto ilaalinta gacanta iyo ka hortagga kansarka, taas oo muujinaysa in Nrf2 laga yaabo inay noqoto daaweyn wax ku ool ah oo lagu maareeyo cudurrada neurodegenerative iyo kansarrada la rumeysan yahay inay sababaan cadaadiska oksaydhka. Dr. Alex Jimenez DC, CCST Insight
Gabagabaynta Hadalka
Inkasta oo su'aalo badan ay weli furan yihiin, caddaynta tijaabada ah ee la heli karo waxay si cad u muujinaysaa in Nrf2 uu yahay ciyaaryahan muhiim u ah dayactirka mitochondrial homeostasis iyo sharafta qaabdhismeedka. Doorkan ayaa si gaar ah muhiim ugu ah xaaladaha oksaydhka, elektiroonigga, iyo bararka bararka marka awoodda lagu hagaajinayo jawaabaha cytoprotective ee dhexdhexaadka ah ee Nrf2 ay saameyn ku yeelato caafimaadka guud iyo badbaadada unugyada iyo noolaha. Doorka Nrf2 ee shaqada mitochondrial waxay ka dhigan tahay lakab kale oo ka mid ah hababka cytoprotective ee ballaadhan ee ay habeeyeen qodobkan qoraalka ah. Maaddaama xaalado badan oo bini-aadmi ah ay leeyihiin cadaadiska oksaydhka, caabuqa, iyo cillad-xumada mitirka sida qaybaha muhiimka ah ee pathogenesis-kooda, firfircoonida dawooyinka ee Nrf2 waxay haysaa ballanqaadka ka hortagga iyo daaweynta cudurka. Fahamka dhamaystiran ee hababka saxda ah ee Nrf2 ay u saamayso shaqada mitochondrial ayaa lagama maarmaan u ah naqshadeynta macquulka ah ee tijaabooyinka caafimaad ee mustaqbalka waxaana laga yaabaa inay bixiso biomarkers cusub si loo kormeero waxtarka daaweynta.
Ujeedada maqaalka kor ku xusan waxay ahayd in laga hadlo sidoo kale muujinta doorka soo ifbaxa ee Nrf2 ee shaqada mitochondrial. Nrf2, ama factor erythroid 2-la xidhiidha, waa nidaamiye soo baxaya oo ah caabbinta gacanta ee oksidants kaas oo gacan ka geysan kara cadaadiska oksaydhka, saameynaya shaqada gacanta oo u horseedaysa horumarinta sunta, cudurada joogtada ah, iyo xitaa kansarka. Iyadoo wax soo saarka oksaydhiyeyaasha ee jirka bini'aadamka ay u adeegi karto ujeeddooyin kala duwan, oo ay ku jiraan kala qaybinta unugyada, caabuqa, shaqada difaaca, autophagy, iyo jawaab celinta cadaadiska, waxaa lagama maarmaan ah in la xakameeyo wax soo saarkooda xad-dhaafka ah si looga hortago arrimaha caafimaadka. Baaxadda macluumaadkayadu waxay ku kooban tahay xanuunka loo yaqaan 'chiropractic' iyo arrimaha caafimaadka laf dhabarta. Si aad ugala hadasho mawduuca, fadlan xor u noqo inaad waydiiso Dr. Jimenez ama nagala soo xidhiidh at�915-850-0900 .
Nrf2 waxay taageertaa firfircoonida koox ka mid ah antioxidant iyo sunta enzymes iyo hiddo-wadaha kuwaas oo jirka bini'aadamka ka ilaaliya saameynta arrimaha caafimaadka ee la xidhiidha heerarka korodhka cadaadiska oksaydhka, sida cudurka Alzheimers. Walxaha kala duwan ee dabiiciga ah ayaa la soo bandhigay si ay u dhaqaajiyaan dariiqa Nrf2, kaas oo gacan ka geysan kara maareynta calaamadaha cudurrada neurodegenerative. Ujeedada maqaalka hoose waa in laga wada hadlo doorka muhiimka ah ee Nrf2 oo ay sababtay caabuq dabadheeraad ah.
aan la taaban karin
Caabuqa ayaa ah qaabka ugu badan ee cudurro badan oo dabadheeraad ah iyo dhibaatooyin, iyadoo door muhiim ah ka ciyaaraya kansarka. Daraasado dhowr ah ayaa muujiyay in Nrf2 ay gacan ka geysato geeddi-socodka ka-hortagga-bararka iyadoo la habeynayo qorista unugyada bararka iyo xakameynta muujinta hidda-wadaha iyada oo loo marayo qaybta jawaabta antioxidant (ARE). Keap1 (Kelch-like ECH-laxiriira borotiinka) / Nrf2 (NF-E2 p45-related factor 2)/ ARE calaamadinta dariiqa inta badan waxay xakameysaa muujinta hiddaha caabuqa waxayna joojisaa horumarka caabuqa. Sidaa darteed, aqoonsiga phytochemicals-ku-tiirsanaanta-ku-tiirsanaanta cusub ee Nrf2 waxay noqotay barta ugu muhiimsan ee helitaanka daroogada. Dib-u-eegisgan, waxaanu kaga hadlaynaa xubnaha Keap1/Nrf2/ARE ee dariiqa calaamadaha iyo hidde-sideheeda hoose, saamaynta dariiqan ee noocyada xayawaanka ee cudurrada bararka, iyo is-dhaafsiga jidka NF-?B. Intaa waxaa dheer, waxaan sidoo kale ka wada hadalnaa sharciyeynta NLRP3 inflammasome by Nrf2. Taas ka sokow, waxaan soo koobeynaa xaaladda hadda jirta ee horumarinta phytochemicals anti-inflammatory iyo kuwa kale ee dhexdhexaadiya jidka Nrf2/ARE.
Caabuqa waa hannaan adag oo yimaada marka unugyadu ay caabuqaan ama ay dhaawacmaan kicinta waxyeellada leh sida cudur-sidaha, waxyeellada, ama cuncunka. Unugyada difaaca jirka, xididdada dhiigga, iyo dhexdhexaadiyeyaasha molecular ayaa ku lug leh jawaabtan ilaalinta ah [1]. Caabuqa sidoo kale waa ifafaale cudur-sifooloji ah oo la xidhiidha xaalado cudur oo kala duwan oo ay sababaan arrimo jireed, kiimiko, bayooloji, iyo nafsiyeed. Ujeedada caabuqa waa in la xaddido oo la baabi'iyo sababaha dhaawaca unugga, nadiifinta iyo/ama nuugista unugyada necrotic iyo unugyada, iyo in la bilaabo dayactirka unugyada. Laba nooc oo kala duwan oo caabuq ah ayaa la kala soocay: ba'an iyo mid dabadheeraad ah. Caabuqa ba'an waa is-xakameyn wuxuuna faa'iido u leeyahay qofka martida loo yahay, laakiin bararka dabadheeraad ah ee dabadheeraadku waa muuqaal caadi ah oo cudurro badan oo dabadheeraad ah iyo dhibaatooyin. Galitaanka tooska ah ee unugyo badan oo difaaca mononuclear ah sida monocytes, macrophages, lymphocytes, iyo unugyada plasma, iyo sidoo kale soo saarista cytokines bararka, waxay u horseedaa barar dabadheeraad ah. Waxaa la aqoonsan yahay in bararka dabadheeraadku uu door muhiim ah ka ciyaaro kansarka [2]. Guud ahaan, labadaba dariiqyada calaamadaynta pro- iyo ka-hortagga-bararka waxay la falgalaan habka bararka caadiga ah.
Geedi socodka bararka cudurada pathological, unugyada mast, monocytes, macrophages, lymphocytes, iyo unugyada kale ee difaaca ayaa marka hore la hawlgeliyay. Kadibna unugyada waxaa lagu qoraa goobta dhaawaca, taasoo keentay jiilka noocyada oksijiinta falcelinta (ROS) ee waxyeelleeya macromolecules oo ay ku jiraan DNA. Isla mar ahaantaana, unugyadan bararsan waxay sidoo kale soo saaraan xaddi badan oo dhexdhexaadiyeyaasha bararka sida cytokines, chemokines, iyo prostaglandins. Dhexdhexaadiyayaashani waxay si dheeraad ah u qoraan makrophages goobaha bararka ee maxaliga ah waxayna si toos ah u dhaqaajiyaan calaamado badan oo gudbin ah iyo arrimo qoraal ah oo la xidhiidha bararka. NF-?B (cutubka nukliyeerka kappa B), MAPK (mitogen-activated protein kinase), iyo JAK (janus kinase) -STAT (bandhigayaasha calaamadaha iyo hawl-wadeennada qoraalka) waddooyinka calaamadaha ayaa ku lug leh horumarinta dariiqa qadiimiga ah ee caabuqa. [3], [4], [5]. Daraasadihii hore ayaa shaaca ka qaaday in qodobka Nrf2 (NF-E2 p45-xiriir laxiriira 2) uu nidaamiyo muujinta wajiga II detoxifying enzymes oo ay ku jiraan NADPH, NAD (P) H quinone oxidoreductase 1, glutathione peroxidase, ferritin, heme oxygenase-1 (HO). -1), iyo hidde-sideyaasha antioxidant-ka ka ilaaliya unugyada dhaawacyo kala duwan iyada oo loo marayo saameyntooda ka hortagga bararka, sidaas darteed saameynaya habka cudurka [6], [7], [8].
Iyadoo la tixgelinayo natiijooyinkan cajiibka ah, horumarinta dawooyinka daweynta ee loogu talagalay cudurrada caabuqa iyada oo loo marayo waddooyinka calaamadaynta ayaa soo jiidatay xiiso badan sannadihii la soo dhaafay. Dib u eegistaan, waxaan ku soo koobeynaa cilmi baarista Keap1 (Kelch-like ECH protein laxiriira) / Nrf2 (NF-E2 p45-related factor 2) / ARE (cutubka jawaabta antioksidanter) ee dariiqa calaamadaha caabuqa.
Qaab dhismeedka iyo Xeerarka Nrf2
Xeerka Keap1-ku-tiirsanaanta Nrf2
Nrf2 waxay iska leedahay Cap �n� Collar (CNC) qoys hoose waxayna ka kooban tahay todobo qaybood oo shaqeynaya, Neh (Nrf2-ECH homology) 1 ilaa Neh7 [9], [10]. Neh1 waa domain CNC-bZIP kaas oo u ogolaanaya Nrf2 in ay heterodimerize la musculoaponeurotic fibrosarcoma (Maf) borotiinka yar yar, DNA, iyo la-hawlgalayaasha kale qoraal iyo sidoo kale samaynta isku dhafan nuclear la ubiquitin-conjugating enzyme UbcM2 [11], [12]. Neh2 wuxuu ka kooban yahay laba arrimood oo muhiim ah oo loo yaqaan DLG iyo ETGE, kuwaas oo lagama maarmaan u ah isdhexgalka ka dhexeeya Nrf2 iyo maamulaheeda taban Keap1 [13], [14].
Keap1 waa adabtarada substrate-ka ah ee cullin-based E3 ubiquitin ligase, kaas oo xannibaya dhaqdhaqaaqa qoraalka ee Nrf2 iyada oo loo sii marayo meelaynta iyo hoos u dhigista borotiinka ee xaaladaha caadiga ah [15], [16], [17]. Qaybaha KELCH ee Keap1 homodimer waxay ku xidhan yihiin DLG iyo ETGE motifs ee Nrf2-Neh2 ee cytosol, halkaas oo ETGE u dhaqmo sidii mid isku xidhan oo xidhiidh sare leh iyo DLG u dhaqmo sidii xidhid [18]. Marka la eego cadaadiska oksaydhka ama marka la soo bandhigo firfircoonayaasha Nrf2, Nrf2 waxay ka soocaysaa Keap1 xidhitaanka sababtoo ah wax ka beddelka thiol ee hadhaaga cysteine ee Keap1 kaas oo ugu dambeyntii ka hortagaya Nrf2 ubiquitination iyo hoos u dhaca borotiinka [19]. Kadib Nrf2 waxay u gudubtaa nukleus, heterodimerizes leh borotiinno Maf yar yar, oo waxay dhaqaajisaa batari ARE ah ee hiddo-wadaha (Jaantus. 1A). Karboxy-terminal-ka Neh3 wuxuu u shaqeeyaa sidii goob ganacsi isagoo la falgalaya wada-hawlgaliyaha qoraalka ee loo yaqaan CHD6 (chromo-ATPase/helicase DNA binding protein) [20]. Neh4 iyo Neh5 sidoo kale waxay u dhaqmaan sidii xayndaabyo wax-is-weydaarsi, laakiin waxay ku xidhaan wada-shaqeeye kale oo qoraal ah oo loo yaqaan CBP (caMP-jawaab-cunsurka-ku-xidha borotiinka-binding protein) [21]. Waxaa intaa dheer, Neh4 iyo Neh5 waxay la falgalaan isku-xidhka nukliyeerka RAC3 / AIB1 / SRC-3, taasoo horseedaysa kobcinta Nrf2-bartilmaameedka ARE muujinta hiddaha [22]. Neh5 waxay leedahay calaamad dib-u-dejin-xasaasi ah oo nukliyeerka-dhoofinta kaas oo muhiim u ah nidaamka iyo meelaynta gacanta ee Nrf2 [23].
Jaantuska 1 Keap1-ku-tiirsanaanta iyo-sharciga madax-bannaan ee Nrf2. (A) Marka la eego xaaladaha aasaasiga ah, Nrf2 waxaa lagu daraa Keap1 iyada oo loo eegayo labadeeda motif (ETGE iyo DLG) taas oo u horseedda CUL3 dhexdhexaadinta meelaynta oo ay ku xigto hoos u dhaca borotiinka. Marka la eego diiqada oksaydhka, Nrf2 waxay ka soocdaa Keap1, waxay u beddeshaa nukleus oo waxay kicisaa batteriga ARE-gene. (B) phosphorylates GSK3 Nrf2 tanina waxay fududaynaysaa aqoonsiga Nrf2 by ?-TrCP ee CUL1-dhexdhexaadinta meelaynta iyo hoos-u-dhac ku yimaada borotiinka. (C) p62 waxaa lagu taxaabay Keap1, taasoo u horseedaysa hoos u dhaceeda autophagic, xoraynta Nrf2, iyo kordhinta calaamadaynta Nrf2.
Keap1-Xeerka Madaxbanaan ee Nrf2
Cadaymaha soo baxaya ayaa daaha ka qaaday hannaan cusub oo ah xeerka Nrf2 kaas oo ka madax banaan Keap1. Qaybta hodanka ku ah serine-ka Neh6 ee Nrf2 ayaa door muhiim ah ka ciyaarta qaanuunkan iyada oo ku xidhaysa labadeeda motifs (DSGIS iyo DSAPGS) ilaa ?-transducin borotiinka ku-celceliska ah (?-TrCP) [24]. ?-TrCP waa soo-dhoweeyaha substrate-ka ee Skp1�Cul1�Rbx1/Roc1 ubiquitin ligase complex kaas oo bartilmaameedsada Nrf2 meelaynta iyo hoos u dhaca boroteasomal. Glycogen synthase kinase-3 waa borotiin muhiim ah oo ku lug leh Keap1-madax-bannaan ee Nrf2 xasilinta iyo nidaaminta; waxay fosforylates Nrf2 ee domain Neh6 si ay u fududayso aqoonsiga Nrf2 by ?-TrCP iyo hoos u dhaca borotiinka [25] (Jaantus. 1B).
Nidaamiyeyaasha kale ee Nrf2
Khad kale oo caddayn ah ayaa shaaca ka qaaday dariiqa aan caadiga ahayn ee p62-ku-tiirsanaanta Nrf2 kaas oo p62 sequesters Keap1 si ay u burburiyaan autophagic taas oo ugu dambeyntii keenta xasilinta Nrf2 iyo dhaqdhaqaaqa Nrf2-ku-tiirsanaanta [26], [27], 28], [29] (Jaantus. 1C).
Caddaynta ururintu waxay soo jeedinaysaa in dhowr miRNAs ay door muhiim ah ka ciyaaraan nidaaminta waxqabadka Nrf2 [30]. Sangokoya iyo al. [31] waxay muujisay in miR-144 ay si toos ah hoos ugu dhigto dhaqdhaqaaqa Nrf2 ee xariiqda unugyada lymphoblast K562, unugyada asaasiga ah ee erythroid bini'aadamka, iyo cudurka sickle-cell reticulocytes. Daraasad kale oo xiiso leh oo ku saabsan unugyada epithelial naasaha ee bini'aadamka ayaa muujiyay in miR-28 ay joojiso Nrf2 iyada oo loo marayo habka Keap1-madax-bannaan [32]. Sidoo kale, miRNA-yada sida miR-153, miR-27a, miR-142-5p, iyo miR144 waxay hoos u dhigaan muujinta Nrf2 ee khadka unugyada neerfaha SH-SY5Y [33]. Singh iyo al. [34] waxay muujisay in muujinta ectopic ee miR-93 ay hoos u dhigto muujinta hiddo-wadaha Nrf2-regulated ee 17?-estradiol (E2) -qaabka jiirka ee naasaha kansarka naasaha.
Daah-fur dhowaan laga helay shaybaadhkayaga ayaa aqoonsaday horjoogaha endogenous ee Nrf2 oo loo yaqaan retinoic X receptor alpha (RXR?). RXR? waa qaboojiyaha nukliyeerka, wuxuu la falgalaa qaybta Neh7 ee Nrf2 (hadhaaga amino-acid 209�316) iyada oo loo sii marayo domain-ku-xidhka DNA-da (DBD), oo si gaar ah u xannibaya dhaqdhaqaaqa Nrf2 ee nukleus. Waxaa intaa dheer, qaboojiyeyaasha kale ee nukliyeerka ah sida peroxisome proliferator-activated reseptor-?, ER?, receptor-estrogen-la xiriira-?, iyo glucocorticoid reseptors ayaa sidoo kale lagu soo warramey inay yihiin horjoogayaasha endogenous ee dhaqdhaqaaqa Nrf2 [9], [10].
Doorka Ka-hortagga caabuqa ee dhidibka Nrf2/HO-1
HO-1 waa isoform-ka xad-dhaafka ah iyo enzyme-ka xaddidaya heerka-xakamaynta kaas oo kicinaya hoos u dhaca heme galay carbon monoxide (CO) iyo birta bilaashka ah, iyo biliverdin ilaa bilirubin. Hoos u dhigista enzymatic ee heme bilaashka ah ee pro-bararka iyo sidoo kale soo saarista xeryahooda ka hortagga caabuqa sida CO iyo bilirubin waxay door weyn ka ciyaaraan ilaalinta saameynta ilaalinta HO-1 (Jaantus 2).
Jaantuska 2 Dulmar guud ee dariiqa Nrf2/HO-1. Marka la eego shuruudaha aasaasiga ah, Nrf2 waxay ku xidhan tahay cadaadiskeeda Keap1 taas oo u horseedda meel-ka-baxa oo ay ku xigto hoos u dhaca borotiinka. Inta lagu jiro diiqada oksaydhka, Nrf2 bilaash ah waxay u beddeshaa nukleus, halkaas oo ay ku dhufato xubnaha qoyska Maf yar oo ay ku xirto ARE hiddo-wadaha sida HO-1. HO-1 oo la hagaajiyay ayaa heme-ga u horseeda CO, bilirubin, iyo birta bilaashka ah. CO waxay u shaqeysaa sidii horjooge ka mid ah dariiqa NF-?B taasoo keenta hoos u dhaca muujinta cytokines pro-inflammatory, halka bilirubin uu sidoo kale u dhaqmo sida antioxidant. Intaa waxaa dheer, HO-1 waxay si toos ah u joojisaa cytokines-ka proinflammatory iyo sidoo kale kicinta cytokines-ka-hortagga caabuqa, sidaas awgeed waxay keenaysaa dheellitirka habka bararka.
Nrf2 waxay kicisaa hiddo-wadaha HO-1 iyadoo kordhinaysa mRNA iyo muujinta borotiinka waana mid ka mid ah hidda-wadaha Nrf2 ee caadiga ah kaas oo si weyn loogu isticmaalo daraasado badan oo gudaha vitro iyo vivo ah. Daraasado dhowr ah ayaa muujiyay in HO-1 iyo dheef-shiid kiimikaadku ay leeyihiin saameyno anti-bararka oo ay dhexdhexaadiyaan Nrf2. Kor u qaadista muujinta HO-1 ee dhexdhexaadinta Nrf2 ee firfircoon waxay keenaysaa joojinta NF?B calaamadaha waxay keenaysaa hoos u dhaca dhaawaca mindhicirka mindhicirka iyo cidhiidhiga cidhiidhiga ah ee ragga Sprague-Dawley qaabka beerka beerka beerka [35]. Kordhinta Nrf2-ku-tiirsanaanta HO-1 waxay ka ilaalin kartaa jiirka ka soo jeeda C2C12 myoblast H2O2 cytotoxicity [36]. Nrf2-ku-tiirsanaanta HO-1 waxay saameyn ku leedahay lipopolysaccharide (LPS) - jawaabaha bararka dhexdhexaadka ah ee RAW264.7-ama mouse peritoneal macrophage-ka-soo-baxa unugyada xumbo. Dhaqdhaqaaqa Nrf2 ayaa desensitized xumbo unug macrophages phenotype iyo ka hortagga bararka aan dhexdhexaad ahayn ee macrophages, kuwaas oo door muhiim ah ka ciyaara horumarinta atherosclerosis [37]. Nrf2 / HO-1 dhidibka wuxuu saameeyaa LPS jiirka jiirka BV2 unugyada microglial iyo jiirka hippocampal HT22 unugyada, oo saameyn ku leh neuroinflammation. Kordhinta muujinta HO-1 iyada oo loo marayo dariiqa Nrf2 ee jiirka BV2 unugyada microglial kaas oo difaacaya dhimashada unugyada jiirka hippocampal HT22 unugyada [38]. Intaa waxaa dheer, molecules-ku-salaysan kobalt-ku-saleysan (HYCOs) oo isku daraya Nrf2 inducer oo leh soo-saaraha kaarboon monoxide (CO) waxay kordhisaa muujinta Nrf2 / HO-1, xoraynta CO waxayna sameeyaan dhaqdhaqaaqa ka hortagga caabuqa ee vitro. HYCOs waxay sidoo kale hagaajiyaan unugyada HO-1 waxayna bixiyaan CO ee dhiiga ka dib maamulka gudaha vivo, iyagoo taageeraya isticmaalkooda suurtagalka ah ee xaaladaha bararka [39]. Kordhinta Nrf2 / HO-1 waxay yaraynaysaa bararka iyadoo kordhinaysa waxqabadka efferocytic ee macrophages murine oo lagu daaweeyay chloramines taurine [40]. Isku soo wada duuboo, moodooyinka tijaabada ah ee kor ku xusan ayaa shaaca ka qaaday in Nrf2 / HO-1 dhidibka uu door weyn ka ciyaaro shaqada ka hortagga bararka, taas oo soo jeedinaysa in Nrf2 ay tahay bartilmaameedka daaweynta cudurrada caabuqa.
Intaa waxaa dheer, waxyaabaha ka soo baxa HO-1 sida CO, bilirubin, waxay u dhaqmaan sida antioxidant awood leh inta lagu jiro cadaadiska oksaydhka iyo dhaawaca unugyada [41], [42]; waxay xakameysaa encephalomyelitis autoimmune iyo cagaarshow [43], [44]; waxayna ka ilaalisaa jiirarka iyo jiirka shoogga endotoxic iyadoo ka hortagaysa jiilka iNOS iyo NO [45], [46], [47]. Intaa waxaa dheer, Bilirubin wuxuu yareeyaa firfircoonida endothelial iyo shaqada [48]. Waxa xiisaha lihi leh, bilirubin waxa ay yaraynaysaa isu-gudbinta leukocytes endothelial iyada oo loo marayo molecule adhesion-1 [49]. Tixraacyadan gaarka ah ee tilmaamaya ma aha oo kaliya HO-1 u dhaqmo sida wakiilka xooggan ee ka hortagga bararka laakiin sidoo kale dheef-shiid kiimikaad.
Dhexdhexaadiyeyaasha bararka iyo Enzymes-ka ay joojiyeen Nrf2
Cytokines iyo Chemokines
Cytokines waa borotiinno miisaankoodu yar yahay iyo polypeptides oo ay siiyeen unugyo kala duwan; waxay nidaamiyaan korriinka unugyada, kala duwanaanshaha, iyo shaqada difaaca, waxayna ku lug leeyihiin bararka iyo bogsiinta boogaha. Cytokines waxaa ka mid ah interleukins (ILs), interferon, factor necrosis factor (TNF), factor colony-stimulating, chemokines, iyo arrimaha koritaanka. Qaar ka mid ah cytokines ayaa lagu tiriyaa inay yihiin dhexdhexaadiyeyaasha pro-bararka halka kuwa kalena ay leeyihiin hawlo ka hortagga bararka. Soo-gaadhista diiqada oksaydhisku waxay keentaa soo-saarka xad-dhaafka ah ee cytokines kaas oo keena cadaadiska oksaydhka ee unugyada bartilmaameedka ah. Dhowr cytokines pro-bararka ayaa si xad dhaaf ah u soo saara marka NF-?B ay shaqeyso walaaca oksaydhka. Intaa waxaa dheer, diiqada oksidheerka ee pro-bararka waxay sababtaa firfircoonida dheeraadka ah ee NF-?B iyo soo-saarka xad-dhaafka ah ee cytokines. Hawlgelinta nidaamka Nrf2/ARE ayaa door muhiim ah ka ciyaara carqaladaynta wareeggan. Chemokines waa qoys ka kooban cytokines yaryar, taas oo doorka ugu weyni ay tahay inay hagto socdaalka unugyada bararka. Waxay inta badan u shaqeeyaan sidii chemoattractants ee leukocytes, monocytes, neutrophils, iyo unugyada kale ee waxtarka leh.
Waxaa la soo wariyay in firfircoonida Nrf2 ay ka hortagayso kor u qaadista qoraalka LPS ee cytokines pro-inflammatory, oo ay ku jiraan IL-6 iyo IL-1? [50] IL-1? iyo wax soo saarka IL-6 ayaa sidoo kale lagu kordhiyey Nrf2?/? jiirarka leh dextran sulfate-induced colitis [51], [52]. Nrf2 waxay joojisaa wax soo saarka IL-17 ee hoose iyo arrimaha kale ee caabuqa Th1 iyo Th17, waxayna xakameysaa habka cudurka ee qaabka tijaabada ah ee sclerosis, autoimmune encephalitis [53]. Nrf2-ku-tiirsanaanta anti-oxidant HO-1, NQO-1, Gclc, iyo Gclm block TNF-?, IL-6, monocyte chemo soo jiidashada borotiinka-1 (MCP1), borotiinka caabuqa macrophage-2 (MIP2), iyo bararka bararka. dhexdhexaadiyayaal. Laakiin marka laga hadlayo jiirarka Nrf2-knockout, saameynta anti-bararka ma dhacdo [54]. Peritoneal neutrophils ee jiirarka Nrf2-knockout ee lagu daweeyay LPS waxay leeyihiin heerar aad u sarreeya oo cytokines ah (TNF-? iyo IL-6) iyo chemokines (MCP1 iyo MIP2) marka loo eego unugyada duurjoogta ah (WT) [54]. In vitro, u wareejinta hidda-wadaha Nrf2 ee bini'aadamka iyo unugyada muruqa aortic aortic ee bakaylaha ayaa xakameynaya dheecaanka MCP1 [8], [55], iyo Nrf2-ku-tiirsanaanta HO-1 waxay xakameysaa TNF-?-kicin NF-?B iyo MCP-1 dheecaanka ku jira unugyada endothelial xididka xudunta aadanaha [56]. Natiijooyinkani waxay tilmaamayaan in, ka jawaab celinta kicinta bararka, kor u qaadista calaamadaha Nrf2 ay joojiso soo-saarka xad-dhaafka ah ee cytokines-pro-inflammatory iyo chemokines iyo sidoo kale xaddididda firfircoonida NF-?B.
Unugyada Adhesion Molecules
Unugyada adhesion molecules (CAMs) waa borotiinno ku xidhan unugyada ama matrixka unugyada ka baxsan. Waxay ku yaalliin dusha sare ee unugga, waxay ku lug leeyihiin aqoonsiga unugga, firfircoonida unugyada, gudbinta calaamadaha, fidinta, iyo kala duwanaanta. Ka mid ah CAM-yada, ICAM-1 iyo VCAM-1 waa xubno muhiim ah oo ka tirsan qoyska superfamily ee immunoglobulin. ICAM-1 waxay ku jirtaa xaddi yar oo leukocyte ah iyo xuubabka unugyada endothelial. Marka la kiciyo cytokine, diiradda ayaa si weyn u kordheysa. ICAM-1 waxaa keeni kara IL-1 iyo TNF waxaana lagu muujiyaa endothelium vascular, macrophages, iyo lymphocytes. Waa ligand for integrin, reseptor ah oo laga helo leukocytes. Marka buundada ICAM-1-integrin la hawlgeliyo, leukocytes waxay ku xidhaan unugyada endothelial ka dibna waxay u guuraan unugyada subendothelial [57]. VCAM-1 waxay dhexdhexaadisaa adhesion of lymphocytes, monocytes, eosinophils, iyo basophils ilaa endothelium vascular waxayna gacan ka geysataa qoritaanka leukocyte, taas oo ugu dambeyntii keenta dhaawaca unugyada sababtoo ah cadaadiska oksaydhka. Nrf2 waxay joojisaa dhaqdhaqaaqa dhiirigeliyaha ee VCAM-1 [58]. Hiddaha-hoosaadka Nrf2-ku-habboon ee HO-1 waxay saameyn kartaa muujinta E-selectin iyo VCAM-1, molecules adhesion ee la xidhiidha unugyada endothelial [59]. Dareenka sambabada ee dhowr CAM-yada sida CD-14, TREM1, SELE, SELP, iyo VCAM-1 ayaa aad uga sarreeya Nrf2?/? jiirarka Nrf2+/+ jiirarka [60]. Nrf2 ee unugyada xuubka xuubka aortic ee bini'aadamka ayaa xakameynaya TNF-?-VACAM-1 muujinta waxayna farageliyaan TNF-? Muujinta xad dhaafka ah ee Nrf937 waxay sidoo kale joojisaa muujinta hidda-wadaha VCAM-8 ee TNF-? Antioxidant 2-hydroxyanthranilic acid (HA), mid ka mid ah dheef-shiid kiimikaadka l-tryptophan ee laga sameeyay vivo iyadoo la raacayo dariiqa dheef-shiid kiimikaadka loo yaqaan dariiqa kynurenine inta lagu jiro caabuqa ama caabuqa, ayaa lagu ogaadaa inay keento muujinta HO-1 iyo inay kiciso Nrf61 ee xuddunta aadanaha. unugyada endothelial xididka (HUVECs). Nrf3-ku-tiirsanaanta HO-1 ee ay keentay HA waxay joojisaa dheecaanka MCP-2, muujinta VCAM-2 iyo firfircoonida NF-kB ee la xidhiidha dhaawaca xididada iyo bararka atherosclerosis [1]. Ka-hortagga-proliferative iyo ka-hortagga-bararka chalcone-ka-soo-saarka 1?,1?,56?-tris (methoxymethoxy) chalcone waxay joojisaa ICAM-2, cytokine pro-inflammatory IL-4?, iyo TNF-? muujinta unugyada gumeysiga ee jiirarka lagu daaweeyay trinitrobenzene sulfonic acid [6]. Kordhinta Nrf1 waxay joojisaa muujinta TNF-? -ku-dhawaaqa ICAM-1 ee unugyada epithelial pigment retinal ee lagu daweeyay lycopene [62]. Dhammaan cilmi-baarisyadani waxay soo jeedinayaan in Nrf2 ay door muhiim ah ka ciyaarto habka caabuqa iyada oo la xakameynayo socdaalka iyo dhexgalka unugyada bararka unugyada bararka.
Matrix Metalloproteinase (MMPs)
MMP-yadu waxay si weyn ugu jiraan matrix-ka-ka-baxsan waxayna ku lug leeyihiin hababka jireed iyo jireed sida kororka unugyada, socdaalka, kala-soocidda, bogsiinta boogaha, angiogenesis, apoptosis, iyo metastasis-ka burada. Waxaa la sheegay in dhidibka Nrf2 / HO-1 uu xannibay MMP-9 ee macrophages iyo MMP-7 ee unugyada epithelial mindhicirka ee bani'aadamka, tani waxay faa'iido u leedahay daaweynta cudurrada mindhicirka bararka [62], [64]. Dhaawaca maqaarka ee shucaaca UV ayaa aad uga daran Nrf2-knockout marka loo eego jiirarka WT iyo heerka MMP-9 ayaa aad u sarreeya, taas oo muujinaysa in Nrf2 ay yarayso muujinta MMP-9. Sidaa darteed, Nrf2 waxaa loo arkaa inay ka ilaalinayso shucaaca UV [65]. Daraasad kale ayaa sidoo kale sheegtay in dhaqdhaqaaqa hoos u dhaca qoraalka ee MMP-9 ee ku-soo-noqoshada unugyada burooyinka iyo caabuqa lagu xakameeyo iyada oo la xakameynayo dariiqa calaamadaynta NF-kB [66]. Dhaawaca laf-dhabarka dhaawaca ah, dariiqa calaamadaynta NF-kB ayaa sidoo kale ka qayb qaadanaysa habeynta heerarka mRNA ee MMP-9 [67]. Sidaa darteed, bararka qawaaniinta MMP-yada waxaa si toos ah u saameeya dariiqa Nrf2 ama si aan toos ahayn iyada oo loo marayo dariiqa NF-?B ee saameeya Nrf2.
Tijaabooyin taxane ah oo ku saabsan jiirarka Nrf2-knockout ayaa muujiyay doorkeeda muhiimka ah ee caabuqa iyo habaynta hiddo-wadaha pro-bararka sida COX-2 iyo iNOS. Markii ugu horeysay, Khor et al. ayaa sheegay in kor u kaca muujinta cytokines pro-bararka sida COX-2 iyo iNOS ee unugyada gumeysiga ee Nrf2?/? jiirarka marka la barbar dhigo WT Nrf2 +/+ jiirarka, taas oo muujinaysa in Nrf2 uu xakameeyo hawlahooda [51]. Warbixin kale oo ku saabsan daaweynta hore ee sulforaphane, mid ka mid ah firfircoonayaasha Nrf2 ee caanka ah ee ku jira khudaarta cruciferous, waxay muujisay saameynteeda ka hortagga bararka ee joojinta muujinta TNF-?, IL-1?, COX-2, iyo iNOS labadaba mRNA iyo heerarka borotiinka ee macrophages xuubka hoose ee Nrf2 +/+ jiirarka marka la barbar dhigo kuwa Nrf2?/? jiirarka [68]. Sidoo kale, hippocampus ee jiirarka Nrf2-knockout oo leh bararka LPS ayaa sidoo kale muujinaya muujinta sare ee calaamadaha caabuqa sida iNOS, IL-6, iyo TNF-? marka loo eego jiirarka WT [69]. Sidoo kale, jiirarka Nrf2-knockout waxay u nugul yihiin cadaadiska oksaydhka ee ay keento 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine iyo sidoo kale muujinta mRNA iyo borotiinka korodhka calaamadaha caabuqa sida COX-2, iNOS , IL-6, iyo TNF-? [70]. Intaa waxaa dheer, beerka ka Nrf2?/? Jiirarka lagu loolamayo methionine-iyo cunto-yarida choline-ku waxay leeyihiin ~ 5-laab ka sarreeya muujinta mRNA ee Cox2, iyo iNOS marka loo eego kuwa ka soo jeeda jiirarka WT ee isla cuntada, taasoo soo jeedinaysa doorka ka hortagga caabuqa ee Nrf2 [71]. Dhawaan, Kim et al. waxay muujisay in phytochemical ethyl pyruvate ay sameyso saameynteeda anti-bararka iyo anti-oxidative iyadoo hoos u dhigaysa muujinta iNOS iyada oo loo marayo Nrf2 calaamadaha unugyada BV2. Waxay muujiyeen in ethyl pyruvate ay kiciso tarjumaadda nukliyeerka ee Nrf2, taas oo ugu dambeyntii joojisay isdhexgalka u dhexeeya p65 iyo p300, taasoo keentay hoos u dhaca muujinta iNOS [72]. Intaa waxaa dheer, analoogga carbazole ee LCY-2-CHO wuxuu kiciyaa Nrf2 wuxuuna keenaa beddelaadkiisa nukliyeerka, taasoo horseedaysa xakamaynta COX2 iyo iNOS muujinta [73] ee unugyada xididdada xididdada dhiigga ee jilicsan.
Doorka is barbar yaaca ee Nrf2 ee Xeerka NLRP3 iIflammasome�
Qoyska NLR, domain pyrin oo ka kooban 3 (NLRP3) barar waa isku dhafan borotiinno badan oo u shaqeeya sidii soo-dhoweeyaha aqoonsiga pathogene (PRR) oo aqoonsanaya baaxadda ballaaran ee microbial, calaamadaha cadaadiska oksaydhka sida qaababka molecular-la-xidhiidha pathogene (PAMPs), Burbur- Unugyada moodeelka molecular ee la xidhiidha (DAMPs) iyo ROS [74]. Bararka NLRP3 ee firfircoon wuxuu dhexdhexaadiyaa kala-goynta caspase-1 iyo dheecaanka pro-bararka cytokine interleukin-1? (IL-1?) Taas oo ugu dambeyntii keenta habka dhimashada unugyada loo yaqaan 'pyroptosis' kaas oo ka ilaaliya martigeliyaha ka hortagga cudurro badan oo kala duwan [75]. Si kastaba ha ahaatee, firfircoonida qallafsan ee bararka waxay la xiriirtaa cudurrada borotiinka qaldamaya sida spongiform encephalopathies la kala qaado, cudurka Alzheimers, cudurka Parkinson iyo sidoo kale nooca 2 ee sonkorowga [76], kansarka [77], gout, iyo atherosclerosis [78].
Kormeer dhawaan ka yimid kooxda Rong Hu ee ururka Nrf2 oo leh nidaam xun oo barar ah ayaa shaaca ka qaaday in, Nrf2 ay kiciso muujinta NQO1 taas oo horseedaysa joojinta NLRP3 firfircoonida caabuqa, dillaac-1 dillaac iyo IL-1? jiilka ee macrophages. Intaa waxaa dheer, Nrf2 activator si fiican loo yaqaan, tert-butylhydroquinone (tBHQ) ayaa si xun u habeeyey qoraalka NLRP3 iyada oo la hawlgelinayo ARE iyada oo loo marayo habka Nrf2-ku-tiirsanaanta [79]. Marka lagu daro indho-indheynta kor ku xusan, koox isku mid ah ayaa sidoo kale shaaca ka qaaday in, dimethyl fumarate (DMF) ay ka hortagto colitis-ka DSS iyada oo la adeegsanayo habka Nrf2 ee calaamadaynta kaas oo ku lug leh Nrf2 beddelka nukliyeerka iyo xakameynta NLRP3 inflammasome shirkii [80].
Tijaabooyin taxane ah oo isticmaalaya xeryahooda dabiiciga ah iyo kuwa synthetic ayaa sidoo kale shaaca ka qaaday saameynta xannibaadda ee Nrf2 ee NLRP3 firfircoonida caabuqa. Tusaale ahaan, daaweynta epigallocatechin-3-gallate (EGCG) ee jiirarka lupus nephritis waxay muujisay hoos u dhigista firfircoonida kelyaha ee NLRP3 ee caabuqa kaas oo ay dhexdhexaadiso Nrf2 habka calaamadaha [81]. Sidoo kale, citral (3,7-dimethyl-2,6-octadienal), oo ah xarun firfircoon oo weyn oo ku jirta dawada geedaha Shiinaha ee Litsea cubeba, waxay joojisaa firfircoonida NLRP3 ee caabuqa iyada oo loo marayo Nrf2 habka calaamadaynta antioxidant ee dardargelinta iyo nooca jiirka ee Lupus Nephritis (ASLN). [82]. Sidoo kale, biochanin-ka ayaa ka ilaaliya LPS/GalN-ku-dhaawaca beerka iyadoo la hawlgelinayo dariiqa Nrf2 iyo joojinta NLRP3 firfircoonida bararka ee ragga BALB / c jiirarka [83]. Intaa waxaa dheer, mangiferin ayaa sidoo kale lagu muujiyay in ay kor u qaaddo muujinta Nrf2 iyo HO-1 ee habka qiyaasta-ku-tiirsanaanta iyo la xakameeyey LPS/D-GalN-ku-nooca beerka NLRP3, ASC, caspase-1, IL-1? iyo TNF-? muujinta [84].
Inkasta oo xeerka xun ee NLRP3 ee Nrf2, waxay sidoo kale kicisaa shaqada NLRP3 iyo AIM2. Haitao Wen iyo asxaabtiisuba waxay ogaadeen taas, Nrf2 ?/? macrophages mouse waxay muujiyeen firfircoonida cilladaysan ee NLRP3 iyo AIM2 Inflammasome laakiin maaha NLRC4 inflammasome [85]. Waxa xiiso leh, indho-indhayntani waxay muujinaysaa hawlaha aan la garanayn ee Nrf2 ee macnaha guud ee cudurrada la xidhiidha caabuqa; sidaas awgeed aad bay muhiim u tahay in la sii barto si loo muujiyo habka Nrf2 uu u kiciyo shaqada bararka ka hor inta aan loo tixgelin bartilmaameedka daaweynta.
Xakamaynta Qoraalka Cytokine Pro-Inflammatory by Nrf2
Baadhitaan aad u dhow oo ku salaysan chromatin immunoprecipitation (ChiP) -seq iyo ChIP-qPCR natiijooyinka macrophages mouse ayaa shaaca ka qaaday in Nrf2 ay ku xiran tahay gobollada dhiirrigeliyeyaasha ee cytokines pro-inflammatory sida IL-6 iyo IL-1? oo ay joojiso qorista RNA Pol II. Natiijo ahaan, RNA Pol II ma awoodo inay socodsiiso hawlgelinta qoraalka qoraalka ah ee IL-6 iyo IL-1? taas oo ugu dambeyntii keenta in la joojiyo muujinta hiddaha. Markii ugu horeysay, kooxda Masayuki Yamamoto ayaa shaaca ka qaaday habka cusub ee Nrf2 kaliya aysan u gudbin hiddo-wadaha hoose iyada oo loo marayo AREs, laakiin sidoo kale waxay xakameysaa dhaqdhaqaaqa qoraalka ee hiddo-wadaha gaarka ah oo leh ama aan lahayn ARE iyada oo la xakameynayo qoritaanka RNA Pol II [50].
Isdhaafsiga u dhexeeya Nrf2 iyo NF-?B Pathways
NF-?B waa kakan borotiin ah oo mas'uul ka ah qoraalka DNA ee laga helo ku dhawaad dhammaan noocyada unugyada xayawaanka oo ku lug leh habab kala duwan sida caabuqa, apoptosis, jawaabta difaaca, koritaanka unugyada, iyo horumarka. p65, oo ah borotiinka Rel ee qoyska NF-?B, ayaa leh qayb wax kala beddelasho ah halka p50 aanu lahayn oo uu u baahan yahay heterodimerization oo leh borotiinka Rel si loo hawlgeliyo qoraalka. Inta lagu jiro cadaadiska oksaydhiyaha, I?B kinase (IKK) waa la hawlgeliyaa oo keena fosforyaalka I?B, taasoo keentay sii daynta iyo beddelka nukliyeerka ee NF-?B. NF-?B waxay sababtaa qoraalka dhexdhexaadiyeyaasha pro-bararka sida IL-6, TNF-?, iNOS, IL-1, iyo adhesion intracellular COX-2.
Nidaaminta aan caadiga ahayn ee NF-?B waxay ku xiran tahay rheumatoid arthritis-ka, neefta, cudurka bararka mindhicirka, iyo xanuunka Helicobacter pylori ee xanuunka gaasaska [86]. Hadda waxaa loo arkaa in dhaqdhaqaaqa NF-kB uu saameyn ku yeesho dariiqa calaamadaynta Keapl/Nrf2/ARE inta badan saddex dhinac: marka hore, Keap1 waxay hoos u dhigtaa IKK? iyada oo loo marayo meel kasta, sidaas darteed la joojiyo dhaqdhaqaaqa NF-?B [87]. Marka labaad, geeddi-socodka bararku wuxuu keenaa dhexdhexaadiyeyaasha caabuqa sida COX2 oo laga soo qaatay cyclopentenone prostaglandin 15d-PGJ2, koronto xoog leh oo la falgasha Keap1 oo kicisa Nrf2, sidaas darteed bilaabaya qorista hidda-socodka iyadoo la xakameynayo isku mar ee waxqabadka NF-kB [58], [88] ( Sawirka 3 A, B). Saddexaad, NF-?B waxay isku dari kartaa tartanka Nrf2 co-activator transcriptional co-activator CBP [89], [90] (Jaantus. 3 C, D).
Jaantuska 3 Isdhaafsiga u dhexeeya waddooyinka Nrf2 iyo NF-?B. (A) Keap1 waxa ay IKK u hagtaa CUL3-dhexdhexaadin ah oo meel kasta oo ay joogaan iyo hoos u dhaca borotiinka kaas oo ugu dambeyntii keenaya in la joojiyo fosforyaalka NF-?B iyo habkani waxa kale oo uu u shaqeeyaa sidii tartanka Nrf2 iyo IKK ee Keap1. (B) Cadaadiska Oxidative wuxuu kiciyaa IKK kaas oo fosfooraska NF-?B, taasoo keentay in loo beddelo xudunta iyo firfircoonida cytokines proinflammatory sida COX-2. Badeecada dhamaadka COX-2 ee loo yaqaan 15d-PGJ2 waxay u dhaqantaa sidii kicinta Nrf2 taasoo ugu dambeyntii keenta xakamaynta cadaadiska oksaydhka. (C) Nrf2 waxay ku xidhan tahay isku xidhkeeda qoraalka ah ee CBP oo ay weheliso Maf yar iyo mashiinno kale oo qoraal ah si loo bilaabo muujinta hidda-wadaha ee ARE-drive. (D) Marka NF-? B ay ku xirto CBP si tartan ah, waxay joojisaa ku-xidhka CBP ee Nrf2, taas oo horseedaysa joojinta Nrf2 transactivation.
Waxaa loo malaynayaa in Nrf2 iyo NF-B dariiqyada calaamadaha ay is dhexgalaan si loo xakameeyo qoraalka ama shaqada borotiinnada bartilmaameedka hoose. Marka la caddeeyo malo-awaalkan tusaalayaal badan ayaa muujinaya in firfircooni toos ah ama mid aan toos ahayn iyo xannibaaddu ay ka dhex dhacaan xubnaha Nrf2 iyo NF-?B waddooyinka (Sawir. 4). Iyada oo laga jawaabayo LPS, garaacista Nrf2 waxay si weyn u kordhisaa waxqabadka NF-?B ee qoraalka iyo NF-? Intaa waxaa dheer, muujinta korodhka ah ee Nrf2-ku-tiirsanaanta hoose ee HO-1 waxay joojisaa dhaqdhaqaaqa NF-?B. Marka unugyada kansarka qanjirka 'prostate' ay si kooban ula kulmaan ?-tochopheryl succinate, oo ka soo jeeda fiitamiin E, muujinta HO-1 ayaa la hagaajiyaa. Alaabooyinka ugu dambeeya ee HO-1 ayaa xannibaya beddelka nukliyeerka ee NF-?B [92]. Kuwan daraasadaha vivo waxay soo jeedinayaan in Nrf2 ay si xun u maamusho dariiqa calaamadaynta NF-kB. LPS waxay kicisaa NF-?B DNA-da dhaqdhaqaaqa xidhidhiyaha iyo heerka p65-subnit ee NF-?B ayaa si aad ah ugu sarreeya soosaarka nukliyeerka ee sambabada Nrf2?/? marka loo eego jiirarka WT, oo soo jeedinaya doorka xun ee Nrf2 ee firfircoonida NF-?B. Intaa waxaa dheer, Nrf2?/? Fibroblast embriyaha jiirka oo lagu daaweeyay LPS iyo TNF-? muujiyaan firfircooni NF-?B oo aad u caan ah oo ay sababtay hawlgelinta IKK iyo I?B-? hoos u dhac [60]. Iyo nadiifinta fayraska syncytial ee neef-mareenka ayaa si weyn hoos ugu dhacay halka NF-?B waxqabadka DNA-da lagu kordhiyo Nrf2?/? jiirarka marka la barbar dhigo jiirarka WT [93]. Lupus nephritis-ka Pristane ee Nrf2?/? Jiirarka lala daaweeyay sulforaphane waxay leeyihiin dhaawac culus oo kelyaha ah iyo isbeddellada pathological iyo sidoo kale kor u kaca iNOS muujinta iyo NF-?B firfircoonida marka la barbar dhigo WT, taasoo soo jeedinaysa in Nrf2 ay hagaajiso lupus nephritis iyada oo la xakameynayo NF-? B dariiqa calaamadaynta iyo nadiifinta ROS [94] ]. Dhaqdhaqaaqa NF-?B wuxuu kaloo dhacaa marka unugyada lagu daaweyo Nrf2 inducer oo ay la socdaan LPS iyo TNF-?. Tusaale ahaan, derivative chalcone synthetic waxay joojisaa TNF-? -ku-dhaqdhaqaaqa NF-?B labadaba si toos ah iyo si aan toos ahayn iyo qayb ahaan iyada oo la adeegsanayo muujinta HO-1 ee unugyada epithelial xiidmaha xiidmaha ee HT-29 [62]. Xakamaynta NF-? B beddelka iyo dhaqdhaqaaqa DNA-ku-xidha iyo sidoo kale xakamaynta muujinta iNOS ee hepatocytes waxaa la helaa marka jiirka F344 lagu daweeyo 3H-1,2-dithiole-3-thione (D3T) [95]. Ka dib wada-daawayn lala yeeshay sulforaphane iyo LPS, muujinta ay keentay LPS ee iNOS, COX-2, iyo TNF-? gudaha Raw 264.7 macrophages ayaa hoos loo dhigay, oo la soo jeediyay in sulforaphane uu leeyahay waxqabad ka-hortagga caabuqa iyada oo la xakameynayo NF-?B DNA-da isku-xidhka [96]. In kasta oo dhowr daraasadood oo tijaabo ah la sameeyay si loo sharxo xidhiidhka ka dhexeeya dariiqyada Nrf2 iyo NF-?B, natiijooyinka is khilaafaya ayaa weli ah. Xeerarka togan iyo kuwa taban labadaba ayaa laga soo sheegay inta u dhaxaysa Nrf2 iyo NF-kB [97]. Caadi ahaan, kiimiko-ka-hortagga electrophiles 3H-1,2-dithiole-3-thione, sulforaphane iyo Triterpenoid CDDO-Me waxay dhaqaajiyaan Nrf2 iyagoo xakameynaya NF-kB iyo gen-keeda hoos loo dhigay [98], [99], [100]. Taas bedelkeeda, dhowr wakiil ama xaalado sida ROS, LPS, cadaadiska qulqulka qulqulka, LDL oksaydhka, iyo qiiqa sigaarka ayaa la muujiyay inay kordhiyaan labadaba Nrf2 iyo NF-kB dhaqdhaqaaqa [97]. Intaa waxaa dheer, daraasadaha vivo waxay daaha ka qaadeen in dhaqdhaqaaqa NF-kB uu hoos u dhacay beerka ka go'doomay Nrf2?/? jiirarka iyo NF-?B dhaqdhaqaaqa xidhidha ayaa ka hooseeya Nrf2?/? Marka loo eego Nrf2 +/+ jiirarka [101]. Si kastaba ha ahaatee, unugyada xuubka aortic ee bini'aadamka ee lagu daaweeyay adenoviral vector Nrf2 waxay joojisaa NF-?B hiddo-wadaha hoose iyada oo aan saameyn ku yeelan waxqabadka NF-?B [8].
Jaantuska 4 Wareegtada nidaaminta ee Nrf2 iyo NF-?B. Jidka Nrf2 wuxuu xannibaa firfircoonida NF-?B isagoo ka hortagaya hoos u dhaca I?B-? iyo kordhinta muujinta HO-1 iyo difaacayaasha antioxidant kuwaas oo ka takhalusaya ROS iyo kiimikooyinka sunta ka saaraya. Natiijo ahaan, hawlgelinta NF-?B ee ku xidhan ROS waa la xakameeyey. Sidoo kale, NF-?B-dhexdhexaadinta qoraalka waxay yaraynaysaa firfircoonida Nrf2 iyada oo la dhimayo�WAAQoraal hidde-sidaha iyo borotiinka xidhidhiyaha CREB ee bilaashka ah adiga oo la tartamaya Nrf2 ee CBP. Waxaa intaa dheer, NF-?B waxay kordhisaa qoritaanka histone deacetylase (HDAC3) ee gobolka ARE oo markaa Nrf2 firfircoonida qoraalka waa laga hortagayaa.
Dhaqdhaqaaqa dariiqa calaamadaynta Nrf2 waxay door weyn ka ciyaartaa muujinta enzymes iyo hiddo-wadaha ku lug leh sun-saaridda oksaydhiyeyaasha fal-celinta iyada oo kor u qaadeysa awoodda antioxidant ee unugyada jidhka bini'aadamka. Iyadoo daraasado badan oo cilmi baaris ah la heli karo maanta, hababka sharciyeynta ee firfircoonida Nrf2 si buuxda looma fahmin. Doorka suurtagalka ah ee dariiqa calaamadaynta Nrf2 ee daaweynta bararka ayaa sidoo kale la helay. Dr. Alex Jimenez DC, CCST Insight
Doorka Nrf2 ee Cudurada Bararka
Daraasadaha Vivo waxay muujiyeen in Nrf2 ay door muhiim ah ka ciyaaraan cudurrada caabuqa ee saameeya hababka kala duwan; Kuwaas waxaa ka mid ah gastritis, colitis, arthritis, pneumonia, dhaawaca beerka, cudurrada wadnaha iyo xididada, cudurka neurodegenerative, iyo dhaawaca maskaxda. Daraasadahan, Nrf2?/? xayawaanku waxay muujiyeen calaamado aad uga daran caabuqa iyo dhaawaca unugyada marka loo eego xayawaanka WT. Sidaa darteed, waxaa la rumeysan yahay in dariiqa calaamadaynta Nrf2 ay leedahay saameyn difaac ah cudurrada caabuqa. Rakibaadda intracheal ee elastase pankreatit porcine waxay keentaa cudur daba-dheeraada ee sambabada, gaar ahaan emphysema. Jiirarka Nrf2-yar ayaa aad ugu nugul emphysema, iyo hoos u dhaca muujinta HO-1, PrxI, iyo hidda-wadaha antiprotease SLPI waxay ku dhacaan macrophages alveolar. Nrf2 waxaa loo tixgeliyaa inuu yahay nidaamiye fure u ah nidaamka difaaca dhexdhexaadinta ee makrophage ee ka hortagga dhaawaca sambabada [102]. Jiirarka Nrf2-yar oo leh emphysema oo ay keentay soo-gaadhista qiiqa tubaakada ee bilaha 6 waxay muujinayaan kororka bararka bronchoalveolar, muujinta kor u kaca ee calaamadaha cadaadiska oksaydhka ee alveoli, iyo kororka unugyada alveolar apoptosis, taasoo soo jeedinaysa in Nrf2 ay ka soo horjeedo emphysema-ka tubaakada iyada oo loo marayo muujinta sii kordheysa ee antioxidant hiddo-sideyaasha [102], [103]. Burburinta Nrf2, caabuqa hawo-mareenka-xasaasiga ah iyo neefta iyadoo la adeegsanayo isku-dhafka ovalbumin waxay muujinayaan kororka caabuqa marin-haweedka, marin-u-dhaqdhaqaaqa hawo-mareenka, hyperplasia ee unugyada goblet, iyo heerarka sare ee Th2 ee bronchoalveolar lavage iyo splenocytes, halka Nrf2-dhexdhexaadinta dariiqa calaamadaynta xaddidaadda marin-haweedka eosinophilia , xab-xab-xabeedka, iyo fal-celinta marin-haweedka iyo sidoo kale kicinta hidde-sideyaal badan oo antioxidant ah oo ka hortagaya horumarinta neefta [104]. Cirbadeynta Carrageenan ee godka xuubka xuubka ayaa keena pleurisy, iyo 15d-PGJ2 ururinta unugyada Nrf2 waxay ku xiran yihiin makrophages peritoneal mouse. Inta lagu jiro marxaladda hore ee caabuqa, 15d-PGJ2 waxay kicisaa Nrf2 waxayna nidaamisaa habka bararka iyada oo loo marayo soo-saarka HO-1 iyo PrxI. Daraasad ayaa sidoo kale soo jeedisay in COX-2 ay leedahay saameyn anti-bararka wajiga hore ee soo saarista 15d-PGJ2 [105]. Maamulka afka ee 1% dextran sulfate sodium ee toddobaadka 1 wuxuu keenaa colitis oo la xidhiidha isbeddellada taariikhiga ah oo ay ku jiraan gaabin crypts iyo dhexgalka unugyada bararka ee unugyada xiidmaha. Si loo ilaaliyo daacadnimada mindhicirka ee colitis, Nrf2 waxay ka ciyaari kartaa door muhiim ah iyada oo la xakameynayo cytokines pro-inflammatory iyo kicinta wajiga II detoxifying enzymes [51]. Qaabka Nrf2-knockout mouse ee sepsis sambabada sambabada ay keentay LPS, NF-?B dhaqdhaqaaqa ayaa nidaamiya saamaynta cytokines bararka sida COX-2, IL-113, IL-6, iyo TNF? kuwaas oo lagama maarmaan u ah bilaabista iyo kor u qaadida caabuqa [60]. Nrf2 waxay yaraynaysaa dhaawaca bararka iyadoo nidaamisa arrimahan bararka. Moodooyinkan bararka ba'an, xakamaynta korodhka ah ee enzymes antioxidant, cytokines pro-inflammatory, iyo dhexdhexaadiyeyaasha ee habka Nrf2 waxay yaraynaysaa dhaawaca bararka ee xayawaanka WT. Waxa xiisaha lihi leh, tan ayaa sidoo kale laga soo sheegay jiirarka Nrf2-knockout kuwaas oo astaamuhu si muuqata uga sii daraan marka loo eego jiirarka WT.
Cilmi-baadhis ku saabsan Dawooyinka Ka-hortagga-Bararka ee Ku-tiirsanaanta Nrf2
Marka la soo koobo, waxaan ka wada hadalnay tijaabooyin muujinaya in dariiqa Nrf2 ee calaamaduhu ay door ka ciyaaraan door nidaamsan meelo badan oo caabuq ah, sidaas darteed Nrf2-ku-tiirsanaanta wakiilada anti-bararka ayaa muhiim u ah daaweynta cudurrada bararka.
Dhirtu waxay ahaayeen ilo qani ah oo aan caadi ahayn oo xeryahooda ah kuwaas oo dhaqaajiya Nrf2 factor transcription, taasoo keentay hagaajinta hiddo-wadaha cytoprotective. Dhawaan, daraasado dhowr ah ayaa la sameeyay si loo baaro saameynta wakiilada kala duwan ee anti-bararka, inta badan asalka dhirta. Tusaale ahaan, curcumin waa walaxda firfircoon ee turmeric waxaana sidoo kale laga helaa xaddi yar oo sinjibiil ah; isothiocyanates, gaar ahaan phenylisothiocyanates waxay ka yimaadaan brokoli, celery, iyo khudaar kale; iyo anthocyanins waxay ka yimaadaan miraha iyo canabka [124]. Daraasaduhu waxay muujiyeen in dhammaan wakiiladan aysan ahayn kaliya antioxidants wanaagsan laakiin sidoo kale waxay leeyihiin saameyn xooggan oo ka hortagga bararka iyada oo loo marayo Nrf2 induction [125], [126]. Sidaa daraadeed, horumarinta cusub ee ka-hortagga caabuqa Nrf2 ee ka soo baxa dhirta ayaa soo jiidatay xiiso badan oo cilmi-baaris caafimaad ah.
Sanadihii la soo dhaafay, tijaabooyin badan oo xayawaan ah ayaa la sameeyay si loo xaqiijiyo ficilada xeryahooda. Artesunate waxaa inta badan loo isticmaalaa duumada daran, duumada maskaxda, iyo cudurrada difaaca jirka ee rheumatic; waxay sidoo kale waxtar u leedahay dhaawaca sambabada septic. Artesunate waxay kicisaa Nrf2 iyo HO-1 muujinta, kan dambena wuxuu yareeyaa qulqulka cytokines pro-inflammatory iyo leukocytes ee unugyada si looga hortago caabuqa [127]. Isovitexin, oo laga soo saaro qolofta bariiska Oryza sativa, ayaa loo maleynayaa inay leedahay sifooyin anti-bararka iyo antioxidant; waxay ka ciyaartaa door difaac ah oo ka dhan ah LPS-ay keentay dhaawaca ba'an ee sambabada iyadoo dhaqaajisay dariiqa Nrf2/HO-1 oo joojisay MAPK iyo NF-?B [128]. Fimasartan, oo ah xannibaadaha cusub ee angiotensin II ee caanka ah ee ku shaqeeya nidaamka renin-angiotensin, wuxuu yareeyaa cadaadiska dhiigga; Isticmaalka fimasartan si loogu daweeyo jiirarka leh qalliin-ku-abuuray xannibaadda kaadi-mareenka ee hal-dhinac ah waxay yaraynaysaa cadaadiska oksaydhka, caabuqa, iyo fibrosis iyada oo la hagaajinayo Nrf2 iyo dariiqa antioxidant iyo joojinta RAS iyo MAPKs [129]. Sappanone waxaa si ballaaran loogu qaybiyaa Koonfur-bari Aasiya, halkaas oo loo isticmaalo sida ka-hortagga hargabka, ka-hortagga xasaasiyadda, iyo daawada neuroprotective; waxay kicisaa Nrf2 waxayna joojisaa NF-?B sidaas darteed waxaa laga yaabaa inay faa'iido u leedahay daaweynta Nrf2- iyo / ama NF-? B ee cudurada la xiriira [130]. Bixin laga soo saaray iniinaha Bixin orellana waxa loo isticmaalaa cudurrada faafa iyo caabuqa ee Mexico iyo Koonfurta Ameerika; waxay hoos u dhigtaa dhexdhexaadiyeyaasha bararka, dheecaanka alveolar capillary, iyo dhaawaca oksaydhka ee Nrf2-ku-tiirsanaanta si loo yareeyo dhaawaca sambabada ee hawo-mareenka iyo dib u soo celinta qaabka caadiga ah ee sambabada [131]. Xeryaha kale ee dhirta, sida epigallocatechin gallate, sulforaphane, resveratrol, lycopene, iyo soosaarida shaaha cagaaran waxay leeyihiin saameyn daweyn ah oo ku saabsan cudurrada caabuqa iyada oo loo marayo jidka Nrf2 [132], [133], [134]. Dhawaan phytochemical kale, eriodictyol, oo ku jira miro liinta, ayaa lagu soo warramey inay leedahay saameyn liddi ku ah bararka iyo saameynta antioxidant ee cisplatin-ku-dhacey dhaawaca kelyaha iyo sepsis-ku-dhacey dhaawaca sambabada ba'an iyadoo la xakameynayo Nrf2, xakameynaya NF-?B, iyo joojinta muujinta cytokines ee macrophages [135], [136]. Si kastaba ha ahaatee, phytochemicals badan ayaa muujinaya ballanqaad weyn oo ku saabsan ka hortagga iyo daaweynta cudurrada kala duwan ee bini'aadamka, qaarna waxay horey u soo galeen marxaladda tijaabooyinka bukaan-socodka (Shaxda 2).
Xeryahooda dhirtani waxay ku hawlgeliyaan dariiqa calaamadaynta Nrf2 inta badan qaabka qalabka elektiroonigga ah ee wax ka beddelaya hadhaaga cysteine ee Keap1, taasoo horseedaysa nukliyeer Nrf2 oo bilaash ah oo ku xiran ARE, taasoo keentay in la dhaqaajiyo qoraalka hidda-socodka u dhigma.
Sulforaphane iyo Saameyntiisa Kansarka, Dhimashada, Gabowga, Maskaxda iyo Dhaqanka, Cudurrada Wadnaha & in ka badan
Isothiocyanates waa qaar ka mid ah xeryahooda dhirta ee ugu muhiimsan ee aad ka heli karto cuntadaada. Fiidiyowgaan waxaan u sameynayaa kiiskii ugu badnaa ee abid la sameeyo. Fiiro gaar ah oo gaaban? U gudub mawduuca aad jeceshahay adiga oo gujinaya mid ka mid ah dhibcaha wakhtiga hoose. Jadwalka wakhtiga oo buuxa hoos
Qaybaha muhiimka ah:
00:01:14 - Kansarka iyo dhimashada
00:19:04 - gabowga
00:26:30 - Maskaxda iyo dhaqanka
00:38:06 - Dib u soo koobid kama dambays ah
00:40:27 - Qiyaasta
Waqtiga buuxa:
00:00:34 - Horudhaca sulforaphane, diiradda weyn ee fiidiyowga.
00: 31: 21 - Daraasada jiirka iyadoo la adeegsanayo 10 nooc oo kala duwan oo niyad-jabka ah ayaa muujinaya sulforaphane si la mid ah waxtarka sida fluoxetine (prozac).
00: 32: 00 - Daraasadu waxay muujineysaa in si toos ah loo nuugo glucoraphanin ee jiirarka ay si la mid ah waxtar ugu leedahay ka hortagga niyad-jabka ee ka timaadda qaabka cadaadiska bulshada.
Hadda, cilmi-baaris badan ayaa diiradda saarey doorka Nrf2 / Keap1 / ARE ee dariiqa calaamadaynta caabuqa. Waxaa ka mid ah enzymes-ka ay hagaajisay Nrf2, HO-1 waa mid ka mid ah enzymes jawaab-celinta walaaca. HO-1 waxay leedahay sifooyin anti-bararka oo caan ah. Guud ahaan, dariiqa calaamadaynta Nrf2 ayaa sidoo kale si xun u xakameynaya cytokines, kiimikooyinka sii daaya arrimaha, MMPs, iyo dhexdhexaadiyeyaasha kale ee bararka COX-2 iyo iNOS, kuwaas oo si toos ah ama si aan toos ahayn u saameeya waddooyinka NF-kB iyo MAPK ee khuseeya iyo shabakadaha kale ee xakameynaya caabuqa. Waxaa la soo jeediyay in Nrf2 iyo NF-B waddooyinka calaamadaha ay is dhexgalaan si loo xakameeyo qoraalka ama shaqada borotiinnada bartilmaameedka hoose. Cadaadiska ama firfircoonida NF-?B-dhexdhexaadinta dhaqdhaqaaqa qoraalka ee dhexdhexaadinta iyada oo loo marayo Nrf2 waxay u badan tahay inay ku dhacdo marxaladda hore ee caabuqa, sida NF-?B ay maamusho de novo synthesis ee isku-dhafka dhexdhexaadiyeyaasha pro-bararka. Si kastaba ha noqotee, weli waxaa jira xaddidaadyo cilmi-baaris ah sida haddii ay jiraan xiriiro u dhexeeya Nrf2 iyo waddooyinka kale ee calaamadaha sida JAK / STAT, muhiimadda hadda jira ee Nrf2 firfircoon ee ka soo jeeda ilaha dhirta dabiiciga ah ee caabuqa, iyo sida loo hagaajiyo dhaqdhaqaaqa noolaha. iyo kor u qaadida beegsiga xeryahooda. Kuwani waxay u baahan yihiin xaqiijin tijaabo ah oo dheeraad ah.
Intaa waxaa dheer, dariiqa calaamadaynta Nrf2 waxay nidaamin kartaa> 600 hiddo-wadaha [163], kuwaas oo> 200 ay ku dhejiyaan borotiinnada cytoprotective [164] kuwaas oo sidoo kale la xiriira caabuqa, kansarka, cudurrada neurodegenerative, iyo cudurrada kale ee waaweyn [165]. Caddaymaha sii kordhaya ee soo jeedinaya in, dariiqa calaamadaynta Nrf2 ayaa laga saaray kansarro badan, taasoo keentay muujinta aberrant Nrf2 batteriga hidda-wadaha ku tiirsan. Waxaa intaa dheer, bararku wuxuu door weyn ka ciyaaraa cudurrada la xiriira cadaadiska oksaydhka gaar ahaan kansarka. Codsiga dhowr firfircoon oo Nrf2 ah si looga hortago caabuqa ayaa laga yaabaa inay keento muujinta aberrant ee Nrf2 hiddo-wadaha hoose ee keena oncogenesis iyo iska caabinta kemo iyo / ama daaweynta raadiyaha. Sidaa darteed, hawl-wadeennada aadka u gaarka ah ee Nrf2 ayaa laga yaabaa in la horumariyo si loo yareeyo saameynteeda pleiotropic. Dhawr ka mid ah hawl-wadeennada Nrf2 ayaa muujiyay horumar weyn oo ku saabsan hawlaha ka hortagga bararka ee cudurrada la xidhiidha cadaadiska oksaydhka. Tusaalaha ugu fiican ee Nrf2 activator ay ansixisay FDA oo si weyn loogu isticmaalo daaweynta cudurrada caabuqa sida Multiple sclerosis (MS) waa dimethyl fumarate. Tecfidera� (magaca dimethyl fumarate ee Biogen ka diiwaan gashan) ayaa si wax ku ool ah loo isticmaalo si loogu daweeyo foomamka soo noqnoqda ee sclerosis badan oo bukaanno badan ah [152]. Si kastaba ha ahaatee, waxtarka isticmaalka Nrf2 activators si loo daaweeyo cudurrada caabuqa waxay u baahan tahay ansaxinta dheeraadka ah si looga fogaado saameynta xun ee Nrf2. Sidaa daraadeed, horumarinta daawaynta waxqabadka ka-hortagga caabuqa ee dhexdhexaadinta Nrf2 waxay yeelan kartaa saameyn caafimaad oo weyn. Daraasadaha socda ee dariiqa calaamadaynta Nrf2 ee adduunka oo dhan waxay u heellan yihiin horumarinta wakiilada daaweynta aadka loo bartilmaameedsado si loo xakameeyo calaamadaha caabuqa, iyo ka hortagga iyo daaweynta kansarka iyo sidoo kale neurodegenerative iyo cudurrada kale ee waaweyn.
Xanuunka jilibka waa calaamad caan ah oo ku dhici karta dhaawacyo jilibka ah iyo/ama xaalado kala duwan, oo ay ku jiraandhaawacyada isboortiga. Jilibku waa mid ka mid ah kala-goysyada ugu adag ee jidhka bini'aadamka maadaama uu ka kooban yahay isgoysyada afar lafo, afar seediyo, seedooyin kala duwan, laba menisci, iyo carjawda. Sida laga soo xigtay Akademiyada Maraykanka ee Dhakhaatiirta Qoyska, sababaha ugu badan ee xanuunka jilibka waxaa ka mid ah subluxation patellar, tendinitis patellar ama jilibka jumper, iyo cudurka Osgood-Schlatter. Inkasta oo xanuunka jilibka ay u badan tahay inuu ku dhaco dadka ka weyn 60 sano, xanuunka jilibka wuxuu sidoo kale ku dhici karaa carruurta iyo dhalinyarada. Xanuunka jilibka waxaa lagu daweyn karaa guriga iyadoo la raacayo hababka RICE, si kastaba ha ahaatee, dhaawacyada daran ee jilibka ayaa laga yaabaa inay u baahdaan daryeel caafimaad oo degdeg ah, oo ay ku jiraan daryeelka xanuunka loo yaqaan 'chiropractic care'. �
Cudurrada neerfayaasha, sida cudurka Alzheimers iyo cudurka Parkinson, waxay saameeyaan malaayiin qof oo adduunka ah. Doorashooyin kala duwan oo daaweyn ah ayaa diyaar u ah in lagu daaweeyo calaamadaha dhowr cudur oo neerfaha ah inkastoo natiijadu ay inta badan xaddidan tahay. Daraasadaha cilmi-baarista ayaa lagu ogaaday in cadaadiska oksaydhka ee ay sababaan arrimaha gudaha iyo dibaddaba ay sabab u noqon karaan horumarinta cudurrada neurodegenerative. The qodobka qoraalka, Nrf2, ayaa la go'aamiyay in uu u shaqeeyo sidii hab difaac weyn oo ka dhan ah diiqada oksaydhka. Ujeedada maqaalka hoose waa in la muujiyo saameynta Nrf2 ee cudurada neurodegenerative.
Beddelka Proteostasis ee Qodobka Qoraalka NRF2
Cudurada neurodegenerative waxay ku xiran yihiin ururinta isku-darka borotiinka gaarka ah, oo soo jeedinaya xiriir hoose oo u dhexeeya maskaxda dhaawacan iyo luminta borotiinka. Proteostasis waxaa loola jeedaa dhammaan hababka ay unugyadu u xakameeyaan badnaanta iyo laalaabidda borotiinka iyada oo ay ugu mahadcelinayaan shabakad ballaaran oo isku xirta nidaaminta waddooyinka calaamadaha, muujinta hidda-socodka iyo hababka hoos u dhaca borotiinka. Dib-u-eeggani wuxuu isku dayaa inuu soo koobo natiijooyinka ugu habboon ee ku saabsan habaynta qoraalka ee proteostasis ee ay samaysay qodobka NRF2 (cutubka nukliyeerka (erythroid-derived 2) -sida 2). NRF2 ayaa si heersare ah loo tixgeliyey inay tahay maamulaha sare ee jawaabta unugga antioxidant, inkasta oo ay hadda u soo baxayso qayb muhiim ah oo ka mid ah mashiinnada gudbinta si loo ilaaliyo proteostasis. Sida aan ka wadahadli doonno, NRF2 waxaa loo arki karaa inay tahay xarun ururisa calaamadaha degdega ah ee ka soo baxa borotiinka isku-duuban si loo dhiso jawaab-celin qoraal ah oo la isku dubariday oo waara. Tan waxaa lagu gaaraa hawlaha NRF2 ee la xidhiidha xakamaynta hiddo-wadaha ku lug leh dayactirka physiology endoplasmic reticulum physiology, proteasome iyo autophagy.
Qodobka Nukliyeerka (erythroid-derived 2) -sida 2 (NRF2) waa borotiinka aasaasiga ah-leucine-zipper ee loo arko maalmahan inuu yahay maamulaha sare ee homeostasis-ka gacanta. Waxay xakameysaa basal iyo diiqada-inducible ee in ka badan 250 hiddo-wadayaasha wadaaga wadaaga kobcinta cis-qabta ee loo yaqaan element jawaab-celinta antioxidant (ARE) [1], [2], [3], [4], [5]. Hidde-sidayaashani waxay ka qaybqaataan wajiga I, II iyo III falcelinta sun-saaridda, glutathione iyo peroxiredoxin / thioredoxin dheef-shiid kiimikaad, wax soo saarka NADPH iyada oo loo marayo dariiqa phosphate pentose iyo enzyme malic, oksaydhka dufanka dufanka leh, dheef-shiid kiimikaadka birta, iyo proteostasis [6]. Marka la eego hawlahan cytoprotective ballaaran, waxaa suurtagal ah in hal farmaajo oo ku dhuftay NRF2 ay yareyn karto saameynta dembiilayaasha ugu waaweyn ee cudurrada daba-dheeraada, oo ay ku jiraan oksidatative, bararka iyo walbahaarka borotiinka. Doorka NRF2 ee isbeddelka difaaca antioxidant-ka iyo xallinta bararka ayaa lagu xalliyay daraasado badan (dib u eegis lagu sameeyay [7]). Halkan, waxaan diirada saari doonaa doorkeeda proteostasis, ie, xakameynta homeostatic ee isku dhafka borotiinka, laalaabka, ka ganacsiga iyo hoos u dhaca. Tusaalooyinka waxaa lagu bixin doonaa macnaha guud ee cudurada neurodegenerative.
Astaanta guud ee cudurrada neurodegenerative waa dhacdooyinka isku-darka aberrant ee borotiinnada qaarkood. Sidaa darteed, isku-darka borotiinka ee ?-synuclein (?-SYN) ayaa laga helaa cudurka Parkinson's (PD), ?-amyloid (A?) plaques iyo hyper-phosphorylated TAU neurofibrillary tangles ee cudurka Alzheimers (AD), huntingtin (Htt) gudaha Cudurka Huntington (HD), superoxide dismutase 1 (SOD1) iyo borotiinka TAR DNA ee isku xira 43 (TDP-43) ee amyotrophic lateral sclerosis (ALS), borotiinka prion (PrP) ee spongiform encephalopathies, iwm. Isku geynta borotiinku waxay saameyn ku yeelan karaan dhowr waddooyinka gacanta, taas oo iyana laga yaabo inay saameyn ku yeelato heerarka NRF2 iyo dhaqdhaqaaqa.
Lakabyada kala duwan ee Xeerarka Si Adag u Xakameeya Hawsha NRF2
Xaaladaha jir ahaaneed, unugyadu waxay muujinayaan heerarka borotiinka NRF2 hooseeya sababtoo ah isbeddelka degdega ah. Iyada oo laga jawaabayo kicinta kala duwan, borotiinka NRF2 waa la ururiyaa, wuxuu galaa nukleus wuxuuna kordhiyaa qoraalka hiddo-wadaha ARE-ka kooban. Sidaa darteed, maaraynta heerarka borotiinka ee NRF2 waa qodob muhiim ah oo ay tahay in la isku daro calaamadaha taban ee togan iyo kuwa taban. Sida aan ka sii falanqayn doono, NRF2 waxaa hawlgeliya habab isku dhafan oo kala duwan si loo abaabulo jawaab celin degdeg ah oo hufan laakiin dhinaca kale NRF2 waa la joojin karaa, malaha weji labaad, si loo damiyo jawaabteeda.
Marka laga eego aragtida caadiga ah, firfircoonida NRF2 ayaa loo tixgeliyey natiijada jawaabta gacanta ee xeryahooda oksidat ama korantada. Marka la eego, ubiquitin E3 ligase adabtarada Kelch-sida ECH-ku xiran borotiinka 1 (KEAP1) ayaa door muhiim ah ka ciyaara. Faahfaahinta molecular waxaa si dheeraad ah looga hadli doonaa Qaybta 4.1. Marka la soo koobo, KEAP1 waxay u shaqeysaa sidii dareeme redox sababtoo ah hadhaaga cysteine ee muhiimka ah ee keenaya NRF2 meelaynta iyo hoos u dhaca boroteasomal. Waxa u dheer habayntan caadiga ah, NRF2 waxaa si qoto dheer u nidaamiya dhacdooyinka calaamadaynta. Runtii, kinase kala duwan ayaa la tusay in ay fosfoorilateri iyo nidaamiyaan NRF2. Tusaale ahaan, NRF2 waxaa lagu dari karaa fosfooraska by mitogen activated protein kinases (MAPKs), inkasta oo wax ku biirinta NRF2 ay tahay mid aan caddayn [8], [9], [10], [11]. PKA kinase iyo sidoo kale qaar ka mid ah PKC isozymes [12], CK2 [13] ama Fyn [14] fosfooraska NRF2 oo wax ka beddelaya xasilloonida. Shaqadii hore ee kooxdayada ayaa sheegtay in glycogen synthase kinse-3? (GSK-3?) Waxay joojisaa NRF2 ka saarista nukliyeerka iyo hoos u dhigista borotiinka [15], [25], [26], [27], [28], [29], [30]. Faahfaahinta molecular waxa lagaga hadli doonaa qaybta 4.1. Intaa waxaa dheer, NRF2 waxaa loo gudbiyaa noocyada kale ee qaanuunka. Tusaale ahaan, NRF2 acetylation by CBP / p300 waxay kordhisaa hawsheeda [17], halka ay xannibayso miR153, miR27a, miR142-5p, iyo miR144 [16], ama methylation of cytosine-guanine (CG) jasiiradaha ku dhex jira NRF2. [18]
Saamaynta Isku-darka Borotiinku ku yeelanayo Hababka Nidaaminta ee NRF2
Qaybtan waxaan diiradda saari doonaa sida ururinta borotiinka la qalday ay saameyn ugu yeelan karto dhaqdhaqaaqa NRF2 siinta qaar ka mid ah waddooyinka kor lagu soo sheegay tusaaleyaal tusaaleyaal ah. Marka hore, waxaan u baahannahay inaan tixgelinno in ururinta borotiinka si adag loola xiriiriyay waxyeellada oksaydhka. Runtii, isku-ururinta borotiinka iyo isku-ururinta borotiinka ee la qalday ayaa keenaya soo-saarka aan caadiga ahayn ee noocyada ogsijiinta fal-celinta (ROS) ee mitochondria iyo ilo kale [19]. Sida kor ku xusan, ROS waxay wax ka beddeli doontaa ceymiska xasaasiga ah ee KEAP1 taasoo horseedaysa sii deynta, xasilinta iyo meelaynta nukliyeerka ee NRF2.
Marka laga hadlayo borotiinka, tusaale ahaan dhacdooyinka calaamadaha cilladaysan ee saameyn kara NRF2 waxaa bixiya firfircoonida GSK-3? ee AD. GSK-3?, oo sidoo kale loo yaqaan TAU kinase, waxay ka qaybqaadataa fosforyaalka borotiinkan microtubule-ku xiran, taasoo keentay isku-darka, samaynta tangles neurofibrillary iyo joojinta gaadiidka axonal (dib u eegis [20]). Dhanka kale, GSK-3? waxay si aad ah u yaraynaysaa heerarka NRF2 iyo dhaqdhaqaaqa sida kor ku xusan. Inkasta oo aan si weyn loo aqbalin, amyloid cascade wuxuu soo jeedinayaa suntan A? oligomers waxay kordhiyaan GSK-3? waxqabadyo ay la socdaan TAU-hyperphosphorylation iyo dhimashada neerfaha [21], [22]. Waxaa jira noocyo kala duwan si ay u sharxaan sida A? ixsaan GSK3-? hawlqabad. Tusaale ahaan, A? waxay ku xidhaa soo-dhoweeyaha insuliinka oo waxay hor istaagtaa PI3K iyo AKT dariiqooyinka calaamadaha, kuwaas oo muhiim u ah ilaalinta GSK-3? Fosphorylation-ka oo aan shaqaynayn ee N-terminal Ser9 hadhaaga [23]. Dhanka kale, extracellular A? waxay la falgalaan soo-dhoweeyayaasha Frizzled, xannibaadda calaamadaha WNT [24] iyo mar labaad taasoo keentay sii deynta firfircoon ee GSK-3?. Marka la soo koobo, A? ururintu waxay keentaa kicinta aan caadiga ahayn ee GSK-3?, sidaas darteed waxay wiiqaysaa jawaabta NRF2 ee habboon.
Sida lagu falanqeeyay qaybta soo socota, borotiinnada la qalday waxay u horseedaan firfircoonida PERK iyo MAPKs, kuwaas oo kor u qaadaya NRF2 [31], [8], [9], [10], [11]. Waxaa intaa dheer, dhaqdhaqaaqa CBP / p300 ee aan la xakameynin ayaa lagu soo warramey dhowr borotiinnopathies [32] iyo hoos u dhaca caalamiga ah ee methylation DNA ee maskaxda AD ayaa sidoo kale la muujiyay [33], sidaas darteed bixinta sababo lagu sahamiyo ku habboonaanta natiijooyinkaan ee NRF2.
Annaga iyo kuwa kale waxaan ku aragnay necropsies ee PD iyo AD bukaannada kororka heerarka borotiinka NRF2 iyo qaar ka mid ah bartilmaameedyada, sida heme oxygenase 1 (HMOX1), NADPH quinone oxidase 1 (NQO1), p62, iwm, labadaba immunoblot iyo by immunohistochemistry [34], [35], [36], [37], [38], [39]. Kor-u-qaadista NRF2 ee cudurradan waxaa loo tarjumay isku day aan lagu guuleysan oo maskaxda buka ah si ay u soo kabsato qiyamka homeostatic. Si kastaba ha ahaatee, daraasad kale ayaa muujisay in NRF2 ay inta badan ku sugan tahay cytoplasm ee AD hippocampal neurons, oo soo jeedinaysa hoos u dhigista NRF2 dhaqdhaqaaqa maskaxda ee maskaxda [40]. Waxaa la qiyaasi karaa in kala duwanaanshaha indha-indhayntani ay la xiriirto isbeddelada ku yimaada arrimaha xakameynaya NRF2 ee marxaladaha horumarka ee neurodegeneration.
Saddex nidaam oo waaweyn ayaa gacan ka geysta borotiinka, kuwaas oo ah jawaabta borotiinka ee aan la daboolin (UPR), nidaamka borotiinka ee ubiquitin (UPS) iyo autophagy. Marka xigta, waxaanu soo bandhigaynaa caddayn si loo qiyaaso NRF2 inay tahay xarun isku xirta calaamadaha xaaladaha degdegga ah ee ay dhaqaajiyaan isku-darka borotiinka iyo mishiinka soo saarista borotiinka.
NRF2 waxay ka qaybqaadataa jawaabta borotiinka ee aan la furin (UPR)
Dhaqdhaqaaqa NRF2 ee ka jawaabaya UPR
Laalaabida borotiinka Oxidative ee ER-da waxaa dhaqaajiya dhowr waddo oo kala duwan, kuwa ugu badan ee la ilaaliyo oo ay ku jiraan borotiinka disulfide-isomerase (PDI) iyo sulfhydryl oxidase endoplasmic oxidoreductin 1 (ERO1? iyo ERO1? ee naasleyda) sida deeq bixiye disulfide. Si kooban, PDI waxay kicisaa samaynta iyo jebinta xidhmooyinka disulfide ee u dhexeeya hadhaaga cysteine ee borotiinnada, markay isku laabmaan, iyadoo ay ugu wacan tahay hoos u dhaca iyo oksaydhka ee amino acids cysteine gaar ah. PDI waxaa dib loo warshadeeyay ficilka ERO1 ee ilaalinta guriga, taas oo dib u soo celisa curaarta disulfide gudaha PDI [41]. Ogsajiinta molecular waa aqbalaha elektaroonigga ah ee ERO1, kaas oo soo saara qaddarka stoichiometric ee hydrogen peroxide ee curaarta disulfide kasta oo la soo saaro [42]. Peroxidases (PRX4) iyo glutathione peroxidases (GPX7 iyo GPX8) waa enzymes muhiim ah si loo yareeyo hydrogen peroxide gudaha ER. Marka nidaamkan oksida-yar-yar uusan si sax ah u shaqeynin, ururinta aan caadiga ahayn ee borotiinnada khaldan waxay ku dhacdaa ER iyo calaamado calaamado ah oo lagu magacaabo jawaabta borotiinka ee aan la daboolin (UPR) ayaa loo gudbiyaa cytoplasm iyo nucleus si dib loogu soo celiyo ER homeostasis [43]. Saddex borotiino oo xuub-xiran ayaa loo aqoonsaday in lagu dareemo walaaca ER ee eukaryotes: firfircoonida qoraalka qoraalka 6 (ATF6), ER eIF2? kinase (PERK, sidoo kale labajibbaaran RNA-firfircoonida borotiinka kinase-like ER kinase), iyo inositol-u baahan kinase1 (IRE1). Qaybta nalka ee dareeme kasta waxa uu ku xidhan yahay 78 kDa chaperone oo lagu magacaabo borotiinka habaysan gulukoos (GRP78/BIP). BIP waxay kala qaybsantaa cadaadiska ER si ay u xidho borotiinnada furfuran, taasoo horseedaysa hawlgelinta saddexda dareemayaal [44].
NRF2 iyo homologue NRF1, oo sidoo kale la xidhiidha jawaab-celinta antioxidant, waxay ka qaybqaataan gudbinta UPR ee nukleus. Xaaladda NRF1, borotiinkani wuxuu ku yaalaa xuubka ER wuxuuna maraa beddelka nukliyeerka marka uu deglycosylation ama dillaaco. Kadibna, firfircoonida UPR waxay keenaysaa farsamaynta NRF1 iyo ururinta nukliyeerka ee qaybta ka soo baxday qaybta nukliyeerka. Si kastaba ha noqotee, awoodda lagu dhaqaajiyo hiddo-wadaha ARE-ka kooban ee jajabkan NRF1 ayaa wali ku jira dood [45].
Glover-Cutter iyo la-shaqeeyayaashu waxay muujiyeen firfircoonida NRF2 orthologue ee C. elegans, SKN-1, oo leh cadaadisyo ER oo kala duwan. Kordhinta muujinta SKN-1 waxay ku tiirsan tahay dhexdhexaadiyeyaasha UPR ee kala duwan, oo ay ku jiraan IRE1 ama PERK worm orthologues [46]. Unugyada PERK-yar, isku-darka borotiinka daciifka ah wuxuu keenaa ururinta peroxides endogenous iyo apoptosis xiga [47]. Saamaynta ay isticmaasho PERK si ay uga ilaaliso ER-ka peroxides waxay noqon kartaa NRF2, maadaama la soo sheegay in PERK fosforylates NRF2 at Ser40, sidaas darteed ka hortagga hoos u dhaca KEAP1 [31]. Soo saarista ASK1 waxay sidoo kale u badan tahay inay door ku yeelato jidkan iyada oo loo marayo ficilka kinase dhexdhexaadinta ee TRAF2 ee IRE1 [48]. Inkasta oo doorka MAPKs ee xeerka NRF2 uu weli muran ka taagan yahay, waxaa dhawaan la soo jeediyay in dariiqa IRE1-TRAF2-ASK1-JNK laga yaabo inuu dhaqaajiyo NRF2 [49] (Jaantus 1). Waxa xiiso leh, gudaha C. elegans iyo unugyada bini'aadamka, caddaynta cusub waxay soo jeedinaysaa in cysteine sulfonylation of IRE1 kinase at loop activation ay joojiso IRE1-dhexdhexaadinta UPR waxayna bilaabeysaa jawaabta p38 antioxidant ee ay wado NRF2. Xogtu waxay soo jeedinaysaa in IRE1 ay leedahay shaqo qadiimi ah sida sentinel cytoplasmic ah oo dhaqaajiya p38 iyo NRF2 [50].
Jaantuska 1 Xeerka NRF2 ee UPR. Isku soo wada duuboo borotiinada aan lalaabin ama la qalday ee gudaha xuubka endoplasmic reticulum waxay bilaabi kartaa jawaab celinta borotiinka (UPR). Marka hore, chaperone BIP waxaa laga sii daayaa qaybta intraluminal ee dareemayaasha ER IRE1 iyo PERK si loogu xidho borotiinnada la furay/lalaawday. Tani waxay awood u siinaysaa kala-soocida iyo ka-soo-saarka-auto-phosphorylation ee xayndaabkooda cytosolic. Natiijooyinka firfircoonida PERK ee NRF2 fosfooraska tooska ah ee Ser40, taasoo keentay NRF2 u wareejinta xudunta iyo firfircoonida hiddo-wadaha bartilmaameedka ah. Firfircoonida IRE1 waxay kicisaa qorista TRAF2 oo ay ku xigto ASK1 iyo fosforyaalka JNK iyo hawlgelinta. Sida JNK loogu sheegay fosfooraska oo uu dhaqaajiyo NRF2, waa macquul in loo maleynayo in firfircoonida IRE1 ay horseedi doonto kordhinta dhaqdhaqaaqa NRF2.
Daraasado badan oo ku saabsan kicinta UPR ayaa lagu sameeyay xannibaadaha glycosylation tunicamycin. NRF2 waxay u muuqataa inay lagama maarmaan u tahay ka-hortagga dhimashada unugyada apoptotic ee tunicamycin-ku-dhacday [31] iyo hawlgelinteeda xaaladahan waxaa keena hoos u dhaca autophagic ee KEAP1 [51]. Sidaas awgeed, aamusnaanta shRNA-dhexdhexaadinta ee muujinta NRF2 ee unugyada TC-6, murine insulinoma Dhanka kale, NRF10 firfircoonida 2-dithiole-1,2-thione (D3T) waxay hoos u dhigtay cytotoxicity tunicamycin waxayna hoos u dhigtay muujinta CHOP3 iyo PERK [10]. Waxa xiisaha lihi leh, neerfayaasha olfaca ee loo gudbiyay codsiga nidaamka ee tunicamycin ayaa kordhay NRF52 iyada oo la mid ah xubnaha kale ee UPR sida CHOP, BIP, XBP2 [1]. Natiijooyinkan ayaa lagu kordhiyey daraasadaha vivo, sida faleebo faleebo ah oo tunicamycin ah oo jiirka ku jira muujinta PERK iyo NRF53 ee hippocampus oo ay weheliso yaraanta garashada ee muhiimka ah, kororka fosforyaalka TAU iyo kaydka A?2 [42].
NRF2 waxay hagaajisaa Hidde-yaasha Muhiimka ah ee Dayactirka Jidhka ER
Lumen-ka ER wuxuu u baahan yahay sahay fara badan oo GSH ah cytosol si loo ilaaliyo kimistariga disulfide. NRF2 waxay beddeshaa enzymes muhiimka ah ee dheef-shiid kiimikaad ee maskaxda, sida gaadiidka cystine / glutamate, ?-glutamate cysteine synthetase (?-GS), glutamate-cysteine ligase catalytic iyo modulator subunits (GCLC iyo GCLM), glutathione reductase (GR) iyo glutathione peroxidase (GPX) ( dib loo eegay [55]). Ku habboonaanta NRF2 ee dayactirka GSH ee ER waxaa lagu taageeray helitaanka in dhaq-dhaqaaqa dawooyinka ama hidda-socodka ee NRF2 ay kordhiso isku-darka GSH iyada oo loo marayo GCLC / GCLM, iyada oo la xakameynayo muujinta enzymes-ka ee NRF2-garaaca ayaa sababay ururinta waxyeellada. borotiinada ku jira ER-da taasoo horseedda firfircoonida UPR [56].
Gudaha C. elegans dhowr qaybood oo ka mid ah hiddo-wadaha bartilmaameedka UPR ee ay maamusho SKN-1, oo ay ku jiraan Ire1, Xbp1 iyo Atf6. Inkasta oo NRF2 ay kor u qaaddo muujinta dhowr peroxidase (PRX) iyo glutathione peroxidase (GPX) ee naasleyda (dib u eegis lagu sameeyay [57]), kaliya GPX8 waa enzyme ku habboon ER-maxalli ah, oo ilaalinaya calaamadda dib u soo celinta KDEL [58]. Luminta GPX8 waxay sababtaa firfircoonida UPR, daadinta ERO1?-ka-soo-baxa hydrogen peroxide ee cytosol iyo dhimashada unugga. Hydrogen peroxide ma laga soo qaatay ERO1? Dhaqdhaqaaqa kama faafi karo ER ilaa cytosol sababtoo ah ficilka wadajirka ah ee GPX8 iyo PRX4 [59]. Marka la eego, falanqaynta habka difaaca antioxidant-ka-soo-jeedinta hidda-wadaha iyadoo la adeegsanayo RNA laga bilaabo nooca duurjoogta ah iyo NRF2-null null unug, ayaa shaaca ka qaaday in muujinta GPX8 ay hoos u dhacday maqnaanshaha NRF2 [60]. Iyadoo la raacayo tan, falanqaynta transcriptome ee shaybaarrada bukaanka ee la ildaran neoplasms myeloproliferative, polycythemia ama myelofibrosis, cudurrada ayaa sidoo kale la xidhiidha cadaadiska oksaydhka iyo caabuqa joogtada ah ee hooseeya, waxay muujinayaan heerarka hoose ee muujinta NRF2 iyo GPX8 marka la barbardhigo maadooyinka xakamaynta [61]. Weli ma jiraan daraasado si gaar ah ugu lug leh GPX8 ilaalinta maskaxda bini'aadamka laakiin falanqaynta qoraalka ee jiirarka waxay muujinaysaa korodhka magdhowga GPX8 ee jawaabta sunta Parkinsonian MPTP [62].
Saamaynta NRF2 ee Nidaamka Habboon ee UPR ee Cudurrada Neurodegenerative
Waxqabad la'aanta enzymes PDI iyo firfircoonida joogtada ah ee UPR ayaa laga yaabaa inay markaa ka dib bilaabaan ama dardargeliyaan neurodegeneration. Neurons-cudurrada ay saameeyeen, moodooyinka xayawaanka ee cudurka neurodegenerative iyo sidoo kale unugyada bini'aadamka ee dhimashada ka dib ayaa caddaynaya kor u qaadida dhowr calaamado UPR ee inta badan cilladahan. Beddelka dariiqa PDI / UPR ee cudurada neerfayaasha ayaa si wanaagsan dib loogu eegay [63] laakiin waxyaabaha soo socda ee muunadaha maskaxda ee dhimashada ka dib waa in la tixgeliyaa. Heerarka PDI ayaa lagu kordhiyey neerfayaasha isku-dhafan iyo kuwa Lewy Bodies ee AD iyo bukaannada PD, siday u kala horreeyaan [64], [65]. PDI iyo ERP57 ayaa lagu hagaajiyay CSF ee bukaanka ALS iyo maskaxda maadooyinka CJD [66], [67], [68]. BIP, PERK, IRE1 iyo ATF6 ayaa sare loogu qaaday shaybaarada bukaanada qaba AD, PD ama ALS [69], [70], [71], [67]. BIP, CHOP iyo XBP1 ayaa sare loogu qaaday shaybaarada maskaxda ee dhimashada ka dib HD [72], [73]. Waxaa intaa dheer, kor-u-qaadista ERP57, GRP94 iyo BIP ayaa laga helay unugyada kortex ee bukaannada CJD [74]. Isku soo wada duuboo, caddayntani waxay daaha ka qaadaysaa in ururinta borotiinnada khaldan ee maskaxda ee parenchyma ay keento firfircooni joogto ah oo UPR ah. Waxa xiiso leh, waxaa jirta daraasad dhowaan la sameeyay oo isku xidhaysa firfircoonida NRF2 ee PERK horraantii AD. Daraasaddan, qorayaashu waxay falanqeeyeen in cadaadiska oksaydhisku uu dhexdhexaadiyay isbeddelada NRF2 iyo UPR laga yaabo inay ka dhigaan dhacdooyin hore ee pathogenesis AD iyadoo la adeegsanayo unugyada dhiigga ee bini'aadamka iyo qaabka jiirka AD transgenic ee heerar cudur oo kala duwan. Kordhinta cadaadiska oksaydhka iyo korodhka pSer40-NRF2 ayaa lagu arkay unugyada unugyada mononuclear-ka ee bini'aadamka ee ka go'ay shakhsiyaadka leh cillad garaadka fudud. Waxaa intaa dheer, waxay soo sheegeen ER kalsiyum homeostasis daciif ah iyo calamadaha ER-stress oo la hagaajiyay ee unugyadan oo ka yimid shakhsiyaadka qaba cillad garaadka fudud iyo AD [75].
Xeerarka wadaagga ah ee NRF2 iyo nidaamka Ubiquitin Proteasome�System (UPS)
UPS waxay beddeshaa Heerarka Protein NRF2
UPS waxay ka qaybqaadataa hoos u dhaca borotiinnada dhaawacan ama la qalday waxayna maamulaan heerarka molecule sharciyeedka muhiimka ah ee cytosol iyo nukleus. Xudunta dhexe ee nidaamkani waa ensaymes badan oo subunit ah kaas oo ka kooban iskudhaf firfircoon oo proteolytic ah oo lagu magacaabo 20S. Proteasome-ka xudunta u ah 20S waxa uu hoos u dhigaa borotiinada furfuran, laakiin ku xidhidhaynta dhismeyaasha borotiinka ee nidaamsan ee kala duwan waxa ay beddeshaa gaar ahaan substrate-keeda iyo hawlaheeda. Tusaale ahaan, ku darida hal ama laba qaybood oo hoos yimaada 19S ee xudunta 20S waxay ka dhigan tahay 26S proteasome waxayna beddeshaa gaar ahaaneed ee borotiinnada laalaaban [76], [77]. Nabaad-guurka Proteasomal wuxuu u baahan yahay xidhid wada jir ah oo ah ubiquitin. Isku xirka ubiquitin wuxuu ku soo baxaa qaab saddex-tallaabo ah oo cascade ah. Marka hore, ubiquitin-ka-dhaqdhaqaaqa enzyme E1 wuxuu ka shaqeeyaa ubiquitin ee falcelinta u baahan ATP. Kadibna, hal E2 enzyme (protein-carrier protein ama ubiquitin-conjugating enzyme) waxay u wareejisaa ubiquitin-ka firfircoon ee E1 ilaa substrate kaas oo si gaar ah ugu xiran xubin ka tirsan qoyska ligase-protein- ubiquitin, oo loo yaqaan E3. Inkasta oo qaddarka saxda ah ee borotiinka-biquitinated-protein uu ku xirnaan doono dabeecadda silsiladda ubiquitin, habkani guud ahaan wuxuu keenaa hoos u dhaca 26S proteasome [78].
E3-ligase KEAP1 waa ka hortagga ugu caansan ee NRF2. Habka nidaamka KEAP1 wuxuu si xarrago leh u sharxayaa sida heerarka NRF2 ay ula qabsadaan isbeddellada oksaydhka. Marka la eego xaaladaha aasaasiga ah, NRF2 cusub oo la soo saaray waxaa qabtay homodimer KEAP1, kaas oo ku xiraya hal NRF2 molecule oo ah laba qaybood oo amino acid ah oo hooseeya (aspartate, leucine, glycine; DLG) iyo sare (glutamate, threonine, glycine, glutamate; ETGE). Is dhexgalka KEAP1 wuxuu caawiyaa inuu u soo bandhigo NRF2 dhismaha borotiinka CULLIN3/RBX1, taasoo keentay meel-ka-baxnimadiisa iyo hoos u dhaca boroteasomal-ka. Si kastaba ha ahaatee, wax ka beddelka KEAP1 ayaa caqabad ku ah soo bandhigida NRF2 ee UPS ee uu matalo CULLIN3/RBX1. Natiijo ahaan, NRF2 cusub oo la isku daray ayaa ka baxsanaysa hoos u dhaca ku tiirsanaanta KEAP1, waxay ku ururtaa xudunta waxayna kicisaa hiddo-wadaha ARE-ka kooban [79], [80], [81], [82].
Adabtarka E3-ligase ?-TrCP sidoo kale waa homodimer ka qaybqaata dhacdooyinka calaamadaynta ee la xidhiidha fosforyaalka NRF2 ee GSK-3?. Fosforyaalka kinase-kan ayaa hadhaaga serine ee gaarka ah ee NRF2 (aspartate, serine, glycine, serine isoleucine; DSGIS) si loo abuuro domain hoos u dhac kaas oo markaa loo aqoonsaday ?-TrCP oo loogu calaamadeeyay nabaad-guurka borotiinka ee isku dhafan CULLIN1/RBX1. Aqoonsiga asiidhyada amino-yada gaarka ah ee ay fosforyaalku ku jirto GSK-3? Degron-kan waxaa lagu sameeyay isku-dar ah mutagenesis-ku hagaya goobta Neh6, 2D-gel electrophoresis [15], [26] iyo mass spectroscopy [83]. Sidaa darteed, joojinta GSK-3? Daawooyinka aadka loo xushay ama siRNAs ee ka soo horjeeda GSK-3 isoforms waxay keentay korodhka heerarka borotiinka NRF2. Natiijooyin la mid ah ayaa laga helay siRNA-yada lidka ku ah?-TrCP isoforms 1 iyo 2. Dejinta NRF2 ee raacaya GSK-3? Xannibaadda ayaa ka dhacday KEAP1-jiir-yaraanta embriyaha fibroblasts iyo ectopically lagu muujiyay NRF2 mutant tirtiridda ka maqan ETGE muhiimka ah ee hadhaaga xiriirka sare ee KEAP1, taas oo sii muujinaysa qaanuun madax-bannaan KEAP1.
Marka la eego cudurrada neurodegenerative, waxaan ku qiyaasi karnaa isbeddelka NRF2 ee UPS laba siyaabood oo kala duwan. Dhinaca kale, nidaamka KEAP1 waxa uu dareemi doonaa dheellitir la'aanta dib-u-dhiska ee ka soo jeeda ururinta borotiinka ee khaldan, halka GSK-3/?-TrCP dhidibka uu u dhaqmi doono sidii ka qaybqaataha firfircoon ee gudbinta calaamadaynta beddelka luminta borotiinka (Jaantus. 2).
Jaantuska 2 UPS waxay si adag u maamusho heerarka NRF2. Xaaladaha homeostatic, heerarka hoose ee NRF2 waxaa lagu ilaaliyaa ficilka E3 ligases adapters KEAP1 iyo ?-TrCP. Bidix, NRF2 waxay ku xidhan tahay xayndaabyada Kelch ee KEAP1 homodimer iyada oo loo marayo qaab hooseeya (DLG) iyo mid sare (ETGE) affinity. Iyada oo loo marayo xayndaabkeeda BTB, KEAP1 waxay isku mar ku xidhan tahay isku-dhafka CULLIN3/RBX1, taasoo awood u siinaysa NRF2 meelaynta iyo hoos u dhigista 26 S proteasome. Intaa waxaa dheer, GSK-3? fosforylates Ser335 iyo Ser338 hadhaaga NRF2 si loo abuuro domain deradation (DpSGIpSL) ka dibna lagu aqoonsaday adabtarada ubiquitin ligase ?-TrCP oo lagu calaamadeeyay nabaad-guurka proteasome ee dhismaha CULLIN3/RBX1. Sax, Marka la soo bandhigo noocyada ogsijiinta falcelinta ama electrophiles-ka muhiimka ah ee hadhaaga Cys ee KEAP1 waa la bedelay, taasoo ka dhigaysa KEAP1 inay awoodi wayday inay si hufan ula falgasho NRF2 ama CULLIN3/RBX1 ka dibna qodobkan qoraalku wuxuu kordhiyaa nolosheeda nuska ah iyo dhaqdhaqaaqa qoraalka ee ARE-genes. Dariiqyada calaamadaynta ee keena xannibaadda GSK-3?, Sida AKT fosforyaalka ee Ser9, waxay keenaysaa NRF2 hoos u dhac ku yimaada proteasome, ururinta iyo soo-saarka hiddo-wadaha bartilmaameedka ah.
NRF2 waxay kordhisaa Hawsha UPS iyada oo loo marayo Xakamaynta Qoraal ee Qaybaha Proteasome
NRF2 waxay kor u qaadeysaa muujinta dhowr qaybood oo proteasome ah, sidaas darteed waxay ka ilaalinaysaa unugga uruurinta borotiinnada sunta ah. Labaatan proteasome-iyo hiddo-wadaha la xidhiidha meelaynta ayaa u muuqda in lagu xakameynayo NRF2, marka loo eego falanqaynta microarray ballaaran ee beerka RNA oo lagu dejiyay NRF2 inducer D3T [84]. Daraasad dambe, isla qorayaashu waxay caddeeyeen in muujinta qaybaha ugu badan ee 26S proteasome ay kor u qaadeen ilaa saddex laab oo beerka ah oo ka yimid jiirarka lagu daaweeyay D3T. Heerarka borotiinka subunit iyo dhaqdhaqaaqa borotiinka ayaa si wadajir ah loo kordhiyay. Si kastaba ha ahaatee, wax soo saar laguma arag jiirarka halkaas oo qodobka qoraalka NRF2 la carqaladeeyey. Dhaqdhaqaaqa dhiirigeliyaha ee PSMB5 (20S) qaybta proteasome ayaa kordhay iyada oo la adeegsanayo NRF2 xad-dhaaf ah ama daawaynta firfircoonayaasha fibroblasts embriyaha ee jiirka, iyo AREs ayaa lagu aqoonsaday dhiirrigeliyaha u dhow ee PSMB5 [85]. Dhaqdhaqaaqa dawooyinka ee NRF2 waxay keentay heerarka muujinta sare ee qaybaha proteasome-ka ee wakiillada (PSMA3, PSMA6, PSMB1 iyo PSMB5) kaliya ee fibroblasts-ka bini'aadamka ee aan dareenka lahayn ee ka kooban NRF2 [86]. Dhaqdhaqaaqa NRF2 inta lagu guda jiro la qabsiga cadaadiska oksaydhisku waxay keenaysaa muujinta sare ee PSMB1 (20S) iyo PA28? subunits (ama S11, proteasome regulator) [87]. Waxaa intaa dheer, natiijooyinka ka soo baxa unugyada tarma ee embriyaha bini'aadamka ayaa shaaca ka qaaday in NRF2 ay xakameyso muujinta borotiinka korriinka borotiinka (POMP), oo ah proteasome chaperone, taas oo bedeleysa kororka unugyada tarma ee embriyaha ee bini'aadamka, saddex lakab oo jeermis ah iyo dib-u-habeyn unug. 88]. Isku soo wada duuboo, daraasadahani waxay muujinayaan in NRF2 ay kor u qaadayso muujinta qaybaha muhiimka ah ee UPS oo sidaas darteed si firfircoon uga qaybqaata nadiifinta borotiinnada haddii kale noqon lahaa sun.
NRF2-UPS Axis ee Cudurrada Neurodegenerative
Doorka UPS ee cudurada neurodegenerative waa goob dood degdeg ah. Daraasadihii ugu horreeyay ayaa sheegay in hoos u dhac ku yimid dhaqdhaqaaqa borotiinka ee necropsies aadanaha ee bukaannada ay saameeyeen dhowr cudur oo neerfaha. Si kastaba ha ahaatee, daraasado kale oo ka shaqeynaya in vitro iyo in vivo hababka ayaa lagu ogaaday in aan isbeddelin ama xitaa kor u kaca dhaqdhaqaaqa borotiinka (dib u eegis [89]). Mid ka mid ah sharraxaadda suurtagalka ah ee farqigan ayaa ah in heerarka qaybaha UPS ay isbeddeli karaan inta lagu jiro horumarka cudurka iyo gobollada maskaxda ee kala duwan sida loo soo jeediyay NRF2-bartilmaameedyada.
Iyadoo uu jiro murankan, waa in la ogaadaa in kor-u-qaadista ARE-ka kooban hiddo-wadaha borotiinka ay xoojin doonto UPS iyadoo kordhinaysa nadiifinta borotiinnada sunta ah ee maskaxda. Runtii, baabi'inta NRF1, oo sidoo kale ah modulator-ka jawaabta antioxidant-ka, ee unugyada neerfaha waxay keenaysaa firfircoonida borotiinka iyo neurodegeneration. Tijaabooyin difaac difaac oo Chromatin ah iyo falanqayn qoraal ah ayaa muujiyay in PSMB6 ay maamusho NRF1. Intaa waxaa dheer, muujinta hidda-wadaha waxay keentay aqoonsiga NRF1 oo ah xakameynta qoraalka muhiimka ah ee hiddo-wadaha proteasome ee neerfayaasha, taas oo soo jeedinaysa in dhibaatooyinka NRF1 ay gacan ka geysan karaan pathogenesis ee cudurrada neurodegenerative [90]. Waxa xiisaha lihi leh, NRF1 iyo isoformkeeda dheer ee loo yaqaan TCF11 ayaa lagu muujiyey inay hagaajiyaan ARE-ka kooban hiddo-wadaha borotiinka ee xannibaadda borotiinka ee wareegga jawaab-celinta si loo magdhabo waxqabadka borotiinka ee la dhimay [91], [92].
Marka la eego NRF2, waxaa jira xiriir ka dhexeeya dhimista NRF2, RPT6 (19 S) iyo PSMB5 (20 S) heerarka maskaxda dhexe ee jiirarka DJ-1-daaweeyay ee paraquat neurotoxin [93]. Intaa waxaa dheer, sulforaphane-ka si dabiici ah u dhaca (SFN) wuxuu siinayaa sawir aad u adag oo NRF2 ah oo ah modulator muhiim u ah UPS. Tijaabooyinka vitro ee murine neuroblastoma Unugyada Neuro2A waxay caddeeyeen muujinta la xoojiyey ee qayb-hoosaadka proteasome, iyo sidoo kale hawlaheeda peptidase ee jawaabta SFN. Daawadani waxay unugyada ka ilaalisay hydrogen peroxide-dhexdhexaadinta cytotoxicity iyo oksaydhka borotiinka si ay ugu xidhan tahay shaqada borotiinka [94]. Intaa waxaa dheer, Liu iyo la-shaqeeyayaashu waxay shaqaaleeyeen jiirka wariye si ay ula socdaan dhaqdhaqaaqa UPS iyaga oo ka jawaabaya SFN ee maskaxda. Jiirarkani waxay si cad u muujinayaan borotiinka fluorescence-ga cagaaran (GFP) oo ku milmay calaamad hoos u dhigaysa taas oo kor u qaadaysa xaalufintiisa degdega ah ee UPS (GFPu). Kortex maskaxeed, SFN waxay hoos u dhigtay heerka GFPu iyada oo korodhka barbar socda ee chymotrypsin-like (PSMB5), caspase-like (PSMB2), iyo trypsin-like (PSMB1) ee hawlaha 20 S proteasome. Intaa waxaa dheer, daaweynta unugyada Huntington-derived with SFN ayaa shaaca ka qaaday in firfircoonida NRF2 ay kor u qaadday hoos u dhaca mHtt iyo hoos u dhigista mHtt cytotoxicity [95]. Habka ugu weyn ee ficilka SFN waa iyada oo la adeegsanayo NRF2 [96]. Wax ku biirinta gaarka ah ee NRF2 waa in wax laga qabtaa iyadoo la adeegsanaayo nidaamyada NRF2-null ee daraasado dheeraad ah.
Xidhiidhka shaqaynaya ee u dhexeeya NRF2 iyo Macroautophagy
Heerarka borotiinka NRF2 waxaa habeeyay Adapter Protein P62
Autophagy waxaa loola jeedaa hoos u dhaca qaybaha cytosolic ee gudaha lysosomes. Nidaamkan waxaa loo isticmaalaa nadiifinta borotiinnada muddada dheer jira iyo kuwa qalloocan iyo sidoo kale xubnaha dhaawacmay. Xiriir toos ah oo u dhexeeya NRF2 iyo autophagy ayaa markii ugu horreysay lagu arkay iyada oo la xiriirta borotiinka adabtarada p62, oo sidoo kale loo yaqaan SQSTM1 [97], [98], [99], [100], [101]. Borootiinkani waxa uu u xidhaa borotiinada meel walba laga saaray ee mishiinada wax u dhimaya boroteasomal iyo lysosomal iyo sequesters waxa ay waxyeelo gaadhsiiyeen borotiinada isku darka ka hor burburkooda. P62 waxay soo bandhigaysaa domain la xidhiidha (UBA), si loogu xidho borotiinnada la wada baabbi'iyey, iyo LC3-isdhexgalka gobolka (LIR) si loogu daro xuubka autophagosomal iyada oo loo marayo autophagy reseptor LC3.
Inkasta oo dhexdhexaadinta p62-dhexdhexaadinta ee NRF2 iyo hiddo-wadeyaasha bartilmaameedka ah ayaa markii ugu horreysay lagu soo warramey 2007 [102], habka molecular si buuxda looma fahmin ilaa laga helo isdhexgalka KEAP1 [103], [98], [99], [100] ], [101]. Komatsu iyo shaqaaluhu waxay aqoonsadeen gobolka KEAP1 ee isdhexgalka (KIR) ee p62 kaas oo ku xidhay KEAP1 isla jeebka dusha sare ee NRF2 iyo xiriir la leh ETGE motif ee NRF2, oo soo jeedinaya tartanka u dhexeeya p62 iyo NRF2. Fosforyaalka Ser351 ee ku jira motif KIR ee p62 (349-DPSTGE-354) ayaa lagu muujiyay in ay kordhiso xidhiidhka KEAP1, iyada oo la tartamaysa NRF2 xidhitaankeeda oo u oggolaanaysa ururinteeda iyo dhaqdhaqaaqa qoraalka ee hiddo-wadaha bartilmaameedka ah [98], [99]. Dhab ahaantii, p62 xad-dhaaf ah ayaa keentay hoos u dhigista NRF2 iyo xasilinta natiijada iyo sidoo kale soo-gelinta hiddo-wadaha bartilmaameedka ah [104]. Kinasesyada qaarkood ayaa la soo jeediyay inay ka qayb qaataan fosforyaalka p62. Bartilmaameedka naasleyda ee rapamycin complex 1 (mTORC1) ayaa laga yaabaa in lagu lug yeesho, sida daawaynta mTOR inhibitor rapamycin ay xakamaysay fosforyaalka p62 iyo hoos u dhigista KEAP1 ee daaweynta arsenite. Dhawaan, waxaa la muujiyay in TGF-?-activated kinase 1 (TAK1) ay sidoo kale karto fosfooraska p62, kor u qaadida hoos u dhaca KEAP1 iyo NRF2-up-regulation. Qorayaasha daraasaddan waxay soo jeedinayaan in tani ay tahay hab lagu xakameeyo redoxtasis-ka gacanta ee xaaladaha deg-degga ah, sida TAK1-yarida-u-xakameyso ROS maqnaanshaha wax oksidant ah oo ka baxsan unugyada kala duwan ee mouse-ka oo barbar socda hoos u dhaca heerarka borotiinka NRF2 [105]. ].
Dhismaha p62 ee ka maqan domainka UBA ayaa wali awood u leh inuu xidho KEAP1, taas oo muujinaysa in isdhexgalka uusan ku xirnayn KEAP1 [101]. Si kastaba ha ahaatee, p62 homologue ee Drosophila melanogaster, oo loo yaqaan Ref(2), kuma jiraan motif KIR oo si toos ah ulama falgalo DmKEAP1, in kasta oo ay ku xidhi karto DmKEAP1 oo dhan iyada oo loo marayo domain UBA. Waxaa intaa dheer, DmKEAP1 waxay si toos ah ula falgeli kartaa Atg8 (hoomologue to mammalian LC3). Natiijooyinka yaraanta KEAP1 ee Atg8 iyo autophagy induction ku tiirsan NRF2 orthologue CncC oo madax banaan TFEB/MITF [106]. Xidhiidhka u dhexeeya NRF2 iyo autophagy wuxuu u muuqdaa mid la dhawray, inkastoo ay muujinayso ku habboonaanta shaqada.
Soo saarista NRF2 ee p62 waa natiijada labadaba tartanka lagu xirayo KEAP1 iyo hoos u dhigista KEAP1 ee lysosome. Aamusnaanta p62 ee siRNA waxay labanlaabtay KEAP1 nolosha nuska ah iyada oo la barbar dhigo hoos u dhaca NRF2 iyo hiddo-wadaha bartilmaameedka ah [101]. Heshiiskii, baabi'inta muujinta p62 ayaa caddaynaysa heerarka korodhay ee KEAP1 marka la barbar dhigo jiirarka nooca duurjoogta ah. Aad u khuseysa, kororka heerarka KEAP1 ma aysan saameynin ka-hortagga proteasome-ka laakiin waxaa hoos loo dhigay gaajo-u-qaadista autophagy [107]. Dhab ahaantii, KEAP1 waxay ku jirtaa unugyada naasleyda ee ku jira xuubka autophagic ee lagu qurxiyey p62 iyo LC3 [99], [100], [103]. Dhammaan xogtani waxay soo jeedinaysaa in KEAP1 ay tahay substrate mashiinnada macroautophagy, laakiin arrintan waa in si faahfaahsan loo falanqeeyaa sababtoo ah jiritaanka natiijooyin muran leh. Heerarka borotiinka KEAP1 ayaa lagu kordhiyey jiirarka Atg7-null, oo ah saameyn muhiim ah oo ah macroautophagy [107], laakiin xakameynta dawooyinka macroautophagy ee torin1, E64 / pepstatin ama bafilomycin ayaa ku guuldareystay inay uruuriso KEAP1 [107], [100]. Guud ahaan, natiijooyinkani waxay soo jeedinayaan in kororka heerarka p62 ee isku xigxiga KEAP1 ee loo yaqaan 'autophagic vacuoles' oo laga yaabo in natiijooyinkani ay keenaan hoos u dhigista KEAP1 autophagic taasoo u oggolaanaysa firfircoonida NRF2 (Jaantus. 3). Laba daraasadood oo kala duwan ayaa sheegay in sulfinic acid reductases SESTRINS ay door muhiim ah ka ciyaaraan macnaha guud. SESTRIN 2 waxay la falgashaa p62, KEAP1 iyo RBX1 waxayna fududaysaa hoos u dhigista p62-ku-tiirsanaanta KEAP1 iyo NRF2 firfircoonida hidda-socodka [108]. Daraasad kale ayaa muujisay in SESTRIN 2 ay la falgashay ULK1 iyo p62, kor u qaadida fosforyaalka p62 ee Ser403 taas oo fududaysay hoos u dhigista borotiinka xamuulka oo ay ku jiraan KEAP1 [109].
Jaantuska 3 heerarka NRF2 waxaa nidaamiya borotiinka adabtarada p62. Fosforyaalka Ser 351 ee ku jira motif KIR ee p62 (349-DPSTGE-354) ee mTORC1, TAK1 ama kinases kale waxay keenaysaa xidhiidhka korodhka ee ku xidhidhiyaha KEAP1 sababtoo ah u ekaanshaha ETGE motif ee NRF2. Natiijo ahaan, phosphorylated p62 waxay meesha ka saartaa NRF2 waxayna xidhaa KEAP1. Ujeedada LIR ee p62 waxay awood u siinaysaa isdhexgalka LC3 ee xuubka autophagosomal, si p62-KEAP1 ka kooban yahay ugu dambeyntii hoos u dhaco lysosome. Natiijo ahaan NRF2 waxay awood u leedahay inay uruuriso, u gudubto xudunta waxayna kordhisaa qoraalka hiddo-wadaha ARE-ka kooban, oo ay ku jiraan p62. Habkan nidaamintu wuxuu bixiyaa jawaab celin NRF2 waara, maadaama KEAP1 ay tahay in dhawaan la soo saaro si loo joojiyo dhaqdhaqaaqa NRF2.
Wax-ka-beddelka Hidde-yaasha Macroautophagy ee NRF2
NRF2 waxay xakameysaa muujinta hiddo-wadaha khuseeya macroautophagy iyo sidoo kale waxay u sameyso UPR iyo UPS. Caddaynta ugu horreysa waxay ka timid daraasado muujinaya p62 muujinta in lagu soo bandhigay soo-gaadhista electrophiles, ROS iyo nitric oxide [110], [111], [112]. Habka soo saarista waxaa lagu sifeeyay dhowr sano ka dib markii la ogaaday in p62 ay ka kooban tahay ARE shaqeyneysa dhiirrigeliyeheeda hidde-wadaha [99]. Daraasad dhowaan la sameeyay, dhowr ARE-yo kale oo shaqeynaya ayaa la helay oo la ansixiyay ka dib falanqaynta bioinformatics iyo tijaabooyinka ChIP. Waxaa intaa dheer, mouse fibroblasts embriyaha iyo neerfaha kortikal ee jiirarka Nrf2-knockout waxay soo bandhigeen muujinta p62 oo hoos u dhacday, kaas oo lagu badbaadin karo NRF2-muujinta lentivirus. Sidoo kale, yaraanta NRF2 waxay hoos u dhigtay heerarka p62 ee neerfayaasha dhaawacmay ee jiirarka hippocampus [36]. Sidaa darteed, waxaa la soo jeediyay in firfircoonida NRF2 ay kordhiso heerarka p62, taasoo keentay hoos u dhaca KEAP1 iyo doorbidida xasilinta NRF2 dheeraad ah ee wareegga jawaab-celinta togan. Habkan aan caadiga ahayn ee NRF2 soo-gelinta waxay u baahan tahay isbeddel ku yimaada muujinta hidda-wadaha waxaana laga yaabaa inay noqoto jawaab-celin ku habboon cadaadiska gacanta ee dheeraadka ah.
Borotiinka aqoonsiga xamuulka ee NDP52 waxaa la tusay in si qoraal ah loo habeeyey NRF2. NDP52 waxay u shaqeysaa si la mid ah p62, iyada oo aqoonsanaysa borotiinnada meel walba la joogo iyo la falgalka LC3 iyada oo loo marayo domain LIR, si ay shixnadaha u hoos u dhacaan lysosomes. Shan ARE oo dhejis ah ayaa laga helay Ndp52 dhiirrigeliye DNA isku xigxiga. Seddex ka mid ah waxaa lagu aqoonsaday dhismayaal mutant oo kala duwan iyo qiimeynta ChIP sida lagama maarmaanka u ah NRF2-dhexdhexaadinta Ndp52 qoraal [113]. Xusuusin, Ndp52 mRNA heerarka ayaa lagu dhimay hippocampus ee jiirarka Nrf2-knockout. Mid ka mid ah taxanahan ayaa sidoo kale lagu ansixiyay daraasad madax-bannaan sida NRF2-xukuntay ARE [36].
Si kastaba ha ahaatee, doorka NRF2 ee habaynta autophagy kuma koobna soo saarista labadan borotiin ee aqoonsiga xamuulka. Si loo helo aragti qoto dheer oo ku saabsan doorka NRF2 ee isbeddelka hiddo-wadaha dheeraadka ah ee la xidhiidha autophagy, kooxdeenu waxay baareen kaydka xogta difaaca jirka ee chromatin ENCODE ee laba borotiino, MAFK iyo BACH1, kuwaas oo ku xiraya NRF2-regulated AREs. Anaga oo adeegsanayna qoraal laga soo saaray is-afgaradka JASPAR waa isku xigxiga, waxaan ku aqoonsannay dhowr ARE oo jeexjeexan oo ku jira hiddo-wadeyaal badan oo autophagy. Laba iyo toban ka mid ah taxanahan ayaa la ansaxiyay sida NRF2 ay maamusho ARE ee sagaal hiddo-wadaha autophagy, kuwaas oo muujintoodu ay hoos u dhacday embriyaha fibroblasts ee jiirka Nrf2-knockout laakiin waxaa dib loo soo celin karaa NRF2-muujinta lentivirus. Daraasaddeenu waxay muujisay in NRF2 ay dhaqaajiso muujinta hiddo-wadaha qaarkood ee ku lug leh tillaabooyinka kala duwan ee habka autophagic, oo ay ku jiraan bilaabista autophagy (ULK1), aqoonsiga xamuulka (p62 iyo NDP52), sameynta autophagosome (ATG4D, ATG7 iyo GABARAPL1), dheereynta (ATG2B iyo ATG5). ), iyo nadiifinta autolysosome (ATG4D). Sidaa darteed, qulqulka autophagy ee ka jawaabaya hydrogen peroxide ayaa daciifay markii NRF2 ay maqan tahay [36].
Muhiimadda NRF2-Mediated Macroautophagy Muujinta Hidde-yaasha ee Cudurrada Neurodegenerative
Cudurka 'autophagy' ee cilladaysan ayaa lagu muujiyay inuu door muhiim ah ka ciyaaro dhowr cudur oo neurodegenerative [114] iyo baabi'inta autophagy waxay keentaa neurodegeneration ee jiirarka [115], [116]. Jiirarka Atg7-knockout ayaa shaaca ka qaaday in yaraanta autophagy ay keento ururinta p62 ee unugyada ka mid noqoshada ee togan. KEAP1 ayaa lagu soo koobay hay'adahan ka mid noqoshada, taasoo keentay NRF2 xasilinta iyo kicinta hiddo-wadaha bartilmaameedka ah [103]. Muhiimad ahaan, ururinta xad-dhaafka ah ee p62 oo ay weheliso borotiinno la wada leeyahay ayaa lagu aqoonsaday cudurrada neerfayaasha, oo ay ku jiraan AD, PD iyo ALS [117]. Dhab ahaantii, neurons-yada muujinaya heerarka sare ee APP ama TAU ee bukaannada AD ayaa sidoo kale muujiyay p62 iyo nukliyeerka NRF2, iyaga oo soo jeedinaya iskudaygooda ah inay hoos u dhigaan isku-darka intraneuronal iyada oo loo marayo autophagy [36].
La'aanta NRF2 waxay sii xumaynaysaa isku-darka borotiinka ee macnaha guud ee AD. Dhab ahaantii, heerarka korodhka fosfooraska iyo sarkosyl-la'aanta TAU ayaa laga helaa jiirarka Nrf2-knockout, inkastoo aan farqi u dhexeeya kinase ama phosphatase-ka la ogaan karin marka la barbardhigo asalka nooca duurjoogta ah [113]. Muhiimad ahaan, NDP52 ayaa la muujiyay in ay la wadaagto TAU ee neerfayaasha xuubka xuubka iyo isdhexgalka tooska ah ee u dhexeeya fosfo-TAU iyo NDP52 ayaa lagu muujiyay tijaabooyin isku-dhafan oo isku-dhafan labadaba jiirarka iyo shaybaarrada AD, iyaga oo tilmaamaya doorkeeda hoos u dhaca TAU. Waxa xiiso leh, aamusnaanta NDP52, p62 ama NRF2 ee neerfayaasha waxay keentay kororka fosfo-TAU [113], [118]. Waxaa intaa dheer, korodhka isku-darka isku-darka APP-da ee neerfaha ayaa laga helay jiirarka hippocampus ee APP/PS1?E9 marka NRF2 ay maqan tahay. Tani waxay la xiriirtaa calaamadaha is-beddelka ee is-beddelka, oo ay ku jiraan fosfo-mTOR / mTOR oo kordhay iyo phospho-p70S6k / p70S6k (tusaale ahaan xannibaadda autophagy), heerarka la kordhiyay ee pre-cathepsin D iyo tiro badan oo ah jirro isku dhafan [119]. Jiirarka wada-muujinta aadanaha APP (V717I) iyo TAU (P301L), yaraanta NRF2 waxay keentay heerarka korodhka wadarta iyo fosfo-TAU ee jajabka aan la milmi karin iyo kororka isku-darka APP-da ee intraneuronal, oo ay weheliso heerarka neerfaha ee p62, NDP52, ULK1, ATG5 iyo GABARAPL1. Isku-dubarid ka dhexeeya borotiinka adabtarada p62 iyo APP ama TAU waa la dhimay maqnaanshaha NRF2 [36]. Guud ahaan, natiijooyinkani waxay muujinayaan muhiimada NRF2 ee autophagy neuronal.
Qodobbada qoraalka kala duwan ayaa si isku-dubarid ah u dhaqma si loo beddelo Proteostasis
Marka la eego xaaladaha degenaansho, proteostasis waxaa lagu xakameynayaa isdhexgalka borotiinka iyo borotiinka iyo wax ka beddelka ka dib markii la helo jawaab degdeg ah. Si kastaba ha ahaatee, la qabsiga gacanta waxa uu u baahan yahay habaynta qoraalka ee UPR, UPS iyo hiddo-wadaha autophagy. Iyadoo la tixgelinayo in unugyada dareemayaasha si joogto ah loogu gudbiyo cayda sunta ah ee hooseeya, oo ay ku jiraan cadaadiska oksaydhka iyo borotiinka, xoojinta proteostasis ee ay keentay qaabaynta qoraalka ayaa laga yaabaa inay ka caawiso ka hortagga burburka maskaxda.
Xaaladda UPR, kicinta mid kasta oo ka mid ah saddexda gacmood ayaa ugu dambeyntii keeni doonta soo-saarka hiddo-wadaha qaarkood (oo dib loo eegay [43]). Tusaale ahaan, jajab ATF6-derived (ATF6f) wuxuu ku xidhaa walxaha jawaab-celinta ER-stress (ERSE) waxayna kicisaa muujinta hiddo-wadaha dhowr ah, oo ay ku jiraan XBPI, BIP iyo CHOP. Intaa waxaa dheer, calaamadaynta PERK waxay keenaysaa kicinta qodobka qoraalka ATF4, kaas oo xakameynaya muujinta hiddo-wadaha badan ee UPR iyo qaar kale oo ay ku jiraan NRF2 hiddo-wadaha Hmox1 iyo p62. Ugu dambeyntii, firfircoonida IRE1 waxay dhalisaa abuurista arrin qoraal ah oo firfircoon, XBP1 (XBP1s), oo la jajabiyey, taas oo maamusha qoraalka hidda-socodyada borotiinnada ku lug leh isku-laabashada borotiinka.
Dhanka kale, NRF1 ayaa lagu muujiyay inay lagama maarmaan u tahay muujinta hidda-wadaha proteasomal ee maskaxda, sida jiirarka Nrf1-knockout ayaa muujiyay hoos u dhigida muujinta hiddo-wadaha oo qeexaya qaybo kala duwan oo ah xudunta 20S, iyo sidoo kale dhismaha nidaaminta 19S oo ay weheliso shaqeynta proteasomal daciif ah [90] ]. Labada NRF1 iyo NRF2 labaduba waxay ku xiran yihiin ARE taxane ah oo ku yaala gobollada dhiirrigeliyeyaasha ee hiddo-wadaha bartilmaameedka ah, taas oo soo jeedinaysa inay leeyihiin waxqabadyo qoraal ah oo isku dhafan, inkasta oo ay ku kala duwan yihiin hababkooda sharciyeynta iyo meelaynta gacanta [120].
Qodobbada qoraalka ee sanduuqa Forkhead O (FOXO) qoyska ayaa xakameynaya muujinta hiddo-wadaha badan ee la xiriira autophagy. Si la mid ah waxa ku dhaca NRF2, waxaa jira dhowr lakab oo nidaaminaya dhaqdhaqaaqa xubnaha FOXO, kuwaas oo lagu kicin karo culeyska nafaqada ama oksaydhka [121]. Ugu dambeyntii, qodobka qoraalka ee TFEB, oo loo tixgeliyey maamulaha sare ee biogenesis-ka lysosomal, ayaa door muhiim ah ka ciyaara nidaaminta autophagy ee xaaladaha walaaca nafaqeynta. Sidaa daraadeed, xannibaadda mTORC1 waxay keenaysaa beddelka nukliyeerka ee TFEB iyo kicinta muujinta hiddo-wadaha autophagy [122].
Guud ahaan, jiritaanka nidaamiyayaal qoraaleedyo kala duwan oo mashiinadan ayaa sidoo kale soo jeedinaya isdhaafsiga iyo habab qayb ahaan aan loo baahnayn kuwaas oo xaqiijin kara borotostasis xaalado kala duwan. Sidaa awgeed, NRF2 ayaa laga yaabaa inay door ku habboon tahay unugyada taageera heerarka sare ee cadaadiska oksaydhka. Tusaale ahaan, NRF2 diiqada oksaydhative-ku waxay ku shaqayn kartaa xaaladaha nafaqo-hodanka ah si kor loogu qaado habaynta autophagy, oo la mid ah waxa laga helay TFEB ee xaaladaha gaajada. Waxaa intaa dheer, maskaxdu waxay si weyn ugu shaqeysaa xaaladaha hodanka ah ee nafaqada, iyagoo NRF2 u soo bandhigaya hab ku habboon oo lagu dhaqaajiyo autophagy ee neerfaha.
Ballanqaadka
Dhowrkii sano ee la soo dhaafay, horumar weyn ayaa laga gaaray aqoonta doorarka sharciyeynta ee UPR, UPS iyo autophagy ee waxqabadka NRF2, iyo sidoo kale qoritaanka NRF2-dhexdhexaadinta ee qaybaha saddexdan nidaam. Sidaa darteed, fursadaha daweynta cusub ayaa laga yaabaa inay soo baxaan iyadoo lagu saleynayo ka faa'iidaysiga NRF2 oo ah xakameyn muhiim ah oo nadiifinta borotiinka ee cudurrada neurodegenerative.
Si kastaba ha ahaatee, su'aasha muhiimka ah ee hadhay ayaa ah inay faa'iido u yeelan doonto ama ay wax u dhimayso kordhinta heerarka NRF2 ee maskaxda. Falanqaynta xogta cudurrada faafa ayaa laga yaabaa inay bixiso jawaab qayb ah, maadaama ay muujinayso in hidda-wadaha NFE2L2 uu yahay mid aad u sarreeya iyo qaar ka mid ah polymorphisms-ka nucleotide ee laga helay gobolkeeda sharciyeynta ayaa laga yaabaa inay bixiso kala duwanaansho nafsiyeed oo kala duwan oo muujinta hidda-wadaha heerka dadweynaha iyo qaar ka mid ah haplotypes. ayaa lala xiriiriyay khatarta hoos u dhacday iyo/ama daahitaanka AD, PD ama ALS [123]. Waxaa intaa dheer, sida ay ka wadahadleen Hayes iyo asxaabtooda [124], Saamaynta NRF2 waxay yeelan kartaa jawaab-celin U-qaabeeya, taasoo la micno ah in heerarka NRF2 aad u hooseeya ay keeni karaan lumitaanka cytoprotection iyo kordhinta u nuglaanshaha walaacyada, halka NRF2 aad u badan laga yaabo inay carqaladeyso dheelitirka homeostatic ee dhinaca xaalad dhimis ah ( stress dhimis ), kaas oo door bidi lahaa in borotiinku qaldamo iyo isu geynta. Heerarka NRF2 ee hooseeya ee maskaxdu waxay taageeraan fikradda ah in nidaam yar oo kor u kaca ah ay ku filnaan karto in lagu gaaro faa'iido marka la eego xaaladaha cudurada. Dhab ahaantii, doorka ilaalinta ee NRF2-dhexdhexaadinta firfircoonida ee nadiifinta borotiinka ayaa lagu muujiyay dhaqamada unugyada neurodegeneration ee kala duwan iyo qaababka vivo.
SFN waa firfircooni NRF2 farmashiye ah oo la muujiyay si uu u keeno muujinta hidda-wadaha proteasomal iyo autophagy [95], [36]. Waxa xiiso leh, Jo iyo asxaabtiisuba waxay muujiyeen in SFN ay hoos u dhigtay heerarka fosfooraska TAU iyo korodhka Beclin-1 iyo LC3-II, soo jeedinta NRF2 firfircoonida waxay fududeyn kartaa hoos u dhigista borotiinkan sunta ah iyada oo loo marayo autophagy [113]. Waxaa intaa dheer, hoos u dhigista mHtt waxaa lagu wanaajiyay SFN, tanna waxaa lagu soo celiyay isticmaalka MG132, taasoo muujineysa hoos u dhaca borotiinka borotiinkan sunta ah [95]. Hoosudhaca phospho-iyo-TAU-da ee aan la milmi karin ee autophagy-dhexdhexaadin ah ayaa lagu soo warramey fisetin-ka flavonoid-ka organic. Xaruntani waxa ay awooday in ay keento autophagy iyada oo isla mar ahaantaana kor u qaadaysa firfircoonida iyo wareejinta nukliyeerka ee TFEB iyo NRF2, oo ay la socdaan qaar ka mid ah hiddo-wadaha bartilmaameedka ah. Jawaabtan waxaa ka hortagay TFEB ama NRF2 aamusnaanta [125]. Bott iyo asxaabtiisuba waxay soo sheegeen saamaynta faa'iidada leh ee NRF2, NRF1 iyo HSF1 isku mar ah oo ku saabsan sunta borotiinka ee laf-dhabarka iyo atrophy muruqa, xanuunka neurodegenerative oo ay sababtay ballaarinta polyglutamine-encoding CAG oo soo noqnoqda taas oo isku-darka borotiinka ay joogaan [126]. Awoodda firfircoonida NRF2 ee daaweynta xanuunada neurodegenerative ayaa lagu muujiyay ogolaanshaha BG-12, qaabka afka ee NRF2 inducer dimethyl fumarate (DMF), loogu talagalay daaweynta sclerosis badan [127], [128]. Ku guuleysiga DMF ee cudurrada difaaca jirka oo leh qayb xooggan oo barar ah ayaa soo jeedinaysa in cudurrada neurodegenerative ay ka faa'iideysan karaan dib u dhigista daawadan. Daraasad dhowaan la sameeyay oo ku saabsan qaabka ?-synucleinopathy ee PD, DMF ayaa lagu muujiyay inay tahay neuroprotective sababtoo ah, qayb ahaan, soo-galinteeda autophagy [129]. Daraasadaha ka warbixinaya saameynta faa'iidada leh ee NRF2 ee neurodegeneration laakiin aan diiradda saarin saameynta ay ku leedahay nadiifinta borotiinka ayaa xitaa aad u badan (dib u eegis dhamaystiran, eeg [7]). Tani waa mid aad u habboon, maadaama ay iftiiminayso hababka waxyeellada badan ee isku mar lagu beegsan karo hal mar oo NRF2 ah, oo ay ku jiraan cadaadiska oksaydhka, caabuqa neuroinflammation ama cillad maskaxeed. Si kastaba ha noqotee, shaqada mustaqbalka ayaa loo baahan doonaa si hubaal ah loo go'aamiyo haddii firfircoonida dawooyinka ee NRF2 ay noqon karto istiraatiijiyad sax ah si loo fududeeyo nabaad-guurka borotiinnada sunta ah ee maskaxda.
Sidii hore loo sharaxay, GSK-3 ka sii daray? Dhaqdhaqaaqa ayaa lagu soo warramey cudurada neurodegenerative waxaana la qiyaasayey in natiijada NRF2 dhimis ay qayb ahaan mas'uul ka tahay natiijada tirtirka ah. Xaaladahan pathological, GSK-3 inhibitors waxay sidoo kale iska kaashan karaan si ay u kordhiyaan heerarka NRF2 iyo proteostasis. Saamaynta faa'iidada leh ee GSK-3 inhibitors ayaa lagu soo warramey noocyo kala duwan oo neurodegeneration ah iyo, aad u xiiso badan, GSK-3 cadaadis ayaa lagu muujiyay in la yareeyo heerarka borotiinka sunta ah [130], [131], [132], [133]. Inkasta oo aysan jirin xiriir toos ah oo ka dhexeeya GSK-3 xannibaadda iyo NRF2-qanuunka tarjumaadda ee hiddo-wadaha kor u qaadaya proteostasis ayaa weli la arkay, waa macquul in la qiyaaso in hoos-u-dhigga dhaqdhaqaaqa GSK-3 uu keeni doono heerarka NRF2 ee kordhay, taas oo ugu dambeyntii keeni doonta xoojinta. proteostasis.
Dhaqdhaqaaqa qoraalka ee NRF2 iyo sidoo kale awoodda gacanta si loo ilaaliyo proteostasis hoos u dhaca da'da, khatarta ugu weyn ee horumarinta cudurrada neurodegenerative. Waa macquul in la fekero in xoojinta NRF2 iyo, sidaas awgeed, proteostasis ay, ugu yaraan, dib u dhigi doonto ururinta isku-darka borotiinka iyo neurodegeneration. Runtii, daaweynta fibroblasts dareenka bini'aadamka ee leh 18?-glycyrrhetinic acid (18?-GA) triterpenoid waxay kor u qaadday firfircoonida NRF2, taasoo horseedaysa soo saarista borotiinka iyo kor u qaadista nolosha. Daraasadani waxay soo jeedinaysaa in firfircoonida dawooyinka ee NRF2 ay suurtagal tahay xitaa nolosha dambe [86]. Waxaa intaa dheer, daraasad dambe ayaa muujisay in xaruntani ay dhexdhexaadisay SKN-1 iyo firfircoonida proteasome ee C.elegans oo leh saameyn faa'iido leh oo ku saabsan horumarka AD ee moodooyinka nematode ee khuseeya [134].
Dhammaan waxyaalihii la tixgeliyey, NRF2-dhexdhexaadin dhexdhexaadin ah ee hiddo-wadaha la xidhiidha proteostasis waxay u muuqataa inay faa'iido u leedahay borotiinnopathies kala duwan.
Sulforaphane iyo Saameyntiisa Kansarka, Dhimashada, Gabowga, Maskaxda iyo Dhaqanka, Cudurrada Wadnaha & in ka badan
Isothiocyanates waa qaar ka mid ah xeryahooda dhirta ee ugu muhiimsan ee aad ka heli karto cuntadaada. Fiidiyowgaan waxaan u sameynayaa kiiskii ugu badnaa ee abid la sameeyo. Fiiro gaar ah oo gaaban? U gudub mawduuca aad jeceshahay adiga oo gujinaya mid ka mid ah dhibcaha wakhtiga hoose. Jadwalka wakhtiga oo buuxa hoos
Qaybaha muhiimka ah:
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00:00:34 - Horudhaca sulforaphane, diiradda weyn ee fiidiyowga.
00: 31: 21 - Daraasada jiirka iyadoo la adeegsanayo 10 nooc oo kala duwan oo niyad-jabka ah ayaa muujinaya sulforaphane si la mid ah waxtarka sida fluoxetine (prozac).
00: 32: 00 - Daraasadu waxay muujineysaa in si toos ah loo nuugo glucoraphanin ee jiirarka ay si la mid ah waxtar ugu leedahay ka hortagga niyad-jabka ee ka timaadda qaabka cadaadiska bulshada.
Marka loo eego maqaalka kore, halka calaamadaha cudurrada neurodegenerative lagu daweyn karo siyaabo kala duwan oo daaweyn ah, cilmi baaris ayaa muujisay in firfircoonida Nrf2 ay noqon karto hab daaweyn waxtar leh. Sababtoo ah Dhaqdhaqaaqayaasha Nrf2 waxay beegsadaan hababka ballaaran ee cudurka, Dhammaan cudurrada neurodegenerative waxay ka faa'iideysan karaan isticmaalka Nrf2 factor transcription. Natiijooyinka Nrf2 waxay wax ka beddeleen daaweynta cudurrada neurodegenerative. Baaxadda macluumaadkayadu waxay ku kooban tahay xanuunka loo yaqaan 'chiropractic' iyo arrimaha caafimaadka laf dhabarta. Si aad ugala hadasho mawduuca, fadlan xor u noqo inaad waydiiso Dr. Jimenez ama nagala soo xidhiidh at�915-850-0900 .
Xanuunka jilibka waa calaamad caan ah oo ku dhici karta dhaawacyo jilibka ah iyo/ama xaalado kala duwan, oo ay ku jiraandhaawacyada isboortiga. Jilibku waa mid ka mid ah kala-goysyada ugu adag ee jidhka bini'aadamka maadaama uu ka kooban yahay isgoysyada afar lafo, afar seediyo, seedooyin kala duwan, laba menisci, iyo carjawda. Sida laga soo xigtay Akademiyada Maraykanka ee Dhakhaatiirta Qoyska, sababaha ugu badan ee xanuunka jilibka waxaa ka mid ah subluxation patellar, tendinitis patellar ama jilibka jumper, iyo cudurka Osgood-Schlatter. Inkasta oo xanuunka jilibka ay u badan tahay inuu ku dhaco dadka ka weyn 60 sano, xanuunka jilibka wuxuu sidoo kale ku dhici karaa carruurta iyo dhalinyarada. Xanuunka jilibka waxaa lagu daweyn karaa guriga iyadoo la raacayo hababka RICE, si kastaba ha ahaatee, dhaawacyada daran ee jilibka ayaa laga yaabaa inay u baahdaan daryeel caafimaad oo degdeg ah, oo ay ku jiraan daryeelka xanuunka loo yaqaan 'chiropractic care'. �
Cadaadiska Oxidative waxaa lagu sifeeyaa dhaawaca unugyada ay sababaan xagjirrada xorta ah, ama molecules aan xasilloonayn, kuwaas oo ugu dambeyntii saameyn kara shaqada caafimaadka leh. Jidhka bini'aadamku wuxuu abuuraa xagjirnimo bilaash ah si uu u baabi'iyo bakteeriyada iyo fayrasyada, si kastaba ha ahaatee, arrimaha dibadda, sida oksijiinta, wasakhowga, iyo shucaaca, ayaa sidoo kale soo saari kara xagjirayaal xor ah. Cadaadiska Oxidative ayaa lala xiriiriyay arrimo caafimaad oo badan.
Cadaadiska Oxidative iyo walbahaarka kale waxay shidaan hababka ilaalinta gudaha kuwaas oo gacan ka geysan kara nidaaminta jawaabta antioxidant-ka jirka bini'aadamka. Nrf2 waa borotiin dareemo heerarka cadaadiska oksaydhiyaha oo u suurtageliya unugyada inay naftooda ka ilaaliyaan arrimaha gudaha iyo dibadda. Nrf2 ayaa sidoo kale la soo bandhigay si ay u caawiso habaynta hiddo-wadaha ku lug leh soo saarista enzymes-ka antioxidant-ka iyo hiddo-wadaha ka jawaab celinta walaaca. Ujeedada maqaalka hoose waa in la sharaxo saamaynta Nrf2 kansarka.
aan la taaban karin
Dariiqa Keap1-Nrf2 waa maamulaha ugu weyn ee jawaabaha cytoprotective ee cadaadiska oksaydhka iyo korantada. Inkasta oo dariiqyada calaamadaha unugyada ay kiciyaan qodobka qoraalka Nrf2 waxay ka hortagayaan bilawga kansarka iyo horumarka unugyada caadiga ah iyo kuwa hore, unugyada si buuxda u xun ee Nrf2 waxay bixisaa faa'iido korriin iyadoo kordhinaysa chemoresistance kansarka iyo kor u qaadida koritaanka unugyada burooyinka. Dib-u-eegis garaafkan, waxaanu ku siinaynaa dulmar guud ee dariiqa Keap1-Nrf2 iyo habacsanaanteeda unugyada kansarka. Waxaan sidoo kale si kooban u soo koobeynaa cawaaqibka firfircoonida Nrf2 ee unugyada kansarka iyo sida tan looga faa'iidaysan karo daaweynta hidda-wadaha kansarka.
Waddada Keap1-Nrf2 waa maamulaha ugu weyn ee jawaabaha cytoprotective ee cadaadiska endogenous iyo exogenous oo ay sababaan noocyada ogsijiinta falcelinta (ROS) iyo electrophiles [1]. Borotiinnada calaamadaha muhiimka ah ee ku dhex jira dariiqa ayaa ah qodobka qoraalka Nrf2 (cudurka nukliyeerka erythroid 2 ee la xidhiidha 2) kaas oo isku xira borotiinnada Maf yar yar ee qaybta jawaabta antioxidant (ARE) ee gobollada sharciyeynta ee hiddo-wadaha, iyo Keap1 (Kelch ECH) borotiinka isku xidha 1), borotiinka cadaadiska ee ku xidhan Nrf2 oo kor u qaadaya nabaad-guurka iyada oo loo marayo dariiqa proteasome ee ubiquitin (Jaantus 1). Keap1 waa borotiin hodan ku ah cysteine-ka, jiirka Keap1 oo leh wadar ahaan 25 iyo 27 hadhaaga cysteine-ka bini'aadamka ah, kuwaas oo intooda badan lagu beddeli karo vitro by oksidants iyo electrophiles kala duwan [2]. Saddex ka mid ah kuwan haraaga ah, C151, C273 iyo C288, ayaa lagu muujiyay inay ciyaaraan door wax ku ool ah iyaga oo beddelaya qaabka Keap1 ee keenaya beddelka nukliyeerka ee Nrf2 iyo soo-jeedinta hidda-wadaha bartilmaameedka [3] (Jaantus 1). Habka saxda ah ee wax ka beddelka cysteine-ka ee Keap1 ay u horseeddo firfircoonida Nrf2 lama yaqaan, laakiin labada moodal ee jira laakiin aan is-dhaafsaneyn ayaa ah (1) moodeelka suunka iyo xirmada, kaas oo Keap1 wax ka beddelka hadhaaga thiol ee deggan IVR ee Keap1 carqaladeeyaan isdhexgalka Nrf2 taasoo keenaysa isku-dheelitirnaan la'aanta hadhaaga lysine ee gudaha Nrf2 oo aan mar dambe la sii ahaan karin polyubiquitinylated iyo (2) qaabka ay wax ka beddelka thiol u keenayso kala-baxa Cul3 ee Keap1 [3]. Labada noocba, Keap2-ku-xidhaha-inducer-la beddelay iyo Nrf1-ku-xidhan Keap2 waa dabcay, sidaas awgeed, borotiinnada Nrf1 ee dhowaan la sameeyay waxay dhaafaan Keap2 waxayna u beddelaan xudunta, ku xidha ARE oo kaxeeya muujinta hiddo-wadaha bartilmaameedka Nrf1 sida NAD (P) H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX2), glutamate-cysteine ligase (GCL) iyo glutathione S transferases (GSTs) (Jaantus 1). Marka lagu daro wax ka beddelka Keap2 thiols taasoo keentay Nrf21 bartilmaameedka hiddo-wadaha, borotiinnada sida p62 iyo p2 waxay ku xidhi karaan Nrf1 ama Keap2 si ay u carqaladeeyaan isdhexgalka u dhexeeya Nrf1 iyo Keap1 [3], [3] (Jaantus XNUMX).
Jaantuska 1. Qaab dhismeedka Nrf2 iyo Keap1 iyo koodhka cysteine-ka. (A) Nrf2 wuxuu ka kooban yahay 589 amino acids wuxuuna leeyahay lix qaybood oo horumar ahaan aad loo ilaaliyo, Neh1-6. Neh1 waxa ku jira motif bZip, oo ah gobol aasaasi ah � leucine zipper (L-Zip), qaab dhismeedka, halkaas oo gobolka aasaasiga ahi uu mas'uul ka yahay aqoonsiga DNA-ga iyo L-Zip-ku dhexdhexaadiyo kala-soocida borotiinno Maf yar yar. Neh6 wuxuu u shaqeeyaa sidii deron si uu u dhexdhexaadiyo hoos u dhaca Nrf2 ee nukleus. Neh4 iyo 5 waa goobo ganacsi. Neh2 ka kooban ETGE iyo DLG motifs, kuwaas oo looga baahan yahay is dhexgalka Keap1, iyo gobolka hydrophilic ee haraaga lysine (7 K), kuwaas oo lagama maarmaan u ah Keap1-ku-tiirsanaanta polyubiquitation iyo hoos u dhigista Nrf2. (B) Keap1 waxa uu ka kooban yahay 624 amino acid hadhaa ah waxana uu leeyahay shan qaybood. Labada fikradood ee isdhexgalka borotiinka, domainka BTB iyo qaybta Kelch, waxaa kala soocay gobolka dhex galka ah (IVR). Qaybta BTB oo ay weheliso qaybta N-terminal ee IVR waxay dhexdhexaadinaysaa isku-dhafka Keap1 iyo ku xidhidhiyaha Cullin3 (Cul3). Qaybta Kelch iyo gobolka C-terminal waxay dhexdhexaadiyaan isdhexgalka Neh2. (C) Nrf2 waxay la falgashaa laba molecule ee Keap1 iyada oo loo sii marayo Neh2 ETGE iyo DLG motifs. Labaduba ETGE iyo DLG waxay ku xidhan yihiin goobo la mid ah oogada hoose ee Keap1 Kelch motif. (D) Keap1 waxay qani ku tahay hadhaaga cysteine-ka, oo leh 27 cysteines borotiinka aadanaha. Qaar ka mid ah cysteins-yadan waxay ku yaalliin meel u dhow hadhaagii aasaasiga ahaa, sidaas darteedna waa bartilmaameedyo aad u wanaagsan oo ah electrophiles iyo oxidants. Habka wax ka beddelka ee hadhaaga cysteine-ka ee elektrofileyaasha waxaa loo yaqaanaa koodhka cysteine. Mala-awaalka koodhka cysteine wuxuu soo jeedinayaa in qaabdhismeed kala duwan Nrf2 wakiilada firfircooni ay saameeyaan Keap1 cysteines kala duwan. Wax ka beddelka cysteine-ka ayaa horseedaya isbeddello is-beddel ah oo ku yimaadda Keap1 oo carqaladeeya is-dhexgalka ka dhexeeya Nrf2 DLG iyo Keap1 Kelch domains, sidaas darteed xannibaya polyubiquitation Nrf2. Muhiimadda shaqeynta ee Cys151, Cys273 iyo Cys288 ayaa la muujiyay, sida Cys273 iyo Cys288 looga baahan yahay xakamaynta Nrf2 iyo Cys151 si ay u kiciyaan Nrf2 by inducers [1], [3].
Jaantuska 2. Jidka calaamadaynta Nrf2-Keap1. (A iyo B) ee xaaladaha aasaasiga ah, laba Keap1 molecules waxay ku xidhan yihiin Nrf2 iyo Nrf2 waa polyubiquitylated by Cul3-based E3 ligase complex. polyubiquitilation-kani waxa uu keenaa hoos u dhac degdeg ah Nrf2 by proteasome. Qayb yar oo ka mid ah Nrf2 ayaa ka baxsanaysa isku-dhafka xannibaadda waxayna ku ururtaa xudunta si ay u dhexdhexaadiso muujinta hiddaha-ku-tiirsanaanta basal ARE, taas oo ilaalinaysa homeostasis-ka gacanta. (C) Marka la eego xaaladaha walaaca, soo-saarayaashu waxay wax ka beddelaan Keap1 cysteines taasoo horseedaysa xannibaadda Nrf2 meelaynta iyada oo loo marayo kala-baxa isku-dhafka xannibaadda. (D) Marka loo eego qaabka miskaha iyo daboolka, wax ka beddelka hadhaaga Keap1 cysteine ee gaarka ah waxay keenaysaa isbeddello is-waafaji ah oo ku jira Keap1 taasoo keentay ka go'itaanka Nrf2 DLG motif ee Keap1. Dib u habeynta Nrf2 waa la carqaladeeyay laakiin ku-xidhka ujeeddada ETGE ayaa weli ah. (E) Qaabka kala qaybinta Keap1-Cul3, isku-xidhka Keap1 iyo Cul3 waa la carqaladeeyey iyada oo laga jawaabayo electrophiles, taasoo horseedaysa baxsashada Nrf2 ee nidaamka qulqulka. Labada nooc ee la soo jeediyay, inducer-la beddelay iyo Nrf2-ku xidhan Keap1 waa hawl-gal, sidaa darteed, borotiinada Nrf2 ee dhowaan la sameeyay waxay dhaafaan Keap1 oo u beddelaan xudunta, ku xidh Element Response Antioxidant (ARE) oo kaxeeya muujinta bartilmaameedka Nrf2 Hidde-sideyaasha sida NQO1, HMOX1, GCL iyo GSTs [1], [3].
Jaantuska. 3. Farsamaynta ururinta nukliyeerka ee Nrf2 ee kansarka. (A) Isbeddellada Somatic ee Nrf2 ama Keap1 waxay carqaladeeyaan is-dhexgalka labadan borotiin. Nrf2, isbeddellada waxay saameeyaan ETGE iyo motifs DLG, laakiin Keap1 isku beddelka ayaa si siman loo qaybiyaa. Intaa waxaa dheer, firfircoonida oncogene, sida KrasG12D [5], ama carqaladaynta burooyinka burooyinka, sida PTEN [11] waxay u horseedi kartaa induction transcription ee Nrf2 iyo kororka nukliyeerka Nrf2. (B) Hypermethylation ee dhiirigeliyaha Keap1 ee sambabada iyo kansarka qanjirka 'prostate' waxay keenaysaa hoos u dhigista muujinta Keap1 mRNA, taas oo kordhisa ururinta nukliyeerka ee Nrf2 [6], [7]. (C) Kansarka kelyaha ee papillary ee qoyska, luminta firfircoonida fumarate hydratase enzyme waxay keentaa ururinta fumarate oo ay sii dheeraato in la suuliyo hadhaaga Keap1 cysteine (2SC). Beddelka tarjumaada kadib waxay keenaysaa carqaladaynta isdhexgalka Keap1-Nrf2 iyo ururinta nukliyeerka ee Nrf2 [8], [9]. (D) Isku-ururinta borotiinnada carqaladeeya sida p62 iyo p21 waxay carqaladayn karaan Nrf2-Keap1 xidhitaanka waxayna keentaa kororka Nrf2 nukliyeerka. p62 waxay ku xidhan tahay Keap1 oo isku dhejinaya jeebka xidhitaanka ee Nrf2 iyo p21 waxay si toos ah ula falgalaan DLG iyo ETGE motifs ee Nrf2, si ay ula tartamaan Keap1 [10].
Farsamooyinka Dhaqdhaqaaqa iyo Nidaaminta Nrf2 ee Kansarka
Inkasta oo cytoprotection ay bixiso firfircoonida Nrf2 ay muhiim u tahay chemoprevention kansarka ee unugyada caadiga ah iyo kuwa hore, unugyada si buuxda u xun Nrf2 waxqabadka ayaa bixiya faa'iido korriin iyadoo kordhinaysa chemoresistance kansarka iyo kor u qaadida koritaanka unugyada burooyinka [4]. Dhowr habab oo ay dariiqa calaamadaynta Nrf2 si toos ah uga hawl galaan kansarrada kala duwan ayaa lagu sharraxay: (1) isbeddellada somatic ee Keap1 ama Keap1 xidhitaanka domain ee Nrf2 oo carqaladeeya is-dhexgalka; (2) aamusnaanta epigenetic ee muujinta Keap1 taasoo horseedaysa cadaadiska cilladaysan ee Nrf2; (3) ururinta borotiinnada carqaladeeya sida p62 taasoo horseedaysa kala-baxa isku-dhafka Keap1-Nrf2; (4) soo-gelinta qoraalka Nrf2 ee K-Ras oncogenic, B-Raf iyo c-Myc; iyo (5) beddelka ka dib tarjumaada Keap1 cysteines by succinylation kaas oo ku dhaca kansarka kelyaha papillary qoyska sababtoo ah luminta fumarate hydratase enzyme function [3], [4], [5], [6], [7], 8], [9], [10] (Jaantus. 3). Barootiinka Nrf2 oo si weyn u badan ayaa sababa muujinta kororka hiddo-wadaha ku lug leh dheef-shiid kiimikaadka daroogada taasoo kordhinaysa iska caabbinta daawooyinka kiimikaad iyo daawaynta shucaaca. Intaa waxaa dheer, heerka sare ee borotiinka Nrf2 wuxuu la xiriiraa saadaasha liidata ee kansarka [4]. Nrf2 aad u firfircoon ayaa sidoo kale saameeya kororka unugyada iyada oo u hagaya gulukooska iyo glutamine ee waddooyinka anabolic ee kor u qaadaya isku-dhafka purine iyo saameyn ku yeelashada dariiqa fosfatka pentose si kor loogu qaado faafinta unugyada [11] (Jaantus. 4).
Jaantuska 4. Doorka laba-geesoodka ah ee Nrf2 ee tumorigenesis. Xaaladaha jir ahaaneed, heerarka hoose ee nukliyeerka Nrf2 ayaa ku filan dayactirka homeostasis-ka gacanta. Nrf2 waxay joojisaa bilawga buro iyo metastasis kansarka iyada oo la tirtirayo kansarka, ROS iyo wakiilada kale ee DNA-da waxyeeleeya. Inta lagu jiro tumorigenesis, aruurinta dhaawaca DNA-da waxay keenaysaa firfircoonida isku-dhafka ah ee Nrf2 taasoo ka caawisa unugyada malignantiga ah ee iskood u adkaysta inay u adkeystaan heerarka sare ee ROS endogenous iyo inay iska ilaaliyaan apoptosis. Heerarka Nrf2 ee nukliyeerka ee joogtada ah waxay dhaqaajiyaan hiddo-wadaha dheef-shiid kiimikaadka marka lagu daro hidda-socodka cytoprotective ee ka qaybqaata dib-u-habaynta dheef-shiid kiimikaadka iyo kororka unugyada unugyada. Kansarrada leh heerarka sare ee Nrf2 waxay la xiriiraan saadaasha liidata sababtoo ah raadiyaha iyo kimoresistance iyo kororka unugyada kansarka gardarrada ah. Sidaa daraadeed, dhaqdhaqaaqa dariiqa Nrf2 ayaa ilaalinaya marxaladaha hore ee tumorigenesis, laakiin waxyeello u leh marxaladaha dambe. Sidaa darteed, ka hortagga kansarka, kor u qaadida dhaqdhaqaaqa Nrf2 ayaa ah hab muhiim ah halka daaweynta kansarka, Nrf2 la joojiyo waa suurad wacan [4], [11].
Marka la eego in dhaqdhaqaaqa sare ee Nrf2 uu caadi ahaan ku dhaco unugyada kansarka leh natiijooyin xun, waxaa jira baahi loo qabo daaweyn si loo joojiyo Nrf2. Nasiib darro, sababtoo ah isku mid ahaanshaha qaabdhismeedka xubnaha kale ee bZip, horumarinta Nrf2 horjoogayaasha gaarka ah waa hawl adag oo kaliya dhowr daraasadood oo ku saabsan joojinta Nrf2 ayaa la daabacay ilaa taariikhda. Iyadoo la baarayo alaabta dabiiciga ah, Ren et al. [12] waxay u aqoonsadeen brusatol xarun antineoplastic sida Nrf2 inhibitor kaas oo kor u qaadaya waxtarka kiimikaad ee cisplatin. Intaa waxaa dheer, PI3K inhibitors [11], [13] iyo Nrf2 siRNA [14] ayaa loo isticmaalay in lagu joojiyo Nrf2 unugyada kansarka. Dhowaan, waxaanu isticmaalnay hab kale, oo loo yaqaan daaweynta hidda-wadaha kansarka, si loo beegsado unugyada kansarka ee leh heerarka sare ee Nrf2. Nrf2-driven vectors lentiviral [15] oo ay ku jiraan thymidine kinase (TK) ayaa loo wareejiyaa unugyada kansarka oo leh waxqabad sare oo ARE ah waxaana unugyada lagu daaweeyaa dawo-yaqaan, ganciclovir (GCV). GCV waxaa la dheefshiido GCV-monofosfate, kaas oo ay sii dheeraatay fosforyaal ay sii wadaan kinase unuggu una beddelo qaab triphosphate sun ah [16] (Jaantus. 5). Tani waxay keenaysaa dil wax ku ool ah oo aan ahayn TK oo keliya oo ay ku jiraan unugyada burooyinka, laakiin sidoo kale unugyada deriska ah sababtoo ah saameynta is-hortaagga [17]. ARE- nidaamsan ee daaweynta hidda-wadaha TK/GCV ayaa lagu sii wanaajin karaa iyada oo la isku darayo wakiilka kemotherabi ee kansarka doxorubicin ee daawaynta [16], taageeridda fikradda ah in habkani uu faa'iido u yeelan karo iyada oo lala kaashanayo daawaynta dhaqameed.
Jaantuska 5. Daaweynta hidda-socodka is-dilitaanka. Nrf2 ururinta nukliyeerka ee unugyada kansarka ayaa laga faa'iidaysan karaa iyadoo la isticmaalayo Nrf2-driven vector fayraska daaweynta hidde-is-dilista [16]. Habkan, vector lentiviral (LV) oo muujinaya thymidine kinase (TK) ee hoos yimaada dhiirigeliyaha ugu yar ee SV40 oo leh afar AREs ayaa loo beddelaa unugyada adenocarcinoma sambabada. Heerarka nukliyeerka sare ee Nrf2 waxay horseedaan muujinta adag ee TK iyada oo loo marayo Nrf2 xidhitaanka. Unugyada ayaa markaa lagu daaweeyaa daawada pro-daroog, ganciclovir (GCV), kaas oo ay fosforyl ka tahay TK. Triphosphorylated GCV wuxuu carqaladeeyaa isku-dhafka DNA-da wuxuuna horseedaa dil wax ku ool ah oo aan ahayn TK oo keliya oo ay ku jiraan unugyada burooyinka, laakiin sidoo kale unugyada deriska ah sababtoo ah saameynta taagan.
Nrf2 waa nidaamiye sare oo kiciya soo saarida antioxidants awood leh oo ku jira jidhka bini'aadamka kaas oo gacan ka geysta ciribtirka cadaadiska oksaydhka. Enzymes antioxidant kala duwan, sida superoxide dismutase, ama SOD, glutathione, iyo catalase, ayaa sidoo kale lagu hawlgeliyaa iyada oo loo marayo waddada Nrf2. Intaa waxaa dheer, phytochemicals qaarkood sida turmeric, ashwagandha, bacopa, shaaha cagaaran, iyo yamaaruggii caanaha, waxay dhaqaajiyaan Nrf2. Daraasado cilmi-baaris ah ayaa lagu ogaaday Nrf2 firfircoonida waxay si dabiici ah u wanaajin kartaa ilaalinta gacanta waxayna dib u soo celin kartaa dheelitirka jidhka bini'aadamka.
Dr. Alex Jimenez DC, CCST Insight
Sulforaphane iyo Saameyntiisa Kansarka, Dhimashada, Gabowga, Maskaxda iyo Dhaqanka, Cudurrada Wadnaha & in ka badan
Isothiocyanates waa qaar ka mid ah xeryahooda dhirta ee ugu muhiimsan ee aad ka heli karto cuntadaada. Fiidiyowgaan waxaan u sameynayaa kiiskii ugu badnaa ee abid la sameeyo. Fiiro gaar ah oo gaaban? U gudub mawduuca aad jeceshahay adiga oo gujinaya mid ka mid ah dhibcaha wakhtiga hoose. Jadwalka wakhtiga oo buuxa hoos
Qaybaha muhiimka ah:
00:01:14 - Kansarka iyo dhimashada
00:19:04 - gabowga
00:26:30 - Maskaxda iyo dhaqanka
00:38:06 - Dib u soo koobid kama dambays ah
00:40:27 - Qiyaasta
Waqtiga buuxa:
00:00:34 - Horudhaca sulforaphane, diiradda weyn ee fiidiyowga.
00: 31: 21 - Daraasada jiirka iyadoo la adeegsanayo 10 nooc oo kala duwan oo niyad-jabka ah ayaa muujinaya sulforaphane si la mid ah waxtarka sida fluoxetine (prozac).
00: 32: 00 - Daraasadu waxay muujineysaa in si toos ah loo nuugo glucoraphanin ee jiirarka ay si la mid ah waxtar ugu leedahay ka hortagga niyad-jabka ee ka timaadda qaabka cadaadiska bulshada.
Gabagabadii, qodobka nukliyeerka (erythroid-derived 2) -sida 2, oo sidoo kale loo yaqaan NFE2L2 ama Nrf2, waa borotiin kor u qaada soosaarka antioxidants kaas oo jirka bini'aadamka ka ilaaliya cadaadiska oksaydhka. Sida kor lagu sharaxay, kicinta dariiqa Nrf2 ayaa ah daraasado loogu talagalay daaweynta cudurrada ay keento cadaadiska oksaydhka, oo ay ku jiraan kansarka. Baaxadda macluumaadkayadu waxay ku kooban tahay xanuunka loo yaqaan 'chiropractic' iyo arrimaha caafimaadka laf dhabarta. Si aad ugala hadasho mawduuca, fadlan xor u noqo inaad waydiiso Dr. Jimenez ama nagala soo xidhiidh at�915-850-0900 .
Xanuunka jilibka waa calaamad caan ah oo ku dhici karta dhaawacyo jilibka ah iyo/ama xaalado kala duwan, oo ay ku jiraandhaawacyada isboortiga. Jilibku waa mid ka mid ah kala-goysyada ugu adag ee jidhka bini'aadamka maadaama uu ka kooban yahay isgoysyada afar lafo, afar seediyo, seedooyin kala duwan, laba menisci, iyo carjawda. Sida laga soo xigtay Akademiyada Maraykanka ee Dhakhaatiirta Qoyska, sababaha ugu badan ee xanuunka jilibka waxaa ka mid ah subluxation patellar, patellar tendinitis ama jilibka jumper, iyo cudurka Osgood-Schlatter. Inkasta oo xanuunka jilibka ay u badan tahay inuu ku dhaco dadka ka weyn 60 sano, xanuunka jilibka wuxuu sidoo kale ku dhici karaa carruurta iyo dhalinyarada. Xanuunka jilibka waxaa lagu daweyn karaa guriga iyadoo la raacayo hababka RICE, si kastaba ha ahaatee, dhaawacyada daran ee jilibka ayaa laga yaabaa inay u baahdaan daryeel caafimaad oo degdeg ah, oo ay ku jiraan daryeelka xanuunka loo yaqaan 'chiropractic care'.
DNA-du waxay taageertaa qiyaastii 20,000 oo hidde-sideyaal ah, mid kastaa wuxuu hayaa barnaamij loogu talagalay abuurista borotiin ama enzyme looga baahan yahay qaab nololeed caafimaad leh. Mid kasta oo ka mid ah qaababkan wuxuu u baahan yahay in si joogto ah loo habeeyo nooc ka mid ah "kormeeriyaha" kaas oo maamula sida saxda ah inta ay le'eg tahay shay kasta iyo/ama kiimikaad kasta iyo xaaladaha ay kuwani sidoo kale ku koraan.
Adigoo ku xiraya nooc gaar ah oo ka mid ah meelaha wax-soo-boodeyaasha u eg, oo loo yaqaan Cunsurka Jawaabta Antioxidant, ama ARE, Nrf2 factorWaxay taageertaa xawaaraha abuurka boqolaal hiddo-sideyaal kala duwan kuwaas oo awood u siinaya unugyada inay ku noolaadaan duruufo walaac leh. Hidde-sidayaashan ayaa markaa soo saara xulashada enzymes-ka antioxidant-ka kuwaas oo horumariya shabakad difaaca iyaga oo ka takhalusaya oksaydhiyeyaasha iyo nadiifinta sunta ka soo baxda wax soo saarkooda, marka lagu daro caawinta soo celinta waxyeelada ay keeneen.
Waa maxay Walwalka Oomida?
Dhowr oksaydhiyeyaasha sida xagjirka superoxide, ama O2-., iyo hydrogen peroxide, ama H2O2, ayaa la abuuray iyada oo loo marayo dhaqanka gubashada walxaha iyo/ama kiimikooyinka ilaaliya jidhka bini'aadamka. Jidhka bini'aadamku waxa uu haystaa enzymes-ka-antioxidant kaas oo dhexdhexaadiya oo ka saara cuntooyinka iyo cabbitaannada fal-celiska ah ee aynu isticmaalno. Nrf2 waxay wax ka beddeleysaa wax soo saarkooda si ay u ilaaliso dheellitirka waxayna hoosta ka xariiqaysaa baahida loo qabo dhammaan enzymes-kan. Isku-dheelitirnaantan waxaa joojin kara dhowr arrimood, oo ay ku jiraan da'da.
Markaan da'eyno, jirka bini'aadamka wuxuu abuuraa Nrf2 yar oo dheellitirkaan jilicsan wuxuu si tartiib tartiib ah u bilaabi karaa inuu u leexdo dhinaca oksidatiga, xaalad loo tixraaco cadaadiska oksaydhka. Cudurku waxa kale oo laga yaabaa inuu keeno wax-soo-saarka oksidayaasha. Caabuqyada, xasaasiyadda, iyo cilladaha difaaca jirka ayaa sidoo kale kicin kara unugyadeena difaaca si ay u abuuraan oksaydhiyeyaasha fal-celiska ah, sida O2-. , H2O2, OH iyo HOCl, halkaasoo unugyada caafimaadka qaba ay dhaawacmaan oo ay uga jawaabaan barar. Cudurada la xidhiidha gabowga, oo ay ku jiraan wadna xanuunka, istaroogga, kansarka, iyo xaaladaha neurodegenerative sida cudurka Alzheimers, ayaa sidoo kale kordhiya horumarinta oksaydhiyeyaasha, abuurista walaaca iyo jawaab-celinta caabuqa.
Waa maxay Nrf2 Activators?
borotiinka Nrf2, oo sidoo kale loo yaqaanno qodob qoraal ah oo ay ugu wacan tahay habka uu u taageeri karo loona xakameyn karo enzymes iyo gen, waa unugga sirta ah ee isku xigxiga falcelinta biochemical ee gudaha unugga kaas oo ka falceliya isbeddelada dheellitirka garashada iyo sidoo kale dheellitirka oksaydhka. Waxyaabaha dareema ee dariiqan ayaa wax ka beddela oo soo daaya Nrf2, iyaga oo kicinaya si ay ugu faafto xudunta unugyada ee DNA-da. Nrf2 waxa laga yaabaa in beddelkeeda daarto ama damiso hiddo-wadaha iyo enzymes-ka ay taageerto si ay u ilaaliso unugga.
Nasiib wanaag, walxo kala duwan oo ah Nrf2 activators waxay ku horumaraan isticmaalka dhirta qaarkood iyo waxyaabaha laga soosaaray qarniyo ka hor dawooyinka dhaqameed ee Shiinaha iyo Maraykanka. Kiimikooyinkan phytochemicals waxay u muuqdaan inay si isku mid ah u awood badan yihiin oo leh saameyno-dhinacyo yar, sida Nrf2-dhaqdhaqaaqa daawooyinka daawooyinka ee maanta la isticmaalo.
Qodobka Nukliyeerka ee erythroid 2, oo inta badan loo yaqaan Nrf2, waa arrin qoraal ah oo ka ilaalisa unugga iyada oo nidaaminaysa hiddo-wadaha, enzymes iyo jawaabaha antioxidant. Qodobbada qoraalku waa nooc ka mid ah borotiinka ku dheggan DNA-da si kor loogu qaado abuuritaanka walxo gaar ah iyo kiimikooyin, oo ay ku jiraan glutathione S-transferases, ama GST-yada. Dhaqdhaqaaqa Nrf2 wuxuu keenaa soo saarida borotiinno firfircoon kuwaas oo soo bandhigaya awood antioxidant xoog leh si ay u caawiso hoos u dhigista cadaadiska oksaydhka.
Dr. Alex Jimenez DC, CCST Insight
Sayniska Ka Dambeeyay Dhaqdhaqaaqa Nrf2
Markii bilowga Nrf2-dhaqdhaqaaqa kabka cuntada la abuuray 2004, macluumaadka ugu yar ayaa la ogaa oo ku saabsan shaqada dariiqa Nrf2. Ku dhawaad 200 oo wargeysyo ah oo ku jira suugaanta Nrf2, oo sidoo kale loo yaqaano nukliyeerka-sida 2 ama NFE2L2, ayaa jiray, cilmi-baarayaashuna waxay bilaabeen kaliya inay ogaadaan jawaabta antioxidant ee Nrf2 ee naasleyda. Ilaa 2017, si kastaba ha ahaatee, in ka badan 9,300 daraasado cilmi baaris ah oo ku saabsan "maamulaha sare," ayaa la daabacay.
Xaqiiqda, Nrf2 waxay xakameysaa enzymes badan oo antioxidant ah kuwaas oo aan la xiriirin hiddo-wadaha, halkii, waxay bixiyaan ka-hortagga xaalado kala duwan oo la xiriira walbahaarka kuwaas oo ay la kulmaan unugyada, xubnaha iyo ugu dambeyntii noolaha, ee hoos yimaada xaaladaha caafimaadka iyo cudurada. Iyada oo ku saleysan tiradan cusub ee macluumaadka laga helay daraasadaha cilmi-baarista akadeemiyadeed ee la daabacay, cilmi-baarayaashu hadda waxay u kobcin karaan si ka sii wanaagsan Nrf2 kaabista cuntada.
Laga bilaabo 2007, daraasaadka cilmi-baaristu waxay muujiyeen shaqada adag ee waddada Nrf2. Dhaqdhaqaaqayaasha Nrf2 ayaa la ogaaday inay ku dayanayaan qodobbada qaababka kala duwan ee jidhka bini'aadamka. Iyadoo loo marayo dariiqyadan, firfircoonayaasha Nrf2 ayaa loo qalabeeyay inay dareemaan xaaladaha isbeddelka ee unugga oo dhan si ay u ilaaliyaan dheelitirka oo ay uga jawaabaan shuruudaha isbeddelka ee hiddo-wadaha.
Waa maxay sababta loo isticmaalo Kaabayaasha Dhaqdhaqaaqa Nrf2?
Sida Nrf2-awoodda firfircoonidu u yaraato da'da noolaha, isbeddellada ayaa laga yaabaa inay bilaabaan inay dhacaan. Daraasadaha cilmi-baaristu waxay muujiyeen in diiradda Nrf2 ee unugyadu ay hoos u dhacaan da'da, oo muujinaysa calaamadaha korodhka cadaadiska oksaydhka. Cudurada kala duwan ee da'da la xiriira sida atherosclerosis iyo cudurada wadnaha, arthritis, kansarka, buurnaanta, nooca 2aad ee sonkorowga, hypertension, cataracts, iyo cudurka Alzheimers iyo sidoo kale cudurada Parkinson ayaa ku dhici kara isbedeladan. Cadaadiska Oxidative ayaa laga helay arrimahan caafimaadka.
Iyadoo la kicinayo awoodda unugga si loo kordhiyo wax soo saarka Nrf2 activators, Nrf2 kaabista cuntada waxay gacan ka geysan kartaa dib u soo noolaynta awoodda jidhka bini'aadamka si uu uga hortago saameynta cadaadiska oksaydhka. Asiidhka dufanka leh ee polyunsaturated, ama PUFAs, waa mid ka mid ah unugyaraha oksaydhka ah ee ugu diyaarsan waxayna si gaar ah ugu nugul yihiin inay waxyeelo ka soo gaarto xagjirrada xorta ah. Thiobarbituric acid, ama TBARS, wax soo saarku wuxuu kordhin karaa da'da, taas oo muujinaysa cadaadiska oksaydhka ee sarreeya oo ay weheliso hoos u dhaca waddooyinka Nrf2.
Nafley ahaan, soo saarista hiddo-wadaha waa hab aad u gaabis ah, oo guud ahaan u baahan saacado in lagu wareejiyo dariiqa. Natiijo ahaan, ensaymes badan ayaa leh dab-damisyo iyaga u gaar ah oo ay ku kici karaan daqiiqado gudahood enzymes nidaamsan oo kala duwan. Cilmi baadhayaashu waxay soo saareen halabuuro gaar ah oo Nrf2 activators kuwaas oo ka faa'iidaysanaya saldhigga aqoonta hawlgelinta. Dhaqdhaqaaqa Nrf2 wuxuu ka kooban yahay kaliya ma aha Nrf2 qoraalka qoraalka ee laga soo saarayo xannibaadihiisa oo u guuraya xudunta unugyada, laakiin sidoo kale waxay ku xiran tahay taxane DNA oo gaar ah si loo dhiirrigeliyo muujinta hidda-wadaha cytoprotective, nidaaminta xawaaraha Nrf2 ayaa laga soo saaray nukleus.
Fahamka nidaamka ciribtirka iyo kicinta Nrf2 ee jirka bini'aadamka ayaa u oggolaatay cilmi-baarayaasha in ay dhisaan isku-dhafka Nrf2 ee kala duwan si ay u fuliyaan milicsiga hiddo-wadaha iyada oo loo marayo habaynteeda. Isku darka saldhigga aqoonta, oo ay weheliso daraasado kale oo cilmi-baaris oo kala duwan ayaa caawiyay soo saarista firfircoonayaasha Nrf2 si loogu isticmaalo kabitaannada cuntada. Baaxadda macluumaadkayadu waxay ku kooban tahay xanuunka loo yaqaan 'chiropractic' iyo arrimaha caafimaadka laf dhabarta. Si aad ugala hadasho mawduuca, fadlan xor u noqo inaad waydiiso Dr. Jimenez ama nagala soo xidhiidh at�915-850-0900 .
Xanuunka jilibka waa calaamad caan ah oo ku dhici karta dhaawacyo jilibka ah iyo/ama xaalado kala duwan, oo ay ku jiraandhaawacyada isboortiga. Jilibku waa mid ka mid ah kala-goysyada ugu adag ee jidhka bini'aadamka maadaama uu ka kooban yahay isgoysyada afar lafo, afar seediyo, seedooyin kala duwan, laba menisci, iyo carjawda. Sida laga soo xigtay Akademiyada Maraykanka ee Dhakhaatiirta Qoyska, sababaha ugu badan ee xanuunka jilibka waxaa ka mid ah subluxation patellar, patellar tendinitis ama jilibka jumper, iyo cudurka Osgood-Schlatter. Inkasta oo xanuunka jilibka ay u badan tahay inuu ku dhaco dadka ka weyn 60 sano, xanuunka jilibka wuxuu sidoo kale ku dhici karaa carruurta iyo dhalinyarada. Xanuunka jilibka waxaa lagu daweyn karaa guriga iyadoo la raacayo hababka RICE, si kastaba ha ahaatee, dhaawacyada daran ee jilibka ayaa laga yaabaa inay u baahdaan daryeel caafimaad oo degdeg ah, oo ay ku jiraan daryeelka xanuunka loo yaqaan 'chiropractic care'.
Antioxidants waxaa cilmi ahaan loogu yeeraa xeryahooda xaddidaya habka oksaydheynta ee jirka bini'aadamka, taas oo haddii aan la xakameynin, ay abuuri karaan xag-jiryo xor ah kuwaas oo keeni kara falcelin silsilado badan oo keeni kara dhaawac unugyada. Nasiib wanaag, jidhka bini'aadamku wuxuu abuuri karaa hababka difaaca ee ku dhisan, si kastaba ha ahaatee, marka la kordhiyo noocyada ogsijiinta falcelinta, ama ROS, ma awoodaan in la dhexdhexaadiyo, waxay qiyaasaan olol yar oo ka baxa xakamaynta marka lagu daro ogsijiinta, waxyeelladu waa inay dhacdaa. .
Si loo sii wado ballaarinta tusaalaha ololka, sheyga kama dambaysta ah ee aan lahayn awood u leh inuu ka takhaluso saameynta ROS, ama noocyada oksijiinta falcelinta, waa dhaawac iyo sidoo kale barar, si kale haddii loo dhigo, jidhka bini'aadamka ayaa dhab ahaantii dab ku shidan. Waxyaabaha cajiibka ah ayaa ah inay jiraan antioxidants kuwaas oo si weyn uga caawin kara la dagaallanka arrintan caafimaadka iyo antioxidant-kan waa glutathione. Inkasta oo la helay 1889-kii, saamaynta antioxidant-ka glutathione waxay noqotay mid ka mid ah mawduucyada ugu xiisaha badan daraasadaha cilmi-baarista casriga ah.
Master of Antioxidants: Glutathione
Walaxda xoogga leh waa tripeptide oo ka soo baxda cysteine, glutamic acid, iyo glycine. Sababtoo ah awoodda ay u leedahay in ay ka ilaaliso jidhka bini'aadamka ka hortagga abuurista xagjirnimada xorta ah, glutathione waxay ugu dambeyntii gacan ka geysan kartaa kor u qaadida habka difaaca caafimaadka leh. Iyada oo ku saleysan Warbixinada Sayniska ee 2015, waxaa la go'aamiyay in awoodda glutathione ay si isku mid ah ugu shaqeyso peroxiredin iyo catalase ay ka caawiso unugyada ilaalinta hydrogen peroxide. Habkan isku-dhafka ah wuxuu u shaqeeyaa lidka ku ah noocyada ogsijiinta falcelinta, ama ROS. Glutathione, peroxidredin iyo catalase ayaa ah walxaha lagama maarmaanka u ah korodhka homeostasis-ka gacanta, kaas oo ah habka lagama maarmaanka u ah unugyada caafimaadka qaba, unugyada iyo xubnaha guud ahaan.
Intaa waxaa dheer, glutathione waxay kordhisaa qaabka guud ee habka difaaca jirka iyo shaqada iyadoo la isticmaalayo saameynteeda muhiimka ah ee hawlaha lymphocyte. Sida laga soo xigtay Waaxda Immunochemistry, si habboon u kabista heerarka glutathione ee jidhka bini'aadamka waxay si weyn u kordhin kartaa falcelinta difaaca. Tusaale ahaan, laba tijaabo oo la xakameeyey placebo-la kala soocay ayaa muujiyay in daaweynta daaweynta bukaannada difaaca jirran ee N-acetyl-cysteine , ama NAC, ay keentay, labadaba, korriin la taaban karo ee hababka difaaca jirka oo dhan oo ay ku jiraan dib u soo kabashada oo dhan. dhaqdhaqaaqa unugyada dilaaga dabiiciga ah. N-acetyl-cysteine, ama NAC, waxay isticmaashaa baaruudda glutathione waxayna ku daraa molecules sun ah, ka dibna noqda kuwo biyo-milmi leh oo laga soo daayo jidhka bini'aadamka.
Glutathione sidoo kale waxay awood u leedahay inay dib u soo noolayso lipoic acid iyo sidoo kale inay dib u warshadeeyaan Vitamin C iyo E, kuwaas oo lagama maarmaan u ah in la bilaabo hababka nidaamka qaarkood adoo u diraya elektarooniga si ay uga takhalusaan xagjirnimada xorta ah. Iyada oo ku saleysan daraasad cilmi baaris ah oo ka timid QALABKA HALKAN, glutathione waxay saamaysay bukaanada qaba metillus sokorowga, ama T2DM, iyo qaaxada mycobacterium. Caadi ahaan, shakhsiyaadka leh habdhiska difaaca ee daciifka ah waxay u janjeeraan inay muujiyaan soo-gaadhis weyn M. tb, ama qaaxada mycobacterium, cudur ama caabuq. Intaa waxaa dheer, shakhsiyaadka qaba Metillus nooca 2 ee sonkorowga, ama T2DM, ayaa laba ilaa saddex jeer uga nugul qaaxada marka loo eego dadka aan lahayn T2DM. Daraasada cilmi baarista ayaa sidoo kale soo jeedisay in kor loo qaado heerarka glutathione ee macrophages ee ka go'ay bukaanada qaba T2DM ay keentay in la hagaajiyo xakameynta cudurka M.Tb ama caabuqa. Natiijooyinkani waxay muujinayaan in heerarka hoose ee glutathione ee bukaannada qaba T2DM ay gacan ka geysato kor u kaca fursadda cudurka M. tb ama caabuqa. Waxaa intaa dheer, ku tiirsan Dietro Ghezzi oo ku yaal Brighton iyo Dugsiga Caafimaadka Sussex, cadaadiska oksaydhiyuhu wuxuu ugu dambeyntii sababi karaa qaab-dhismeedka difaaca oo liita iyo shaqada.
Nasiib wanaag, glutathione waxay door lama huraan ah ka ciyaartaa xoojinta iyo xakamaynta xasaanadda. Tusaale ahaan, glutathione waxay lagama maarmaan u tahay hababka gudaha iyo la-qabsiga ee habka difaaca jirka, oo ay ku jiraan kororka T-lymphocyte, waxqabadka phagocytic ee neutrophils polymorphonuclear, iyo hawlaha unugyada dendritic, taas oo noqon karta mid aasaasi ah sababtoo ah kuwani waxay ka kooban yihiin unugyo soo bandhigaya antigen. . Difaaca unug-maskaxeed waxaa ka mid ah antigens-ka borotiinka kaas oo markii hore bilaabay inuu hoos u dhaco xuubka endocytic ee macrophages iyo unugyada dendritic, sidaas darteed, peptides yar yar ayaa lagu muujiyay dusha sare si ay u kiciyaan faafinta unugyada T-ga ee antigen-ga gaarka ah. Intaa waxaa dheer, glutathione waxay gacan ka geysataa abuurista cytokines, waxaana lagama maarmaan ah in la ilaaliyo wax soo saarka interferon-gamma ee unugyada dendritic, taas oo muhiim u ah ilaalinta cudurada intracellular ee ay ku jiraan mycobacteria.
N-acetyl-cysteine, ama NAC, oo cilmi ahaan loogu yeero horudhaca glutathione, sidoo kale waa antioxidant unug aad u awood badan oo loo isticmaalo sida antioxidant xagjirka xorta ah. Caadi ahaan loo aqoonsaday doorkeeda ka hortagga sunta acetaminophen, NAC, ama N-acetyl-cysteine, ayaa la muujiyey inay leedahay faa'iidooyin caafimaad iyo fayoobi badan. Sida laga soo xigtay Wargeyska Unugga, NAC waxay gacan ka geysataa taageeridda jawaab-celinta caabuqa caafimaadka leh waxayna si togan u saameyn kartaa muddada bini'aadamka iyo foosha. Daraasada cilmi-baadhistu waxay soo gabagabaysay in dumarka dhalmada hore ee dhalmada ka hor iyo bakteeriyada vaginosis, 0.6 garaam oo NAC ah maalintii oo afka laga qaato progesterone ka dib toddobaadka 16 ee uurka laga ilaaliyo soo noqoshada dhalmada ka hor iyo hagaajinta natiijada dhallaanka. Gabagabadii, saamaynta togan ee NAC ee dhismaha murqaha ayaa sidoo kale la ogaaday. Saddex daqiiqo oo foosha joogtada ah ka dib, waxaa jiray wax soo saar boqolkiiba 15 ah oo la xoojiyey, taas oo muujinaysa sida NAC ay door aasaasi ah uga qaadato hagaajinta dhismaha murqaha iyo yaraynta daalka guud inta lagu jiro foosha.
Cilmi-baarayaashu waxay kaloo ogaadeen in NAC, ama N-acetyl-cysteine, laga yaabo inay ka faa'iidaystaan kuwa qaba cudurka polycystic ovary syndrome, ama PCOS. PCOS, ama polycystic ovary syndrome, waa cudur qanjidhada la xidhiidha qanjidhada endocrine ee caadiga ah kaas oo saameeya qiyaastii 5 ilaa 10 boqolkiiba haweenka da'da taranka. Bukaannada noocan oo kale ah, waxaa jirta khatar weyn oo ah inay la kulmaan cilladda dheef-shiid kiimikaadka, halkaasoo isticmaalka NAC ay ka caawisay soo celinta heerarka insulinta caafimaadka leh iyo dareenka.
Dr. Alex Jimenez's Insight
Glutathione waxaa loogu yeeraa "master of antioxidants" sababtoo ah doorkeeda aasaasiga ah ee ku aaddan xaqiijinta iyo ilaalinta guud ahaan caafimaadka iyo fayoobaanta. Iyadoo jidhka bini'aadamku awood u leeyahay inuu soo saaro glutathione u gaar ah, nafaqo xumo, wasakhowga, sunta, isticmaalka xad dhaafka ah ee daroogooyinka iyo / ama daawooyinka, walbahaarka, dhaawacyada, gabowga, cudurada iyo shucaaca ayaa dhamaantood hoos u dhigi kara heerarka dabiiciga ah ee glutathione. Tani waxay sidoo kale ka dhigi kartaa shakhsiyaadka kuwo aad ugu nugul dhaawaca unugyada ka yimaada cadaadiska oksaydhka, xagjirka xorta ah, caabuqyada iyo kansarka. Kaabista Glutathione waxay markaa ku yeelan kartaa faa'iidooyin aad u weyn jidhka bini'aadamka. Si wada jir ah oo leh xulashooyinka daaweynta kale, sida daryeelka xanuunka loo yaqaan 'chiropractic care', heerarka glutathione ayaa mar kale la xakameyn karaa si loo hagaajiyo fayoobaanta.
Intaa waxaa dheer, xirfadlayaasha daryeelka caafimaadku waxay soo jeediyeen in la hirgeliyo isticmaalka kabka glutathione oo ay weheliso xulashooyin kale oo daaweyneed, sida daryeelka bukaan-jiifka, si loo sii wanaajiyo guud ahaan caafimaadka iyo fayoobaanta. Antioxidants ayaa muhiim u ah ilaalinta fayoobida ugu badan iyo sidoo kale in la joojiyo falcelinta silsilada ee xagjirka xorta ah ee sababa dhaawaca unugyada ama dhaawaca. Antioxidants xooggan sida glutathione, sida hore loogu soo sheegay kor, ugu dambeyntii waxay gacan ka geystaan habeynta horumarinta xagjiryadan xorta ah waxayna bixiyaan jawaab celin caafimaad oo caafimaad leh. Daraasado cilmi-baaris ah ayaa lagu ogaaday daryeelka bukaan-jiifka Waxa kale oo laga yaabaa inay door lama huraan ah ka ciyaarto geeddi-socodkan, si dabiici ah kor loogu qaado waxqabadka antioxidants ee jidhka bini'aadamka. Daryeelka lafdhabarta waa hab daaweyn oo ammaan ah oo wax ku ool ah kaas oo isticmaala isbeddelka laf-dhabarka iyo manfacyada gacanta si loo saxo cilladaha laf-dhabarka, ama subluxations, si loogu oggolaado jidhka bini'aadamka inuu si dabiici ah isu bogsiiyo iyada oo aan la isticmaalin daroogo / daawooyin iyo / ama waxqabadyo qalliin.
Ugu dambeyntii, antioxidants waxay muujiyaan hantidooda bayooloji iyada oo loo marayo faa'iidooyin caafimaad oo aad u badan, kuwaas oo laga yaabo inay lagama maarmaan noqoto in ka badan sidii hore iyada oo ay sii kordhayaan weerarrada walaaca, cudurrada iyo wasakhowga adduunkeena casriga ah, kuwaas oo dhammaantood gacan ka geysta waxyeelada unugyada iyo / ama dhaawaca. . Glutathione iyo horudhaceeda, NAC, ama N-acetyl-cysteine, waxay sii wadaan inay muujiyaan xaaladdooda xoogga badan ee saaxadda antioxidants. Si wada jir ah oo leh xulashooyin daaweyn oo kale, sida daryeelka xanuunka loo yaqaan 'chiropractic care', dadku waxay ka faa'iideysan karaan dhammaan faa'iidooyinka ay leedahay antioxidant-kan xoogga leh. Baaxadda macluumaadkayadu waxay ku kooban tahay xanuunka loo yaqaan 'chiropractic' iyo sidoo kale dhaawacyada laf dhabarta iyo xaaladaha. Si aad ugala hadasho mawduuca, fadlan xor u noqo inaad waydiiso Dr. Jimenez ama nagala soo xidhiidh at�915-850-0900 .
Waxaa soo saaray Dr. Alex Jimenez
Mawduucyo Dheeraad ah: Xanuunka Dhabarka
Xanuunka dhabarka waa mid ka mid ah sababaha ugu badan ee naafanimada iyo maalmaha shaqada laga waayo adduunka oo dhan. Sida xaqiiqda ah, xanuunka dhabarka ayaa loo aaneynayaa inuu yahay sababta labaad ee ugu badan ee booqashooyinka xafiiska dhakhtarka, oo ka badan kaliya caabuqyada neef-mareenka sare. Qiyaastii 80 boqolkiiba dadku waxay la kulmi doonaan nooc ka mid ah xanuunka dhabarka ugu yaraan hal mar noloshooda oo dhan. Laf-dhabarta waa qaab dhismeed kakan oo ka kooban lafo, kala-goysyo, seedaha iyo murqaha, iyo unugyo kale oo jilicsan. Taas awgeed, dhaawacyada iyo/ama xaaladaha sii xumeeyay, sida maqaarka herniated, ugu dambeyntii waxay keeni kartaa calaamadaha xanuunka dhabarka. Dhaawacyada isboortiga ama dhaawacyada shilalka baabuurta ayaa inta badan ah sababta ugu badan ee xanuunka dhabarka, si kastaba ha ahaatee, mararka qaarkood dhaqdhaqaaqa ugu fudud ayaa keeni kara natiijooyin xanuun leh. Nasiib wanaag, xulashooyinka daaweynta kale, sida daryeelka xanuunka loo yaqaan 'chiropractic care', ayaa kaa caawin kara yareynta xanuunka dhabarka iyada oo loo marayo isticmaalka isbeddelka laf-dhabarka iyo manfacyada gacanta, ugu dambeyntii hagaajinta xanuunka.
Saynis ku salaysan Chiropractor Dr. Alexander Jimenez eegayaa cadaadiska qiiqa, waxa ay tahay, sida ay u saamayso jidhka iyo difaaca antioxidant si ay u xaliyaan xaaladda.
Esra Birben PhD,1 Umit Murat Sahiner MD,1 Cansin Sackesen MD,1 Serpil Erzurum MD,2 iyo Omer Kalayci, MD1
Soo koobid: Noocyada ogsijiinta fal-celiska ah (ROS) waxaa soo saaray noolaha taasoo ka dhalatay dheef-shiid kiimikaad ee caadiga ah iyo arrimaha deegaanka, sida wasakhowga hawada ama qiiqa sigaarka. ROS waa unugyo firfircoon oo firfircoon waxayna dhaawici karaan qaab-dhismeedka unugyada sida karbohaydraytyada, asiidhyada nucleic-ka, dufanka, iyo borotiinada waxayna beddelaan shaqadooda. Isbeddelka dheelitirka u dhexeeya oksaydhiyeyaasha iyo antioxidants ee u janjeera oksaydhiyeyaasha waxa loo yaqaan �oxidative stress Noolaha Aerobic waxay leeyihiin habab antioxidant isku dhafan, kuwaas oo ay ku jiraan enzymatic iyo non-enzymatic antioxidants kuwaas oo inta badan waxtar u leh xannibista waxyeelada ROS. Si kastaba ha noqotee, xaaladaha pathological, nidaamyada antioxidant-ka ayaa laga adkaan karaa. Cadaadiska Oxidative wuxuu ka qayb qaataa xaalado badan oo pathological iyo cuduro, oo ay ku jiraan kansarka, xanuunka neerfaha, atherosclerosis, hypertension, ischemia/perfusion, sonkorowga, xanuunka neef-mareenka ee degdega ah, idiopathic pulmonary fibrosis, cudurada sambabada xanniba ee joogtada ah, iyo neefta. Dib u eegistaan, waxaan ku soo koobeynaa oxidant-ka gacanta iyo hababka antioxidant waxaanan ka wada hadalnaa saameynta gacanta iyo hababka cadaadiska oksaydhka.
Noocyada ogsijiinta fal-celiska ah (ROS) waxaa soo saara noolaha taas oo ay sabab u tahay dheef-shiid kiimikaad ee caadiga ah. Heerarka hoose iyo kuwa dhexdhexaadka ah, waxay ka shaqeeyaan hababka unugyada physiological, laakiin marka ay sarreeyaan, waxay soo saaraan isbeddello xun oo ku yimaada qaybaha unugyada, sida lipids, borotiinka, iyo DNA-da. Cadaadiska Oxidative-ku waxa uu ka qayb qaataa xaalado badan oo pathological, oo ay ku jiraan kansarka, xanuunka neerfaha, 1-6 atherosclerosis, hypertension, ischemia/perfusion, 7-10 sonkorowga, xanuunka neef-mareenka xanuunka, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease. ,11 iyo xiiqda Si kastaba ha noqotee, xaaladaha pathological, nidaamyada antioxidant-ka ayaa laga adkaan karaa. Dib-u-eegisgan, waxaanu ku soo koobaynaa oxidant-ka gacanta iyo hababka antioxidant-ka iyo nidaaminta hoos u dhigista iyo oxidizing (redox) ee gobolka caafimaadka iyo cudurrada.
OXIDANTS
Ilaha Endogenous ee ROS
ROS waxaa laga soo saaraa ogsijiin molecular taasoo ka dhalatay dheef-shiid kiimikaad ee caadiga ah. ROS waxaa loo qaybin karaa 2 kooxood: xagjirka xorta ah iyo kuwa aan xagjirka ahayn. Unugyada ay ku jiraan hal ama in ka badan oo elektaroonik ah oo aan lammaane ahayn oo markaa siinaya falcelinta molecule-ka waxaa loo yaqaannaa xagjirrada xorta ah. Marka 2 xagjirayaal xor ah wadaagaan elektaroonnada aan la isku xidhin, qaabab aan xagjir ahayn ayaa la abuuraa. 3-da ROS ee ugu waaweyn ee leh muhimada jireed waa superoxide anion (O22.), hydroxyl radical (OH), iyo hydrogen peroxide (H2O2). ROS waxa lagu soo koobay shaxda 1.
Anion Superoxide waxaa lagu sameeyaa ku darida 1 elektarooniga ah ee ogsijiinta molecular.22 Nidaamkan waxaa dhexdhexaadiya nicotine adenine dinucleotide phosphate [NAD (P) H] oxidase ama xanthine oxidase ama habka mitochondrial electron transport system. Goobta ugu weyn ee laga soo saaro anion superoxide waa mitochondria, mishiinka unuga si loo soo saaro adenosine triphosphate. Caadi ahaan, elektaroonnada waxaa lagu gudbiyaa silsiladda gaadiidka elektaroonigga ah ee mitochondrial si loo dhimo ogsijiinta biyaha, laakiin qiyaastii 1 ilaa 3% dhammaan elektaroonnada ayaa ka soo daada nidaamka waxayna soo saaraan superoxide. NAD(P)H oxidase waxaa laga helaa leukocytes polymorphonuclear, monocytes, iyo macrophages. Marka phagocytosis, unugyadani waxay soo saaraan dilaaca superoxide taasoo u horseedda firfircoonida bakteeriyada. Superoxide waxa loo rogaa hydrogen peroxide iyada oo la adeegsanayo falcelinta superoxide dismutases (SODs, EC 1.15.1.1). Hydrogen peroxide waxay si fudud ugu faaftaa xuubka balaasmaha. Hydrogen peroxide sidoo kale waxaa soo saara xanthine oxidase, amino acid oxidase, iyo NAD(P)H oxidase�23,24 iyo in peroxisomes iyadoo la isticmaalayo oksijiinta molecular ee falcelinta dheef-shiid kiimikaadka. Dareen-celin isdaba joog ah oo loo yaqaan falcelinta Haber Weiss iyo Fenton, H2O2 waxay u burburi kartaa OH2 iyadoo ay joogaan biraha gudbinta sida Fe21 ama Cu21.25
Fe31 +�.O2�?Fe2 +�O2 Haber Weiss
Fe2 +�H2O2�?Fe3 +�OH�+ .OH Fenton falcelinta
O2 lafteedu waxay sidoo kale la falcelin kartaa H2 O2 waxayna dhalin kartaa OH Waxa kale oo ay ku bilaabi kartaa peroxidation lipid iyada oo ka qaadanaysa elektarooniga asiidh dufanka badan ee polyunsaturated.
Enzymes Granulocytic waxay sii ballaadhinaysaa falcelinta H2O2 iyada oo loo sii marayo eosinophil peroxidase iyo myeloperoxidase (MPO). Neutrophils firfircoon, H2O2 waxaa isticmaala MPO. Marka ay jirto ion chloride, H2O2 waxa loo beddelaa hypochlorous acid (HOCl). HOCl waa mid aad u sarreeya waxayna door muhiim ah ka ciyaartaa dilka cudurada faafa ee marinnada hawada.28 Si kastaba ha ahaatee, HOCl waxay sidoo kale la falgali kartaa DNA-da waxayna kicin kartaa isdhexgalka borotiinka DNA waxayna soo saartaa alaabada oxidation pyrimidine waxayna ku dartaa chloride saldhigyada DNA.29,30 Eosinophil peroxidase iyo MPO waxa kale oo ay gacan ka geystaan cadaadiska oksaydhiyeyaasha ah iyada oo la beddelayo borotiinnada iyada oo la adeegsanayo halogenations, nitration, iyo borotiinka iskutallaabyada borotiinka iyada oo loo marayo xaglaha tyrosyl.31�33
Xagjirrada kale ee Ogsajiinta ka soo jeeda ee xorta ah waa radicals peroxyl (ROO$). Nooca ugu fudud ee xag-jirradan waa hydro-peroxyl radical (HOO$) waxayna door ku leedahay peroxidation dufanka leh. Xagjirrada xorta ah waxay kicin karaan falcelinta silsiladda lipid peroxidation iyagoo ka soo saaraya atamka hydrogen ka silsiladda methylene kaarboon. Xagga dufanka ayaa markaas la falgala ogsijiin si uu u soo saaro radical peroxyl. Xagjirka Peroxyl wuxuu bilaabaa falcelinta silsiladda wuxuuna u beddelaa asiidh dufan leh oo polyunsaturated ah una beddela lipid hydroperoxides. Lipid hydroperoxides waa kuwo aan degganayn oo si fudud u burburiya alaabada labaad, sida aldehyde (sida 4-hydroxy-2,3-nonenal) iyo malondialdehydes (MDAs). Isoprostanes waa koox kale oo ka mid ah alaabta lipid peroxidation kuwaas oo lagu soo saaro peroxidation ee arachidonic acid iyo sidoo kale la ogaaday in ay sare u kacday balasmaha iyo neefta neefta ee neefta. qaab dhismeedka xuubka.
Hydrogen peroxide, radical superoxide, oxidized glutathione (GSSG), MDAs, isoprostanes, carbonyls, iyo nitrotyrosine si fudud ayaa looga qiyaasi karaa balaasmaha, dhiiga, ama muunadaha faleebada bronchoalveolar sida biomarkers of oksaydhaynta iyada oo la raacayo qiimayn la jaanqaadaysa.
Isha Exogenous ee Oxidants
Qiiqa Sigaarka
Qiiqa sigaarku wuxuu ka kooban yahay oksaydhiyeyaasha badan iyo radicals lacag la'aan ah iyo xeryahooda organic, sida superoxide iyo nitric oxide.36 Intaa waxaa dheer, neefsashada qiiqa sigaarka ee sambabada waxay sidoo kale kicisaa qaar ka mid ah hababka endogenous, sida ururinta neutrophils iyo macrophages, taas oo sii kordhinaysa dhaawaca oksida. .
Soo-gaadhista Ozone
Soo-gaadhista ozone waxay sababi kartaa xuubka peroxidation waxayna keeni kartaa qulqulka neutrophils ee epithelium marin-haweedka. Soo-gaadhista muddada-gaaban ee ozone waxay sidoo kale keentaa sii-deynta dhexdhexaadiyeyaasha caabuqa, sida MPO, eosinophil cationic proteins iyo sidoo kale lactate dehydrogenase iyo albumin. Walxaha yaryar (isku-darka walxaha adag iyo dhibcaha dareeraha ah ee hawada ku jira) waxay kicinaysaa dhimista ogsijiinta.
Hyperoxia
Hyperoxia waxaa loola jeedaa xaaladaha heerarka ogsijiinta ka sarreeya cadaadiska qaybta caadiga ah ee oksijiinta ee sambabada ama unugyada kale ee jirka. Waxay keentaa wax soo saar weyn oo ah ogsijiin fal-celisa iyo noocyada nitrogen.40,41
Raadinta Ionicing
Ionizing shucaaca, iyadoo ay jirto O2, waxay u beddeshaa xaglaha hydroxyl, superoxide, iyo radicals organic una beddelo hydrogen peroxide iyo hydroperoxides organic. Noocyadan hydroperoxide waxay ka falceliyaan redox birta firfircoon ee firfircoon, sida Fe iyo Cu, iyada oo loo marayo falcelinta Fenton oo sidaas awgeed keena cadaadiska oksida. wax soo saarka iyada oo loo marayo xuubka plasma-ku xiran NADPH oxidase.42,43 Moleekulaha gudbinta signalka, sida kinase-ka-xukunka-ka-baxsan ee kinase 44 iyo 2 (ERK2/2), c-Jun N-terminal kinase (JNK), iyo p2, iyo qodobbada qoraalka, sida Protein activator-44 (AP-1), nukliyeerka-kB (NF-kB), iyo p2, ayaa la hawlgeliyay, taas oo keenta muujinta jawaab-celinta shucaaca ee hiddo-wadaha. iyada oo la kicinayo sawir-qaadayaasha endogenous, sida porphyrins, NADPH oxidase, iyo riboflavins. 1-Oxo-2- dihydroguanine (38-oxoGua) waa sheyga ugu muhiimsan ee UVA-dhexdhexaadinta DNA-da oo ay samaysay oksaydhka OH radical, 1-electron oxidants, iyo oksijiinta hal-abuurka ah oo inta badan la falgasha guanine.1 Samaynta guanine radical cation ee DNA go'doonsan ayaa la muujiyay in ay si hufan u dhacdo iyada oo loo marayo saamaynta tooska ah ee shucaaca ionizing.53 Ka dib marka la soo bandhigo shucaaca ionizing, heerka intracellular heerka glutathione (GSH) ayaa hoos u dhacaya muddo gaaban laakiin haddana mar kale kordhiya.45
Mid ka mid ah hababka ugu muhiimsan ee dhexdhexaadinta birta ee dhexdhexaadinta jiilka xorta ah waa iyada oo loo marayo falcelinta nooca Fenton. Ion-Superoxide iyo hydrogen peroxide waxay la falgali karaan biraha kala-guurka, sida birta iyo naxaasta, iyagoo sii maraya falcelinta birta ee HaberWeiss/Fenton si ay u sameeyaan xag-jirrada OH.
Marka laga soo tago nooca Fenton iyo hababka nooca Haber Weiss, ion birta qaarkood waxay si toos ah ula falcelin karaan unugyadu si ay u abuuraan xag-jiryo xor ah, sida thiol radicals, ama ay keenaan dariiqyada calaamadaha unugyada. Xagjirayaashani waxa kale oo laga yaabaa inay la falgalaan molecules kale ee thiol si ay u dhaliyaan O22.. O22. Waxaa loo beddelaa H2O2, taas oo sababta jiilka xagjirka ah ee ogsijiinta dheeraadka ah. Biraha qaarkood, sida arsenite, waxay u horseedaan samaynta ROS si dadban iyadoo la dhaqaajinayo hababka wax soo saarka xagjirka ah ee unugyada.56
Arsenic waa curiye sun ah oo soo saara noocyo kala duwan oo ROS ah, oo ay ku jiraan superoxide (O2 2), oxygen singlet (1O2), peroxyl radical (ROO), nitric oxide (NO), hydrogen peroxide (H2O2), iyo dimethylarsinic peroxyl radicals. CH3)2AsOO. - iyagoo ku socda kooxahooda sulfhydryl (�SH).57
Lead waxay kordhisaa lipid peroxidation.62 Hoos u dhac weyn oo ku yimid dhaqdhaqaaqa unugyada SOD iyo maskaxda GPx ayaa la soo sheegay ka dib soo-gaadhista sunta rasaasta. Soo-gaadhista sunta rasaasta waxay sababi kartaa xannibaadda GST-da iyadoo saamaynaysa thiols-ka unugyada.
ROS oo ay dhaliso falcelinta birta-catalyzed waxay wax ka beddeli kartaa saldhigyada DNA-da. Saddexda beddelka aasaasiga ah, G / C, G / T, iyo C / T, waxay ku dhici karaan natiijada dhaawaca oksaydhka ee ion birta, sida Fe21, Cu21, iyo Ni21. Reid et al65 waxay muujisay in G / C ay inta badan soo saartay Fe21 halka C / T beddelka uu ahaa Cu21 iyo Ni21.
Antioxidants
Jirka bini'aadamka waxaa lagu qalabeeyaa noocyo kala duwan oo ah antioxidants kuwaas oo u adeega si ay uga hortagaan saameynta oksidayaasha. Dhammaan ujeedooyinka la taaban karo, kuwan waxaa loo qaybin karaa 2 qaybood: enzymatic (Shaxda 2) iyo nonenzymatic (Shaxda 3).
Enzymatic Antioxidants
Antioxidants enzymatic ugu weyn ee sambabada waa SODs (EC 1.15.1.11), catalase (EC 1.11.1.6), iyo GSH-Px (EC 1.11.1.9). Marka lagu daro enzymes-yada waaweyn, antioxidants kale, oo ay ku jiraan heme oxygenase-1 (EC 1.14.99.3), iyo borotiinnada redox, sida thioredoxins (TRXs, EC 1.8.4.10), peroxiredoxins (PRXs, EC 1.11.1.15), iyo glutaredoxins , sidoo kale waxaa la ogaaday in ay door muhiim ah ka ciyaaraan difaacayaasha antioxidant ee sambabada.
Maadaama superoxide uu yahay ROS-ka aasaasiga ah ee laga soo saaro ilo kala duwan, kala-baxa SOD waxay muhiimad weyn u leedahay unug kasta. Dhammaan 3-da nooc ee SOD, taas oo ah, CuZn- SOD, Mn-SOD, iyo EC-SOD, ayaa si weyn loogu muujiyey sambabada aadanaha. Mn-SOD waxay ku kooban tahay matrixka mitochondria. EC-SOD waxay ugu horrayn ku kooban tahay matrixka unugyada ka baxsan, gaar ahaan meelaha ay ku jiraan xaddi badan oo ah nooca I kolajka iyo agagaarka marinnada sambabada iyo habdhiska. Waxa kale oo laga helay epithelium bronki, alveolar epithelium, iyo alveolar macrophages.66,67 Guud ahaan, CuZn-SOD iyo Mn-SOD ayaa guud ahaan loo maleynayaa inay u dhaqmaan sida bulk scavengers of superoxide radicals. Heerka sare ee EC-SOD ee sambabada iyada oo si gaar ah loogu xirayo qaybaha matrixka ka baxsan unugyada ayaa laga yaabaa inay matalaan qayb aasaasi ah oo ilaalinta matrix sambabada.68
H2O2 oo ay soo saarto ficilka SODs ama ficilka oxidases, sida xanthine oxidase, ayaa lagu dhimay biyaha by catalase iyo GSH-Px. Catalase waxay u jirtaa tetramer ahaan ka kooban 4 monomers oo isku mid ah, kuwaas oo mid walba uu ka kooban yahay koox heme ah oo goobta firfircoon ku sugan. Burburinta H2O2 waxa lagu dhammeeyaa is beddelka u dhexeeya 2 qaab oo ah catalase-ferricatalase (birta isku-dubbaridan biyaha) iyo isku-darka I (birta lagu kariyey atamka oksijiinta). Catalase sidoo kale waxay ku xidhaa NADPH sida hoos u dhigista u dhiganta si looga hortago kicinta oksaydhka ee ensaymka (formation of compound II) ee H2O2 sida loo yareeyo biyaha.69
Enzymes ee ku jira wareegga redox ee mas'uulka ka ah dhimista H2O2 iyo lipid hydroperoxides (oo ka dhashay natiijada xuubka peroxidation) waxaa ka mid ah GSH-Pxs.70 GSH-Pxs waa qoys ka mid ah enzymes tetrameric oo ka kooban amino acid selenocysteine gaar ah gudaha goobaha firfircoon oo isticmaal thiols-molecular-hooseeya, sida GSH, si loo yareeyo H2O2 iyo lipid peroxides khamriga u dhigma. Afar GSH-Pxs ayaa lagu sifeeyay, oo lagu dhejiyay hiddo-sideyaal kala duwan: GSH- Px-1 (cellular GSH-Px) waa meel kasta oo waxay yaraynaysaa H2O2 iyo fatty acid peroxides, laakiin aan la nadiifin lipids peroxyl. -Px-71 (phospholipid hydroperoxide GSH-Px), kaas oo isticmaali kara dhowr thiols miisaan yar oo kala duwan si loo yareeyo wax u dhigma. GSH-Px-4 (gastrointestinal GSH-Px) waxay ku kooban tahay unugyada epithelial ee mindhicirka halkaasoo ay u adeegto si loo yareeyo peroxides dietary.2 GSH-Px-72 (extracellular GSH-Px) waa xubinta kaliya ee qoyska GSH-Px ee degan qaybta unugyada ka baxsan oo la rumaysan yahay inay tahay mid ka mid ah enzyme-ka ugu muhiimsan ee ka baxsan unugga antioxidant ee naasleyda. Kuwaas oo ka mid ah, GSH-Px ka baxsan unugga ayaa inta badan lagu baaraa sambabada bini'aadamka.3
Laba TRXs iyo TRRs ayaa lagu gartaa unugyada bini'aadamka, kuwaas oo ku jira labadaba cytosol iyo mitochondria. Sambabada, TRX iyo TRR waxaa lagu muujiyay bronki iyo epithelium alveolar iyo macrophages. Lix PRX oo kala duwan ayaa laga helay unugyada bini'aadamka, kuwaas oo ku kala duwan qaybintooda ultrastructural. Daraasadaha tijaabada ah ayaa shaaca ka qaaday muhiimada PRX VI ee ilaalinta epithelium alveolar. Sambabka bini'aadamku waxay muujinayaan dhammaan PRXs ee epithelium bronki, alveolar epithelium, iyo macrophages.75 PRX V ayaa dhawaan la ogaaday in ay u shaqeyso sidii peroxynitrite reductase,76 taas oo macnaheedu yahay in ay u shaqeyn karto sidii xarun difaac oo suurtagal ah horumarinta ROS-dhexdhexaadinta dhaawaca sambabada. .77
Mid ka mid ah antioxidants-kan ayaa ah shuruudaha NADPH sida dhimista wax u dhigma. NADPH waxay ku ilaalisaa catalase qaabka firfircoon waxaana loo isticmaalaa isku-xidhaha TRX iyo GSH reductase (EC 1.6.4.2), taas oo GSSG u beddesha GSH, iskudarka GSH-Pxs. Intracellular NADPH, markeeda, waxaa soo saaray hoos u dhigista NADP1 by glucose-6-fosfate dehydrogenase, ugu horeysay iyo heerka xaddidaya enzyme dariiqa phosphate Pentose, inta lagu guda jiro beddelka of glucose-6-fosfate ilaa 6-phosphogluconolactone. Marka la soo saaro NADPH, gulukoos-6-fosfate dehydrogenase waa go'aamiye muhiim ah oo ku saabsan awoodda kaydinta cytosolic GSH (GSH/ GSSG) iyo, sidaas darteed, waxaa loo tixgelin karaa lagama maarmaan, enzyme antioxidant nidaamsan.78,79
GSTs (EC 2.5.1.18), qoys kale oo enzyme antioxidant ah, dheef-shiid kiimikaad sare ee aan firfircoonayn, sida aldehyde aan saturated, epoxides, iyo hydroperoxides. Saddex qoys oo waaweyn oo GSTs ah ayaa lagu sifeeyay: cytosolic GST, mitochondrial GST,80,81 iyo membran-Associated microsomal GST oo door ku leh eicosanoid iyo GSH metabolism. Pi, Sigma, Theta, Omega, iyo Zeta.82�83 Inta lagu jiro xaaladaha aan cadaadiska lahayn, fasalka Mu iyo Pi GSTs waxay la falgalaan kinases Ask86 iyo JNK, siday u kala horreeyaan, oo ay joojiyaan kinases kuwaas.1 JNK oo ka jawaabeysa cadaadiska oksaydhka.87 GSTP89 sidoo kale jir ahaan waxay la falgalaan PRX VI waxayna keenaysaa dib u soo kabashada dhaqdhaqaaqa enzyme PRX iyada oo loo marayo glutathionylation ee borotiinka oksaydhka.1
Nonenzymatic Antioxidants
Antioxidants Nonenzymatic waxaa ka mid ah xeryahooda miisaankoodu yar yahay, sida fiitamiinnada (fitamiinnada C iyo E), b-carotene, uric acid, iyo GSH, tripeptide (Lg-glutamyl-L-cysteinyl-L-glycine) oo ka kooban thiol sulfhydryl) koox.
Vitamin C (ascorbic acid)
Faytamiin C-da biyaha ku milma (ascorbic acid) ayaa bixiya intracellular iyo extracellular aqueous-phase awood antioxidant ugu horrayn iyada oo la nadiifinayo xag-jirrada xorta ah ee ogsijiinta. Waxay u beddeshaa fiitamiin E radicals-yada xorta ah oo dib ugu celisa fitamiin E. Heerarka balaasmaha ayaa la muujiyay inay hoos u dhacaan da'da.91,92
Vitamin E (a-Tocopherol)
Faytamiin E-ku-milmi kara waxa uu ku urursan yahay goobta gudaha ee hydrophobic ee xuubka unugga waana difaaca ugu muhiimsan ee ka hortagga dhaawaca xuubabka oksidheertu ay keento. Faytamiin E wuxuu ugu deeqaa elektarooniga peroxyl radical, kaas oo la soo saaro inta lagu jiro peroxidation lipid. a-Tocopherol waa qaabka ugu firfircoon ee fitamiin E iyo antioxidant-ka xuub-ku-xidhan ee weyn ee unugga. Faytamiin E waxa uu kiciyaa apoptosis ee unugyada kansarka waxana uu joojiyaa samaynta xagjirnimada xorta ah.93
Glutathione
GSH aad bay ugu badan tahay dhammaan qaybaha unugyada waana antioxidant-ka milmay ee ugu weyn. Saamiga GSH/GSSG waa go'aamiye weyn ee diiqada oksaydhka. GSH waxay siyaalo kala duwan u muujisaa saamaynta antioxidant-keeda.94 Waxay nadiifisaa hydrogen peroxide iyo lipid peroxides iyada oo loo marayo ficil GSH-Px. GSH waxay ku deeqdaa elektaroonkeeda H2O2 si ay uga dhigto H2O iyo O2. GSSG waxaa mar kale lagu soo koobay GSH GSH reductase kaas oo u isticmaala NAD(P)H ku deeqaha elektarooniga ah. GSH-Pxs sidoo kale waxay muhiim u yihiin ilaalinta xuubka unugga ee lipid peroxidation. Glutathione oo la dhimay ayaa borotoonnada ugu deeqa xuubka xuubka waxayna ka ilaalisaa weerarada oksaydhiyeyaasha.95
GSH waa qaybiye dhowr enzymes oo sun-saaraya, sida GSH-Px iyo wareejinta. Waxay door ku leedahay u beddelashada fiitamiin C iyo E inay ku noqdaan foomamkoodii firfircoonaa. GSH waxay unugyada ka ilaalisaa apoptosis iyada oo la falgasha dariiqyada calaamadaynta proapoptotic iyo antiapoptotic.94 Waxay sidoo kale nidaamisaa oo kicisaa dhowr arrimood oo qoraal ah, sida AP-1, NF-kB, iyo Sp-1.
Carotenoids (b-Carotene)
Carotenoids waa midabyo laga helo dhirta. Asal ahaan, b-carotene ayaa la ogaaday in ay la falgasho peroxyl (ROO), hydroxyl (OH), iyo superoxide (O22.) radicals.96 Carotenoids waxay muujiyaan saameyntooda antioxidant ee cadaadiska qayb ka mid ah oksijiinta laakiin waxaa laga yaabaa inay saameyn ku yeeshaan pro-oxidant at oxygen sare fiirsashada.97 Carotenoids iyo retinoic acids (RAs) labaduba waxay awood u leeyihiin inay nidaamiyaan qodobbada qoraalka. Carotenoids waxay sidoo kale saameeyaan apoptosis ee unugyada. Saamaynta ka hortagga faafinta ee RA ayaa lagu muujiyay dhowr daraasadood. Saamayntan RA waxaa dhexdhexaadiya inta badan receptors retinoic acid waxayna ku kala duwan yihiin noocyada unugyada. Unugyada kansarka naasaha, reseptors retinoic acid ayaa lagu muujiyay in uu kiciyo xakameynta koritaanka iyada oo la kicinayo wareegga unugyada, apoptosis, ama labadaba.98
Cadaadiska Oxidative wuxuu dhacaa marka dheellitirka u dhexeeya antioxidants iyo ROS la carqaladeeyo sababtoo ah labadaba antioxidants ama ururinta ROS. Marka cadaadiska oksaydhiyuhu dhaco, unugyadu waxay isku dayaan inay ka hortagaan saamaynta oksaydhiyaha oo ay dib u soo celiyaan dheelitirka redox-ka iyagoo kicinaya ama aamusinaya hiddo-wadaha dhigaya ensaymes difaaca, qodobbada qoraalka, iyo borotiinnada qaab-dhismeedka. ee go'aamiyaasha muhiimka ah ee cadaadiska oksida ee jirka. Wax soo saarka sare ee ROS ee jirka ayaa laga yaabaa inuu beddelo qaab-dhismeedka DNA-da, natiijada wax ka beddelka borotiinnada iyo lipids-ka, firfircoonida dhowr arrimood oo qoraal ah oo walaac-ku-abuuray, iyo soo-saarka cytokines-bararka iyo anti-bararka.
Saamaynta Cadaadiska Oxidative ee DNA
ROS waxay u horseedi kartaa wax ka beddelka DNA-da siyaabo dhowr ah, taas oo ku lug leh hoos-u-dhac ku yimaada saldhigyada, jebinta DNA-da hal-ama laba-geesoodka ah, purine, pyrimidine ama isbeddellada ku xiran sonkorta, isbeddelka, tirtirka ama beddelka, iyo isku-xidhka borotiinnada. Inta badan isbeddelladan DNA-da (Jaantus. 1) waxay aad ugu habboon yihiin kansarka, gabowga, iyo neurodegenerative, cudurrada wadnaha iyo xididdada dhiigga. Qiiqa tubaakada, biraha redox-ka ah, iyo biraha aan redox-ka ahayn, sida birta, cadmium, chrome, iyo arsenic, ayaa sidoo kale ku lug leh kansarka iyo gabowga iyaga oo abuuraya xagjirnimo xor ah ama ku xidhan kooxaha thiol. Samaynta 8-OH-G waa dhaawaca DNA-ga ugu caansan ee ku dhaca diiqada oksaydhiyaha waana calaamadiye suurtagal ah oo loogu talagalay kansarka.
Gobollada hiddo-wadaha dhiirrigeliya waxay ka kooban yihiin taxane la isku raacsan yahay ee qodobbada qoraalka. Qodobadan qoraalka ah ee goobaha xidhidha waxay ka kooban yihiin taxane GC qani ku ah kuwaas oo u nugul weerarada oksaydhisku. Samaynta 8-OH-G DNA ee goobaha isku xidhka factor transcription waxay wax ka beddeli kartaa xidhitaanka qodobbada qoraalka oo markaa beddelaa muujinta hidda-wadaha la xidhiidha sida lagu muujiyey taxanaha bartilmaameedka AP-1 iyo Sp-1 Ka sokow 103-OH-G, 8 -cyclo-8,59 -deoxyadenosine (cyclo-dA) ayaa sidoo kale la muujiyay in ay joojiso qoraalka hidda-wadaha weriyaha ee nidaamka unugga haddii uu ku yaal sanduuqa TATA. . Ku-xidhka borotiinka-ku-xidhan ee TATA waxaa laga yaabaa inuu wiiqo joogitaanka cyclo-dA.
Cadaadiska Oxidative wuxuu keenaa xasillooni darrada microsatellite (tandem gaaban oo soo noqnoqda) gobollada. Redox biraha firfircoon ee firfircoon, hydroxyl radicals waxay kordhiyaan xasilloonida microsatellite.105 Inkasta oo jebinta DNA-da hal-xidhaale ee ay sababto dhaawaca oksidantu ay si fudud u dulqaadan karaan unugyada, jajabyada DNA-da laba-geesoodka ah ee ay sababaan shucaaca ionizing waxay noqon kartaa khatar weyn oo loogu talagalay badbaadada unugyada.106
Methylation ee jasiiradaha CpG ee DNA-da waa hab muhiim ah oo epigenetic ah oo keeni kara aamusnaanta hiddo-wadaha. Oxidation of 5-MeCyt ilaa 5-hydroxymethyl uracil (5-OHMeUra) waxay ku dhici kartaa iyada oo loo marayo falcelinta deamination / oxidation of thymine ama 5-hydroxymethyl cytosine intermediates.107 Marka lagu daro muujinta hidda-wadaha wax ka beddelka, methylation DNA waxay sidoo kale u muuqataa inay saameynayso ururka chromatin.108 Qaababka methylation DNA-ga aberrant ee ay sababeen werarada oxidative waxay sidoo kale saameeyaan waxqabadka dayactirka DNA.
Saamaynta Cadaadiska Oxidative ee Lipids
ROS waxay dhalin kartaa peroxidation lipid waxayna carqaladeyn kartaa nidaamka xuubka dufanka leh kaas oo laga yaabo inay kiciyaan soo-dhoweeyayaasha xuubka-ku-xidhan iyo enzymes waxayna kordhiyaan nudaha permeability. -linkages.109�110 112-Hydroxy-4-aan-nonenal sababa hoos u dhaca GSH intracellular iyo induces of peroxide wax soo saarka,2 activates epidermal factor factor reseptor,113,114 iyo soo saarka fibronectin. , ayaa loo isticmaalay sidii bayoolajiyaal aan toos ahayn ee cadaadiska oksaydhka, iyo heerarka korodhay ayaa lagu muujiyay kondensate neefta la sii daayo ama dheecaanka bronchoalveolar lavage ama sambabada bukaannada cudurrada sambabada ee joogtada ah ama sigaarka.115�116
Saamaynta Cadaadiska Oxidative ee Borotiinnada
ROS waxay sababi kartaa kala-goynta silsiladda peptide-ka, beddelka kharashka korantada ee borotiinnada, isku-xidhka borotiinnada, iyo oksaydhka amino acids-ka gaarka ah sidaa darteedna waxay horseedaa korodhka u nuglaanshaha borotiinka by hoos-u-dhigga borotiinnada gaarka ah.120 Cysteine iyo methionine hadhaagii borotiinku waa gaar ahaan aad ugu nugul oksaydhka.121 Oxidation of sulfhydryl groups ama hadhaaga methionine ee borotiinada waxay sababtaa isbeddelo isbedbeddela, borotiinka soo baxaya, iyo hoos u dhaca.8,121 Beddelka Oxidative ee enzymes ayaa la muujiyay si loo joojiyo hawlahooda.123
Xaaladaha qaarkood, oksaydheynta gaarka ah ee borotiinnada ayaa laga yaabaa inay dhacdo. Tusaale ahaan, methionine wuxuu noqon karaa oxidized methionine sulfoxide126 iyo phenylalanine ilaa o-tyrosine127; Kooxaha sulfhydryl waa la oksaydheyn karaa si ay u sameeyaan curaarta disulfide;128 iyo kooxaha karbonyl waxaa laga yaabaa in lagu soo daro silsiladaha dhinaca ee borotiinnada. fallaadhaha gamma, oksaydhaynta birta-catalyzed, HOCl, iyo ozone waxay sababi karaan samaynta kooxaha karbonyl.129
Saamaynta Cadaadiska Oxidative ee Gudbinta Calaamadaha
ROS waxay dhalin kartaa muujinta hiddo-sideyaal dhowr ah oo ku lug leh gudbinta calaamadaha.1,130 Saamiga sare ee GSH/GSSG ayaa muhiim u ah ka ilaalinta unugga waxyeellada oksaydhka. Burburinta saamigani waxay sababtaa kicinta qodobbada qoraalka xasaasiga ah ee redox, sida NF-kB, AP-1, factor nukliyeerka ee unugyada T ee firfircoon iyo hypoxia-inducible factor 1, kuwaas oo ku lug leh jawaabta bararka. Dhaqdhaqaaqa qodobbada qoraalka ee ROS waxaa lagu gaaraa calaamado gudbinta calaamadaha kuwaas oo u gudbiya macluumaadka dibadda una gudbiya gudaha unugyada. Reseptors Tyrosine kinase, inta badan reseptors factor koritaanka, sida epidermal kobaca factor reseptor, vascular endothelial factor factor receptor, iyo receptor for factor koritaanka platelet ka soo jeeda, protein tyrosine fosfatases, iyo serine/threonine kinases waa bartilmaameedyada ROS.131�133 Kinases-ka-xakamaynta calaamadaha unugga-gaaban, JNK, iyo p38, kuwaas oo ah xubnaha qoyska kinase protein-ka firfircoon ee mitogen-ka oo ku lug leh dhowr habab oo unug ah oo ay ku jiraan kororka, kala-duwanaanta, iyo apoptosis, sidoo kale waxaa lagu xakameyn karaa oksaydhiyeyaasha.
Xaaladaha cadaadiska oksaydhka, hadhaaga cysteine ee goobta DNA-ku-xidha ee c-Jun, qaar ka mid ah qaybaha AP-1, iyo kB kinase ee xannibaya waxay maraan S-glutathiolation dib loo rogi karo. Glutaredoxin iyo TRX ayaa lagu soo warramey inay door muhiim ah ka ciyaaraan nidaaminta dariiqyada calaamadaha dareenka redox-ka, sida NF-kB iyo AP-1, p38 mitogen-activated protein kinase, iyo JNK.134�137
NF-kB waa la dhaqaajin karaa iyada oo laga jawaabayo xaaladaha cadaadiska oksaydhka, sida ROS, radicals free, iyo UV irradiation.138 Phosphorylation of IkB waxay sii daysaa NF-kB waxayna u ogolaataa inay gasho xudunta si ay u dhaqaajiso hidda-wadaha.139 Tiro kinases ah ayaa leh. waxaa lagu soo wargeliyay fosfooraska IkBs ee hadhaaga serine. Kinasesyadani waa bartilmaameedyada calaamadaha oksaydhka ee loogu talagalay firfircoonida NF-kB.140 Yaraynta wakiilada waxay kor u qaadaan NF-kB DNA-da, halka wakiilada oksijiinta ay joojiyaan xiritaanka DNA ee NF-kB. TRX waxaa laga yaabaa inay sameyso 2 ficil oo ka soo horjeeda nidaamka NF-kB: cytoplasm, waxay xannibaysaa hoos u dhigista IkB waxayna joojisaa firfircoonida NF-kB laakiin waxay kor u qaadaysaa NF-kB DNA ee ku xiran xudunta.141 Dhaqdhaqaaqa NF-kB iyada oo loo marayo hoos u dhaca oksidheer ee IkB waxay keentaa firfircoonida dhowr hidde-side difaaca antioxidant. NF-kB waxay xakameysaa muujinta hidde-sideyaal dhowr ah oo ka qaybqaata jawaab-celinta difaaca jirka, sida IL-1b, IL-6, tumor necrosis factor-a, IL-8, iyo dhowr molecules adhesion.142,143 NF-kB sidoo kale waxay xakameysaa angiogenesis iyo kordhinta iyo kala soocidda unugyada.
AP-1 sidoo kale waxaa nidaamiya gobolka redox. Joogitaanka H2O2, ions birta qaarkood waxay keeni karaan firfircoonida AP-1. Kordhinta saamiga GSH/GSSG waxay kor u qaadaysaa isku xidhka AP-1 halka GSSG ay joojinayso xidhitaanka DNA-da ee AP-1.144 DNA ee Fos/Jun heterodimer waxaa kordhay hoos u dhigista hal cysteine ah oo la ilaaliyo ee qaybta DNA-ku xidha ee mid kasta oo ka mid ah. borotiinada,145 halka DNA-da ee AP-1 lagu xakameyn karo GSSG noocyo badan oo unug ah, taasoo soo jeedinaysa in samaynta isku-xidhka disulphide ee haraaga cysteine-ka ay joojiso xiritaanka AP-1 DNA.146,147 Transduction Signal through oxidative stress ayaa lagu soo koobay sawirka 2.
LOOGU TALAGALAY
Cadaadiska Oxidative wuxuu ka dhalan karaa wax soo saarka xad-dhaafka ah ee ROS ee falcelinta dheef-shiid kiimikaadka kuwaas oo isticmaala ogsijiinta oo beddela dheelitirka u dhexeeya oksidant/antioxidant statuses door bidaan oxidants. ROS waxaa soo saara dhaqdhaqaaqyada dheef-shiid kiimikaadka gacanta iyo arrimaha deegaanka, sida wasakhowga hawada ama qiiqa sigaarka. ROS waa unugyo firfircoon oo aad u firfircoon sababtoo ah elektaroonnada aan la isku xirneyn ee qaab-dhismeedkooda waxayna la falgalaan dhowr makromolecule bayooloji ah oo ku jira unugga, sida karbohaydraytyada, asiidhyada nucleic-ka, dufanka, iyo borotiinka, waxayna beddelaan shaqadooda. ROS sidoo kale waxay saamaysaa muujinta hiddo-sideyaal dhowr ah iyada oo la hagaajinayo qodobbada qoraalka xasaasiga ah ee redox iyo dib-u-qaabaynta chromatin iyada oo loo marayo beddelka histone acetylation/deacetylation. Nidaaminta xaaladda redox waxay muhiim u tahay jiritaanka unugga, firfircoonida, fidinta, iyo shaqada xubnaha.
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