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iiseli zisebenzisa i-glucose ukwenza amandla
i-immune system ilwa neebhaktheriya kunye nokudala ukuvuvukala
imizimba inokukhupha izinto ezingcolileyo, i-pesticides, kunye nomsi wecuba
Kukho izigidi zeenkqubo ezenzeka emzimbeni wethu nangaliphi na ixesha elinokubangela ukukhutshwa kwe-oxidation. Nazi iimpawu ezimbalwa:

Ukukhathala
Ukulahleka kweememori kunye nenkohlakalo yengqondo
Intlungu kunye okanye intlungu
Ukuguquka kunye neenwele ezimvu
Ukuncipha kwamehlo
Intloko kunye novelwano kwingxolo
Ukungahambi kakuhle kwizifo
Ukukhetha ukutya okuphilayo kunye nokuphepha i-toxins kwindawo yakho kwenza umahluko omkhulu. Oku, kunye nokunciphisa uxinzelelo, kunokuba luncedo ekunciphiseni i-oxidation.

Umsebenzi ophakamileyo we-Nrf2 kuMsebenzi weMitochondrial

by UGqr Alex Jimenez | Ubuhlungu obungapheliyo, Ukuxutyushwa, LweMpilo, impilo, Medicine Holistic, WeMpilo yeNdalo, isondlo, Uxinzelelo oluxhasayo, ulungiso, Izifundo zoPhando, nezongezo, Unyango, Ukuphila

Izidakamizwa ziveliswa ngendlela elawulwayo ukuze zilawulwe iinkqubo ezibalulekileyo emzimbeni womntu, kubandakanywa ukwahlukana kweeseli, ukuvuvukala, ukusebenza komzimba, ukuzenzekelayo, kunye nokunyamezela ukuphendula. Nangona kunjalo, ukuveliswa okungalawulwayo kwezi baxhasi kungenza inxaxheba uxinzelelo oluxhamlayo, ezinokuchaphazela umsebenzi weselula, ezikhokelela ekuphuhlisweni kwesetyhi, izifo ezingapheliyo nomhlaza. Iindlela zomzimba zokhuselo ezikhuselekileyo zilawulwa ngoluhlu lweendlela ezibalulekileyo ezilawula indlela esabela ngayo iseli kumacidizi. I-nyukliya ye-erythroid ehlobene ne-2, into eyaziwa ngokuba yi-Nrf2, isilawuli esiphumelelayo sokumelana kwamaseli kuma-oxidants. Injongo yendiqendu engezantsi kukuxoxa nokubonisa indima ephumayo yeNrf2 kwimisebenzi ye-mitochondrial.

Abstract

I-transcription factor NF-E2 p45-related factor 2 (Nrf2; igama lofuzo i-NFE2L2) ivumela ukulungelelaniswa kunye nokusinda phantsi kweemeko zoxinzelelo ngokulawula ukubonakaliswa kwejenethi ehlukeneyo ye-cytoprotective proteins, kubandakanywa ne-antioxidant, i-anti-inflammatory, kunye ne-detoxification enzymes ngokunjalo. njengeeprotheyini ezincedisa ekulungiseni okanye ekususeni ii-macromolecules ezonakalisiweyo. I-Nrf2 inendima ebalulekileyo ekugcinweni kwe-redox homeostasis yeselula ngokulawula i-biosynthesis, ukusetyenziswa, kunye nokuhlaziywa kwe-glutathione, i-thioredoxin, kunye ne-NADPH kunye nokulawula ukuveliswa kweentlobo ze-oksijini esebenzayo nge-mitochondria kunye ne-NADPH oxidase. Ngaphantsi kweemeko ze-homeostatic, i-Nrf2 ichaphazela i-membrane ye-mitochondrial, i-fatty acid oxidation, ukufumaneka kwe-substrates (i-NADH kunye ne-FADH2 / i-succinate) yokuphefumula, kunye ne-ATP synthesis. Ngaphantsi kweemeko zoxinzelelo okanye ukukhula kwezinto ezikhuthazayo, ukusebenza kwe-Nrf2 kuchasene nokunyuka kwemveliso ye-oksijini esebenzayo kwi-mitochondria ngokusebenzisa i-transcriptional upregulation ye-protein ye-3 kunye nefuthe le-mitochondrial biogenesis ngokugcina amanqanaba e-nuclear factor 1 kunye ne-peroxisome proliferator-activated receptor? i-coactivator 1?, kunye nokukhuthaza i-purine nucleotide biosynthesis. I-Pharmacological Nrf2 activators, ezifana ne-isothiocyanate sulforaphane eyenzeka ngokwemvelo, inqanda ukuvulwa kwe-oxidant-mediated ye-mitochondrial permeability transition pore kunye nokuvuvukala kwe-mitochondrial. Kuyathakazelisa ukuba i-synthetic 1,4-diphenyl-1,2,3-triazole compound, eyenzelwe ekuqaleni njenge-activator ye-Nrf2, yafunyanwa ukukhuthaza i-mitophagy, ngaloo ndlela igalelo kwi-homeostasis ye-mitochondrial jikelele. Ngaloo ndlela, i-Nrf2 ngumdlali obalaseleyo ekuxhaseni ukunyaniseka kwesakhiwo kunye nokusebenza kwe-mitochondria, kwaye le nxaxheba ibaluleke kakhulu phantsi kweemeko zoxinzelelo.

Internet: Bioenergetics, Cytoprotection, Keap1, iMitochondria, i-Nrf2, i-Radicals yamahhala

Iimbalasane

I-Nrf2 inendima ebalulekileyo ekulondolozeni i-homeostasis yeselula ye-redox.
I-Nrf2 ithinta i-memitane ye-mitochondrial kunye ne-ATP synthesis.
I-Nrf2 ichaphazela i-acidified acid acid oxidation.
I-Nrf2 isekela ingqibelelo yesakhiwo kunye nemisebenzi ye-mitochondria.
Ama-activator ye-Nrf2 aneempembelelo ezilungileyo xa umsebenzi we-mitochondrial uphathwe.

intshayelelo

I-transcription factor NF-E2 p45-related factor 2 (Nrf2; gene name NFE2L2) ilawula ukubonakaliswa kothungelwano lwee-proteins ze-encoding ye-genes kunye nemisebenzi eyahlukeneyo ye-cytoprotective. I-Nrf2 ngokwayo ilawulwa ngokuyinhloko kwinqanaba lokuzinza kweprotheni. Ngaphantsi kweemeko ze-basal, i-Nrf2 yiprotheni ehlala ixesha elifutshane ephantsi kwe-ubiquitination eqhubekayo kunye nokuthotywa kweproteasomal. Kukho iinkqubo ezintathu ezaziwayo ze-ubiquitin ligase ezinegalelo ekuthotyweni kwe-Nrf2. Ngokomlando, umlawuli wokuqala ongalunganga we-Nrf2 oza kufunyanwa yi-Kelch-efana ne-ECH-ehambelana neprotheyini ye-1 (Keap1) [1], iprotheni ye-adapter ye-substrate ye-Cullin 3 (Cul3) / Rbx1 ubiquitin ligase [2], [3], [ 4]. I-Keap1 isebenzisa indlela esebenza kakhulu yomjikelo ukujolisa kwi-Nrf2 yendawo yonke kunye nokuthotywa kweproteasomal, apho i-Keap1 iqhubeka ihlaziywa, ivumela umjikelo ukuba uqhubeke (Umfanekiso 1A) [5]. I-Nrf2 nayo iphantsi kokunciphisa i-glycogen synthase kinase (GSK) 3 /?-TrCP-exhomekeke kwi-Cul1-based ubiquitin ligase [6], [7]. Ngoku kutshanje, kwaxelwa ukuba, ngexesha leemeko zoxinzelelo lwe-endoplasmic reticulum, i-Nrf2 ifumaneka kuyo yonke indawo kwaye ihlaziywe kwinkqubo exutywe yi-E3 ubiquitin ligase Hrd1 [8].

**Umzobo 1 Umzekelo wokuhamba kunye nokuhlaziywa ngokutsha kwe-Keap1-deeddation of Nrf2.** (A) I-Nrf2 ibopha ngokulandelanayo kwi-Keap1 dimer yamahhala: yokuqala ngokubambisana kwayo kunye ne-ETGE (intonga ebomvu) kwisiqulatho esibophayo kwaye emva koko kubambene ne-DLG (iimbosi ezimnyama) ezibophelelayo. Kule nkqubela yeprotheni eyinkimbinkimbi, i-Nrf2 ihambelana no-ubiquitination kwaye ijoliswe ekuhlakalweni kweprotasomal. I-Keap1 yamahhala ivuselelwe kwaye iyakwazi ukubopha kwi-Nrf2 entsha, kwaye umjikelezo uqala kwakhona. (B) I-inducers (amadayimane amhlophe) ayenzeka nge-cysteines ye-Keap1 (intonga ebhakabhaka), ekhokelela ekutshintsheni okuguquguqukayo kunye nomsebenzi ongekho umonakalo we-adapter. I-Keap1 yamahhala ayinakuvuselelwa kwakhona, kwaye iNrf2 esanda kuhlanganiswa iqokelela ize idluliselwe kwinucleus.

Ukongezelela ekusebenzeni njengeprothini ye-ubiquitin ligase substrate ipilitini, uKap1 nayo inzwa yoluhlu olubanzi lwe-activator-molecule ye-Nrf2 (ebizwa ngokuba yi-inducers) [9]. Ukucima umjikelezo we-Keap1-ulwaphulo oludibeneyo lwe-Nrf2 ngokuchitshiyelwa kwemichiza ye-cysteine ethile kwi Keap1 [10], [11] okanye ngokuphazamisa ngqo iKeap1: I-Nrf2 isixhobo sokubopha [12], [13]. Ngenxa yoko, i-Nrf2 ayinakuhlaziywa, kwaye i-factual faction iqokelela kwaye idlulisela kwi-nucleus (i-Fig. 1B), apho yenza i-heterodimer eneprotein encinci; ibophezela kumacandelo e-antioxidant-response, kwimimandla elawulayo ephezulu yamagalethi ayo ekujoliswe kuyo; kwaye iqalise ukubhalwa kwephepha [14], [15], [16]. Iibhetri yeenjongo ze-Nrf2 ziquka iiprotheyini ezinemisebenzi eyahlukeneyo ye-cytoprotective, kuquka i-enzyme ye-xenobiotic metabolism, iiprotheni ezinemisebenzi yamanxuwa kunye ne-anti-inflammatory, kunye nama-subtit ase-proteasomal, kunye nama-proteins alawula i-homeostasis yamaselula kunye nokuthatha inxaxheba kwimetabolism.

Nrf2: uMlawuli oyiNtloko weeLellu Redox Homeostasis

Umsebenzi we-Nrf2 njengomlawuli oyintloko we-cellular redox homeostasis yamkelwa ngokubanzi. I-gene expression of both catalytic and regulatory subunits of ?-glutamyl cysteine ligase, i-enzyme eyenza inyathelo lokunciphisa izinga kwi-biosynthesis yokunciphisa i-glutathione (GSH), ilawulwa ngokuthe ngqo yi-Nrf2 [17]. I-subunit ye-xCT yenkqubo ye-xc-, engenisa i-cystine kwiiseli, ikwayi-transcriptional target ngqo ye-Nrf2 [18]. Kwiseli, i-cystine iguqulelwa kwi-cysteine, isandulela se-biosynthesis ye-GSH. Ukongeza kwindima yayo kwi-GSH biosynthesis, i-Nrf2 ibonelela ngeendlela zokugcina i-glutathione kwindawo yayo encitshisiweyo ngummiselo olungelelanisiweyo wokubhalwa kwe-glutathione reductase 1 [19], [20], eyanciphisa i-glutathione ene-oxidized ukuya kwi-GSH isebenzisa ukulinganiswa kokunciphisa ukusuka kwi-NADPH. . I-NADPH efunekayo inikezelwa yizinqununu ezine ze-NADPH-generating enzymes, i-malic enzyme 1 (ME1), i-isocitrate dehydrogenase 1 (IDH1), i-glucose-6-phosphate dehydrogenase (G6PD), kunye ne-6-phosphogluconate dehydrogenase (PGD), zonke ezo ngokubhaliweyo kulawulwa ngokuyinxalenye ye-Nrf2 (umzobo 2) [21], [22], [23], [24]. Okumangalisayo kukuba, i-Nrf2 iphinda ilawule i-inducible gene expression ye-cytosolic, i-microsomal, kunye ne-mitochondrial ye-aldehyde dehydrogenase [25], esebenzisa i-NAD (P) + njenge-cofactor, eyenza i-NAD (P) H. Enyanisweni, amanqanaba e-NADPH kunye nomlinganiselo we-NADPH / NADP + aphantsi kwi-embryonic fibroblasts ehlukanisiwe kwiigundane ze-Nrf2-knockout (Nrf2-KO) xa kuthelekiswa neeseli ezivela kuhlobo lwazo lwasendle (WT), kwaye amanqanaba e-NADPH ayancipha kwi-Nrf2 knockdown in. imigca yeseli yomhlaza ene-Nrf2 esebenzayo [26]. Njengoko kulindelwe, amanqanaba e-GSH aphantsi kwiiseli apho i-Nrf2 iphazamisekile; ngokuchaseneyo, ukusebenza kwe-Nrf2 ngeendlela zofuzo okanye i-pharmacological kukhokelela ekulawuleni i-GSH [27], [28], [29]. Okubalulekileyo, i-Nrf2 iphinda ilawule i-gene expression of thioredoxin [30], [31], [32], i-thioredoxin reductase 1 [28], [29], [32], [33], kunye ne-sulfiredoxin [34], eziyimfuneko. ukwenzela ukunciphisa i-thiols yeprotheyini ene-oxidized.

**Umzobo 2 Indima ye-Nrf2 kwi-metabolism yeeseli ezandayo ngokukhawuleza.** I-Nrf2 ngumlawuli olungileyo we-gene encoding enzymes kuzo zombini ingalo ye-oxidative [oko kukuthi, i-glucose-6-phosphate dehydrogenase (G6PD) kunye ne-6-phosphogluconate dehydrogenase (PGD)] kunye nengalo ye-nonoxidative [okt, transaldolase 1 (TALDO1) kunye ne-transketolase ( TKT)] yepentose phosphate pathway. I-G6PD kunye ne-PGD zivelisa i-NADPH. I-Nrf2 iphinda ilawule ukubonakaliswa kofuzo lwezinye ezimbini ze-NADPH-ezenza i-enzymes, i-malic enzyme 1 (ME1) kunye ne-isocitrate dehydrogenase 1 (IDH1). Ukubonakaliswa kofuzo lwe-phosphoribosyl pyrophosphate amidotransferase (PPAT), eyenza ukungena kwindlela ye-de novo purine biosynthetic pathway, iphinde ilawulwe ngokufanelekileyo yi-Nrf2, njengoko kubonakaliswa kwe-methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), indima ebalulekileyo ye-mitochondrial kwi-enzyme ukubonelela ngeeyunithi zekhabhoni enye ye-de novo purine biosynthesis. I-Pyruvate kinase (PK) ilawulwa kakubi yi-Nrf2 kwaye ilindeleke ukuba ithande ukwakhiwa kwe-glycolytic intermediates kwaye, kunye ne-G6PD, i-metabolite ye-metabolite nge-pentose phosphate pathway kunye ne-synthesis ye-nucleic acids, i-amino acids, kunye ne-phospholipids. I-Nrf2 ilawula kakubi i-gene expression of ATP-citrate lyase (CL), enokunyusa ukufumaneka kwe-citrate yokusetyenziswa kwe-mitochondrial okanye (nge-isocitrate) ye-IDH1. Ubomvu kunye nohlaza okwesibhakabhaka kubonisa ukulawulwa okulungileyo kunye nokubi, ngokulandelanayo. I-mitochondrion iboniswe ngombala ongwevu. Izifinyezo zeMetabolite: G-6-P, i-glucose 6-phosphate; F-6-P, fructose 6-phosphate; F-1,6-BP, fructose 1,6-bisphosphate; GA-3-P, glyceraldehyde 3-phosphate; 3-PG, 3-phosphoglycerate; I-PEP, i-phosphoenolpyruvate; I-6-P-Gl, i-6-phosphogluconolactone; I-6-PG, i-6-phosphogluconate; R-5-P, ribulose 5-phosphate; I-PRPP, i-5-phosphoribosyl-?-1-pyrophosphate; I-THF, i-tetrahydrofolate; IMP, inosine monophosphate; I-AMP, i-adenosine monophosphate; GMP, guanosine monophosphate.

Ngenxa yenxaxheba ebalulekileyo ye-Nrf2 njengomlawuli we-cellular redox homeostasis, akumangalisi ukuba, xa kuthelekiswa neeseli ze-WT, amanqanaba ezityalo ze-oksijeni ezisebenzayo (ROS) ziphezulu kwiiseli apho iNrf2 iphazamisekile (iNrf2-KO) [35]. Lo mahluko ngokukhethekileyo uhlasela umngeni kunye nama-agent abangela uxinzelelo lwe-oxidative. Ngaphezu koko, iiseli ezingenayo kwi-Nrf2 zininzi ngakumbi kwi-toxicity ye-oxidants of different types kwaye azikwazi ukukhuselwa yi-Nrf2 inducers, apho, phantsi kweemeko ezifanayo, kunika ukukhuseleka okuqhubekayo nokuhlala ixesha elide kwii-WT cells [29], [36] , [37]. Ukongeza kwi-homeostasis ye-redox homeostasis, i-Nrf2 nayo ibaluleke kakhulu ekugcinweni kwe-homeostasis ye-mitochondrial redox. Ngaloo ndlela, xa kuthelekiswa ne-WT, i-pool ye-mitochondrial ye-NADH iyonke inyuke kakhulu kwi-Keap1-KO kwaye yancipha ngokuphawulekayo kwi-Nrf2-KO amaseli [35].

Ukusebenzisa ukucatshulwa kweseli ephilayo, sisanda kuhlola iirhafu zokuveliswa kweROS kwimigangatho ye-glioneuronal cocultures kunye neengcezu zengqondo zecala ezihlukeneyo kwi-WT, Nrf2-KO, okanye i-Keap1-knockdown (Keap1-KD) iigundane [38]. Njengoko kulindeleke, izinga lokuveliswa kweROS likhawuleza kwiiNelf2-KO zeeseli kunye nezicubu ezifaniswa namanye ama-WT. Nangona kunjalo, senze into engalindelekanga yokuba, xa kuthelekiswa neWT, iiseli ze-Keap1-KD nazo zinamazinga aphezulu okuveliswa kweROS, nangona ubukhulu bomehluko phakathi kwe-WT kunye ne-Keap1-KD i-genotypes yayincinci kuneyo phakathi kwe-WT ne-Nrf2-KO . ngoko sihlaziya amanqanaba mRNA of NOX2 kunye NOX4, le subunits zokuphosa le oxidase NADPH ezimbini (Nox) isoforms ukuba sele zikhankanyiwe zokugula ingqondo, bafumana ukuba NOX2 yi landa kakhulu phantsi kweemeko Nrf2 ngxaki, kanti NOX4 ke upregulated xa Nrf2 iyasebenza, kodwa nangona kuncinci. Ukulinganiswa, ubukhulu bokugqithisa kwiiseli kunye nezicubu ezivela kumagundane aguqukayo ziyafana nokunyuka okuhambelana nokuveliswa kweROS [38]. Kuyathakazelisa, kungekhona nje ukuba i-Nrf2 ilawula i-NADPH ye-oxidase, kodwa i-ROS eyenziwa yi-NADPH i-oxidase inokuqalisa i-Nrf2, njengoko kuboniswe kwiiseli ze-epithelial pulmonary and cardiomyocytes [39], [40]. Ngaphezu koko, uphando olutshanje luye lwabonisa ukuba ukusebenza kwe-NADPH-dependence-dependence ye-Nrf2 yindlela yokugcina ekhuselekileyo yokukhusela umonakalo we-mitochondrial kunye nokufa kwesisele entliziyweni ngexesha lokunyanzeliswa kwengcinezelo engapheliyo [41].

Ukongezelela kwinto yokwenza umsebenzi we-NADPH oxidase, ukuphefumula kwe-mitochondrial ngenye imvelaphi engundoqo ye-ROS. Ngokusetyenziswa kweprojektri ye-mitochondria e-MitoSOX, sihlolisise igalelo le-ROS yemvelaphi ye-mitochondrial kwi-ROS jikelele kwimveliso ye-glioneuronal cocultures ukusuka kwi-WT, i-Nrf2-KO, okanye i-Keap1-KD iigundane [38]. Njengoko kulindeleke, iiseli ze-Nrf2-KO zinamanani aphezulu e-ROS mitochondrial production ngaphandle kweWT. Ngokuvumelana neziphumo zoveliso lweROS jikelele, amaxabiso emveliso ye-mitochondrial ROS ku-Keap1-KD yayiphakeme kakhulu xa kuthelekiswa neeseli zeWT. Kubaluleke kakhulu, ukukhusela ubunzima be-rotenone bangela ukwanda okwenkqisayo kwimveliso ye-Rito mitochondrial kwimilo yesibini yeWT neKeap1-KD, kodwa ayizange ibe nempembelelo kwiiseli ze-Nrf2-KO. Ngokuphambene nokunyuka okulindelekileyo kwimveliso ye-Rito mitochondrial kwiiseli ze-WT emva kokungeniswa kwe-pyruvate (ukuphucula ukufumaneka kwe-NADH, ukwandisa umlenze we-mitochondrial, kunye nokugcina ukuphefumla), ukuveliswa kweROS kwanciphise kwi-cell Nrf2-KO. Ngokubakho, ezi ziphumo zibonisa ukuba, ngokungabikho kwe-Nrf2: (i) umsebenzi onzima kakhulu, (ii) umsebenzi ongenakunzima wezinto eziyinkimbinkimbi ngenxa yokunciphisa imida, kunye (iii) nomsebenzi ongenakunzima wezinto ezinzima Ndiyinye yezizathu ezibalulekileyo zokuveliswa kwe-ROS mitochondrial production, mhlawumbi ngenxa yokuguqula i-electron flow from complex II.

I-Nrf2 ithinta i-membrane yeMitochondrial Potential and Respiration

I-membrane ye-mitochondrial enokubakho (??m) luphawu lwendalo yonke lwempilo ye-mitochondrial kunye nemeko ye-metabolic yeseli. Kwiseli esempilweni, i-??m igcinwa litsheyini lokuphefumla lemitochondrial. Okubangela umdla kukuba, i-isotopic ezinzileyo yokubhalwa kwe-isotopic kunye ne-amino acids kwinkcubeko-based based proteomics study kwi-estrogen receptor-negative nontumorigenic human breast epithelial MCF10A cell line ibonise ukuba i-electron mitochondrial icandelo lokuthutha i-NDUFA4 ilawulwa yi-pharmacological activation2 (by) kanti ukulawulwa kofuzo kwe-Nrf2 (nge-Keap1 knockdown) ikhokelela ekuthotyweni kwe-cytochrome c oxidase subunits COX2 kunye ne-COX4I1 [42]. Uphononongo lweproteome yesibindi usebenzisa i-gel electrophoresis ene-dimensional-dimensional kunye ne-matrix-assisted laser desorption / ionization mass spectrometry ifumene ukuba i-Nrf2 ilawula ukubonakaliswa kwe-ATP synthase subunit? [43]. Ukongezelela, iprotheni ye-mitochondrial DJ-1, edlala indima ekugcinweni komsebenzi we-complex I [44], kuye kwabikwa ukuba izinzile i-Nrf2 [45], [46], nangona imiphumo ye-neuroprotective ye-pharmacological or genetic activation. ye-Nrf2 izimeleyo kwi-DJ-1 [47]. Nangona kunjalo, iziphumo zolu qwalaselo lomsebenzi we-mitochondrial ayikaphandwa.

Ngokuvumelana nomsebenzi ophazamisekileyo we-complex I phantsi kweemeko zokusilela kwe-Nrf2, i-basal ??m iphantsi kwi-Nrf2-KO ye-mouse embryonic fibroblasts (MEFs) kunye neeseli ze-glioneuronal eziphambili ezikhuliswe ngokuthelekiswa nabalingani babo be-WT (Fig. 3, inset) [35]. Ngokuchaseneyo, i-basal ??m iphezulu xa i-Nrf2 ilawulwa ngokwemfuza ngokusemthethweni (ngokuwisa okanye ukubethelwa kwe-Keap1). Lo mahluko kwi-??m phakathi kwe-genotypes ibonisa ukuba ukuphefumla kuchatshazelwa ngumsebenzi we-Nrf2. Enyanisweni, ukuvavanywa kokusetyenziswa kwe-oksijeni kwi-basal state kuye kwabonisa ukuba, xa kuthelekiswa ne-WT, ukusetyenziswa kwe-oksijeni kuphantsi kwi-Nrf2-KO kunye ne-Keap1-KO MEFs, nge ~ 50 kunye ne-35%, ngokulandelanayo.

**Umzobo we-3 Inkqubo ephakanyisiweyo yomsebenzi we-mitochondrial phantsi kweemeko ze-Nrf2.** (1) Amanqanaba anciphileyo e-ME1, i-IDH1, i-G6PD, kunye ne-PGD ibangela amanqanaba aphantsi e-NADPH. (2) Amanqanaba e-GSH nawo aphantsi. (3) Umsebenzi ophantsi we-ME1 unokunciphisa i-pool ye-pyruvate engena kwi-mitochondria. (4) Isizukulwana se-NADH sihamba kancinci, sikhokelela ekusebenzeni kakubi kwe-complex I kunye nokwanda kwemveliso ye-ROS ye-mitochondrial. (5) Ukunciphisa i-FAD kwi-FADH2 kwiiprotheni ze-mitochondrial nazo ziyancipha, zinciphisa ukuhamba kwe-electron ukusuka kwi-FADH2 ukuya kwi-UbQ nakwi-complex III. (6) Ukubunjwa okucothayo kwe-UbQH2 kunokunciphisa umsebenzi we-enzyme ye-succinate dehydrogenase. (7) Amanqanaba anyusiweyo e-ROS anokuthintela ngakumbi umsebenzi we-complex II. (8) Ukusebenza okuphantsi kwe-fatty acid oxidation kunegalelo ekunciphiseni ukufumaneka kwe-substrate yokuphefumula kwe-mitochondrial. (9) I-Glycolysis iphuculwe njengendlela yembuyekezo yokunciphisa imveliso ye-ATP kwi-phosphorylation ye-oxidative. (10) I-ATP synthase isebenza ngasemva ukugcina i-??m. Ubomvu kunye nohlaza okwesibhakabhaka kubonisa ukunyuswa kunye nokunciphisa, ngokulandelanayo. Iibhokisi zibonisa ukufumaneka kobungqina bokulinga. I-inset ibonisa imifanekiso ye-mitochondria ye-WT kunye ne-Nrf2-KO cortical astrocytes ebonwa nge-potentiometric fluorescent probe tetramethylrhodamine methyl ester (TMRM; 25 nM). Isikali bar, 20 �m.

Lo mahluko kwi-??m kunye nokuphefumla phakathi kwe-genotypes ubonakaliswa yisantya sokusetyenziswa kwee-substrates zokuphefumla kwe-mitochondrial. Ukusetyenziswa kwesubstrate zomjikelo we-tricarboxylic acid (TCA) (malate/pyruvate, ethi inyuse imveliso ye-complex I substrate NADH) okanye i-methyl succinate, i-substrate ye-complex II, ibangela ukunyuka kwe-stepwise kwi-??m kuzo zombini i-WT kunye ne-Keap1-KD neurons, kodwa izinga lokunyuka liphezulu kwiiseli ze-Keap1-KD. Okubaluleke ngakumbi, iimilo zokuphendula kwezi substrates zomjikelezo we-TCA zahlukile phakathi kwee-genotypes ezimbini, apho ukunyuka okukhawulezileyo kwi-??m kwiiseli ze-Keap1-KD phezu kokudibanisa kwe-substrate kulandelwa kukuhla ngokukhawuleza kunokuba i-plateau, iphakamisa ngokungaqhelekanga. ukusetyenziswa kwe-substrate ngokukhawuleza. Ezi ziphumo zihambelana ngokusondeleyo kunye namanqanaba asezantsi kakhulu (ngo-50�70%) we-malate, i-pyruvate, kunye ne-succinate eye yabonwa emva kwe-1-h pulse ye- [U-13C6] glucose kwi-Keap1-KO xa kuthelekiswa ne-WT MEF. iiseli [24]. Kwi-Nrf2-KO neurons, yi-pyruvate kuphela ekwazi ukunyusa i-??m, kanti i-malate kunye ne-methyl succinate ibangela ukuchithwa okuncinci. Impembelelo ye-Nrf2 kwimveliso ye-mitochondrial substrate ibonakala iyona ndlela iphambili apho i-Nrf2 ichaphazela umsebenzi we-mitochondrial. Isalathiso se-mitochondrial NADH redox index (ibhalansi phakathi kokusetyenziswa kwe-NADH nge-complex I kunye nokuveliswa kwe-NADPH kumjikelo we-TCA) iphantsi kakhulu kwiiseli ze-Nrf2-KO xa kuthelekiswa nabalingane babo be-WT, kwaye ngaphezu koko, amaxabiso okuhlaziywa kwamachibi echibi. I-NADH kunye ne-FADH2 emva kokuvinjelwa kwe-IV eyinkimbinkimbi (ngokusetyenziswa kwe-NaCN) iyancipha kwiiseli eziguqukayo.

Kwi-mitochondria eyodwa kwingqondo ye-murine kunye nesibindi, ukuxhaswa kwee-substrates ze-complex I okanye kwi-complex II kwandisa izinga lokusetyenziswa kwe-oksijini ngakumbi xa i-Nrf2 ivuliwe kwaye ingasebenzi kakuhle xa i-Nrf2 iphazamiseka [35]. Ngaloo ndlela, i-malate ibangela izinga eliphezulu lokusetyenziswa kwe-oksijini kwi-Keap1-KD xa kuthelekiswa ne-WT, kodwa umphumo wayo ubuthathaka kwi-Nrf2-KO mitochondria. Ngokufanayo, phambi kwe-rotenone (xa i-complex ivaliwe), i-succinate yenza ukusetyenziswa kwe-oksijini kusebenze kakhulu kwi-Keap1-KD xa kuthelekiswa ne-WT, ngelixa impendulo kwi-Nrf2-KO mitochondria iyancipha. Ukongezelela, i-Nrf2-KO iinkcubeko eziphambili ze-neuronal kunye neegundane zivakalelwa ngakumbi kwi-toxicity ye-II inhibitors i-3-nitropropionic acid kunye ne-malonate, kanti i-intrastriatal transplantation ye-Nrf2-overexpressing astrocytes ikhusela [48], [49]. Ngokufanayo, iigundane ze-Nrf2-KO zivakalelwa ngakumbi, ngelixa i-genetic okanye i-pharmacological activation ye-Nrf2 ineziphumo zokukhusela, i-neurotoxicity ebangelwa yi-complex I-inhibitor 1-methyl-4-phenylpyridinium ion kwi-1-methyl-4-phenyl-1,2,3,6, I-49-tetrahydropyridine imodeli yezilwanyana ze-Parkinson? [50], [51], [52], [53].

Umlinganiselo wokulawula ukuphefumula (RCR), umlinganiselo we-State 3 (i-ADP-ivuselelwe) kwi-State 4 yokuphefumula (akukho ADP ekhoyo), iyancipha ngokungabikho kwe-Nrf2, kodwa i-RCR ifana phakathi kwe-Keap1-KD kunye ne-WT mitochondria [35] ]. Njengoko i-RCR ibonakalisa iqondo lokudityaniswa komsebenzi wekhonkco lokuphefumla le-mitochondrial kwi-phosphorylation ene-oxidative, oku kufunyaniswayo kubonisa ukuba izinga eliphezulu lokuphefumla kwi-Keap1-KD mitochondria alikho ngenxa yokudibanisa i-phosphorylation ene-oxidative. Iphinda iphakamise ukuba i-phosphorylation ye-oxidative isebenze ngakumbi xa i-Nrf2 ivuliwe. Izinga eliphezulu lokuphefumla kwi-Keap1-KD mitochondria iyahambelana namanqanaba aphezulu emveliso ye-ROS ye-mitochondrial njengoko amazinga aphezulu okuphefumla anokukhokelela ekwandeni kokuvuza kwe-electron. Nangona kunjalo, phantsi kweemeko zokuxinzezeleka kwe-oxidative, ukuveliswa kwe-ROS okwandisiweyo kuchasene ne-Nrf38-exhomekeke kwi-transcriptional upregulation ye-protein ye-2 (UCP3), eyandisa i-proton conductance ye-membrane yangaphakathi ye-mitochondrial kwaye ngenxa yoko iyancipha ukuveliswa kwe-superoxide [3]. Ngoku kutshanje, kuboniswe ukuba imveliso ye-lipid peroxidation i-62-hydroxy-4-nonenal idibanisa i-Nrf2 exhomekeke kwi-UCP2 kwi-cardiomyocytes; oku kunokubaluleka ngokukodwa ekukhuseleni phantsi kweemeko zoxinzelelo lwe-oxidative ezifana nezo ngexesha le-ischemia-reperfusion [3].

I-Nrf2 ichaphazela ukuphumelela kwe-Phosphorylation ye-Oxyidative kunye ne-Synthesis ye-ATP

Ngokuvumelana nefuthe le-Nrf2 ekuphefumleni, kwingqondo kunye nesibindi se-mitochondria, ukusilela kwe-Nrf2 kubangela ukunciphisa ukusebenza kakuhle kwe-phosphorylation ye-oxidative (njengoko kuqikelelwa ngumlinganiselo we-ADP kwi-oksijeni, esetyenziselwa i-ATP synthesis), kanti i-Nrf2 isebenze (Keap1) -KD) inesiphumo esichasayo [35]. Xa kuthelekiswa ne-WT, amanqanaba e-ATP aphezulu kakhulu kwiiseli kunye ne-constitutive upregulation ye-Nrf2 kwaye iphantsi xa i-Nrf2 ichithwa phantsi [64] okanye iphazamisekile [35]. Ngaphezu koko, ukusetyenziswa kwe-inhibitors ye-oxidative phosphorylation (oligomycin) okanye i-glycolysis (iodoacetic acid) ibonise ukuba i-Nrf2 iguqula indlela iiseli ezivelisa ngayo i-ATP. Ke, kwi-WT neurons, i-oligomycin ibangela ukuhla okupheleleyo kwe-ATP kunye ne-iodoacetic acid ayinayo enye isiphumo. Ngokuphawulekayo, kwiiseli ze-Nrf2-KO, i-oligomycin yandisa amanqanaba e-ATP, athi ke acothe, kodwa ngokupheleleyo, aphelelwe yi-iodoacetic acid, ebonisa ukuba ukungabikho kwe-Nrf2, i-glycolysis, kunye ne-phosphorylation ye-oxidative, iyona mthombo oyintloko wemveliso ye-ATP. Kuyathakazelisa ukuba, nangona ukwanda kokusebenza kakuhle kwe-phosphorylation ye-oxidative kwiiseli ze-Keap1-KD, ukongezwa kwe-oligomycin kubangela ukuhla kwe-~80% kumanqanaba e-ATP, kunye ne-iodoacetic acid ibangela ukuhla kwe-~20%. Ngaloo ndlela, ukusilela kwe-Nrf2 okanye ukusetyenziswa kwayo kunciphisa igalelo le-phosphorylation ye-oxidative kwaye yandisa igalelo le-glycolysis malunga nokuhlanganiswa kwe-ATP. Esi siphumo sivakaliswa ngokukodwa xa i-Nrf2 ingekho kwaye ihambelana nokuxhomekeka kwe-??m kubukho be-glucose phakathi [35] kunye namanqanaba okwanda kwe-glycolytic intermediates (G-6-P, F-6-P). , i-dihydroxyacetone phosphate, i-pyruvate, kunye ne-lactate) emva kokubethelwa kwe-Nrf2 [24].

Ukunyuka kwamanqanaba e-ATP emva kokuvinjelwa kwe-F1F0-ATPase nge-oligomycin ibonisa ukuba ukungabikho kwe-Nrf2, i-F1F0-ATPase isebenza njenge-ATPase kwaye kungekhona i-synthase ye-ATP, oko kukuthi, isebenza ngasemva. Olu tshintsho luhle kakhulu lubonisa imfuneko yokumpompa iiprotons ngapha kwenwebu ye-mitochondrial engaphakathi kwinzame zokugcina i-??m, eyona nto ibalulekileyo kwimfezeko yokusebenza kwale organelle. Ukuguqulwa komsebenzi we-F1F0-ATPase kubonakaliswe yi-depolarization ye-mitochondrial eqatshelweyo ekulawuleni i-oligomycin kwiiseli ze-Nrf2-KO, ezihluke kakhulu kwi-hyperpolarization eyenzekayo kwi-WT okanye i-Keap1-engenayo i-35]. Ngokubanzi, kubonakala ngathi phantsi kweemeko ze-Nrf2 ukusilela kwe-ATP iveliswa ngokuyinhloko kwi-glycolysis, kwaye le ATP isetyenziswe ngokuyinxalenye yi-F1F0-ATPase ukugcina i-??m.

I-Nrf2 Iphucula i-Acidity Acidity Acid Oxidation yeMitochondrial

Isiphumo sokusilela kwe-Nrf2 kwi-??m sichazwa ngokukodwa xa iiseli zifakwe phakathi ngaphandle kwe-glucose, kwaye i-??m i-~50% ephantsi kwi-Nrf2-KO xa kuthelekiswa neeseli ze-WT [35]. Ngaphantsi kweemeko zokunciphisa i-glucose, i-mitochondrial fatty acid oxidation (FAO) ngumboneleli omkhulu we-substrates yokuphefumula kunye ne-phosphorylation ye-oxidative, ebonisa ukuba i-Nrf2 inokuchaphazela i-FAO. Enyanisweni, ukusebenza kakuhle kwe-FAO kuzo zombini i-chain-long-chain (C16: 0) i-fatty acid palmitic acid kunye ne-short-chain (C6: 0) i-hexanoic acid iphezulu kwi-Keap1-KO MEFs kunye nentliziyo eyedwa kunye ne-mitochondria yesibindi kune-mitochondria yabo. Abalingani be-WT, ngelixa iphantsi kwiiseli ze-Nrf2-KO kunye ne-mitochondria [65]. Ezi ziphumo zibaluleke kakhulu ebantwini: ngokwenene, utshintsho lwe-metabolic lubonisa ukuhlanganiswa okungcono kwe-FAO kunye nomsebenzi womjikelezo we-TCA kuye kwabikwa ukuba kwenzeke kwizifundo zongenelelo lwabantu kunye nokutya okutyebileyo kwi-glucoraphanin, i-precursor ye-classical Nrf2 activator sulforaphane [ 66].

Ngexesha lenyathelo lokuqala le-FAO ye-mitochondrial, i-pro-R hydrogen ye-?-carbon ishiya njenge-hydride enciphisa i-FAD cofactor kwi-FADH2, ethi idlulisele ii-electron kwi-ubiquinone (UbQ) kwikhonkco lokuphefumla, ekugqibeleni libe negalelo kwimveliso ye-ATP. . Nangona ukukhuthazwa kwe-FAO ngepalmitoylcarnitine ngokungabikho kweglucose kubangela ukunyuka okulindelweyo kumanqanaba e-ATP kwi-WT kunye neeseli ze-Keap1-KO, kunye nokunyuka kwe-ATP ngokukhawuleza kwiiseli ze-Keap1-KO, unyango olufanayo aluvelisi utshintsho lwe-ATP kwi-Nrf2-KO. MEFs [65]. Olu vavanyo lubonisa ukuba, ngokungabikho kwe-Nrf2, i-FAO icinezelwe, kwaye ngaphezu koko, ibandakanya ukunyanzeliswa kwe-FAO njengenye yezizathu zamanqanaba aphantsi e-ATP phantsi kweemeko ze-Nrf2 [35], [64].

Ngokucacileyo, iifom ze-293 T zabantu apho iNrf2 ikhutshwe ngayo i-CPT1 kunye ne-CPT2 [67], ii-isoform ze-carnitine palmitoyltransferase (CPT), i-enzyme yokunciphisa isantya kwi-FAO ye-mitochondrial. Ngokuvumelana, ama-mRNA amanqanaba e-Cpt1 aphantsi kwi-Nrf2-KO xa kuthelekiswa namagundane e-WT [68]. I-CPT ivuselela ukudluliselwa kweqela le-acyl ye-acyl-CoA e-long-fat chain-coA esuka kwi-coenzyme A ukuya kwi-carnitine kwaye ngoko ivumela ukungenisa kwe-acylcarnitine ukusuka kwi-cytoplasm ukuya kwi-mitochondria. Nangona oku kungakhange kuhlolwe kuze kube yimini, kunokwenzeka ukuba ngaphezu kweempembelelo ze-CPT1, iNrf2 inokuchaphazela nomsebenzi wale nzyme ngokulawula amanqanaba e-allosteric inhibitor yayo eyintloko, i-malonyl-CoA. Oku kungenxa yokuba, ngeendlela ezingabonakali ngokucacileyo, i-Nrf2 ilawula kakubi ukubonakaliswa kwe-coaroyl CoA desaturase (SCD) [69] kunye ne-citrate lyase (CL) [69], [70]. Okumangalisayo kukuba, ukunqonkqoza okanye ukuvinjelwa kwe-SCD kukhokelela ekwandiseni i-phosphorylation kunye nokusebenza kwe-protein kinase (AMPK) esebenzayo ye-AMP [71], [72], [73], kwaye kunokucingelwa ukuba, ngokungabikho kwe-Nrf2, amanqanaba eSDD iya kunyuka, ngokunciphisa umsebenzi we-AMPK. Oku kungaphakanyiswa ngakumbi ngamanqanaba eeprotheyini ancitshisiweyo e-AMPK aye afunyaniswa kwiimbambiso ze-Nrf2-KO amagundane [68], ukufumanisa okukufutshane kwesivumelwano kunye namazinga e-AMPK awandisiweyo, achazwe kwi-Liap1-KD amagundane [74]. Esinye isiphumo somsebenzi we-AMPK owehlayo ukukhutshwa kwe-phosphorylation ye-inhibitory (kwi-Ser79) ye-acetyl-CoA carboxylase (i-ACC) [75], enokubakho ngokubanzi ngokubhalwa komthetho ngokungabikho kwe-Nrf2 kuba ilawulwa yi-Nrf2 isebenze [70 ]. Umsebenzi ophezulu we-ACC, ngokubambisana nenkcazo ye-CL ephakanyisiweyo eyokwandisa umveliso we-acetyl-CoA, umgca we-ACC, unokugcina ukwandiswa kwamanqanaba emveliso ye-ACC, malonyl-CoA. Amanqanaba aphakamileyo ye-malonyl-CoA aya kuvimbela i-CPT, ngaloo ndlela anciphise ukuthuthwa kwe-acid acids kwi-mitochondria. Ekugqibeleni, i-Nrf2 ilawula kakuhle i-CD36 [76], i-translocase ehambisa i-acids acids kwi-plasma nakumamembrane e-mitochondrial. Ngaloo ndlela, enye indlela iNrf2 inokuchaphazela ngayo ukusebenza kwe-FAO yemithachondrial kukulawula ukungenisa kwama-acids e-long chain acids kwi-mitochondria.

Ukongezelela ukuhanjiswa komthetho we-transcription, i-Nrf2 inokuguqula nokusebenza kakuhle kwe-FAO ye-mitochondrial ngeziphumo zayo kwi-cell redox metabolism. Oku kunokwenzeka ngokukhethekileyo xa umsebenzi we-Nrf2 uphantsi okanye ungekho, iimeko ezitshintsha isimo se-redox yeselula kwi-oxidized state. Enyanisweni, ii-enzyme ezininzi ze-FAO ziye zachongwa nje ngokuba zijongene nokutshintsha kwe-redox. Enye ye-enzyme i-acyl-CoA dehydrogenase (i-VLCAD) eninzi kakhulu, eyenza ngaphezu kwe-80% kwimisebenzi ye-palmitoyl-CoA yokuqheliswa komzimba kumathambo omntu [77]. Okuthakazelisayo, u-Hurd et al. [I-78] ibonise ukuba i-VLCAD iqulethe i-cysteine resi resies eguqula kakhulu isimo sayo se-redox xa kuvezwa i-heart rate ye-rod mitochondria kwi-H2O2. Ukongezelela, i-S-nitrosylation yeVLCAD ye-murine hepatic kwiCys238 ithuthukisa ukusebenza kakuhle kwe-enzyme [79], kwaye mhlawumbi i-oxidation ye-cysteine efanayo ingaba nefuthe echaseneyo, ekugqibeleni iyanciphise ukusebenza kwe-FAO yemithachondrial. Ngoko ke kunokwenzeka ukuba, nangona amaqondo e-VLCAD ahlukanga kakhulu kwi-WT, i-Nrf2-KO, okanye i-Keap1-KO MEFs [i-65], umsebenzi we-VLCAD umsebenzi we-enzyme ungaphantsi ekungabikho kwe-Nrf2 ngenxa yamanqanaba aphakamileyo yeROS.

Ngokusekelwe kuzo zonke ezi ziphumo, kunokuphakanyiswa ukuba (umzobo 3): ngokungabikho kwe-Nrf2, amanqanaba e-NADPH aphantsi ngenxa yokunciphisa ukubonakaliswa kwe-ME1, i-IDH1, i-G6PD, kunye ne-PGD. Amanqanaba okunciphisa i-glutathione nawo aphantsi ngenxa yokunciphisa ukubonakaliswa kwe-enzymes ethatha inxaxheba kwi-biosynthesis yayo kunye nokuvuselelwa kunye namanqanaba aphantsi e-NADPH afunekayo ukuguqulwa kwe-oxidized kwifom encitshisiweyo ye-glutathione. Ukubonakaliswa okuphantsi kwe-ME1 kuya kunciphisa ichibi le-pyruvate elingena kwi-mitochondria, kunye ne-glycolysis ibe ngumthombo omkhulu we-pyruvate. Isizukulwana se-NADH sihamba kancinci, sikhokelela ekusebenzeni kakubi kwe-complex I kunye nokwanda kwemveliso ye-ROS ye-mitochondrial. Ukuncitshiswa kwe-FAD ukuya kwi-FADH2 nako kucotha, ubuncinci kwinxenye ngenxa ye-oxidation ye-fatty acid engasebenzi kakuhle, ebeka emngciphekweni ukuhamba kwe-electron ukusuka kwi-FADH2 ukuya kwi-UbQ nakwi-complex III. Njengoko i-UbQH2 i-activator ye-succinate dehydrogenase [80], ukunciphisa ukubunjwa kwayo kunokunciphisa umsebenzi we-enzyme ye-succinate dehydrogenase. Ukunyuka kwamanqanaba e-superoxide kunye ne-hydrogen peroxide kunokuthintela umsebenzi onzima we-II ngakumbi [81]. Ukusebenza okuphantsi kwe-fatty acid oxidation kunegalelo ekunciphiseni ukufumaneka kwe-substrate yokuphefumula kwe-mitochondrial kunye nokuveliswa kwe-ATP kwi-phosphorylation ye-oxidative. Njengendlela yokubuyisela, i-glycolysis iphuculwe. I-ATP synthase isebenza ngomva, njenge-ATPase, kumzamo wokugcina i-??m.

I-Nrf2 kunye ne-Mitochondrial Biogenesis

Kuye kwaxelwa ukuba, xa kuthelekiswa ne-WT, izibindi ze-Nrf2-KO zeegundane zinomxholo ophantsi we-mitochondrial (njengoko kunqunywe ngumlinganiselo we-mitochondrial kwi-nuclear DNA); oku kuncipha ngakumbi nge-24-h ngokukhawuleza kuzo zombini iimpuku ze-WT kunye ne-Nrf2-KO; ngokuchaseneyo, nangona kungekho nto yahlukileyo kwi-WT phantsi kweemeko eziqhelekileyo zokutya, umxholo we-mitochondrial kwiigundane ezinomsebenzi ophezulu we-Nrf2 awuchaphazeli ngokuzila ukudla [82]. Okuthakazelisayo, ukuxhaswa kunye ne-Nrf2 activator (R)-?-lipoic acid [83], [84], [85] ikhuthaza i-mitochondrial biogenesis kwi-3T3-L1 adipocytes [86]. Iiklasi ezimbini zabalawuli benyukliya abakhutshelweyo badlala indima ebalulekileyo kwi-mitochondrial biogenesis. Iklasi yokuqala zizinto ezikhutshelweyo, ezifana ne-nuclear respiratory factor11 kunye ne-2, elawula ukubonakaliswa kwee-genes encoding subunits ze-complex zokuphefumla ezintlanu, i-mitochondrial translational components, kunye ne-heme biosynthetic enzymes ezibekwe kwindawo ye-mitochondrial matrix [88]. Piantadosi et al. [89] ibonise ukuba i-Nrf2 exhomekeke kwi-transcriptional upregulation ye-nuclear factor 1 ikhuthaza i-mitochondrial biogenesis kwaye ikhusela i-cytotoxicity ye-cardiotoxic anthracycline chemotherapeutic agent doxorubicin. Ngokwahlukileyo, uZhang et al. [82] baye baxela ukuba ukusetyenziswa kofuzo lwe-Nrf2 akuchaphazeli i-basal mRNA ibonakaliso ye-nuclear factor 1 kwisibindi se-murine.

Udidi lwesibini lwabalawuli bombhalo wenyukliya abanemisebenzi ebalulekileyo kwi-mitochondrial biogenesis zi-transcriptal coactivators, ezifana ne-peroxisome proliferator-activated receptor? iicoactivators (PGC)1? kunye ne-1?, ehambelana nezinto ezibhaliweyo, i-basal transcriptional kunye noomatshini be-RNA-splicing, kunye ne-histone-modifying enzymes [88], [90], [91]. Inkcazo yosapho lwe-PGC1 yee-coactivators iphenjelelwa ziimpawu ezininzi zokusingqongileyo. Unyango lwe-fibroblasts yabantu kunye ne-Nrf2 activator sulforaphane ibangela ukwanda kwe-mitochondrial mass kunye nokufakwa kwePGC1? kunye nePGC1? [92], nangona ukuxhomekeka okunokwenzeka kwi-Nrf2 akuzange kuhlolwe kolu cwaningo. Nangona kunjalo, iimpuku zesifo seswekile apho i-Nrf2 inokuthi isebenze yi-Keap1 gene hypomorphic knockdown (db/db:Keap1flox/?:Nrf2+/+) okanye iphazamiseke (db/db:Keap1flox/?:Nrf2?/?) ine-hepatic esezantsi ye-PGC1? amanqanaba okuthetha kunezilwanyana zokulawula (db/db:Keap1flox/+:Nrf2+/+) [93]. Akukho mahluko kumanqanaba e-mRNA yePGC1? zibonwa kwizibindi zeempuku ezingezonondiabetic ezinokuba yi-WT okanye i-Nrf2-KO, ngelixa la manqanaba asezantsi kwi-Nrf2-overexpressing (Keap1-KD kunye nezilwanyana ze-Keap1-KO) ezikhethekileyo [82]. Ngokucacileyo, ukukhawuleza kwe-24-h kwandisa amanqanaba ePGC1? I-mRNA kwizibindi zeempuku zazo zonke i-genotypes, kodwa ukunyuka kukhulu kakhulu kwizibindi ze-Nrf2-KO xa kuthelekiswa ne-WT okanye i-Nrf2-overexpressing mice. Xa kuthelekiswa ne-WT, iimpuku ze-Nrf2-KO ezifumana usulelo lwe-septic okanye ukwenzakala okukhulu kwemiphunga ngenxa yosulelo lubonisa ukunyuswa okubhalwe phantsi kwe-nuclear factor 1 kunye ne-PGC1? [94], [95]. Ngokudibeneyo, olu qwalaselo lucebisa ukuba indima ye-Nrf2 ekugcineni amanqanaba okuphefumla kwenyukliya 1 kunye nePGC1? luntsonkothile kwaye lubonakala kakhulu phantsi kweemeko zoxinzelelo.

Ukongeza ekubonakalisweni kofuzo lwe-encoding mitochondrial proteins, i-mitochondrial biogenesis ifuna ukuhlanganiswa kweenucleotides. Ukusetyenziswa kwe-Genetic ye-Nrf2 kuphucula i-purine biosynthesis ngokuphakamisa indlela ye-pentose phosphate kunye ne-metabolism ye-folate kunye ne-glutamine, ngokukodwa kwiiseli ezikhula ngokukhawuleza (umzobo 2) [24]. Uhlalutyo lwe-transcriptome ye-Drosophila eguquguqukayo elahlekileyo ye-mitochondrial serine / threonine protein kinase I-PTEN-induced putative kinase 1 (PINK1) ibonise ukuba ukungasebenzi kwe-mitochondrial kukhokelela ekukhuselweni kokubhalwa kwemfuza echaphazela i-nucleotide metabolism [96], iphakamisa i-nucleotide metabolism [1], iphakamisa i-nucleotide metabolism. imele indlela yokukhusela kwimiphumo ye-neurotoxic yokunqongophala kwe-PINK2. I-Nrf2 ilawula ukubonakaliswa kwe-phosphoribosyl pyrophosphate amidotransferase (PPAT), eyenza ukungena kwi-de novo purine nucleotide biosynthetic pathway, kunye ne-mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) (Fig. 97). Le yokugqibela yi-enzyme ene-bifunctional ene-dehydrogenase kunye ne-cyclohydrolase imisebenzi ebalulekileyo ekuboneleleni zombini i-glycine kunye ne-formate njengemithombo yeeyunithi zekhabhoni enye ye-purine biosynthesis kwiiseli ezikhula ngokukhawuleza [2]. Ke ngoko kusenokwenzeka ukuba ukusebenza kwe-Nrf1 kunokukhusela kwaye kunokubuyisela umva ukungasebenzi kakuhle kwe-mitochondrial kukusilela kwe-PINK2. Enyanisweni, ukusetyenziswa kwe-pharmacological ye-Nrf408 nge-sulforaphane, okanye i-triterpenoid RTA-1, ibuyisela i-??m kwaye ikhusela iiseli ezinqongopheleyo ze-PINK98 kwi-dopamine toxicity [2]. Nangona iindlela ezisisiseko zibonakala zinzima, kunye, ezi ziphumo zibonisa ukuba umsebenzi we-NrfXNUMX unokuchaphazela i-mitochondrial biogenesis ngokuchaphazela amanqanaba okubonakaliswa kwezinto ezibalulekileyo zokubhaliweyo kunye ne-coactivators, kunye nokuphucula i-nucleotide biosynthesis.

I-Nrf2 ne-Mitochondrial Integrity

Nangona ubungqina obuchanekileyo abukho ngaso sonke isikhathi, kukho izibonakaliso ezinamandla ukuba i-Nrf2 ibalulekile ukuthembeka kwe-mitochondrial, ngokukodwa phantsi kweemeko zoxinzelelo lwe-oxidative. I-Mitochondria eyodwa ngaphandle kwengqondo kunye nesibindi seengwenya eziye zalawulwa enye i-dose ye-Nrf2 activator sulforaphane ayimelana nokuvulwa kweporechondrial empowerment pore transition (mPTP) ebangelwa yi-tert-butylhydroperoxide [99], i-100]. I-MPTP, ubunzima obangela ukuba i-membrane yangaphakathi ye-mitochondrial ibe yinto enokubonakalayo kwiimolyuli kunye nezixuku ukuya kwi-1500 Da, isandul 'ukuza kubonakala ukuba yenziwe kwi-dimers ye-F0F1-ATP synthase [101]. Ukuxhatshazwa kwe-sulforaphane ukuxhatshazwa kwe-mPTP ngokuvelisa i-mtochondrial GSH, i-glutathione peroxidase i-1, i-enzyme ye-malic 3, kunye ne-thioredoxin i-2 yonke iyahlukunyezwa kwiinqununu ze-mitochondrial ezixhomekeke kwizilwanyana eziphathekayo (100].

Umonakalo weprotheyini ye-Mitochondrial kunye nokuphazamiseka kokuphefumla okubangelwa yimveliso ye-electrophilic lipid peroxidation i-4-hydroxy-2-nonenal iyancipha kwi-mitochondria eyodwa kwi-cortex ye-cerebral ye-sulforaphane-treated mice [102]. Kwiiseli ze-renal epithelial kunye nakwizintso, i-sulforaphane ikhusela kwi-cisplatin- kunye ne-gentamicin-induced toxicity kunye nokulahlekelwa kwe-??m[103], [104]. Ukukhuselwa kwiphaneli ye-oxidants (i-superoxide, i-hydrogen peroxide, i-peroxynitrite) kunye ne-electrophiles (i-4-hydroxy-2-nonenal kunye ne-acrolein) kunye nokunyuka kwe-mitochondrial yokukhusela i-antioxidant kuye kwabonwa kunyango lwe-rat aortic smooth muscle cells kunye ne-sulforaphane [105]. ]. Kwimodeli yokulimala kwezintso ezichaseneyo, i-preconditioning ye-ischemic ye-ischemic isandul 'ukuboniswa ukuba ineempembelelo ezikhuselayo, kubandakanywa ukuvinjelwa kokuvulwa kwe-mPTP kunye nokuvuvukala kwe-mitochondrial, ngokusebenza kwe-Nrf2 ngenxa yokuvinjelwa kwe-GSK3? [106].

I-Mitophagy, inkqubo apho i-mitochondria engasebenziyo ifakwe ngokukhethiweyo yi-autophagosomes kwaye isiwe kwi-lysosomes ukuze ithotywe kwaye isetyenziswe kwakhona yiseli, ibalulekile kwi-homeostasis ye-mitochondrial [107], [108]. Nangona kungekho budlelwane be-causative phakathi kwe-Nrf2 kunye ne-mitophagy buye basekwa, kukho ubungqina bokuba i-transcription factor inokubaluleka kulawulo lwekhwalithi ye-mitochondrial ngokudlala indima kwi-mitophagy. Oku kunokubonakala ngakumbi phantsi kweemeko zoxinzelelo lwe-oxidative. Ngaloo ndlela, kumzekelo we-sepsis, ukunyuka kwamanqanaba e-autophagosome marker MAP1 i-chain chain 3-II (LC3-II) kunye neprotheyini ye-cargo p62 kwi-24 h postinfection igxininiswe kwi-Nrf2-KO xa kuthelekiswa neegundane ze-WT [109] . I-inducer encinci ye-molecule ye-mitophagy (ebizwa ngokuba yi-p62-mediated mitophagy inducer, i-PMI) isanda kufunyanwa; le ngqungquthela ye-1,4-diphenyl-1,2,3-triazole ekuqaleni yayiyilwe njenge-activator ye-Nrf2 ephazamisa ukusebenzisana kwe-transcription factor kunye ne-Keap1 [110]. Ngokufana neeseli apho i-Nrf2 ilawulwa ngokofuzo (Keap1-KD okanye i-Keap1-KO), iiseli ezivezwe kwi-PMI zinokuphumla okuphezulu ??m. Okubalulekileyo, ukwanda kwendawo ye-mitochondrial LC3 ebonwa emva kokuba unyango lwe-PMI lweeseli ze-WT lungenzeki kwiiseli ze-Nrf2-KO, ezibonisa ukubandakanyeka kwe-Nrf2.

Ekugqibeleni, ukuhlaziywa kwezixhobo zesibindi kuye kwabonisa ukuba khona kwe-mitochondria ekhunyiweyo kunye ne-curiti eyancitshiweyo kwaye yaphazamisa iimbumba kwi-hepatocytes ye-Nrf2-KO, kodwa kungekhona i-WT, iigundane ezazisondla ukutya okunamafutha amaninzi kwiiveki ze-24; ngokugqithiseleyo, ezi zibopheko zibonisa ubungqina obucacileyo bokuxinzezeleka kweengxaki kunye nokuvuvukala [68]. Ingagqitywa ukuba i-Nrf2 inendima ebalulekileyo ekugcineni ingqibelelo ye-mitochondrial phantsi kweemeko zengcinezelo yokuxhamla nokukhupha.

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

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

Amacandelo aphambili:

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

Umgca wexesha elipheleleyo

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

I-Nrf2 yinto ebhaliweyo yokubhaliweyo eyenza indima ebalulekileyo kwinkqubo yokukhusela i-antioxidant system yomzimba womntu. Into ephendulayo ye-antioxidant, okanye i-ARE, yindlela yokulawula i-gene. Ucwaningo oluninzi luye lwabonisa ukuba i-Nrf2, okanye i-NF-E2 ehlobene ne-2, ilawula iintlobo ezahlukeneyo zeGEN eziqhutywe kuzo zonke iintlobo zeeseli. I-Nrf2 yafunyanwa ukuba idlale indima ebalulekileyo ekukhuselweni kwamaselula kunye ne-anti-carcinogenicity, ebonisa ukuba i-Nrf2 ingaba unyango osebenzayo ekulawuleni izifo ezingenayo i-neurodeergenerative kunye neentsholongwane ezikholelwa ukuba zibangelwa ukunyanzeliswa kwe-oxidative. UDkt Alex Jimenez DC, i-CCST Insight

Ukuphetha

Nangona imibuzo emininzi ihlala ivulekile, ubungqina obukhoyo bovavanyo bubonisa ngokucacileyo ukuba iNrf2 ngumdlali obalulekileyo ekugcinweni kwe-homeostasis ye-mitochondrial kunye nokuthembeka kwezakhiwo. Le nxaxheba ibaluleke ngokukodwa phantsi kweemeko zengxubevange, i-electrophilic, kunye nokuvutha kwengqondo xa ukukwazi ukulungelelanisa iimpendulo ze-NRf2-mediated-response zichaphazela impilo jikelele kunye nokuphila kweseli kunye nomzimba. Indima ye-Nrf2 kumsebenzi we-mitochondrial ibonisa olunye uhla lweendlela ezibanzi ze-cytoprotective ezichanekileyo ngolu hlobo lombhalo. Uninzi lweemeko zesifo sengqondo zinoxinzelelo lwe-oxidative, ukuvuvukala, kunye ne-mitochondrial dysfunction njengezinto ezibalulekileyo ze-pathogenesis, ukusebenza kwe-pharmological yeNrf2 inesithembiso sokuthintela izifo kunye nokunyangwa. Ukuqonda ngokubanzi iinkqubo ezichanekileyo ezenziwa ngu-Nrf2 umsebenzi we-mitochondrial kubalulekile ekuqulunqweni koqulunqo lwezilingo zekliniki ezizayo kwaye unokunika ama-biomarkers amasha ukubeka ingqwalasela ekusebenzeni ngempumelelo.

Imibulelo

Sciencedirect.com/science/article/pii/S0891584915002129

Injongo yeli nqaku lingasentla ibikukuxoxa�kunye nokubonisa �indima evelayo ye-Nrf2 kumsebenzi wemitochondrial. Nrf2, okanye inyukliya yezinto ezinxulumene nezixhobo ze-2, ngumlawuli ovelayo wokuchasana kwamaselula kwii-oxidants ezinokuthi zibe negalelo kuxinzelelo lwe-oxidative, echaphazela ukusebenza kwamaselula kunye nokukhokelela ekuphuhlisweni kobutyhefu, izifo ezingapheliyo, kunye nomhlaza. Ngelixa imveliso yee-oxidants emzimbeni womntu inokusebenzela iinjongo ezahlukeneyo, �kubandakanya ukwahlulwahlulwa kweeseli, ukudumba, ukusebenza komzimba, i-autophagy, kunye nokuphendula koxinzelelo, kubalulekile ukulawula ukuveliswa kwazo okugqithisileyo ukuthintela imiba yezempilo. Ubungakanani bolwazi lwethu lukhawulelwe kwi-chiropractic kunye nemiba yempilo yomgogodla. Ukuxoxa ngalo mbandela, nceda uzive ukhululekile ukubuza uGqr. Jimenez okanye uqhagamshelane nathi apha915-850-0900 .

Ikhutshwe nguDkt. Alex Jimenez

U khankanywe kwi: Sciencedirect.com

Ingxoxo yesihloko esongezelelweyo: cBuhlungu obuBuhlungu

Umqolo obuhlunguSesinye sezona zizathu zixhaphakileyo zokukhubazeka kunye neentsuku eziphosiweyo emsebenzini kwihlabathi liphela. Iimpawu ezibuhlungu zangasemva kwisizathu sesibini esiqhelekileyo sokutyelelwa yi-ofisi kagqirha, ngaphezulu kwenani losulelo oluphezulu lokuphefumla. Phantse iipesenti ezingama-80 zabemi baya kufumana iintlungu zangasemva kube kanye ebomini babo. Umqolo sisakhiwo esintsonkothileyo esenziwe ngamathambo, amalungu, iigaments, kunye nezihlunu, phakathi kwezinye izicwili ezithambileyo. Ngenxa yoku, ukwenzakala kunye / okanye iimeko ezixineneyo, ezinje ngedisni, ekugqibeleni inokukhokelela kwiimpawu zentlungu emva. Ukulimala kwezemidlalo okanye ukulimala kwengozi yemoto kudla ngokuba yimbangela eqhelekileyo yeentlungu zangasemva, nangona kunjalo, ngamanye amaxesha ukunyakaza okulula kunokuba neziphumo ezibuhlungu. Ngethamsanqa, ukhetho olulolunye unyango, olufana nokunyamekela kwe-chiropractic, lunokunceda ukunciphisa intlungu emva kokusetyenziswa kohlengahlengiso lomqolo kunye nokunyanzeliswa kwezandla, ekugqibeleni kuphuculwe intlungu. �

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

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I-Nrf2 Inkqubo yokuBonisa: Iimbopheleleko eziphambili kwi-Inflammation

by UGqr Alex Jimenez | Ubuhlungu obungapheliyo, Ukuxutyushwa, LweMpilo, impilo, Medicine Holistic, Uxinzelelo oluxhasayo, ulungiso, Izifundo zoPhando, Unyango, Ukuphila

Nrf2 ixhasa ukusetyenziswa kweqela le-antioxidant kunye ne-detoxifying enzyme kunye nejeni ezikhusela umzimba womntu kwimiphumo yempilo enxulumene nokunyuka kwengcinezelo yokuxhamla, njenge-Alzheimer's disease. Izinto ezahlukeneyo zemvelo ziye zaboniswa ukuba zisebenzise indlela ye-Nrf2, enokukunceda ukulawula iimpawu zezifo ezingenayo i-neurodeergenerative. Injongo yale nqaku apha ngasentla kukuxubusha indima ebalulekileyo ye-Nrf2 ebangelwa ukuvuvukala okungapheliyo.

Abstract

Ukuvuvukala yinto eqhelekileyo yezifo ezininzi ezingapheliyo kunye neengxaki, ngelixa udlala indima ebalulekileyo kwi-carcinogenesis. Izifundo ezininzi ziye zabonisa ukuba i-Nrf2 inegalelo kwinkqubo yokuchasana nokuvuvukala ngokucwangcisa ukuqeshwa kweeseli ezivuthayo kunye nokulawula ukubonakaliswa kofuzo ngokusebenzisa i-antioxidant response element (ARE). I-Keap1 (i-Kelch-efana ne-ECH-iprotheyini ehambelanayo) / Nrf2 (NF-E2 i-p45-related factor 2) / i-ARE indlela yokubonisa izibonakaliso ilawula i-anti-inflammatory gene expression kwaye inqanda ukuqhubela phambili kokuvuvukala. Ngoko ke, ukuchongwa kwe-Nrf2-ixhomekeke kwi-phytochemicals echasene nokuvuvukala ibe yinto ephambili ekufumaneni iziyobisi. Kolu hlaziyo, sixoxa ngamalungu e-Keap1 / Nrf2 / ARE indlela yesignali kunye ne-genes yayo ephantsi, imiphumo yale ndlela kwiimodeli zezilwanyana zezifo ezivuthayo, kunye ne-crosstalk kunye ne-NF-? B indlela. Ukongeza siphinde sixoxe malunga nokulawulwa kwe-NLRP3 inflammasome yi-Nrf2. Ngaphandle koku, sishwankathela imeko yangoku yophuhliso lwe-phytochemicals echasayo kunye nezinye ezidibanisa indlela ye-Nrf2 / ARE yokubonisa.

Internet: I-Nrf2, i-Keap1, INGABE, Ukuvuvukala, uxinzelelo lwe-Oxidative, i-Phytochemical

izifinyezo

Sciencedirect.com/science/article/pii/S0925443916302861#t0005

intshayelelo

Ukuvuvukala yinkqubo eyinkimbinkimbi eyenzekayo xa izicubu zitshatyalaliswe okanye zenzakaliswe ngongcoliseko olunobungozi ezinjengezilwanyana ezinobungozi, umonakalo, okanye ukugxekwa. Amaseli omzimba omzimba, imithwalo yegazi kunye nabalamli bee-molecular babandakanyeka kule mpendulo yokukhusela [1]. Ukuqhaqhazela kwakhona kwimeko yezilwanyana ezinxulumene nezifo ezahlukahlukeneyo ezibangelwa ikakhulu ngezinto ezibonakalayo zenyama, iichiza, i-biological and psychological. Injongo yokuvuvukala kukunciphisa nokuphelisa izizathu zokulimala kwamangqamuzana, kucace kunye / okanye ukufumana iiseliti kunye nezicubu ezinqamlekileyo, kwaye uqalise ukulungiswa kwezicubu. Iifom ezimbini ezihlukeneyo zokuvuvukala zihlukeneyo: zilukhuni kwaye ziyingxaki. Ukuvuvukala ngokuqhelekileyo kukuzimelela kwaye kunenzuzo kumphathi, kodwa ukuguquka okungapheliyo kuyinto eqhelekileyo yezifo ezininzi ezingapheliyo kunye neengxaki. Ukungena ngokuthe ngqo ngamaseli amaninzi omzimba wesoonuclear ezifana ne-monocytes, macrophages, i-lymphocytes, kunye neeseli ze-plasma, kunye nokuveliswa kwe-cytokines evuthayo, kubangela ukuvuvukala okungapheliyo. Kuyaqaphela ukuba ukuvuvukala okungapheli kudlala indima ebalulekileyo kwi-carcinogenesis [2]. Ngokuqhelekileyo, zombini iinkqubo zokubonisa ukutshabalala ezibandakanyekayo zibandakanya kwinkqubo evamile yokuvuvukala.

Kwinkqubo yokuvuvukala kwe-pathological, iiseli ze-mast, i-monocytes, i-macrophages, i-lymphocytes, kunye nezinye iiseli zokuzivikela ziqala ukusebenza. Emva koko iiseli zigaywa kwindawo yokulimala, okubangela ukuveliswa kweentlobo ze-oxygen esebenzayo (ROS) ezonakalisa i-macromolecules kuquka i-DNA. Kwangaxeshanye, ezi seli ezivuthayo zikwavelisa izixa ezikhulu zabalamli abavuthayo ezifana ne-cytokines, i-chemokines, kunye ne-prostaglandins. Aba balamli baphinda bagaye ii-macrophages kwiindawo ezihlala kwindawo yokudumba kwaye zivule ngokuthe ngqo ii-cascades zokudluliselwa kwemiqondiso emininzi kunye nezinto ezikhutshelweyo ezinxulumene nokudumba. I-NF-?B (i-nuclear factor kappa B), i-MAPK (i-mitogen-activated protein kinase), kunye ne-JAK (janus kinase) -STAT (i-transducers yesignali kunye ne-activators of transcription) iindlela zokubonisa zibandakanyeka ekuphuhliseni indlela yeklasi yokuvuvukala. [3], [4], [5]. Izifundo zangaphambili zibonise ukuba i-transcription factor Nrf2 (NF-E2 p45-related factor 2) ilawula ukubonakaliswa kwesigaba se-II se-enzyme detoxifying enzymes kuquka i-NADPH, i-NAD (P) H i-quinone oxidoreductase 1, i-glutathione peroxidase, i-ferritin, i-heme oxygenase-1 (HO -1), kunye nofuzo lwe-antioxidant olukhusela iiseli kukulimala okuhlukeneyo ngemiphumo yazo yokuchasana nokudumba, ngaloo ndlela kuphembelela indlela yesifo [6], [7], [8].

Ekuqwalaseleni ezi ziphumo eziphawulekayo, ukuphuhliswa kwezidakamizwa ezithintekayo kwizifo ezivuthayo ngokusebenzisa iindlela zokutshintshisa kuye kwandula umdla kuminyaka yakutshanje. Kulo hlalutyo, sishwankathela uphando kwi-Keap1 (iprotheni enxulumene neKelch-like ECH) / iNrf2 (NF-E2 ehlobene ne-45) / I-ARE (element antioxoxant element element) ekutshiseni.

Ulwakhiwo kunye noMgaqo weNrf2

I-Keap1-Impendulo ye-Nrf2

I-Nrf2 yeye-Cap �n� Collar (CNC) subfamily kwaye iquka iindawo ezisixhenxe ezisebenzayo, iNeh (Nrf2-ECH homology) 1 ukuya kuNeh7 [9], [10]. I-Neh1 yi-domain ye-CNC-bZIP evumela i-Nrf2 ukuba i-heterodimerize kunye ne-protein encinci ye-musculoaponeurotic fibrosarcoma (Maf), i-DNA, kunye namanye amaqabane abhaliweyo kunye nokwenza i-complex yenyukliya kunye ne-ubiquitin-conjugating enzyme UbcM2 [11], [12]. I-Neh2 iqulethe i-motifs ezimbini ezibalulekileyo ezaziwa ngokuba yi-DLG kunye ne-ETGE, eziyimfuneko ekusebenzisaneni phakathi kwe-Nrf2 kunye nomlawuli wayo ongalunganga u-Keap1 [13], [14].

I-Keap1 yi-adapter ye-substrate-based based E3 ubiquitin ligase, inqanda umsebenzi we-transcription of Nrf2 nge-ubiquitination kunye ne-proteasomal degradation phantsi kweemeko eziqhelekileyo [15], [16], [17]. Izikhundla ze-KELCH ze-Keap1 homodimer zibopha nge-DLG kunye ne-ETGE motif ye-Nrf2-Neh2 kwisizinda kwi-cytosol, apho i-ETGE ibanjelwa intambo kunye ne-DLG njengezenzo [18]. Ngaphantsi koxinzelelo lwe-oxidative okanye xa kuvezwe kwi-activators ye-Nrf2, iNrf2 iyahlukana kwi-Keap1 yokubopha ngenxa yokuguqulwa kwetyolini ye-Keap1 resiste resisies ekugqibeleni ikhusela i-Nrf2 kunye nokuthotywa kwe-proteasomal [19]. Emva koko i-Nrf2 idlulela kwi-nucleus, i-heterodimerizes neeprotheni ezincinci ze-Maf, kwaye iguqulela i-battery ye-jeni (Fig. 1A). I-carboxy-terminal ye-Neh3 isebenza njengesizinda soqhagamshelwano ngokusebenzisana ne-activator co-transcript eyaziwa njenge-CHD6 (i-chromo-ATPase / i-helicase DNA ebopha iprotheni) [20]. I-Neh4 kunye ne-Neh5 nayo isebenza njengemimandla yokuguqulela, kodwa ibopha kwenye i-activator-trans activist eyaziwa njenge-CBP (i-protein-binding protein-element-binding protein-binding element) [21]. Ngaphezulu, i-Neh4 kunye ne-Neh5 badibanisa ne-coxactor ye-nyukliya i-RAC3 / AIB1 / SRC-3, ekhokelela ekuphuculweni kwe-Nrf2-I-AR gene expression [22]. I-Neh5 ine-signal ye-nyukliya yokuthunyelwa kwe-nyukliya ebonakalayo ebaluleke kakhulu kwimimiselo kunye nokwakhiwa kwamaselula e-Nrf2 [23].

**Umzobo we-1 Keap1-kuxhomekeke kumgaqo-we-Nrf2.** (A) Phantsi kweemeko ezisisiseko, i-Nrf2 ilandelwa kunye ne-Keap1 nge-motifs yayo emibini (ETGE kunye ne-DLG) ekhokelela kwi-CUL3-mediated ubiquitination elandelwa kukuthotywa kweproteasome. Ngaphantsi koxinzelelo lwe-oxidative, i-Nrf2 iyahlukana ne-Keap1, itshintshela kwi-nucleus kwaye isebenze ibhetri ye-ARE-gene. (B) I-GSK3 phosphorylates i-Nrf2 kwaye oku kuququzelela ukuqondwa kwe-Nrf2 ngu-?-TrCP ye-CUL1-mediated ubiquitination kunye nokuthotywa kwe-proteasome okulandelayo. (C) i-p62 ilandelwa kunye ne-Keap1, ekhokelela ekuthotyweni kwayo kwe-autophagic, ukukhululwa kwe-Nrf2, kunye nokunyuka kokubonisa i-Nrf2.

I-Keap1-I-Independent Nrf2 Umgaqo

Ubungqina obuvelayo bubonise indlela entsha yolawulo lwe-Nrf2 oluzimeleyo kwi-Keap1. I-serine-rich Neh6 domain ye-Nrf2 idlala indima ebalulekileyo kulo mmiselo ngokubopha kunye ne-motifs yayo emibini (i-DSGIS kunye ne-DSAPGS) kwi-?-transducin iphinda-equkethe iprotheni (?-TrCP) [24]. ?-TrCP yi-substrate receptor ye-Skp1�Cul1�Rbx1/Roc1 ubiquitin ligase complex ejolise kwi-Nrf2 yendawo yonke kunye nokuthotywa kweproteasomal. I-Glycogen synthase kinase-3 yiprotheni ebalulekileyo ebandakanyekayo kwi-Keap1-ezimeleyo ye-Nrf2 ukuzinza kunye nokulawula; i-phosphorylates i-Nrf2 kwi-domain ye-Neh6 ukuququzelela ukuqatshelwa kwe-Nrf2 nge-?-TrCP kunye nokuthotywa kweprotheyini elandelayo [25] (Umfanekiso 1B).

Abanye abalawuli be-Nrf2

Olunye udidi lobungqina luye lwabonisa indlela engekho yonyaniso ye-P62 exhomekeke kusebenze nge-Nrf2 apho i-p62 ibeka i-Keap1 ukuthotywa kwezinto ezizenzekelayo ekukhokelela ekuqiniseni i-Nrf2 kunye nokuguqulwa kwamagciwane ase-Nrf2-dependent [26], [27], [ 28], [29] (Umzobo 1C).

Ubungqina obuninzi bubonisa ukuba ii-miRNA ezininzi zidlala indima ebalulekileyo kulawulo lomsebenzi we-Nrf2 [30]. Sangokoya et al. [31] ibonise ukuba i-miR-144 inciphisa ngokuthe ngqo umsebenzi we-Nrf2 kwi-lymphoblast K562 cell line, iiseli eziphambili ze-erythroid zabantu, kunye ne-reticulocytes ye-sickle-cell. Olunye uphando olunomdla kwiiseli ze-epithelial zebele lubonise ukuba i-miR-28 inqanda i-Nrf2 nge-Keap1-independent mechanism [32]. Ngokufanayo, i-miRNAs efana ne-miR-153, miR-27a, miR-142-5p, kunye ne-miR144 yehlisa ukubonakaliswa kwe-Nrf2 kwi-neuronal SH-SY5Y umgca weseli [33]. Singh et al. [34] ibonise ukuba i-ectopic expression ye-miR-93 inciphisa ukubonakaliswa kwe-Nrf2-regulated genes kwi-17?-estradiol (E2) -imodeli ye-rat ye-mammary carcinogenesis.

Ukufunyaniswa kwamva nje kwilebhu yethu ichonge inhibitor engapheliyo ye-Nrf2 eyaziwa ngokuba yi-retinoic X receptor alpha (RXR?). RXR? i-nuclear receptor, isebenzisana ne-Neh7 domain ye-Nrf2 (i-amino-acid residues 209�316) ngokusebenzisa i-DNA-binding domain (DBD), kwaye inqanda ngokukodwa umsebenzi we-Nrf2 kwi-nucleus. Ngaphezu koko, ezinye ii-receptors zenyukliya ezifana ne-peroxisome proliferator-activated receptor-?, ER?, i-estrogen ehlobene ne-receptor-?, kunye ne-glucocorticoid receptors nazo ziye zaxelwa ukuba ziyi-endogenous inhibitors ye-Nrf2 umsebenzi [9], [10].

Ulwaphulo-mthetho oluchasayo lwe-Nrf2 / HO-1 Axis

I-HO-1 yi-isoform engabonakaliyo kunye ne-intensive-limiting enzyme eyenza ukuthotywa kwe-heme kwi-carbon monoxide (CO) kunye ne-iron ezamahala, kunye ne-biliverdin kwi-bilirubin. Ukuchithwa kwe-enzymatic ye-hem free-inflammatory free heme kunye nokuveliswa kweempawu ezichasayo ezifana ne-CO kunye ne-bilirubin zidlala indima enkulu ekugcineni i-HO-1 (Fig. 2).

**Umzobo 2 Ubume be-Nrf2 / HO-1.** Ngaphantsi kweemeko ze-basal, i-Nrf2 ibophelela kwi-repressor Keap1 ekhokelela kwi-ubiquitination elandelwa kukuthotywa kweproteasome. Ngexesha lokuxinzezeleka kwe-oxidative, i-Nrf2 yamahhala idlulisela kwi-nucleus, apho iyancipha kunye namalungu entsapho encinci ye-Maf kwaye ibophe kwi-ARE gene ezifana ne-HO-1. I-HO-1 ephakanyisiweyo yenza i-heme ibe yi-CO, i-bilirubin, kunye nentsimbi yamahhala. I-CO isebenza njenge-inhibitor ye-NF-?B indlela ekhokelela ekunciphiseni ukubonakaliswa kwe-cytokines e-pro-inflammatory, ngelixa i-bilirubin isebenza njenge-antioxidant. Ngaphezu koko, i-HO-1 inqanda ngokuthe ngqo i-cytokines ye-proinflammatory kunye nokusebenza kwee-cytokines ezichasayo, oko kukhokelela ekulinganisweni kwenkqubo yokuvuvukala.

I-Nrf2 yenza i-HO-1 gene ngokunyusa i-mRNA kunye nokubonakaliswa kweprotheni kwaye yenye ye-classic ye-Nrf2 elawulwa yi-gene esetyenziswa ngokubanzi kwi-vitro kunye nezifundo ze-vivo. Izifundo ezininzi ziye zabonisa ukuba i-HO-1 kunye ne-metabolites yayo ineempembelelo ezibalulekileyo zokuchasana nokudumba phakathi kwe-Nrf2. Ukuphakama kwenkcazo ye-HO-1 edibeneyo yi-Nrf2 esebenzayo ikhokelela ekuvinjweni kwe-NF? B izibonakaliso zeziphumo zokunciphisa ukulimala kwe-intestinal mucosal kunye nokungasebenzi kakuhle kwindoda ye-Sprague-Dawley imodeli yokutshintshwa kwesibindi [35]. Ukunyuswa kwe-Nrf2-exhomekeke kwi-HO-1 intetho inokukhusela imouse evela kwi-C2C12 myoblasts kwi-H2O2 cytotoxicity [36]. I-Nrf2-exhomekeke kwi-HO-1 inempembelelo kwi-lipopolysaccharide (LPS)-impendulo yokuvuvukala edibeneyo kwi-RAW264.7- okanye i-mouse peritoneal macrophage-derived foam cell macrophages. Umsebenzi we-Nrf2 we-foam cell macrophages phenotype kunye nokuthintela ukuvuvukala okungapheliyo kwe-macrophages, ezo zidlala indima ebalulekileyo ekuqhubekeni kwe-atherosclerosis [37]. I-Nrf2 / HO-1 i-axis ichaphazela i-LPS eyenziwa yi-mouse ye-BV2 iiseli ze-microglial kunye neeseli ze-mouse hippocampal HT22, ezinempembelelo kwi-neuroinflammation. Ukulungiswa kwe-HO-1 intetho ngendlela ye-Nrf2 kwi-mouse ye-BV2 iiseli ze-microglial ezikhusela ukufa kweeseli ze-mouse hippocampal HT22 iiseli [38]. Ngaphezu koko, i-cobalt-based hybrid molecules (HYCOs) ezidibanisa i-Nrf2 inducer kunye ne-relender ye-carbon monoxide (CO) yonyusa i-Nrf2 / HO-1 intetho, i-CO ikhulule kwaye isebenzise umsebenzi wokuchasana nokuvuvukala kwi-vitro. I-HYCOs iphinda ilawule izicubu ze-HO-1 kwaye ihambise i-CO egazini emva kokulawulwa kwi-vivo, ixhasa ukusetyenziswa kwabo okunokwenzeka ngokuchasene neemeko ezivuthayo [39]. Ukunyuswa kwe-Nrf2 / HO-1 kunciphisa ukuvuvukala ngokunyusa umsebenzi we-efferocytic we-murine macrophages ephathwa nge-taurine chloramines [40]. Ngokubanzi, iimodeli zovavanyo ezichazwe ngasentla zibonise ukuba i-Nrf2 / HO-1 i-axis idlala indima enkulu kumsebenzi wokuchasana nokuvuvukala, ebonisa ukuba i-Nrf2 iyinjongo yonyango kwizifo ezinxulumene nokuvuvukala.

Ukongezelela, i-HO-1 efana ne-CO, i-bilirubin, isebenza njenge-antioxidant enamandla ngexesha loxinzelelo lwe-oxidative kunye nomonakalo weeseli [41], [42]; inqanda i-encephalomyelitis kunye ne-hepatitis [43], [44]; kwaye ikhusela iigundane kunye neengqungqangi ngokuxhatshazwa kwe-endotoxic ngokuthintela isizukulwana se-iNOS no-NO [45], [46], [47]. Ngaphezu koko, i-Bilirubin iyanciphisa ukusetyenziswa komsebenzi wokugqibela kunye nokungasebenzi [48]. Ngokuthakazelisayo, i-bilirubin inciphisa ukufuduka kwe-leothecytes ekupheleni kwe-molecule-1 [49]. Ezi ngxelo ezikhankanyiweyo ezingabonakali nje nge-HO-1 zisebenza njenge-artificial anti-inflammatory but also its metabolites.

Abadibanisi beMidiyam kunye nee-Enzyme ezivinjelwe ngu-Nrf2

IiCytokines kunye neKokokines

I-Cytokines ziiprotheni ezinobunzima obuphantsi bemolekyuli kunye ne-polypeptides efihliweyo ziiseli ezahlukeneyo; zilawula ukukhula kweeseli, ukuhlukana, kunye nokusebenza komzimba, kwaye zibandakanyeka ekudumbeni nasekupholiseni amanxeba. IiCytokines ziquka i-interleukins (ILs), i-interferon, i-tumor necrosis factor (TNF), i-colon-stimulating factor, i-chemokines, kunye nezinto ezikhulayo. Ezinye iicytokines zibalwa njengabalamleli abanokudumba ngelixa abanye benemisebenzi echasayo. Ukuvezwa kuxinzelelo lwe-oxidative kubangela ukuveliswa kwe-cytokines ngokugqithisileyo okubangela uxinzelelo lwe-oxidative kwiiseli ekujoliswe kuzo. Uninzi lwe-cytokines ezi-pro-inflammatory zenziwa ngokugqithisileyo xa i-NF-?B yenziwe luxinzelelo lwe-oxidative. Ngaphaya koko, uxinzelelo lwe-pro-inflammatory oxidative lubangela ukuba kusebenze ngakumbi i-NF-?B kunye nokuveliswa ngokugqithisileyo kweecytokines. Ukusebenza kwenkqubo ye-Nrf2/ARE kudlala indima ebalulekileyo ekuphazamiseni lo mjikelo. I-Chemokines yintsapho yee-cytokines ezincinci, indima enkulu yokukhokela ukufuduka kweeseli ezivuthayo. Zisebenza ikakhulu njenge-chemoattractants ye-leukocytes, i-monocytes, i-neutrophils, kunye nezinye iiseli ezisebenzayo.

Kuye kwaxelwa ukuba ukusetyenziswa kwe-Nrf2 kuthintela ukunyanzeliswa kwe-LPS-induced transcriptional upregulation of pro-inflammatory cytokines, kuquka i-IL-6 kunye ne-IL-1? [50]. IL-1? kunye nemveliso ye-IL-6 nayo yonyuswa kwi-Nrf2?/? iimpuku ezine-dextran sulfate-induced colitis [51], [52]. I-Nrf2 inqanda ukuveliswa kwe-IL-17 ephantsi kunye nezinye izinto ezivuthayo i-Th1 kunye ne-Th17, kwaye icinezela inkqubo yesifo kumzekelo wokulinga we-multiple sclerosis, i-encephalitis ye-autoimmune [53]. I-Nrf2 exhomekeke kwi-anti-oxidant genes HO-1, NQO-1, Gclc, kunye ne-Gclm block TNF-?, IL-6, i-monocyte chemo i-protein-1 (MCP1), i-macrophage inflammatory protein-2 (MIP2), kunye nokuvuvukala abalamli. Kodwa kwimeko yeegundane ze-Nrf2-knockout, i-anti-inflammatory effect ayenzeki [54]. I-Peritoneal neutrophils esuka kwi-Nrf2-knockout iigundane eziphathwe nge-LPS zinamazinga aphezulu kakhulu e-cytokines (TNF-? kunye ne-IL-6) kunye ne-chemokines (MCP1 kunye ne-MIP2) kune-wild-type (WT) iiseli [54]. I-In vitro, ukudlulisa i-Nrf2 gene kubantu kunye nomvundla we-aorta ye-aorta egudileyo iiseli zicinezela imfihlo ye-MCP1 [8], [55], kunye ne-Nrf2-exhomekeke kwi-HO-1 intetho icinezela i-TNF-?-evuselelwe i-NF-?B kunye ne-MCP-1 ukukhuselwa kwiiseli ze-umbilical vein endothelial cells [56]. Ezi ziphumo zibonisa ukuba, ekuphenduleni i-stimuli evuthayo, ukulawulwa kwe-Nrf2 yokubonisa ukuvimbela ukuveliswa kwe-pro-inflammatory cytokines kunye ne-chemokines kunye nokunciphisa ukusebenza kwe-NF-?B.

IiMeleleksi zeeSeli

Iimolekyuli zokubambelela kwiiseli (CAMs) ziiprotheyini ezibopha ngeeseli okanye nge-matrix engaphandle kwecellular. Ifumaneka kumphezulu weseli, zibandakanyeka ekuqaphelisweni kweeseli, ukusetyenziswa kweeseli, ukuhanjiswa komqondiso, ukwanda, kunye nokwahlula. Phakathi kwee-CAM, i-ICAM-1 kunye ne-VCAM-1 ngamalungu abalulekileyo e-immunoglobulin superfamily. I-ICAM-1 ikhona kwiindawo eziphantsi kwi-leukocyte kunye ne-endothelial cell membranes. Emva kokuvuselela i-cytokine, ukugxininiswa kwandisa kakhulu. I-ICAM-1 inokunyanzeliswa yi-IL-1 kunye ne-TNF kwaye ibonakaliswe yi-vascular endothelium, i-macrophages, kunye ne-lymphocytes. I-ligand ye-integrin, i-receptor efunyenwe kwi-leukocytes. Xa ibhuloho ye-ICAM-1-integrin ivuliwe, i-leukocytes ibophelela kwiiseli ze-endothelial ize ifudukele kwizicubu ze-subendothelial [57]. I-VCAM-1 idibanisa ukunamathela kwe-lymphocytes, i-monocytes, i-eosinophils, kunye ne-basophils kwi-vascular endothelium kwaye igalelo ekuqeshweni kwe-leukocyte, ekugqibeleni ikhokelela kumonakalo wezicubu ngenxa yoxinzelelo lwe-oxidative. I-Nrf2 inqanda umsebenzi wokukhuthaza we-VCAM-1 [58]. I-Nrf2-elawulwa phantsi kwe-gene HO-1 inokuchaphazela ukubonakaliswa kwe-E-selectin kunye ne-VCAM-1, i-adhesion molecules ezinxulumene neeseli ze-endothelial [59]. Ukubonakaliswa kwemiphunga yee-CAM ezininzi ezifana ne-CD-14, TREM1, SELE, SELP, kunye ne-VCAM-1 ziphezulu kakhulu kwi-Nrf2?/? iimpuku kune-Nrf2+/+ iimpuku [60]. I-Nrf2 kwiiseli ze-aortic endothelial zomntu zicinezela i-TNF-?-eyenziwe i-VCAM-1 intetho kwaye iphazamise i-TNF-?-induced monocytic U937 i-cell adhesion [8]. Ukugqithiswa kwe-Nrf2 kwakhona kuvimbela i-TNF-?-eyenziwe i-VCAM-1 i-gene expression kwiiseli ze-microvascular endothelial cell [61]. I-antioxidant ye-3-hydroxyanthranilic acid (HA) ngokwemvelo, enye ye-l-tryptophan metabolites eyenziwe kwi-vivo kunye nomzila we-metabolic owaziwa ngokuba yi-kynurenine pathway ngexesha lokuvuvukala okanye ukusuleleka, kufumaneka ukukhupha i-HO-1 intetho kunye nokukhuthaza i-Nrf2 kwi-umbilical yomntu. iiseli ze-vein endothelial (HUVECs). Inkcazo ye-Nrf2 exhomekeke kwi-HO-1 eyenziwa yi-HA inqanda i-MCP-1 secretion, i-VCAM-1 ibonakaliso kunye nokusebenza kwe-NF-kB ehambelana nokulimala kwe-vascular kunye nokuvuvukala kwi-atherosclerosis [56]. I-anti-proliferative and anti-inflammatory synthetic chalcone derivative 2?,4?,6?-tris (methoxymethoxy) i-chalcone inqanda i-ICAM-1, i-cytokine ye-pro-inflammatory IL-1?, kunye ne-TNF-? ukubonakaliswa kwi-colonic tissue kwiigundane eziphathwe nge-trinitrobenzene sulfonic acid [62]. Ukunyuswa kwe-Nrf2 inqanda i-TNF-?-eyenziwe i-ICAM-1 ibonakaliso kwi-retinal pigment cell cell epithelial ephathwa nge-lycopene [63]. Zonke ezi zifundo zibonisa ukuba i-Nrf2 idlala indima ephambili kwinkqubo yokuvuvukala ngokulawula ukufuduka kunye nokungena kweeseli ezivuthayo kwizicubu ezivuthayo.

IMatrix Metalloproteinase (MMPs)

Ii-MMPs zikhona ngokubanzi kwi-matrix engaphandle kwaye zibandakanyeka kwiinkqubo ze-physiological and pathological ezifana nokwanda kweeseli, ukufuduka, ukwahlula, ukuphiliswa kwenxeba, i-angiogenesis, i-apoptosis, kunye ne-tumor metastasis. Kuye kwaxelwa ukuba i-Nrf2 / HO-1 i-axis inqanda i-MMP-9 kwi-macrophages kunye ne-MMP-7 kwiiseli ze-epithelial zamathumbu omntu, kwaye oku kunenzuzo kunyango lwesifo sofuba [62], [64]. Umonakalo we-UV owenziwe ngokukhanya kwesikhumba unzima kakhulu kwi-Nrf2-knockout kune-WT iigundane kwaye inqanaba le-MMP-9 liphezulu kakhulu, libonisa ukuba i-Nrf2 inciphisa ukubonakaliswa kwe-MMP-9. Ngoko ke, i-Nrf2 ithathwa njengento ekhuselayo kwi-UV irradiation [65]. Olunye uphononongo luphinde lwaxela ukuba ukusetyenziswa kwe-transcriptal ephantsi ye-MMP-9 kwi-tumor cell invasion kunye nokudumba kulawulwa ngokuthintelwa kwendlela yokubonisa i-NF-kB [66]. Kwingozi yokulimala komgogodla, indlela ye-NF-kB yokubonisa iphinda ithathe inxaxheba ekulawuleni amanqanaba e-mRNA ye-MMP-9 [67]. Ngoko ke, ekudumbeni ukulawulwa kwe-MMPs kuchaphazeleka ngokuthe ngqo kwindlela ye-Nrf2 okanye ngokungathanga ngqo nge-Nrf2-echaphazelekayo ye-NF-?B indlela.

I-Cyclooxygenase-2 (COX2) kunye ne-Nonicible Nitric Oxide Synthase (INOS)

Uluhlu lweemvavanyo kwiigundane ze-Nrf2-knockout lubonise indima yalo ebalulekileyo ekudumbeni kunye nokulawulwa kweejene ze-pro-inflammatory ezifana ne-COX-2 kunye ne-iNOS. Ngethuba lokuqala, uKhor et al. ingxelo yokwanda kokubonakaliswa kwe-cytokines e-pro-inflammatory efana ne-COX-2 kunye ne-iNOS kwii-colonic tissues ze-Nrf2?/? iigundane xa kuthelekiswa ne-WT Nrf2 +/+ iigundane, ebonisa ukuba i-Nrf2 icinezela umsebenzi wabo [51]. Enye ingxelo malunga nokunyangwa kwangaphambili nge-sulforaphane, enye ye-activators ye-Nrf2 eyaziwayo ekhoyo kwimifuno ye-cruciferous, ibonise umphumo wayo wokuchasana nokuvuvukala wokuthintela ukubonakaliswa kwe-TNF-?, IL-1?, COX-2, kunye ne-iNOS kuzo zombini i-mRNA kunye namanqanaba eprotheyini kwii-macrophages eziphambili ze-peritoneal ezivela kwi-Nrf2 +/+ iimpuku xa kuthelekiswa nezo zisuka kwi-Nrf2?/? iimpuku [68]. Ngokufanayo, i-hippocampus ye-Nrf2-knockout iigundane kunye ne-LPS-induced inflammation iphinda ibonise ukubonakaliswa okuphezulu kwamanqaku okuvuvukala afana ne-iNOS, i-IL-6, kunye ne-TNF-? kuneempuku ze-WT [69]. Ngokufanayo, iigundane ze-Nrf2-knockout zi-hypersensitive kuxinzelelo lwe-oxidative eyenziwa yi-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine kunye nokubonisa ukunyuka kwe-mRNA kunye namanqanaba eprotheni yeempawu zokuvutha ezifana ne-COX-2, iNOS. , IL-6, kunye ne-TNF-? [70]. Ngaphezu koko, izibindi ezivela kwi-Nrf2?/? iigundane ezinomngeni nge-methionine- kunye ne-choline-deficient diet ine ~ 5-fold high mRNA expression of Cox2, kunye ne-iNOS kunezo zivela kwi-WT iigundane kwisidlo esifanayo, ebonisa indima echasayo ye-Nrf2 [71]. Kutshanje, uKim et al. ibonise ukuba i-phytochemical ethyl pyruvate isebenzisa i-anti-inflammatory kunye ne-anti-oxidative iziphumo ngokunciphisa ukubonakaliswa kwe-iNOS nge-Nrf2 yokubonisa kwiiseli ze-BV2. Babonise ukuba i-ethyl pyruvate ibangela ukuhanjiswa kwenyukliya ye-Nrf2, ekugqibeleni inqanda ukusebenzisana phakathi kwe-p65 kunye ne-p300, ekhokelela ekunciphiseni ukubonakaliswa kwe-iNOS [72]. Ngaphezu koko, i-carbazole analogue LCY-2-CHO isebenze i-Nrf2 kwaye ibangele ukuhanjiswa kwayo kwenyukliya, okukhokelela ekunyanzelweni kwe-COX2 kunye ne-iNOS intetho [73] kwi-rat aortic vascular smooth muscle cells.

Indima eyiParadoxical ye-Nrf2 kuLawulo lwe-NLRP3 iIflammasome�Umsebenzi

Intsapho ye-NLR, i-pyrin domain equlethe i-3 (NLRP3) i-inflammasome yi-multiprotein complex esebenza njenge-receptor ye-pathogen recognition (PRR) kwaye iyaqaphela uluhlu olubanzi lwe-microbial, izibonakaliso zoxinzelelo lwe-oxidative ezifana neepateni ze-molecular ezinxulumene ne-pathogen (PAMPs), Umonakalo- iimolekyuli zepateni ehambelanayo (i-DAMPs) kunye ne-ROS [74]. I-NLRP3 esebenzayo i-inflammasome idibanisa i-cleavage ye-caspase-1 kunye nemfihlo ye-pro-inflammatory cytokine interleukin-1? (IL-1?) ekugqibeleni ibangela inkqubo yokufa kweeseli eyaziwa ngokuba yi-pyroptosis ekhusela umkhosi ngokuchasene noluhlu olubanzi lwee-pathogens [75]. Nangona kunjalo, ukusetyenziswa kakubi kwe-inflammasome kuhambelana nezifo eziphazamisayo zeprotheni ezifana ne-spongiform encephalopathies, isifo se-Alzheimer, isifo sika-Parkinson kunye nohlobo lwe-2 yeswekile [76], umhlaza [77], i-gout, kunye ne-atherosclerosis [78].

Ukuqwalaselwa kwamva nje kwiqela le-Rong Hu kwintlangano ye-Nrf2 kunye nolawulo olubi lwe-inflammasome lubonise ukuba, i-Nrf2 yenza i-NQO1 ibonakaliso ekhokelela ekuvinjweni kwe-NLRP3 inflammasome activation, caspase-1 cleavage kunye ne-IL-1? isizukulwana kwi macrophages. Ngaphezu koko, i-activator ye-Nrf2 eyaziwayo, i-tert-butylhydroquinone (tBHQ) ilawula kakubi i-NLRP3 transcription ngokuvula i-ARE ngendlela exhomekeke kwi-Nrf2 [79]. Ukongeza koku kuqwalaselwa ngasentla, iqela elifanayo liye lavezwa ukuba, i-dimethyl fumarate (i-DMF) ivimbela i-DSS-induced colitis ngokusebenzisa i-Nrf2 indlela yokubonisa i-Nrf2 ebandakanyekayo kwi-Nrf3 yokudluliselwa kwenyukliya kunye nokuvinjelwa kwe-NLRP80 indibano ye-inflammasome [XNUMX].

Uluhlu lwezilingo zisebenzisa iikhompawundi zendalo kunye nezokwenziwa ziye zabonisa umphumo wokuthintela we-Nrf2 kwi-NLRP3 inflammasome activation. Ngokomzekelo, unyango lwe-epigallocatechin-3-gallate (EGCG) kwiigundane ze-lupus nephritis zibonise ukunciphisa i-renal NLRP3 inflammasome activation edityaniswe ngu-Nrf2 indlela yokubonisa [81]. Ngokufanayo, i-citral (i-3,7-dimethyl-2,6-octadienal), i-compound enkulu esebenzayo kwiyeza laseShayina i-Litsea cubeba, inqanda i-NLRP3 i-inflammasome activation nge-Nrf2 i-antioxidant ye-antioxidant pathway kwi-Accelerated and Severe Lupus Nephritis (ASLN) imodeli yegundane. [82]. Ngokufanayo, i-biochanin ikhuselwe kwi-LPS / GalN-eyenziwe yokulimala kwesibindi ngokuvula indlela ye-Nrf2 kunye nokuvimbela i-NLRP3 i-inflammasome activation kwi-BALB yamadoda / c iigundane [83]. Ngaphezu koko, i-mangiferin nayo yaboniswa ukuba ilawule ukubonakaliswa kwe-Nrf2 kunye ne-HO-1 ngendlela exhomekeke kwi-dose kwaye inhibited LPS/D-GalN-induced hepatic NLRP3, ASC, caspase-1, IL-1? kunye TNF-? intetho [84].

Ngaphandle kokulawulwa kakubi kwe-NLRP3 nge-Nrf2, iphinda isebenze i-NLRP3 kunye ne-AIM2 umsebenzi we-inflammasome. UHaitao Wen kunye noogxa bafumanisa ukuba, Nrf2 ?/? i-macrophages ye-mouse ibonise ukusebenza okungalunganga kwe-NLRP3 kunye ne-AIM2 Inflammasome kodwa kungekhona i-NLRC4 inflammasome [85]. Kuyathakazelisa ukuba lo mbono ubonisa imisebenzi engaziwayo ye-Nrf2 kumxholo wokuvuvukala okuhambelana nezifo; ngoko ke kubaluleke kakhulu ukufundisisa ngokuqhubekayo ukuveza indlela apho i-Nrf2 ivuselela umsebenzi we-inflammasome ngaphambi kokuba ithathelwe ingqalelo njengento ekujoliswe kuyo yonyango.

Ukucinywa kwe-pro-inflammatory Transtocy Cytokine ngu-Nrf2

Uphando olutshanje olusekelwe kwi-chromatin immunoprecipitation (ChIP) -seq kunye ne-ChIP-qPCR iziphumo kwi-macrophages ye-mouse ibonise ukuba i-Nrf2 ibophelela kwimimandla ekhuthazayo ye-cytokines e-pro-inflammatory efana ne-IL-6 kunye ne-IL-1? kwaye inqanda ukuqeshwa kwe-RNA Pol II. Ngenxa yoko, i-RNA Pol II ayikwazi ukucubungula ukusetyenziswa kwe-transcriptional ye-IL-6 kunye ne-IL-1? oko ekugqibeleni kukhokelela ekuthinteleni ukubonakaliswa kwemfuza. Ngethuba lokuqala, iqela likaMasayuki Yamamoto libonise indlela yenoveli apho i-Nrf2 ingatshintshi kuphela iijene zayo ezisezantsi ngee-AREs kodwa iphinde icinezele ukusetyenziswa kwe-transcriptal ye-genes ethile okanye ngaphandle kwe-ARE ngokuvimbela ukuqeshwa kwe-RNA Pol II [50].

I-Crosstalk Phakathi kweNrf2 kunye neNF-?B Iindlela

I-NF-?B yiprotheyini eyinkimbinkimbi ejongene nokubhalwa kwe-DNA efunyenwe phantse kuzo zonke iintlobo zeeseli zezilwanyana kwaye ibandakanyeka kwiinkqubo ezahlukeneyo ezifana nokudumba, i-apoptosis, ukuphendula komzimba, ukukhula kweeseli kunye nophuhliso. I-p65, iprotheni ye-Rel yosapho lwe-NF-?B, inommandla wotshintshiselwano ngelixa i-p50 ayinayo kwaye ifuna i-heterodimerization nge-Rel protein ukuze isebenze ukukhutshelwa. Ngexesha loxinzelelo lwe-oxidative, i-I?B kinase (IKK) iyasebenza kwaye ibangela i-phosphorylation ye-I?B, ekhokelela ekukhululweni kunye nokuhanjiswa kwenyukliya kwe-NF-?B. I-NF-?B ibangela ukubhalwa kwe-pro-inflammatory mediators njenge-IL-6, TNF-?, iNOS, IL-1, kunye ne-intracellular adhesion COX-2.

Ukulawulwa okungaqhelekanga kwe-NF-?B idibaniswe ne-rheumatoid arthritis, i-asthma, isifo sofuba, kunye ne-Helicobacter pylori-induced gastritis [86]. Okwangoku kucingwa ukuba umsebenzi we-NF-kB uphembelela i-Keapl/Nrf2/ARE indlela yomqondiso ikakhulu kwimiba emithathu: okokuqala, i-Keap1 ithoba i-IKK? ngokusebenzisa indawo yonke, ngaloo ndlela inqanda umsebenzi we-NF-?B [87]. Okwesibini, inkqubo yokuvuvukala ibangela abalamlamli abavuthayo njenge-COX2 ephuma kwi-cyclopentenone prostaglandin 15d-PGJ2, i-electrophile enamandla ephendula nge-Keap1 kwaye isebenze i-Nrf2, ngaloo ndlela iqalise ukubhaliswa kwe-gene kunye nokuvinjelwa kwangaxeshanye kwe-NF-kB [58], [88]. Umzobo 3 A, B). Okwesithathu, i-NF-?B inokudibanisa nokhuphiswano lwe-Nrf2 transcriptional co-activator CBP [89], [90] (Umfanekiso 3 C, D).

**Umzobo 3 uCrosstalk phakathi kweendlela ze-Nrf2 kunye ne-NF-?B.** (A) I-Keap1 iyalela i-IKK kwi-CUL3-mediated ubiquitination kunye nokuthotywa kweproteasome ekugqibeleni okukhokelela ekuthinteleni iphosphorylation ye-NF-?B kwaye le ndlela iphinda isebenze njengokubophelela ukukhuphisana kwe-Nrf2 kunye ne-IKK kunye ne-Keap1. (B) Ukuxinezeleka kwe-Oxidative kusebenze i-IKK i-phosphorylates i-NF-? Imveliso ye-terminal ye-COX-2 eyaziwa ngokuba yi-2d-PGJ15 isebenza njenge-inducer ye-Nrf2 ekugqibeleni ikhokelela ekunciphiseni uxinzelelo lwe-oxidative. (C) I-Nrf2 ibophelela nge-transcriptional cofactor CBP kunye ne-Maf encinci kunye nabanye oomatshini bokukhutshelwa ukuze baqalise i-ARE-driven gene expression. (D) Xa i-NF-?B ibophelela i-CBP ngendlela ekhuphisanayo, ithintela ukudityaniswa kwe-CBP ne-Nrf2, nto leyo ekhokelela ekuthinteleni usetyenziso lwe-Nrf2.

Kucingelwa ukuba i-Nrf2 kunye ne-NF-?B iindlela zokubonisa iimpawu zisebenzisana ukulawula ukubhaliswa okanye umsebenzi weeprotheyini ezijoliswe phantsi. Ekuthetheleleni le ngqikelelo imizekelo emininzi ibonisa ukuba ukusebenza ngokuthe ngqo okanye ngokungathanga ngqo kunye nokuthintela kwenzeka phakathi kwamalungu eendlela ze-Nrf2 kunye ne-NF-?B (Fig. 4). Ukuphendula kwi-LPS, i-Nrf2 i-knockdown inyusa kakhulu umsebenzi we-NF-?B wokukhuphela kunye ne-NF-?B exhomekeke kwi-gene transcription, ebonisa ukuba i-Nrf2 ithintela umsebenzi we-NF-?B [60], [91]. Ukongeza, ukubonakaliswa okwandisiweyo kwe-Nrf2-exhomekeke ezantsi kwe-HO-1 inqanda umsebenzi we-NF-?B. Xa iiseli zomhlaza wedlala lobudoda zibonakaliswa ngokufutshane kwi-?-tochopheryl succinate, i-derivative ye-vitamin E, i-HO-1 expression is upregulated. Iimveliso zokugqibela ze-HO-1 zithintela ukuhanjiswa kwenyukliya kwe-NF-?B [92]. Ezi zifundo ze-vivo zibonisa ukuba i-Nrf2 ilawula kakubi i-NF-kB indlela yokubonisa. I-LPS ivuselela i-NF-?B DNA umsebenzi wokubophelela kunye nenqanaba lesuntswana le-p65 le-NF-?B liphezulu kakhulu kwiincindi zenyukliya ezivela kwimiphunga ye-Nrf2?/? kunokusuka kwiimpuku ze-WT, icebisa indima engalunganga ye-Nrf2 kusetyenziso lwe-NF-?B. Ngaphezu koko, Nrf2?/? impuku embryo fibroblasts ephathwa LPS kunye TNF-? bonisa ukusebenza kwe-NF-?B ebalasele ngakumbi ebangelwa yi-IKK kunye ne-I?B-? ukuthotywa [60]. Kwaye ukukhutshwa kwentsholongwane yokuphefumla ye-syncytial yehle kakhulu ngelixa i-NF-?B umsebenzi wokubopha i-DNA wonyuka kwi-Nrf2?/? iimpuku xa kuthelekiswa neempuku ze-WT [93]. I-Pristane-induced lupus nephritis kwi-Nrf2?/? iigundane eziphathwe nge-sulforaphane zinomonakalo omkhulu wezintso kunye nokuguqulwa kwe-pathological kunye nokuphakanyiswa kwe-iNOS intetho kunye ne-NF-?B ukusebenza xa kuthelekiswa ne-WT, ebonisa ukuba i-Nrf2 iphucula i-lupus nephritis ngokuvimbela indlela ye-NF-?B yokubonisa kunye nokucoca i-ROS [94] ]. Umsebenzi we-NF-?B wenzeka kwakhona xa iiseli ziphathwa nge-Nrf2 inducer kunye ne-LPS kunye ne-TNF-? Ngokomzekelo, i-synthetic chalcone derivative inhibits i-TNF-?-eyenziwe i-NF-?B isebenze ngokuthe ngqo nangokungathanga ngqo kwaye ngokuyinxenye ngokungeniswa kwe-HO-1 intetho kwiiseli ze-HT-29 ze-intestinal epithelial [62]. Ukunyanzeliswa kwe-NF-?B yokutshintshwa kunye nomsebenzi wokubopha i-DNA kunye nokunyanzeliswa kwe-iNOS inkcazo kwi-hepatocytes ifunyenwe xa iirats ze-F344 ziphathwa nge-3H-1,2-dithiole-3-thione (D3T) [95]. Emva kokubambisana kunye ne-sulforaphane kunye ne-LPS, i-LPS-induced expression ye-iNOS, i-COX-2, kunye ne-TNF-? kwi-Raw 264.7 macrophages iyancipha, icetyiswa ukuba i-sulforaphane inomsebenzi ochasayo ngokuvinjelwa kwe-NF-?B DNA ebophayo [96]. Nangona uphando oluninzi lwenziwe ukucacisa ikhonkco phakathi kweendlela ze-Nrf2 kunye ne-NF-?B, iziphumo eziphikisanayo zihleli. Zomibini imigaqo emihle neyiyo ibikwe phakathi kwe-Nrf2 kunye ne-NF-kB [97]. Ngokuqhelekileyo, i-electrophile ye-chemopreventive i-3H-1,2-dithiole-3-thione, i-sulforaphane kunye ne-Triterpenoid CDDO-Me isebenzise i-Nrf2 ngokuvimbela i-NF-kB kunye negazi layo elingaphantsi [98], [99], [100]. Ngokwahlukileyo, amanxeba amaninzi okanye iimeko ezifana ne-ROS, i-LPS, ukunyuka kwengxolo ye-shear, i-LDL ene-oxidiweyo kunye nomsi wesigayi kuboniswe ukwandisa umsebenzi we-Nrf2 kunye ne-NF-kB [97]. Ukongeza, izifundo ze-vivo zibonise ukuba umsebenzi we-NF-kB wehlisiwe kwizibindi ezizimeleyo kwi-Nrf2?/? iimpuku kunye ne-NF-?B umsebenzi wokubopha usezantsi kwi-Nrf2?/? kunakwi-Nrf2+/+ iimpuku [101]. Nangona kunjalo, iiseli ze-aortic endothelial zomntu ziphathwa nge-adenoviral vector Nrf2 inhibit i-NF-?B iijene ezisezantsi ngaphandle kokuchaphazela umsebenzi we-NF-?B [8].

**Isazobe 4 Ulawulo lwelophu ye-Nrf2 kunye ne-NF-?B.** Indlela ye-Nrf2 inqanda ukusebenza kwe-NF-?B ngokunqanda ukuthotywa kwe-I?B-? kunye nokwandisa i-HO-1 intetho kunye nokukhusela i-antioxidant eyenza i-ROS ingabi nalutho kunye neekhemikhali ezikhuphayo. Ngenxa yoko, ukusebenza kwe-NF-?B enxulumene ne-ROS kucinezelwe. Ngokunjalo, ushicilelo lwe-NF-?B-mediated lunciphisa ukusebenza kwe-Nrf2 ngokunciphisa�ZI� Ushicilelo lwegene kunye ne-CREB yasimahla ebophelelayo iproteni ngokukhuphisana ne-Nrf2 ye-CBP. Ngaphezu koko, i-NF-?B yonyusa ukufunwa kwe-histone deacetylase (i-HDAC3) ukuya kummandla we-ARE kwaye ngoko ke ukusetyenziswa kwe-Nrf2 okubhaliweyo kuthintelwe.

Ukusebenza kwendlela yokubonakalisa i-Nrf2 kudlala indima enkulu ekuboniseni i-enzyme kunye namajeni afakelwe ukuxutywa kwe-oxidants esebenzayo ngokuphucula amandla okulwa ne-antioxidant yeeseli zomzimba womntu. Nangona uphando olunzulu lukhoyo namhlanje, iindlela zokulawula kwi-Nrf2 kusebenze aziqondi kakuhle. Inxaxheba ekhoyo ye-Nrf2 yokumakishwa kwindlela yokwelashwa sele ifunyenwe. UDkt Alex Jimenez DC, i-CCST Insight

Indima ye-Nrf2 kwizifo ezivuthayo

Izifundo ze-vivo zibonise ukuba iNrf2 inendima ebalulekileyo kwizifo ezivuthayo ezichaphazela iinkqubo ezahlukeneyo; Ezi ziquka i-gastritis, i-colitis, i-arthritis, i-pneumonia, umonakalo wesibindi, isifo senhliziyo, isifo se-neurodeergenerative kunye nomonakalo wengqondo. Kwezi zifundo, Nrf2?/? izilwanyana zibonise iimpawu ezinzulu zokudumba kunye nomonakalo wezicubu kunezilwanyana ze-WT. Ngako oko, kukholwa ukuba indlela yokubonakalisa iNrf2 inomphumo wokukhusela kwizifo ezivuthayo. Ukufakelwa kwe-intra-tracheal ye-porcine pancreatic elastase ikhuthaza isifo esingapheliyo se-pulmonary disease, ngakumbi i-emphysema. Iimfucuza ze-Nrf2 ezingenakucala ziyakwazi ukuthinteka kakhulu kwi-emphysema, kwaye ukuhla kwe-HO-1, PrxI kunye ne-antiprotease gene SLPI zenzeke kwi-macrophages ye-alveolar. I-Nrf2 ithathwa njengomlawuli oyintloko kwinkqubo yokukhusela i-macrophage yokulwa nomonakalo wamaphaphu [102]. Iifom e-Nrf2 ezingenayo i-emphysema ezibangelwa ukutshaya umsi wecuba kwiinyanga ze-6 zibonisa ukunyuka kwe-bronchoalveolar, ukubonakaliswa ngokugqithisileyo kweempawu zokuxinzelela kwi-alveoli, kunye nokwandisa i-septal cell apoptosis, ebonisa ukuba iNrf2 iyayichasa ukutshatyalaliswa kwe-tobacco emphysema ngokubonakalisa ukwanda kwe-antioxidant izakhi zofuzo [102], [103]. Ngokuphazamiseka kwe-Nrf2, ukuvutha kwe-airgen-mediated inflammation kunye ne-asthma usebenzisa i-ovalbumin yinkqubo ebonisa ubunzima bonyuka ukuvutha kwe-airway, u-hyper-reactivity, i-hyperplasia yamaseli e-goblet, kunye namazinga aphezulu eThNUMX kwi-bronchoalveolar ukuhlanjululwa kunye ne-splenocytes, kanti i-Nrf2-mediated-path signaling pathway i-eosinophilia , i-mucus hypersecretion, kunye ne-airway hyper-reactivity kunye nokunciphisa iindiza ezininzi ze-antioxidant ezithintela ukuphuhliswa kwe-asthma [2]. I-carrageenan injection kwi-pleuraly cavity induces pleuriy, kwaye i-15d-PGJ2 ukuqokelela kwii-Nrf2 ezivuthayo zamaseli zigcinwe kwi-mouse ye-macrophages ye-peritoneal. Ngethuba lesigaba sokuqala sokuvuvukala, i-15d-PGJ2 isebenza nge-Nrf2 kwaye ilawula inkqubo yokuvuvukala ngokufakwa kwe-HO-1 ne-PrxI. Uphando luye lwacebisa ukuba i-COX-2 inefuthe elichasayo kwisigaba sokuqala ngemveliso ye-15d-PGJ2 [105]. Ukulawulwa komlomo kwe-1% i-dextran sulfate ye-sodium ye-1 iveki yenza ukuba i-colitis ihambelane neenguqu zakhe ezinokuthi zibandakanye ukunciphisa i-crypts kunye nokungena kweeseli ezivuthayo kwimizimba ye-colon. Ukukhusela intliziyo ye-intestinal kwi-colitis, i-Nrf2 inokudlala indima ebalulekileyo ngokulawula ama-cytokines angama-pro-inflammatory kunye nokunciphisa isigaba II sokuxosha i-enzyme [51]. Kwimodeli yemouse ye-Nrf2-knockout ye-LPS-induced pulmonary sepsis, umsebenzi we-NF-?B ulawula iimpembelelo ze-cytokines ezivuthayo ezifana ne-COX-2, IL-113, IL-6, kunye ne-TNF? eziyimfuneko ekuqaliseni nasekukhuthazeni ukudumba [60]. I-Nrf2 iyanciphisa umonakalo obangelwayo ngokulawula ezi zinto ezivuzayo. Kule mizekelo yokuvuvukala okunzulu, ukulawulwa kwe-enzymes e-antioxidant, i-cytokines ezivuthayo, kunye nabalamlamli nge-Nrf2 yokumaketha kwindlela ekunciphisayo ukulimala okuvuthayo kwizilwanyana ze-WT. Okuthakazelisayo, oku kuye kwaxelwa kwakhona kwiimpawu ze-Nrf2-knockout apho iimpawu zixakeke ngakumbi xa zifaniswa nee-WT amagundane.

Uphando malunga ne-Nrf2-Ixhomekeke kwiZiyobisi ezichasayo

Sishwankathelo, sixoxe ngezilingo ezibonisa ukuba indlela ye-signal ye-Nrf2 idlala indima yokulawula kwiindawo ezininzi zokuqhaqhazela, ngoko-ke i-Nrf2-kuxhomekeke kwi-anti-inflammatory agents iyabalulekile ekwenzeni izifo ezivuthayo.

Izityalo ziye zaba yimithombo ecebile kakhulu yamacomplethi eyenza i-Nrf2 yoshicilelo yoshicilelo, ekhokelela ekulawuleni ukuphakanyiswa kwamagciwane e-cytoprotective. Kungekudala, kwenziwe uphando oluthile ukuphanda iimiphumo ze-anti-inflammatory agents, ikakhulukazi zezityalo. Umzekelo, i-curcumin isithako esisebenzayo se-turmeric kwaye sifumaneka kwixabiso elincinci kwi-ginger; i-isothiocyanates, ngokukodwa i-phenylisothiocyanates iphuma kwi-broccoli, isilimo esidliwayo esinamagatsha anamanzi, kunye nezinye iifuno; kunye ne-anthocyanins zivela kumajikijolo kunye neediliya [124]. Ucwaningo luye lwabonisa ukuba onke la ma-agent ayenayo kuphela i-antioxidants efanelekileyo kodwa eneempembelelo ezinamandla zokuchasana nge-Nrf2 induction [125], [126]. Ngoko ke, ukuphuhliswa kwe-activated anti-inflammatory Nrf2 kwi-extract plant kuye kwabangela umdla omkhulu kwezophando.

Kwiminyaka yakutshanje, kuye kwenziwa uvavanyo oluninzi lwezilwanyana ukuze kuqinisekiswe izenzo zezi khompawundi. I-Artesunate isetyenziselwa ikakhulu isifo seengcongconi, isifo seengcongconi, kunye nezifo ze-rheumatic autoimmune; Ikwasebenza kumonzakalo we-septic lung. I-Artesunate ivuselela i-Nrf2 kunye ne-HO-1 intetho, kwaye okokugqibela kunciphisa ukungena kwe-cytokines e-pro-inflammatory kunye ne-leukocytes kwizicubu zokukhusela ukuvuvukala [127]. I-Isovitexin, ekhutshwe kwii-hulls ze-Oryza sativa irayisi, icingelwa ukuba ine-anti-inflammatory kunye ne-antioxidant properties; idlala indima yokukhusela kwi-LPS-induced acute lung injury ngokuvula indlela ye-Nrf2/HO-1 kwaye inqanda i-MAPK kunye ne-NF-?B [128]. I-Fimasartan, i-blocker ye-angiotensin II esandula ukuthandwa esebenza kwinkqubo ye-renin-angiotensin, inciphisa uxinzelelo lwegazi; ukusebenzisa i- fimasartan ukunyanga iimpuku ngoqhaqho-olubangelwa utyando lwe-ureteral obstruction kunciphisa uxinzelelo lwe-oxidative, ukuvuvukala, kunye ne-fibrosis ngokunyusa i-Nrf2 kunye ne-antioxidant pathway kunye nokuvimbela i-RAS kunye ne-MAPKs [129]. I-Sappanone isasazwa ngokubanzi kwi-Asia-mpuma ye-Asia, apho isetyenziswe njenge-anti-influenza, i-anti-allergic, kunye neyeza ze-neuroprotective; yenza i-Nrf2 isebenze kwaye inqanda i-NF-?B kwaye ngoko ingaba luncedo kunyango lwe-Nrf2- kunye / okanye i-NF-?B izifo ezinxulumene [130]. I-Bixin ekhutshwe kwimbewu ye-Bixin orellana isetyenziselwa izifo ezithathelwanayo kunye nezifo ezivuthayo eMexico naseMzantsi Melika; kunciphisa abalamlamli abavuthayo, ukuvuza kwe-alveolar capillary, kunye nomonakalo oxidative ngendlela exhomekeke kwi-Nrf2 yokunciphisa ukulimala kwe-lung okubangelwa ngumoya kunye nokubuyisela i-morphology ye-lung yesiqhelo [131]. Ezinye iikhompawundi zezityalo, ezifana ne-epigallocatechin gallate, i-sulforaphane, i-resveratrol, i-lycopene, kunye ne-extract tea eluhlaza zineempembelelo zonyango kwizifo ezivuthayo ngokusebenzisa i-Nrf2 indlela yokubonisa [132], [133], [134]. Kungekudala, enye i-phytochemical, i-eriodictyol, ekhoyo kwisiqhamo se-citrus, kuye kwabikwa ukuba ineempembelelo ezichasayo kunye ne-antioxidant kwi-cisplatin-induced kidney damage kunye ne-sepsis-induced acute lung injury ngokulawula i-Nrf2, inhibiting NF-? ukubonakaliswa kwe-cytokines kwi-macrophages [135], [136]. Nangona kunjalo, ezininzi iikhemikhali ze-phytochemicals zibonisa isithembiso esikhulu sokuthintela kunye nokunyangwa kwezifo ezahlukeneyo zabantu, kwaye ezinye sele zingene kwinqanaba lezilingo zekliniki (Itheyibhile 2).

Ezi zityalo zityalo zisebenzise indlela yokubonakalisa iNrf2 ngokugqithiseleyo kwindlela yokwakha i-electrophilic materials eziguqula i-cysteine i-Keap1, ekhokelela kwi-Nrf2 ye-Nuclear ebophayo kunye ne-ARE, ekhokelela ekusebenziseni ukubhalwa kwe-gene efanayo.

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

Amacandelo aphambili:

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

Umgca wexesha elipheleleyo

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

izigqibo

Okwangoku, uphando oluninzi lugxininise kwindima ye-Nrf2 / Keap1 / ARE indlela yokubonakalisa ukuvuvukala. Phakathi kwee-enzymes ezilawulwa yi-Nrf2, i-HO-1 yenye yee-enzymes zokuphendula uxinzelelo. I-HO-1 ineempawu ezichasene nokudumba kunye ne-antioxidant. Ngokuqhelekileyo, i-Nrf2 indlela yokubonisa i-Nrf2 iphinda ilawule kakubi i-cytokines, i-chemokine ekhupha izinto, ii-MMPs, kunye nabanye abalamli abavuthayo i-COX-2 kunye nokuveliswa kwe-iNOS, echaphazela ngokuthe ngqo okanye ngokungathanga ngqo kwi-NF-kB efanelekileyo kunye neendlela ze-MAPK kunye nezinye iinethiwekhi ezilawula ukuvuvukala. Kucetyiswa ukuba i-Nrf2 kunye ne-NF-?B iindlela zokubonisa izibonakaliso zisebenzisana nokulawula ukubhaliswa okanye umsebenzi weeprotheyini ezijoliswe phantsi. Ukunyanzeliswa okanye ukungasebenzi komsebenzi we-NF-?B-mediated transcriptional nge-Nrf2 mhlawumbi kwenzeka kwisigaba sokuqala sokudumba, njengoko i-NF-?B ilawula i-de novo synthesis yoluhlu lwabalamli be-pro-inflammatory. Nangona kunjalo, kusekho imida kuphando olufana nokuba kukho uxhulumaniso phakathi kwe-Nrf2 kunye nezinye iindlela zokubonisa iimpawu ezifana ne-JAK / STAT, ukubaluleka kwe-activators ye-NrfXNUMX yangoku evela kwimithombo yendalo yezityalo ekudumbeni, kunye nendlela yokuphucula umsebenzi we-biological. kunye nokuphucula ukujoliswa kwezi khompawundi. Ezi zifuna ukuqinisekiswa kovavanyo olongezelelweyo.

Ukongezelela, indlela ye-Nrf2 yokubonisa i-Nrf600 inokulawula> i-163 genes [200], apho> i-164 ifake iiprotheni ze-cytoprotective [165] nazo zidibene nokuvuvukala, umhlaza, izifo ze-neurodeergenerative, kunye nezinye izifo ezinkulu [2]. Ubungqina obukhulayo obubonisa ukuba, indlela ye-Nrf2 yokubonisa i-Nrf2 iyekisiwe kwii-cancer ezininzi, okukhokelela ekubonakalisweni kwe-Nrf2 exhomekeke kwi-gene yebhethri. Ngaphezu koko, ukuvuvukala kudlala indima enkulu kwizifo ezinxulumene noxinzelelo lwe-oxidative ngakumbi kumhlaza. Ukusetyenziswa kwee-activators ezininzi ze-Nrf2 ukuchasana nokudumba kunokubangela ukubonakaliswa okugwenxa kwe-Nrf2 yemfuza esezantsi eyenza i-oncogenesis kunye nokuchasana ne-chemo kunye / okanye unyango lwerediyo. Ke ngoko, ii-activators ezikhethekileyo ze-Nrf2 zinokuphuhliswa ukunciphisa iziphumo zayo ze-pleiotropic. Uninzi lwee-activators ze-Nrf152 lubonise ukuphuculwa okubalulekileyo kwemisebenzi yokuchasana nokudumba kwizifo ezinxulumene noxinzelelo lwe-oxidative. Umzekelo obalaseleyo we-Nrf2 activator evunyiweyo yi-FDA kwaye isetyenziswa ngokubanzi kunyango lwezifo ezivuthayo ezifana ne-Multiple sclerosis (MS) yi-dimethyl fumarate. I-Tecfidera� (igama elibhalisiweyo le-dimethyl fumarate yi-Biogen) isetyenziswe ngokufanelekileyo ukunyanga iindlela ezibuyelayo ze-multiple sclerosis kwinani elikhulu lezigulana [2]. Nangona kunjalo, ukuphumelela kokusebenzisa i-activators ye-Nrf2 ukunyanga izifo ezivuthayo kufuna ukuqinisekiswa okungakumbi ukuphepha iziphumo ezinobungozi ze-Nrf2. Ke ngoko, uphuhliso lonyango lomsebenzi wokuchasana nokudumba phakathi kwe-NrfXNUMX lunokuba nempembelelo enkulu yeklinikhi. Izifundo eziqhubekayo ze-NrfXNUMX indlela yomqondiso kwihlabathi jikelele zinikezelwe ekuphuhliseni ii-arhente zonyango ezijoliswe kakhulu ukulawula iimpawu zokudumba, kunye nokuthintela kunye nokunyanga umhlaza kunye ne-neurodeergenerative kunye nezinye izifo ezikhulu.

Imibulelo

Sciencedirect.com/science/article/pii/S0925443916302861#t0005

Ekugqibeleni, i-Nrf2 ivakala ubunzima bexinzelelo emzimbeni emzimbeni womntu kwaye ekugqibeleni inceda ukukhuthaza umonakalo we-antioxidant kunye ne-detoxifying enzyme kunye namajethi. Ngenxa yokuba ukuvuvukala okungapheliyo okubangelwa ngamazinga okwandisa uxinzelelo lwe-oxidative kuye kwahlanganiswa nezifo ezingenayo i-neurodeergenerative, I-Nrf2 inokudlala indima ebalulekileyo kunyango lwemiba yezempilo efana nesifo sika-Alzheimer, phakathi kwabanye. Ubungakanani bolwazi lwethu lukhawulelwe kwi-chiropractic kunye nemiba yempilo yomgogodla. Ukuxoxa ngalo mbandela, nceda uzive ukhululekile ukubuza uGqr. Jimenez okanye uqhagamshelane nathi apha915-850-0900 .

Ikhutshwe nguDkt. Alex Jimenez

U khankanywe kwi: Sciencedirect.com

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

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

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

***

Ukuqonda i-Nrf2 kunye neMpembelelo yayo kwii-Neurodegenerative Diseases

by UGqr Alex Jimenez | Ukuxutyushwa, LweMpilo, impilo, Medicine Holistic, WeMpilo yeNdalo, isondlo, Uxinzelelo oluxhasayo, ulungiso, Izifundo zoPhando, Unyango, Ukuphila

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

Ukumodareyitha kweProteostasis nge-Transcription factor NRF2

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

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

izifinyezo

Sciencedirect.com/science/article/pii/S2213231716304050

intshayelelo

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

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

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

Uluhlu oluhlukeneyo lweMimiselo Ulawulo lwe-NRF2

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

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

Impembelelo yeziNyunithi zeProteyini kwiindlela zeNRF2 zokuLawula

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

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

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

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

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

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

Ukuqaliswa kwe-NRF2 ekuphenduleni i-UPR

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

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

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

**Umqondiso we-1 Umgaqo we-NRF2 ngu-UPR.** Ukuqokelela kweeprotheni ezibonakalayo okanye eziphambeneyo ngaphakathi kwe-endoplasmic reticulum zingaqalisa ukuphendula kweprotheni (UPR). Okokuqala, i-BP-chaperone ikhutshwe kwi-domain ye-intraluminal ye-ER sensors IRE1 kunye ne-PERK ukubopha amaprotheni athile. Oku kwenza ukuba ukunyuka kwegazi kunye ne-trans-auto-phosphorylation kwiindawo zabo ze-cytosolic. Yenza i-PERK iziphumo zokusebenza kwi-NXF2 i-phosphorylation kwi-Ser40, ekhokelela ku-NRF2 ukudluliselwa kwi-nucleus kunye nokusebenza kwamagciwane okujoliswe kuyo. Ukusebenza kwe-IRE1 kwenza ukuba kuqashwe i-TRAF2 elandelwa ngu-ASK1 kunye ne-JNK iphosphorylation kunye nokusebenza. Njengoko i-JNK ibikwa kwi-phosphorylate kwaye isebenze i-NRF2, kunengqiqo ukucinga ukuba ukusebenza kwe-IRE1 kuya kubangela umsebenzi owandisiweyo we-NRF2.

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

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

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

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

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

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

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

I-UPS ihamba neNRF2 Amanqanaba eProtheni

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

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

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

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

**Umzobo 2 I-UPS ilawula ngokukhawuleza amanqanaba e-NRF2.** Ngaphantsi kweemeko ze-homeostatic, amanqanaba asezantsi e-NRF2 agcinwa sisenzo se-E3 ligases adapters KEAP1 kunye? -TrCP. Ekhohlo, i-NRF2 ibophelela kwimimandla ye-Kelch ye-KEAP1 homodimer nge-low (DLG) kunye ne-high (ETGE) ye-motifs. Ngokusebenzisa isizinda sayo se-BTB, i-KEAP1 ibopha ngaxeshanye ubunzima be-CULLIN3 / RBX1, eyenza ukuba i-NRF2 ubiquitination kunye nokuthotywa yi-26 S proteasome. Ngapha koko, i-GSK-3? i-phosphorylates i-Ser335 kunye ne-Ser338 intsalela ye-NRF2 ukwenza i-degradation domain (DpSGIpSL) eyaziwa njenge-adapter ye-ubiquitin ligase? -TrCP kwaye ithegiwe ukonakaliswa kweproteasome yi-CULLIN3 / RBX1 complex. Kulungile, emva kokuvezwa kweentlobo zeoksijini ezisebenzayo okanye ii-electrophiles ezibalulekileyo zeentsalela zeCys kwi-KEAP1 ziguqulwe, zinika i-KEAP1 ukungakwazi ukusebenzisana ngokufanelekileyo ne-NRF2 okanye i-CULLIN3 / RBX1 emva koko le nto yokukhutshelwa yonyusa ubomi bayo besiqingatha kunye nomsebenzi okhutshelweyo oya kwi-ARE-genes. Ukutyikitywa kweendlela ezikhokelela kuthintelo lwe-GSK-3?, Phosphorylation ye-AKT kwi-Ser9, kukhokelela ekonakaleni kwe-NRF2 okonakaliswe yiproteasome, ukuqokelelwa kunye nokungeniswa kohlobo ekujoliswe kulo.

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

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

I-NRF2-UPS Axis kwii-Neurodegenerative Diseases

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

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

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

Uxhumano olusebenzayo Phakathi kwe-NRF2 kunye ne-Macroautophagy

Amanqanaba eeprotheyini ze-NRF2 ziModyuli yiProtheni ye-Adapter iP62

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

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

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

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

**Imifanekiso ye-3 NRF2 ilawulwa yipropytha yepropto p62.** I-phosphorylation ka-Ser 351 kwisimo se-KIR se-P62 (349-DPSTGE-354) ngo-mTORC1, i-TXXUMUMX okanye ezinye i-kinase ziphumela ekubambeni ukuxhamla kwi-KEAP1 ngenxa yokufana ne-ETGE motif kwi-NRF1. Ngenxa yoko, i-phosphorylated p2 iindawo zeNRF62 kwaye ibopha i-KEAP2. I-motif ye-LIR kwi-p1 inceda ukusebenzisana ne-LC62 kumlenze we-autophagosomal, ukuze ubunzima be-p3-KEAP62 bugqitywe kwi-lysosome. Ngenxa yoko i-NRF1 iyakwazi ukuqokelela, idluliselwe kwi-nucleus kwaye ikhulise ukubhalwa kwezinto eziphathekayo ze-ARE, eziquka i-p2. Le ndlela yokulawula inikezela impendulo ye-NRF62 engapheliyo, njengoko i-KEAP2 kufuneka isanda kuqulunqwa ukuze inqande umsebenzi we-NRF1.

Ukumodareyithwa kwe-Macroautophagy Genes by NRF2

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

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

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

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

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

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

UMthetho woBucala beeTranscription ezahlukeneyo ngokuthe ngqo kwi-Modulate Proteostasis

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

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

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

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

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

Ukuthembisa�Amandla okuNyanga kwi-NRF2 kwiiProteinopathies

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

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

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

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

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

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

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

Amacandelo aphambili:

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

Umgca wexesha elipheleleyo

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

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

Ukuphetha

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

**Umzobo 4 NRF2 njengombane odibanisa izibonakaliso eziphuthumayo zeproteotoxic kwimpendulo yokukhusela.** Ukuqokelela kweeprotheni ezibonakalayo / ezifunyenwe ziza kukhokelela ekusebenziseni impendulo yamaprotheni ebonakalayo (i-UPR) kwi-ER. Ukuqaliswa kwe-PERK okanye i-MAPK kunokukhokelela ekufakweni kwe-ER-resident Gpx8 kunye neenzyme eziningana ezilawula amazinga e-GSH, okubalulekileyo ukuqinisekisa ukunyathela kweprotein. Iiprotheyini ezihlanganisiweyo zivimbela umsebenzi weproteasome (UPS), mhlawumbi ukuphepha ukutshabalaliswa kwe-NRF2. I-NRF2 iboniswe ngokucwangcisa ngokuchanekileyo ukubhaliswa kwe-Psma3, i-Psma6, i-Psmb1, i-Psmb5 kunye ne-Gomp genes. Amanye amanqununu aphakanyisiwe-alawulwa ngendlela exhomekeke kwi-NRF2 ngokuphendula ku-D3T, mhlawumbi ukwandisa uluhlu lwee-subunits ezilawulwa yi-NRF2. I-Autophagy yindlela ehamba phambili yokuhlaziywa kweeprotheyini. I-Autophagy iphinda ilawule i-NRF2, idibanisa le ndlela yokuhlambalaza ne-NRF2 yokubhalwa kwe-transcript ye-p62, Ndp52, Ulk1, Atg2b, Atg4c, Atg5, Atg7 kunye ne-Gabarapl1.

Imibulelo

Sciencedirect.com/science/article/pii/S2213231716304050

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

Ikhutshwe nguDkt. Alex Jimenez

Isingqinisiso sivela kwi: Sciencedirect.com

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

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

***

I-Nrf2 icacisiwe: I-Keap1-Nrf2 Pathway

by UGqr Alex Jimenez | YeMhlaza yeMhlaza, Ukuxutyushwa, LweMpilo, impilo, Medicine Holistic, WeMpilo yeNdalo, isondlo, Uxinzelelo oluxhasayo, Izifundo zoPhando, nezongezo, Unyango, Ukuphila

Uxinzelelo lwe-oxidative luboniswa njengomonakalo weseli obangelwa ngama-radical ezamahala, okanye ama-molecule engaqinisekiyo, anokugqithisa ukusebenza ngokusemgangathweni. Umzimba womntu wenza i-radicals yamahhala ukuze i-bacterium kunye ne-virus zithintele, nangona kunjalo, izinto zangaphandle, ezifana ne-oksijini, ukungcoliseka komzimba kunye ne-radiation, kaninzi kunokuvelisa i-radicals yamahhala. Uxinzelelo lwe-oxidative ludibene nemicimbi emininzi yempilo.

Uxinzelelo lwe-oxidative kunye nezinye izixinzelelo zivula iindlela zokukhusela zangaphakathi ezinokukunceda ukulawula ukuphendula komzimba womntu. I-Nrf2 yiprotheyini eqonda amanqanaba okuxinwa kwe-oxidative kwaye yenza ukuba iiseli zikhusele kwizinto zangaphakathi nangaphandle. I-Nrf2 nayo yaboniswa ukunceda ukulawula iizakhi ezibandakanyekayo ekuveliseni i-enzymes e-antioxidant kunye neengxaki zokuphendula ngengcinezelo. Injongo yecandelo elingezantsi kukuchaza iziphumo zeNrf2 nomhlaza.

Abstract

Umzila weKeap1-Nrf2 ngumlawuli omkhulu weempendulo ze-cytoprotective kwi-oxidative kunye ne-electrophilic stress. Nangona isalathisi sokuhamba kweseli ebangelwa yi-transcription factor Nrf2 inqanda ukuqaliswa komhlaza kunye nokuqhubela phambili kwimizimba eqhelekileyo kunye neyokuqala, kumsebenzi we-Nrf2 uhlinzeka ngamathuba okukhula ngokunyusa ukunyanzeliswa kwe-chemoresistance kunye nokwandisa ukukhula kwesantya. Kule ngxelo yokuhlaziya imifanekiso, sinikeza umboniso weKeap1-Nrf2 endleleni kunye nokutshatyalaliswa kwayo kumaseli omhlaza. Sifutshane ngokufutshane ngempembelelo ye-Nrf2 esebenzayo ekusebenziseni amangqamuzana omhlaza kunye nendlela oku kuqhutyelwa ngayo kwindlela yokwelapha isifo somhlaza.

Internet: I-Nrf2, i-Keap1, iCarcer, i-Antioxidant element element, i-Gene

intshayelelo

Indlela ye-Keap1-Nrf2 ngumlawuli omkhulu weempendulo ze-cytoprotective kwiingcinezelo ezingapheliyo kunye nezingaphandle ezibangelwa yi-oxygen esebenzayo (ROS) kunye ne-electrophiles [1]. Iiprotheyini eziphambili zokubonisa ngaphakathi kwendlela yi-transcription factor Nrf2 (i-nuclear factor erythroid 2-related factor 2) edibanisa kunye neeprotheyini ezincinci ze-Maf kwi-antioxidant response element (ARE) kwimimandla yolawulo lwejene ekujoliswe kuyo, kunye ne-Keap1 (Kelch ECH ukudibanisa iprotheyini ye-1), iprotheni ye-repressor ebophelela kwi-Nrf2 kwaye ikhuthaza ukuthotywa kwayo nge-ubiquitin proteasome pathway (Fig. 1). I-Keap1 yiprotheni ene-cysteine-rich kakhulu, i-mouse Keap1 ine-25 iyonke kunye neentsalela ze-cysteine yabantu ezingama-27, uninzi lwayo lunokuguqulwa kwi-vitro ngee-oxidants ezahlukeneyo kunye ne-electrophiles [2]. Ezintathu kwezi ntsalela, i-C151, i-C273 kunye ne-C288, zibonakaliswe ukuba zidlala indima esebenzayo ngokuguqula ukuhambelana kwe-Keap1 ekhokelela ekutshintsheni i-Nrf2 kunye ne-target target gene expression [3] (Fig. 1). Indlela echanekileyo apho ulungiso lwe-cysteine kwi-Keap1 lukhokelela ekusebenzeni kwe-Nrf2 akwaziwa, kodwa imifuziselo emibini ekhoyo kodwa engakhethi cala (1) imodeli �ihinge kunye ne-latch, apho ulungiso lwe-Keap1 kwiintsalela ze-thiol ezihlala kwi-IVR ye-Keap1. ukuphazamisa ukusebenzisana kunye ne-Nrf2 ebangela ukungahambi kakuhle kweentsalela ze-lysine ngaphakathi kwe-Nrf2 engasakwazi ukuba yi-polyubiquitinylated kunye (2) imodeli apho ukuguqulwa kwe-thiol kubangela ukuhlukana kweCul3 kwi-Keap1 [3]. Kuzo zombini iimodeli, i-inducer-modified kunye ne-Nrf2-bound Keap1 ayisebenzi kwaye, ngenxa yoko, iiprotheyini ze-Nrf2 ezisandul 'ukwenziwa zidlula i-Keap1 kwaye zitshintshele kwi-nucleus, zibophe kwi-ARE kwaye ziqhube ukubonakaliswa kwe-Nrf2 yejene ekujoliswe kuyo njenge-NAD (P) H. i-quinone oxidoreductase 1 (NQO1), i-heme oxygenase 1 (HMOX1), i-glutamate-cysteine ligase (GCL) kunye ne-glutathione S transferases (GSTs) (Umfanekiso 2). Ukongeza kwiinguqu ze-Keap1 thiols ezibangelwa i-Nrf2 ekujoliswe kuyo kwi-gene induction, iiprotheyini ezifana ne-p21 kunye ne-p62 zinokubopha kwi-Nrf2 okanye i-Keap1 ngaloo ndlela iphazamise ukusebenzisana phakathi kwe-Nrf2 kunye ne-Keap1 [1], [3] (Umfanekiso 3).

Umzobo 1. Izakhiwo ze-Nrf2 kunye ne-Keap1 kunye nekhowudi ye-cysteine. (A) I-Nrf2 ine-589 amino acids kwaye inemimandla emithandathu egcinwe ngokuguquguqukayo kakhulu, i-Neh1-6. I-Neh1 iqulethe i-bZip motif, ummandla osisiseko � i-leucine zipper (L-Zip) isakhiwo, apho ummandla osisiseko unoxanduva lokuqatshelwa kwe-DNA kunye ne-L-Zip idibanisa i-dimerization kunye neeprotheni ezincinci ze-Maf. I-Neh6 isebenza njenge-degron ukulamla ukuthotywa kwe-Nrf2 kwi-nucleus. I-Neh4 kunye ne-5 ziindawo zentengiselwano. I-Neh2 iqulethe i-ETGE kunye ne-DLG motifs, efunekayo kwintsebenziswano ne-Keap1, kunye nommandla we-hydrophilic weentsalela ze-lysine (7 K), eziyimfuneko kwi-Keap1-exhomekeke kwi-polyubiquitination kunye nokuthotywa kwe-Nrf2. (B) I-Keap1 ineentsalela ze-amino acid ezingama-624 kwaye inemimandla emihlanu. Iiprotheyini ezimbini zeprotheyini zokusebenzisana, i-BTB domain kunye ne-Kelch domain, zohlulwe ngummandla ongenelelayo (IVR). I-domain ye-BTB kunye nenxalenye ye-N-terminal ye-IVR idibanisa i-homodimerization ye-Keap1 kwaye idibanisa ne-Cullin3 (Cul3). Ummandla we-Kelch kunye nommandla we-C-terminal ulamla unxibelelwano kunye ne-Neh2. (C) I-Nrf2 isebenzisana neemolekyuli ezimbini ze-Keap1 nge-Neh2 ETGE yayo kunye ne-DLG motifs. Zombini i-ETGE kunye ne-DLG zibophelela kwiindawo ezifanayo kumphezulu ongezantsi we-Keap1 Kelch motif. (D) I-Keap1 isityebi kwiintsalela ze-cysteine, kunye ne-27 cysteines kwiprotheni yomntu. Ezinye zezi cysteine zibekwe kufutshane neentsalela ezisisiseko kwaye ke ngoko zijolise kakhulu kwii-electrophiles kunye ne-oxidants. Ipateni yokuguqulwa kweentsalela ze-cysteine nge-electrophiles yaziwa ngokuba yikhowudi ye-cysteine. Ikhowudi ye-cysteine hypothesis iphakamisa ukuba i-Nrf2 i-activating agents ezahlukeneyo zichaphazela i-Keap1 cysteines. Ukuguqulwa kwe-cysteine kukhokelela kwiinguqu ezihambelanayo kwi-Keap1 ephazamisa ukusebenzisana phakathi kwe-Nrf2 DLG kunye ne-Keap1 Kelch domains, ngaloo ndlela inqanda i-polyubiquitination ye-Nrf2. Ukubaluleka kokusebenza kwe-Cys151, i-Cys273 kunye ne-Cys288 ibonisiwe, njengoko i-Cys273 kunye ne-Cys288 zifunekayo ukunyanzeliswa kwe-Nrf2 kunye ne-Cys151 ukuze kusebenze i-Nrf2 ngama-inducers [1], [3].

Umzobo 2. Indlela yokubonakalisa iNrf2-Keap1. (A no-B) kwiimeko eziphantsi, iinqununu ezimbini ze-Keap1 zibophelela kwi-Nrf2 kunye ne-Nrf2 i-polyubiquitylwe yi-Cul3-based E3 ligase complex. Le polyubiquitilation iphumela ekuphuculweni kwe-Nrf2 ngokukhawuleza ngeproteasome. Inxalenye encinane ye-Nrf2 iphunyulela ubunzima obunzima kwaye iqokelela kwi-nucleus ukuze idibanise i-SUB-dependence gene gene expression, ngaloo ndlela igcina i-homeostasis yamaselula. (C) Ngaphandle kweemeko zokuxinwa, ama-inducers aguqula i-Keap1 cysteines ekhokelela ekunqandeni i-Nrf2 ubuncwane ngokubambisana kwezinto ezinqabileyo. (D) Ngokwe-hiring kunye ne-latch model, ukuguqulwa kwee-Keap1 ze-cysteine ezihlalayo zikhokelela ekutshintsheni okuguquguqukayo kwi-Keap1 obangela ukuxhamla kwe-Nrf2 DLG motif esuka kuKeep1. Ukungabikho kobulungisa kwe-Nrf2 kuphazamiseka kodwa ukubophelela kwi-ETGE motif remains. (E) Kwi-Keap1-Cul3 yokuhlukanisa imodeli, ukubopha iKeap1 kunye neCul3 kuphazamiseka ngokuphendula kwi-electrophiles, ekhokelela ekuphunyukeni kwe-Nrf2 kwinkqubo yo-ubiquitination. Kuzo zombini ezi imifuziselo ezicetyiswayo, lo inducer-modified kunye Nrf2-wambopha Keap1 na inactivated kwaye, ngenxa yoko, iiprotheni Nrf2 abasandula kuhlanganiswa uzakufun aukugqithisa Keap1 kwaye uwase kungena ngumongo, bakubophe ukuya Antioxidant Response Element (zi) zinokuqhuba amazwi Nrf2 ekujoliswe izakhi ezifana ne-NQO1, i-HMOX1, i-GCL kunye ne-GSTs [1], [3].

Umzobo 3. Iinkqubo zokuqokelela iikryukliya ezakhiweyo ze-Nrf2 kumhlaza. (A) Uguquko lwamaSomatic ku-Nrf2 okanye i-Keap1 luphazamisa ukusebenzisana kwezi ziprotini ezimbini. Kwi-Nrf2, utshintsho luchaphazela i-ETGE ne-DLG motifs, kodwa kwiinguqu ze-Keap1 zihanjiswa ngokufanayo. Ukongezelela, ukusetyenziswa kwe-oncogene, njengeKrasG12D [5], okanye ukuphazanyiswa kwabaxhasi bamathumba, njenge-PTEN [11] kunokukhokelela ekufakweni kwe-Nrf2 kunye nonyuka kwi-Nrf2 yenyukliya. (B) I-Hypermethylation ye-Keap1 umgqugquzeli kwimiphunga kunye nomhlaza wesifo seprotate ukhokelela ekunciphiseni i-Keap1 mRNA ibonakaliso, eyandisa ukuqokelela kwe-nyukliya yeNrf2 [6], [7]. (C) Kwi-papalryal renal renal carcinoma, ukulahlekelwa kwe-fumarate hydratase umsebenzi we-enzyme kubangela ukuqokelela i-fumarate kunye nokuqhubela phambili kwi-Keap1 cysteine residues (2SC). Ukuguqulwa kwesithuba emva kokuguqulela kukhokelela ekuphazamiseni ukusebenzisana kweKeep1-Nrf2 kunye nokuqokelela kweenyukliya ze-Nrf2 [8], [9]. (D) Ukuhlanganiswa kweeprotheni eziphazamisayo ezifana ne-p62 kunye ne-p21 inokuphazamisa iNrf2-Keap1 yokubopha kwaye ibangele ukwandisa kwi-Nrf2 yenyukliya. i-p62 ibophezela kuKeap1 ehamba ngephepha elibophayo le-Nrf2 kwaye i-p21 idibanisa ngqo ne-DLG kunye ne-ETGE motifs ye-Nrf2, ngaloo ndlela ikhuphisana ne Keap1 [10].

Iinkqubo zoQuquzelelo kunye nokuDysregulation kwe-Nrf2 kwiCarcer

Nangona i-cytoprotection ehlinzekwa ngu-Nrf2 kusebenze kubalulekile ukuba i-chemoprevention yomhlaza kwimizimba eqhelekileyo kunye neyoqobo, kwiiselingi ezibi kakhulu I-Nrf2 umsebenzi unikeza inzuzo yokukhula ngokunyusa ukunyamekela kwe-chemoresist kunye nokuphucula ukukhula kwe-cell tumor [4]. Iinkqubo eziliqela apho i-Nrf2 yokubonisa indlela iqhutywe ngayo kwiinkqubo ezahlukeneyo zomsholongwane zichazwe: (1) utshintsho oluthile lwe-Keap1 okanye i-Keap1 kwisizinda sokubopha iNrf2 ukuphazamisa ukusebenzisana kwabo; (2) i-epigenetic silence ye-Keap1 ibinzana ekhokelela ekunciphiseni okungafanelekanga kwe-Nrf2; (3) ukuqokelela kweeprotheni eziphazamisayo ezifana ne-p62 ekhokelela ekukhutsheni i-Keap1-Nrf2 ubunzima; (4) ukufakelwa kwe-Nrf2 nge-oncogenic K-Ras, B-Raf kunye ne-Myc; kwaye (5) ukuguqulwa post-translational of Keap1 cysteines yi succinylation okwenzeka kwiintsapho carcinoma papillary sezintso ngenxa yokulahlekelwa fumarate umsebenzi transcriptase hydratase [3], [4], [5], [6], [7], [ 8], [9], [10] (umzobo 3). Ininzi iprotheni ye-Nrf2 ibangela ukunyuka kwezityalo ezibandakanyekayo kwi-metabolism yezidakamizwa okwandisa ukuchasana neziyobisi ze-chemotherapeutic kunye ne-radiotherapy. Ukongezelela, izinga eliphezulu leprotheni le-Nrf2 lidibaniswa nokuhlaselwa kakubi kumhlaza [4]. I-Nrf2 engathintekiyo inokuchaphazela ukwanda kweseli ngokuqondisa i-glucose kunye ne-glutamine kwiindlela ze-anabolic ezithintela ukuhlanganiswa kwe-purine kunye nefuthe le-pentose phosphate indlela yokukhuthaza ukwanda kweseli [11] (umzobo 4).

Umzobo 4. Inxalenye ebini ye-Nrf2 kwi-tumorigenesis. Ngaphansi kweemeko zomzimba, amanqanaba aphantsi e-Nrf2 akwanele ukugcinwa kwe-homeostasis yamaselula. I-Nrf2 inqanda ukuqaliswa kwesisu kunye nomhlaza we-metastasis ngokuphelisa i-carcinogens, i-ROS kunye nezinye i-DNA ezilimazayo. Ngexesha le-tumorigenesis, ukuxakeka kwe-DNA umonakalo kubangela ukuxhatshazwa kwe-Nrf2 eyenza iiseli ezinobungozi ezizimeleyo ukunyamezela amanqanaba aphezulu e-ROS kwaye iphephe i-apoptosis. Amanqanaba e-Nrf2 enyukliya aphakanyisiweyo asebenzayo asebenze izakhi zofuzo zetekisi ngokubhekisele kwiijethi ze-cytoprotective ezinegalelo kwi-reprogramme reprogramming kunye nokwandiswa kweseli. Amanqanaba aphezulu anamazinga aphezulu eNrf2 adibene ne-prognosis ephosakeleyo ngenxa yomsakazo kunye noxando lwe-chemores kunye nomdlavuza wesifo esichukumisayo. Ngaloo ndlela, umsebenzi we-Nrf2 umkhuseli kumanyathelo okuqala we-tumorigenesis, kodwa inobungozi kwizigaba ezilandelayo. Ngenxa yoko, ukukhusela umhlaza, ukuphucula umsebenzi we-Nrf2 usoloko kuyindlela ebalulekileyo xa unyango lomhlaza, i-Nrf2 inhibition ifaneleka [4], [11].

Ngenxa yokuba umsebenzi ophezulu we-Nrf2 udlalwa kumaseli omhlaza aneziphumo ezimbi, kukho isidingo sokuthintela i-Nrf2. Ngelishwa, ngenxa yokufaniswa kwesakhiwo kunye namanye amalungu omndeni we-BZip, ukuphuhliswa kwe-Nrf2 inhibitors yinto enzima kwaye izifundo ezimbalwa kuphela ze-Nrf2 inhibition zipapashwe kuze kube yimhla. Ngokuphonononga iimveliso zendalo, uRen et al. [12] ichonge i-brusatol ye-antineoplastic njenge-Nrf2 inhibitor eyenza i-cisplatin isebenzise i-chemotherapeutic. Ukongeza, i-PI3K inhibitors [11], [13] ne-Nrf2 siRNA [14] isetyenzisiwe ukuvimbela iNrf2 kumaseli omhlaza. Kungekudala, sisebenzise enye indlela, eyaziwa ngokuba ngumhlaza wegazi wokuzibulala, ukujolisa kwiiseli zomhlaza ezinezinga eliphezulu ze-Nrf2. I-NRF2 eqhutywe nge-lentiviral vectors [15] equkethe i-thymidine kinase (TK) idluliselwa kumaseli omhlaza kunye nomsebenzi ophezulu kunye neeseli zinyangwa nge-pro-drug, ganciclovir (GCV). I-GCV isetyenziselwa i-GCV-monophosphate, eyongezelela i-phosphorylated nge-cellase kinases kwisimo esiyingozi sohlobo lwe-triphosphate [16] (umzobo 5). Oku kuholele ekubulaweni ngokufanelekileyo kweTK engekho kuphela i-TK equkethe iiseli ze-tumor, kodwa kunye neeseli ezingummelwane ngenxa yesiphumo sokumamela [17]. I-TK / GCV yohlobo lwe-gene ephuculweyo ingaphakanyiswa ngakumbi ngokudibanisa i-egyptipeutic agent e-doxorubicin kwonyango [16], exhasa ingcamango yokuba le ndlela ingaba luncedo ekudibaniseni nemithi yendalo.

Umzobo 5. Iyeza lokuzibulala. I-Constrative Nrf2 ukuqokelela kwenyukliya kumaseli omhlaza kunokuxhatshazwa ngokusebenzisa i-Nrf2 ene-viral vector yonyango lokuzibulala lomzimba [16]. Kulo ndlela, i-lentiviral vector (LV) ebonisa i-thymidine kinase (TK) phantsi komncinci we-SV40 kunye nee-ARE zihanjiswa kumaseli e-lung adenocarcinoma. Amanqanaba e-Nrf2 enyukliya aphezulu akhokelela ekubonakaliseni okubonakalayo kweTK ngokusebenzisa iNrf2 ebophayo. Amaseli athatyathwa nge-pro-drug, ganciclovir (GCV), e-phosphorylated yi-TK. I-GCV ye-Triphosphorylated iyaphazamisa ukuveliswa kwe-DNA kwaye ikhokelela ekubulaweni okuthethileyo kungekhona kuphela iTK equkethe iiseli zesisu, kodwa kunye neeseli eziseduze ngenxa yempembelelo yokumelana.

I-Nrf2 ngumlawuli olawulayo obangela ukuveliswa kwama-antioxidants anamandla emzimbeni womntu onceda ukuphelisa uxinzelelo lwe-oxidative. Ama-enzyme ahlukahlukeneyo anokuxhatshazwayo, njenge-superoxide dismutase, okanye i-SOD, glutathione, kunye ne-catalase, nayo isebenza ngeNrf2. Ngaphezulu, ezinye iiprottokicals ezithile ezifana ne-turmeric, ashwagandha, i-bacopa, itiye eluhlaza, kunye ne-milk thistle, sebenzisa iNrf2. Iziphumo zophando zifumene ukuba Nrf2 kusebenze ngokuqhelekileyo unokunyusa ukukhuselwa kwamaselula kunye nokubuyisela umlinganiselo kumzimba womntu.

UDkt Alex Jimenez DC, i-CCST Insight

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

Amacandelo aphambili:

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

Umgca wexesha elipheleleyo

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

Imibulelo

Lo msebenzi wawuxhaswa yi-Academy yaseFinland, iSigrid Juselius Foundation kunye ne-Finnish Cancer Imibutho.

Ukuqukumbela, i-nuclear factor (i-erythroid-derived 2) -efana ne-2, eyaziwa ngokuba yi-NFE2L2 okanye i-Nrf2, iprotheni eyandisa ukuveliswa kwe-antioxidants ekhusela umzimba womntu ngokuchasene noxinzelelo lwe-oxidative. Njengoko kuchazwe ngasentla, ukukhuthazwa kwendlela ye-Nrf2 kukufunda ukunyangwa kwezifo ezibangelwa uxinzelelo lwe-oxidative, kuquka nomhlaza. Ubungakanani bolwazi lwethu lukhawulelwe kwi-chiropractic kunye nemiba yempilo yomgogodla. Ukuxoxa ngalo mbandela, nceda uzive ukhululekile ukubuza uGqr. Jimenez okanye uqhagamshelane nathi apha915-850-0900 .

Ikhutshwe nguDkt. Alex Jimenez

Isingqinisiso sivela kwi: Sciencedirect.com

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

Intlungu yedolo luphawu olwaziwayo olunokuthi lwenzeke ngenxa yeengozi zamadolo kunye / okanye iimeko, kubandakanya ukulimala kwezemidlalo. Amadolo ngenye yezona zinto ezinzima kakhulu emzimbeni womntu njengoko zenziwe yintlupheko yamathambo amane, iigamente ezine, iintlobo ezihlukahlukeneyo, i-menisci emibini, kunye ne-cartilage. Ngokwe-American Academy ye-Family Physicians, izizathu eziqhelekileyo zokubandezeleka kwamadolo zibandakanya i-patellar subluxation, i-patellar tendinitis okanye i-jumper, kunye ne-Osgood-Schlatter. Nangona ubuhlungu beentolo buya kwenzeka kubantu abantu abangaphezu kwe-60 ubudala, ubuhlungu beendolo buya kwenzeka kubantwana nakwishumi elivisayo. Iintlungu zesisu zingaphathwa ekhaya emva kweendlela ze-RICE, nangona kunjalo, ukulimala kwamadolo amakhulu kunokufuna ukunyangwa kwangoko kunyango, kubandakanya ukunakekelwa kwe-chiropractic.

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

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Yintoni eyenziwa nguNrf2 Ukuqalisa?

by UGqr Alex Jimenez | LweMpilo, impilo, WeMpilo yeNdalo, isondlo, Uxinzelelo oluxhasayo, ulungiso, Unyango, Ukuphila

I-DNA isekela iigciwane ze-20,000, nganye ibambe inkqubo yokudala iprotheni okanye i-enzyme efunekayo yokuphila ngendlela enempilo. Yonke enye yala maphepha idinga ukuba ilawulwe rhoqo ngohlobo "lomgqugquzeli" olawula ngokuthe ngqo ukuba yeyiphi imveliso nganye kunye / okanye ikhemikhali eyenziwa kwaye phantsi kwayo le miqathango iya kuphuhliswa.

Ngokudibanisa uhlobo oluthile lweendawo ezikhuthaza ukutshintshana, ezibizwa ngokuba yi-Antioxidant Response Element, okanye i-ARE, Nrf2Ixhasa isantya sendalo kumakhulu ohlobo lwento eyahlukileyo ezenza ukuba iiseli ziphile phantsi koxinzelelo. Ezi zofuzo zivelisa ukhetho lwee-enzyme ze-antioxidant eziphuhlisa uthungelwano lokhuselo ngokuthomalalisa ii-oxidants kunye nokucoca iimveliso ezinobuthi ezishiyeke kwimveliso yazo, ukongeza ekuncedeni ukubuyisela umonakalo owenzileyo.

Yintoni yoxinzelelo lwe-Oxyidative?

Ii-oxidants ezininzi ezifana ne-superoxide radical, okanye i-O2-, kunye ne-hydrogen peroxide, okanye i-H2O2, zenziwe ngokwenza ukutshisa izinto kunye / okanye iikhemikhali ezigcina umzimba womntu. Umzimba womntu ufumene ii-enzyme zokulwa ne-antioxidant ezingathathi hlangothi kwaye zikhuphe ukutya okusebenzayo kunye neziselo esizisebenzisayo. I-Nrf2 imodareyitha imveliso yazo ukugcina ulingano kwaye igxininisa imfuno yazo zonke ezi enzymes. Olu bhalansi lunokuphazanyiswa zizinto ezininzi, kubandakanya ubudala.

Njengokuba sikhula, bodyumzimba womntu wenza i-Nrf2 encinci kwaye oku kulungelelana okuethe-ethe kungathi ngokuthe ngcembe kuqalise ukubuyela kwicala le-oxidative, ilizwe ekubhekiswa kulo njengoxinzelelo lwe-oxidative. Isifo sisenokubangela ukuveliswa kakhulu kwee-oxidants. Usulelo, isifo somzimba, kunye nokuphazamiseka komzimba kungenza ukuba iiseli zethu zomzimba zenze i-oxidants esebenzayo, njenge-O2-. , H2O2, OH kunye ne-HOCl, apho iiseli ezisempilweni zonakaliswa kwaye ziphendule ngokudumba. Izifo ezinxulunyaniswa nokwaluphala, kubandakanya ukubetha kwentliziyo, ukubetha, umhlaza, kunye neemeko ze-neurodegenerative ezinje ngesifo se-Alzheimer, zikwonyusa ukukhula kwe-oxidants, ezenza uxinzelelo kunye nokuphendula kokudumba.

Ziziphi ii-Activators ze-Nrf2?

Iprotheni ye-Nrf2, ebizwa ngokuba yi-factual factor ngenxa yendlela yokwenza inkxaso nokulawula ii-enzyme kunye nejeni, yinto eyimfihlo yokulandelelana kweempendulo ze-biochemical ngaphakathi kweseli ephendula ngokuguqulwa kwendlela yokulinganisa kwengqondo kunye ne-balance balance. Izinto ezivelayo zalo mzila ziguqula kwaye zikhupha i-Nrf2, ibangela ukuba ikwazi ukusasazeka kwinucleus yesisele kwi-DNA. I-Nrf2 ingaphinde ivule okanye isuse amajeni kunye ne-enzyme exhasa ukukhusela iseli.

Ngethamsanqa, iintlobo ezahlukeneyo zezinto ezisetyenziswayo yi-Nrf2 ziphuhlisa ngokusebenzisa izityalo ezithile kunye nezicatshulwa ezisetyenziswa kwiminyaka emininzi edlulileyo kwizonyango zorhwebo zaseShayina naseNative American. Ezi zixhobo zeprotochemicals zibonakala zinamandla kunye neempembelelo ezingaphantsi, njengemveliso ye-Nrf2 eyenza imveliso yezobisi esetyenziswa namhlanje.

Isisombululo senkampani ye-erythroid I-2, eyaziwa ngokuba yi-Nrf2, yinto ebhaliweyo yokukhusela iseli ngokulawula i-gene, i-enzyme kunye nezimpendulo zokulwa ne-antioxidant. Imiba yombhalo we-Transcription iyinhlobo yeprotheni enamathele kwi-DNA ukukhuthaza ukuveliswa kwezinto ezithile kunye neekhemikhali, kuquka i-glutathione S-transfases, okanye i-GSTs. Ukusebenza kwe-Nrf2 kukhuthaza ukuveliswa kweeprotheni ezisebenzayo ezibonisa amandla anamandla okukhusela i-antioxidant ukusiza ukunciphisa uxinzelelo lwe-oxidative.

UDkt Alex Jimenez DC, i-CCST Insight

Inzululwazi ye-Nrf2 isebenze

Emva kokuba i-Nrf2-supplement supplementary supplement yenziwe kwi-2004, ulwazi oluncinci lwaziwa malunga nomsebenzi weNrf2. Malunga namaphephandaba e-200 kwincwadi ka-Nrf2, eyaziwa ngokuba yi-2 okanye i-NFE2L2, ikhona kwaye abaphandi baqala ukufumana impendulo ye-anti-oxidant ye-Nrf2 kwizilwanyana ezincelisayo. Njengoko i-2017, nangona kunjalo, ngokuphanda kwe-9,300 uphando lwezemfundo kulo "mlawuli olawulayo," lishicilelwe.

Enyanisweni, i-Nrf2 ilawula ama-enzyme amaninzi angakhuselekanga kwiijethi, endaweni yoko, inika ukukhuselwa kwiimeko ezinxulumene noxinzelelo ezijongene neengqungquthela, izitho kunye neziganeko ekugqibeleni, phantsi kweemeko ezinempilo kunye nezifo. Ngokusekelwe kulo mbandela omtsha wolwazi oluvela kwizifundo zophando lwezemfundo, abaphandi bangakwazi ukuphucula ngakumbi I-Nrf2 izondlo zokutya.

Ukusukela ngo-2007, izifundo zophando zibonise umsebenzi onzima wendlela yeNrf2. I-Nrf2 activators ifunyenwe ukuba ilinganise izinto zezakhiwo ezahlukeneyo emzimbeni womntu. Ngale ndlela, i-Nrf2 activators ixhotyisiwe ukuba izive zitshintsha imeko kwiseli ukuze kugcinwe ibhalansi kwaye iphendule kwiimfuno eziguqukayo zofuzo.

Kutheni usebenzise i-Nrf2-I-Supplement Supplements?

Njengoko i-Nrf2-amandla okuqalisa iyancipha kunye nobudala kwizinto eziphilayo, utshintsho lunokuqala ukuvela. Uphando luye lwabonisa ukuba i-Nrf2 ekujoliswe kuyo kwiiseli iyancipha kunye nobudala, ibonisa ukunyuka kwamanqaku okuxinzezeleka kwengcinezelo. Izifo ezahlukeneyo ezinxulumene neminyaka ezinjenge-atherosclerosis kunye nesifo senhliziyo, isifo samathambo, umdlavuza, ukukhuluphala, uhlobo lwe-2 yesifo sikashukela, uxinzelelo lwegazi, i-cataracts, nesifo se-Alzheimer kwakunye nezifo ze-Parkinson ziyakhula ngenxa yezi nguqu. Uxinzelelo oluxhasayo lufunyenwe nale miba yempilo.

Ngokukhuthaza amandla eseli ukunyusa umveliso we-Nrf2, I-Nrf2 izondlo zokutya inokukunceda ukuvuselela amandla omzimba womntu ukulwa nemiphumo yokuxinzezeleka kwengcinezelo. I-Polyunsaturated fatty acids, okanye i-PUFAs, enye yee-molecule ezinomsoco kakhulu kwaye zixhatshazwa ngokubhekiselele kwimonakalo ye-radicals yamahhala. I-acid ye-Thiobarbituric, okanye i-TBARS, umveliso unokunyuka ngobudala, obonisa ukunyamezeleka kokuxhamla kunye ne-drop in Nrf2-indlela elawulwayo.

Ngokwebhayoloji, ukungeniswa kofuzo yindlela ecothayo, efuna iiyure zokugqithisa kwindlela. Ngenxa yoko, ii-enzyme ezininzi zinezixhobo zazo zokucima / zokucima ezinokubangelwa yimizuzu ngee-enzymes ezahlukeneyo zolawulo. Abaphandi baye baqulunqa iziqulatho zobunini bezinto ezisebenzayo zeNrf2 ezisebenzisa esi siseko solwazi sokwenza kusebenze. Ukwenza ukuba i-Nrf2 isebenze ayibunjwanga nje kuphela ngento ekhutshelweyo yeNrf2 ekhutshiweyo kwi-inhibitor yayo kunye nokufudukela kwiseli yeseli, kodwa ikwabopha kulandelelwano oluthile lwe-DNA ukukhuthaza intetho yohlobo lwe-cytoprotective, ukulawula isantya sokuba i-Nrf2 ikhutshiwe ngaphandle kwenucleus.

Ukuqonda inkqubo yokupheliswa kunye nokusebenza kwe-Nrf2 emzimbeni womntu kuye kwavumela abaphandi ukuba bakhe indibaniselwano yeentshukumo ezahlukeneyo ze-Nrf2 ukufezekisa ukubonakaliswa kwemfuza ngokumodareyitha kwayo. Umdibaniso wesiseko solwazi, kunye nolunye uphononongo olwahlukileyo lwezifundo zincedile ukuvelisa i-Nrf2 activators ukuba isetyenziswe njengezongezo zokutya. Ubungakanani bolwazi lwethu lukhawulelwe kwimicimbi ye-chiropractic kunye nempilo yomqolo. Ukuxoxa ngomxholo, nceda ukhululeke ukubuza uGqirha Jimenez okanye unxibelelane nathi ku915-850-0900 .

Ikhutshwe nguDkt. Alex Jimenez

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

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

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I-Glutathione: I-Antioxidant Inamandla kakhulu

by UGqr Alex Jimenez | Chiropractic, isondlo, Uxinzelelo oluxhasayo, Izifundo zoPhando, Unyango

I-Antioxidants ichongiwe ngokwesayensi njengamacandelo avimbela inkqubo ye-oxidation emzimbeni womntu, ukuba ukuba ingashiywa ingagqalwa, ingenza i-radicals ekhululekile ekwazi ukuvelisa iimpendulo ezininzi ezinokubangela ukuba umonakalo weselula. Ngethamsanqa, umzimba womntu unokwenza izinto ezinjengezixhobo zokuzikhusela, nangona kunjalo, xa ukukhupha iintlobo ze-oksijeni ezisebenzayo, okanye i-ROS, abakwazi ukuphelelwa yinto engatshatyalaliswayo, bacinge ngelitye elincinci eliphuma ngaphandle kokulawulwa xa lichithwa yi-oksijeni. .

Ukuqhubela phambili ukwandisa kwisalathiso selangatye, umkhiqizo wokugqibela wokungakwazi ukunciphisa impembelelo ye-ROS, okanye iintlobo ze-oksijeni esebenzayo, umonakalo kunye nokuvuvukala, ngamanye amazwi, umzimba womntu uphile ngomlilo. Into emnandi kukuba kukho i-antioxidants enokunceda kakhulu ukulwa nale ngxaki yempilo kwaye le antioxidant yi-glutathione. Nangona ifunyenwe kwi-1889, i-glutathione yempembelelo ye-antioxidant ibe yenye yezona zihloko ezinomdla kakhulu kwizifundo zophando zanamhlanje.

I-Master of Antioxidants: Glutathione

I-substance enamandla yi-tripeptide ephuma kwi-cysteine, i-glutamic acid, kunye ne-glycine. Ngenxa yokukwazi ukukhusela umzimba womntu ekudalweni kweeradicals zamahhala, i-glutathione ekugqibeleni inokunceda ukukhuthaza amajoni omzimba asempilweni. Ngenxa ye IiNgxelo zeSayensi kwi2015, kwakunqunywe ukuba amandla e-glutathione okusebenza ngokubambisana kunye ne-peroxiredin kunye ne-catalase inceda ulinda i-hydrogen peroxide. Ifom ye-synergistic isebenzelana neentlobo ze-oksijeni ezisebenzayo, okanye i-ROS. I-Glutathione, i-peroxidredin kunye ne-catalase zizinto ezibalulekileyo ekunyuseni kwe-homeostasis yamaselula, yinkqubo ebalulekileyo yamaseli enempilo, izicubu kunye nezitho ngokupheleleyo.

Ukongezelela, i-glutathione yandisa isistim somzimba jikelele kunye nomsebenzi usebenzisa umphumo wayo obalulekileyo kwimisebenzi ye-lymphocyte. Ngokutsho kwe KwiSebe le-Immunochemistry, amanqanaba afanelekileyo okongeza i-glutathione emzimbeni womntu inokuphucula kakhulu iimpendulo zomzimba. Ngokomzekelo, izilingo ezimbini ezilawulwa yi-placebo ezilawulwa yi-placebo zibonise ukuba unyango lwonyango lwezigulane ezixhatshazwa ngumzimba nge-N-acetyl-cysteine, okanye i-NAC, kubangele, kuzo zombini matyala, ngokukhula okukhulu kwiinkqubo ezininzi ze-immunological ezibandakanya ukuhlaziywa konke yomsebenzi wecala lombulali. I-N-acetyl-cysteine, okanye i-NAC, isebenzisa isulfure ephuma kwi-glutathione kwaye idibanisa ne-molecule ezinetyhefu, ezo zibe zizinzileyo kwaye zikhutshwe emzimbeni womntu.

I-Glutathione nayo inokukwazi ukuvuselela i-lipoic acid kunye nokubuyisela kwakhona iiVithamini C ne-E, eziyimfuneko ukuze kuqaliswe iinkqubo ezithile zeenkqubo ngokuthumela ama-electron ukuba angadambisi i-radicals yamahhala. Ngokusekelwe kuphando lokuphanda I-PLOS ONE, i-glutathione ichaphazele izigulane ezine-diabetes metillus, okanye i-T2DM, kunye ne-mycobacterium isifo sofuba. Ngokuqhelekileyo, abantu abaneendlela zokuzivikela ezibuthakathaka banomdla wokubonisa ukugqithisa okukhulu kuMn. Tb, okanye i-mycobacterium isifo sofuba, isifo okanye isifo. Ukongezelela, abantu abane-Type 2 i-diabetes metilllus, okanye i-T2DM, babini ngokuphindwe kathathu banokutheleleka kwi-TB kunabantu abangenawo i-T2DM. Uphando olwenziwe uphando luye lwaphakamisa ukuba ukuphakamisa amanqanaba e-glutathione kwi-macrophages ekhulile kwizigulane ezine-T2DM kukhokelela ekulawuleni ukuphucula izifo ze-M.Tb okanye intsholongwane. Ezi ziphumo zibonisa ukuba amanqanaba aphantsi e-glutathione kwizigulane ezine-T2DM inegalelo kwithuba eliphakamileyo le-M TB okanye isifo. Ngaphezu koko, kuxhomekeke kuyo UDietro Ghezzi eBrighton naseSussex Medical School, uxinzelelo lweengcinezelo lunokubangela ukuba i-system immune system kunye nomsebenzi.

Ngethamsanqa, i-glutathione idlala indima ebalulekileyo ekuqiniseni nasekulawuleni umkhuhlane. Ngokomzekelo, i-glutathione ibalulekile kwiinkqubo zangasese kunye nezilungelelaniso kwisistim somzimba sokuzikhusela, kuquka i-T-lymphocyte ukuqhubela phambili, umsebenzi we-phagocytic we-polymorphonic neutrophils, kunye nemisebenzi yeseli ye-dendritic, enokubaluleka ngenxa yokuba le yenziwe ngamaseli a-antigen . Ukuxilongwa kwe-Cell-meditated immunication kubandakanya i-protein antigen eqala ukuhlakala kwi-vesocytic vesicles ze-macrophages kunye neeseli ze-dendritic, ngoko ke, iip peptides ezincinci ziboniswa emzimbeni ukuze kusebenze ukwanda kwamaseli e-antigen. Ukongeza, i-glutathione inceda ekudalweni kwe-cytokines, kwaye kuyimfuneko ukugcina imveliso ye-interferon-gamma ngamaseli e-dendritic, okubalulekileyo ekukhuseleni ama-intracellular pathogens kuquka i-mycobacteria.

I-N-acetyl-cysteine, okanye i-NAC, ebizwa ngokuba ngu-precursor of glutathione, nayo inamandla kakhulu anesifo esithintekayo se-antioxidant esetyenzisiweyo njenge-free radical scavenger antioxidant. Ngokuqhelekileyo iyaqaphela inxaxheba yayo ukukhupha i-acetaminophen yetyhefuI-NAC, okanye�N-acetyl-cysteine, ibonakaliswe ineenzuzo ezininzi zempilo kunye nokuba sempilweni. Ngoku ka Cell Journal, I-NAC inceda ukunika inkxaso impendulo enobulunga obuphilileyo kwaye inokuthi ithintele ngokufanelekileyo ukusebenza kwexesha lomntu kunye nokusebenza kwangaphambili. Uphando olwenziwe uphando lwagqitywa ukuba kubasetyhini abathandana nokuzalwa kwangaphambili kunye ne-bacteria vaginosis, i-0.6 gram ye-NAC ngosuku esetyenziswe ngomlomo kunye neprogesterone emva kweveki ye-16 yokukhulelwa okukhuselekileyo ekukhuselweni kokuzalwa kwangaphambi kokuzalwa nokuphucula iziphumo ze-neonatal. Ekugqibeleni, iziphumo ezilungileyo ze-NAC kwisakhiwo se-muscle nazo zafunyanwa. Emva kwemizuzu emithathu yokuphambaniswa okuqhubekayo, kukho i-15 yepesenti ephuculweyo, kubonisa indlela iNAC idlala ngayo indima ebalulekileyo ekuphuculeni isakhiwo se-muscle nokunciphisa ukukhathala ngexesha lobasebenzi.

Abaphandi baye bafumanisa ukuba i-NAC, okanye N-acetyl-cysteine, inokunceda abo bane-polycystic ovarian syndrome, okanye i-PCOS. I-PCOS, okanye i-polycystic ovarian syndrome, sisifo esixhaphakileyo esinxulumene ne-endocrine echaphazela malunga ne-5 ukuya kwi-10 ekhulwini labasetyhini abaneminyaka yobudala. Kwizigulane ezinjalo, kukho umngcipheko omkhulu wokufumana isifo se-metabolic syndrome, apho ukusetyenziswa kwe-NAC kwanceda ukubuyisela amanqanaba e-insulin enempilo kunye novelwano.

Insight of Dr. Alex Jimenez

I-Glutathione ibizwa ngokuba "yinkosi yama-antioxidants" ngenxa yendima ebalulekileyo ekufezekiseni nasekugcineni impilo nempilo yonke. Nangona umzimba womntu unako ukuvelisa i-glutathione yayo, ukungondleki kakuhle, ukucoceka, i-toxin, ukusetyenziswa kakubi kweziyobisi kunye / okanye unyango, ukuxinezeleka, ukunyamekela, ukuguga, izifo kunye nokusabalaliswa kwemitha kunokunciphisa amanqanaba ethu okwenyama ye-glutathione. Oku kunokukwenza ukuba abantu banomdla wokulimala kwesoli, ukuxilwa kwamahhala, izifo kunye nomhlaza. I-Glutathione supplementation ingaba neenzuzo ezinkulu kumzimba womntu. Kanye kunye nezinye iindlela zokonyango, ezifana nokunyamekela kwe-chiropractic, amazinga a-glutathione angaphinda alawulwe ukuze kuphuculwe impilo.

Ukongezelela, ootitshala bezonyango baye baphakamisa ukuphunyezwa kokusetyenziswa kwe-glutathione kunye nezinye iindlela zokonyango, ezifana ukunakekelwa kwe-chiropractic, ukuphucula uphuculo lwempilo kunye nokuphila kakuhle. I-antioxidants ibalulekile ekugcineni ubume benhlalakahle kunye nokuvimbela ukuphendulwa kweetyuli ze-free radicals ezibangelwa yingozi okanye isonakaliso eselula. Ama-antioxidants anamandla afana ne-glutathione, njengoko kuchazwe ngasentla, ekugqibeleni uncedo lulawula ukuphuhliswa kwezi radicals kunye nonikezelo lwe-immune system. Iziphumo zophando zifumene ukuba ukunakekelwa kwe-chiropractic nazo zinokudlala indima ebalulekileyo kule nkqubo, ngokusesikweni ukukhuthaza umsebenzi we-antioxidants emzimbeni womntu. Ukunyamekela kwe-Chiropractic yindlela ekhuselekileyo neyinkqubo yokunyanga eyenza ukulungiswa kwemigudu kunye neendlela zokuziphatha ngokufanelekileyo ukulungisa ukuphambana kwamagciwane, okanye ukuxhomekeka, ukuze uvumele umzimba womntu ukuba uphilise ngokwawo ngaphandle kokusetyenziswa kweziyobisi / okanye unyango olungenelelo.

Okokugqibela, i-antioxidants ibonisa iipropathi zabo zebhayoloji ngobuninzi bezibonelelo zempilo, ezinokuba yimfuneko ngoku kunanini na ngaphambili ngalo lonke uhlaselo olunyukayo loxinzelelo, izifo kunye nongcoliseko kwihlabathi lethu lanamhlanje, ezithi zonke zibe negalelo kumonakalo weseli kunye / okanye umonakalo. . I-Glutathione kunye ne-precursor yayo, i-NAC, okanye i-N-acetyl-cysteine, iyaqhubeka nokubonisa isimo sabo esinamandla kwindawo ye-antioxidants. Kunye nezinye iindlela zonyango, ezifana nokhathalelo lwe-chiropractic, abantu banokuthatha inzuzo yazo zonke izibonelelo ezinokuthi zinikezelwe yile antioxidant enamandla. Ubungakanani bolwazi lwethu lukhawulelwe kwi-chiropractic kunye nokulimala komgogodla kunye neemeko. Ukuxoxa ngalo mbandela, nceda uzive ukhululekile ukubuza uGqr. Jimenez okanye uqhagamshelane nathi apha915-850-0900 .

Ikhutshwe nguDkt. Alex Jimenez

Imixholo eyongezelelweyo: Ubunzima bokubuyisela

Umqolo obuhlungu enye yezona zizathu ezibangeleko zokukhubazeka kunye neentsuku eziphosakeleyo emhlabeni wonke. Njengokuba kunjalo, iintlungu zenziwa emva kweyona sibini isizathu esivakalayo sokutyelela iofisi yee-dkt. Ngokumalunga neepesenti ze-80 zabemi ziya kuba nolunye uhlobo lweentlungu zentlungu ubuncinane kanye kanye ebomini babo. Umgudu uyisakhiwo esiyinkimbinkimbi esakhiwa ngamathambo, amajoyina, iigaments kunye nezihlunu, phakathi kwezinye iifomthi ezithambileyo. Ngenxa yoko, ukulimala kunye / okanye iimeko ezihlaziyiweyo, ezifana disni, ekugqibeleni unokukhokelela kwiimpawu zentlungu. Ukulimala kwezemidlalo okanye ukulimala kwengozi yeemoto ngokuqhelekileyo kubangelwa yintlungu yokubuhlungu, kodwa ngamanye amaxesha ukuhamba kwezinto ezilula kunokuba neziphumo ezibuhlungu. Ngethamsanqa, ezinye iindlela zokhathalela unyango, ezifana nokunyamekelwa kwe-chiropractic, kunokunceda ukubuyisela intlungu emva kokusetyenziswa kwemilenze kunye nokunyanzeliswa kwemigaqo, ekugqibeleni ukuphucula intlungu.

ISIHLOKO ESIBALULEKILEYO: Ulawulo oluPhantsi lwePain Pain

IINKCUKACHA NGOKUGQITHISILEYO: UKONGEZA KWEZINTLOKO: PainUbuhlungu obungapheliyo kunye nonyango

El Paso, TX Uxinzelelo oluxhasayo kunye noKhuseleko lwe-Antioxidant

by UGqr Alex Jimenez | LweMpilo, Uxinzelelo oluxhasayo

I-Chiropractor esekelwe kwiSayensi uDkt Alexander Jimenez ithatha ujongo uxinzelelo oluxhamlayo, yintoni na, indlela echaphazela ngayo umzimba kunye nokukhusela i-antioxidant ukulungisa imeko.

Esra Birben PhD,1 Umit Murat Sahiner MD,1 Cansin Sackesen MD,1 Serpil Erzurum MD,2 kunye no-Omer Kalayci, MD1

Ubungqina obucacileyo: Iintlobo zeoksijini esebenzayo (ROS) ziveliswa zizinto eziphilayo ngenxa yemetabolism eqhelekileyo yeselula kunye nezinto ezisingqongileyo, ezinje ngongcoliseko lomoya okanye umsi wecuba. I-ROS i-molecule esebenzayo kakhulu kwaye inokonakalisa izakhiwo zeeseli ezifana ne-carbohydrates, i-nucleic acids, i-lipids, kunye neeprotheni kwaye ziguqule imisebenzi yazo. Utshintsho kwibhalansi phakathi kwee-oxidants kunye ne-antioxidants ekuthandeni i-oxidants kuthiwa �i-oxidative stress. Izinto eziphilayo eziAerobic zidibanise iinkqubo zokulwa ne-antioxidant, ezibandakanya i-enzymatic kunye ne-non-enzymatic antioxidants ezihlala zisebenza ekuthinteleni iziphumo ezinobungozi ze-ROS. Nangona kunjalo, kwiimeko ze-pathological, iinkqubo ze-antioxidant zinokugqithiswa. Uxinzelelo lwe-oxidative lunegalelo kwiimeko ezininzi ze-pathological kunye nezifo, kubandakanya umhlaza, ukuphazamiseka kwemithambo-luvo, i-atherosclerosis, uxinzelelo lwegazi, ischemia / perfusion, isifo seswekile, isifo esinzima sokuphefumula, i-idiopathic pulmonary fibrosis, isifo esingapheliyo semiphunga, kunye ne-asthma. Kolu hlaziyo, sishwankathela iinkqubo ze-oxidant kunye ne-antioxidant kwaye sixoxe ngemiphumo yeselula kunye neendlela zoxinzelelo lwe-oxidative.

Amagama aPhambili: i-antioxidant, i-oxidant, uxinzelelo lwe-oxidative, iintlobo ze-oksijini ezisebenzayo, i-redox

(WAO Journal 2012; 5:9�19)

Iintlobo ze-oksijini ezisebenzayo (i-ROS) ziveliswa zizidalwa eziphilayo ngenxa ye-metabolism yeselula eqhelekileyo. Kwiindawo eziphantsi ukuya kwimodareyitha, zisebenza kwiinkqubo zeseli ye-physiological, kodwa ekugxininiseni okuphezulu, zivelisa ukuguqulwa okungalunganga kumacandelo eeseli, ezifana ne-lipids, iiprotheni, kunye ne-DNA. Kubizwa ngokuba luxinzelelo lwe-oxidative. � Uxinzelelo lwe-oxidative lunegalelo kwiimeko ezininzi ze-pathological, kubandakanya umhlaza, ukuphazamiseka kwemithambo-luvo, 1�6 i-atherosclerosis, uxinzelelo lwegazi, ischemia/perfusion,7�10 isifo seswekile, i-acute breathing distress syndrome, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease. ,11 kunye ne-asthma.14�15 Izinto eziphilayo ze-Aerobic zineenkqubo ezidibeneyo zokulwa ne-antioxidant,� ezibandakanya i-enzymatic kunye ne-nonenzymatic antioxidants ezidla ngokusebenzayo ekuthinteleni iziphumo ezinobungozi ze-ROS. Nangona kunjalo, kwiimeko ze-pathological, iinkqubo ze-antioxidant zinokugqithiswa. Kolu hlaziyo, sishwankathela iinkqubo ze-oxidant kunye ne-antioxidant kunye nokulawulwa kokunciphisa kunye ne-oxidizing (i-redox) kwimeko yempilo kunye nezifo.

IZIXHOBO

Imithombo ye-Endogenous ye-ROS

I-ROS iveliswa kwi-oksijeni ye-molekyuli ngenxa ye-metabolism eqhelekileyo yeselula. I-ROS inokwahlulwa ibe ngamaqela ama-2: i-radicals yamahhala kunye ne-nonradicals. Iimolekyuli eziqulethe i-electron enye okanye ezingaphezulu ezingasebenziyo kwaye ngaloo ndlela zinika i-reactivity kwi-molecule zibizwa ngokuba yi-radicals yamahhala. Xa ii-radicals ezi-2 zasimahla zabelana ngee-electron zazo ezingasebenziyo, iifom ze-nonradical ziyadalwa. I-ROS enkulu ye-3 ebalulekileyo ye-physiological i-superoxide anion (O22.), i-hydroxyl radical (OH), kunye ne-hydrogen peroxide (H2O2). I-ROS ishwankathelwa kwiThebhile 1.

I-superoxide anion yenziwe ngokongezwa kwe-electron ye-1 kwi-oksijeni ye-molecular.22 Le nkqubo ixutywe yi-nicotine adenine dinucleotide phosphate [NAD (P)H] oxidase okanye i-xanthine oxidase okanye nge-mitochondrial electron trans-port system. Indawo enkulu yokuvelisa i-superoxide anion yi-mitochondria, oomatshini beseli ukuvelisa i-adenosine triphosphate. Ngokuqhelekileyo, ii-electron zihanjiswa ngekhonkco lothutho lwe-electron ye-mitochondrial ukuze kuncitshiswe ioksijini emanzini, kodwa malunga ne-1 ukuya kwi-3% yazo zonke ii-electron zivuza kwinkqubo kwaye zivelise i-superoxide. I-NAD (P) H oxidase ifumaneka kwi-polymorphonuclear leukocytes, i-monocytes, kunye ne-macrophages. Phezu kwe-phagocytosis, ezi seli zivelisa ukuqhuma kwe-superoxide ekhokelela kumsebenzi we-bactericidal. I-Superoxide iguqulwa ibe yi-hydrogen peroxide ngesenzo se-superoxide dismutases (i-SODs, i-EC 1.15.1.1). Ihydrogen peroxide isasazeke ngokulula kwi-plasma inwebu. I-hydrogen peroxide ikwaveliswa yi-xanthine oxidase, i-amino acid oxidase, kunye ne-NAD(P)H oxidase�23,24 nakwi-peroxisomes ngokusetyenziswa kwe-molecular oxygen reactions. Kulandelelwano lweempendulo ezibizwa ngokuba yi-Haber�Weiss kunye ne-Fenton reaction, i-H2O2 inokophuka iye kwi-OH2 xa kukho iintsimbi zothumelo ezifana ne-Fe21 okanye i-Cu21.25

Fe31 +�.O2�?Fe2 +�O2 Haber Weiss

Fe2 +�H2O2�?Fe3 +�OH�+ .OH Fenton reaction

I-O 2 yona ngokwayo ingasabela nge-H2 O2 kwaye ivelise i-OH�.26,27 I-Hydroxyl radical yeyona isebenzayo kwi-ROS kwaye inokonakalisa iiprotheni, i-lipids, kunye ne-carbohydrates kunye ne-DNA. Inokuthi iqalise i-lipid peroxidation ngokuthatha i-electron kwi-polyunsaturated fatty acids.

I-Granulocytic enzymes yandisa ngakumbi ukusebenza kwakhona kwe-H2O2 nge-eosinophil peroxidase kunye ne-myeloperoxidase (MPO). Kwi-neutrophils esebenzayo, i-H2O2 idliwe yi-MPO. Xa kukho i-chloride ion, i-H2O2 iguqulwa ibe yi-hypochlorous acid (HOCl). I-HOCl i-oxidative kakhulu kwaye idlala indima ebalulekileyo ekubulaleni iintsholongwane kwiindlela zomoya.28 Nangona kunjalo, i-HOCl inokuphinda isebenze kunye ne-DNA kwaye ifake i-DNA'intsebenziswano yeprotheni kwaye ivelise iimveliso ze-pyrimidine oxidation kunye nokongeza i-chloride kwiziseko ze-DNA.29,30 Eosinophil peroxidase kunye ne-MPO nayo inegalelo kuxinzelelo lwe-oxidative ngokuguqulwa kweeprotheni nge-halogenations, i-nitration, kunye ne-protein cross-links nge-tyrosyl radicals.31�33

Ezinye i-oxygen-derived free radicals yi-peroxyl radicals (ROO $). Eyona ndlela ilula yezi radicals yi-hydro-peroxyl radical (HOO $) kwaye inendima kwi-fatty acid peroxidation. Iiradicals zasimahla zinokubangela ukusabela kwetsheyina lelipid peroxidation ngokutsala iathomu yehidrojeni kwitsheyini esecaleni yemethylene carbon. I-lipid radical emva koko idibana neoksijini ukuvelisa i-peroxyl radical. I-Peroxyl radical iqala ukusabela kwekhonkco kwaye iguqule i-polyunsaturated fatty acids ibe yi-lipid hydroperoxides. I-Lipid hydroperoxides ayizinzile kwaye ibola ngokulula kwiimveliso zesibini, ezifana ne-aldehydes (ezifana ne-4-hydroxy-2,3-nonenal) kunye ne-malondialdehydes (MDAs). I-Isoprostanes yenye iqela leemveliso ze-lipid peroxidation eziveliswa nge-peroxidation ye-arachidonic acid kwaye zifunyenwe ziphakanyiswe kwi-plasma kunye nokuphefumula kwe-asthmatics. isakhiwo inwebu.

Ihydrogen peroxide, superoxide radical, oxidized glutathione (GSSG), MDAs, isoprostanes, carbonyls, kunye nenitrotyrosine zinokulinganiswa ngokulula kwiplasma, igazi, okanye ibronchoalveolar lavage iisampulu njenge biomarkers of oxidation ngovavanyo olusemgangathweni.

Umthombo wangaphandle weeOxidants

Umsi weCigarette

Umsi we-cigarette uqukethe i-oxidants kunye ne-radicals yamahhala kunye ne-organic compounds, njenge-superoxide kunye ne-nitric oxide.36 Ukongezelela, ukuphefumla umsi wecuba emphunga kuphinda kusebenze ezinye iindlela ezingapheliyo, ezifana nokuqokelela i-neutrophils kunye ne-macrophages, eyongeza ngakumbi ukwenzakala kwe-oxidant. .

Ukubonakaliswa kweOzone

Ukubonakaliswa kwe-ozone kunokubangela i-lipid peroxidation kwaye kubangele ukungena kwe-neutrophils kwi-epithelium yomoya. Ukutshatyalaliswa kwexesha elifutshane kwi-ozone kubangela ukukhululwa kwabalamli abavuthayo, njenge-MPO, i-eosinophil cationic proteins kunye ne-lactate dehydrogenase kunye ne-albumin.37 Nangona kwizifundo eziphilileyo, ukubonakaliswa kwe-ozone kubangela ukunciphisa imisebenzi ye-pulmonary.38 Cho et al39 baye babonisa ukuba i-particulate matter (umxube wamasuntswana aqinileyo kunye namathontsi angamalwelo axhonywe emoyeni) enza ukuba kucuthwe ioksijini.

Hyperoxia

I-Hyperoxia ibhekisa kwiimeko zamanqanaba aphezulu e-oksijini kunoxinzelelo oluqhelekileyo lweoksijini emiphungeni okanye kwezinye izicubu zomzimba. Ikhokelela kwimveliso enkulu ye-oksijeni esebenzayo kunye neentlobo ze-nitrogen.40,41

I-ionizing Radiation

I-ionizing radiation, phambi kwe-O2, iguqula i-hydroxyl radical, superoxide, kunye ne-organic radicals kwi-hydrogen peroxide kunye ne-organic hydroperoxides. Ezi ntlobo ze-hydroperoxide zisabela nge-redox yensimbi esebenzayo, njenge-Fe kunye ne-Cu, ngokuphendula kwe-Fenton kwaye ngaloo ndlela ibangele uxinzelelo lwe-oxidative. ukuveliswa nge-plasma membrane-eboshwe i-NADPH oxidase.42,43 Iimolekyuli zokutshintshwa kweSignali, ezifana ne-extracellular signal-regulated kinase 44 kunye ne-2 (ERK2 / 2), c-Jun N-terminal kinase (JNK), kunye ne-p2, kunye nezinto ezibhaliweyo, ezifana i-activator protein-44 (AP-1), i-nuclear factor-kB (NF-kB), kunye ne-p2, ziyasebenza, ezikhokelela ekubonakalisweni kwempendulo ye-radiation-related genes. ngokuvuswa kweefotosensitizers ezingapheliyo, ezifana ne-porphyrins, i-NADPH oxidase, kunye ne-riboflavins. I-1-Oxo-2- dihydroguanine (i-38-oxoGua) iyona nto iphambili ye-UVA-mediated DNA oxidation imveliso eyenziwa yi-oxidation ye-OH radical, i-1-electron oxidants, kunye ne-oksijini ye-singlett echaphazela kakhulu i-guanine.1 Ukubunjwa kwe-guanine i-radical cation kwi-DNA eyodwa ibonakaliswe ukuba yenzeke ngokufanelekileyo ngempembelelo echanekileyo ye-ionizing radiation.53 Emva kokuvezwa kwimitha ye-ionizing, i-intracellular level of glutathione (GSH) iyancipha ixesha elifutshane kodwa iphinda inyuke kwakhona.45

I-Ions zentsimbi enzima

I-ion zensimbi ezinzima, ezifana nentsimbi, ithusi, i-cadmium, i-mercury, i-nickel, i-lead, kunye ne-arsenic, inokubangela ukuveliswa kwee-radicals ezisebenzayo kwaye kubangele umonakalo weselula ngokunciphisa imisebenzi ye-enzyme ngokusebenzisa i-lipid peroxidation kunye nokuphendula ngeeprotheni zenyukliya kunye ne-DNA.55.

Enye yeendlela ezibaluleke kakhulu zesinyithi-mediated simahla iradical sizukulwana kukusebenzisa uhlobo lwe-Fenton reaction. I-ion ye-Superoxide kunye ne-hydrogen peroxide inokunxibelelana nesinyithi sokutshintsha, njengentsimbi kunye nobhedu, nge-metal catalyzed Haber'Weiss/Fenton reaction ukwenza i-OH radicals.

Metal31 1 $O2 /Metal21 1 O2 Haber Weiss Metal21 1 H2 O2 /Metal31 1 OH 2 1 $OH Fenton reaction

Ngaphandle kohlobo lwe-Fenton kunye neendlela zohlobo lwe-HaberWeiss, ii-ion ezithile zetsimbi zinokusabela ngokuthe ngqo kunye neemolekyuli zeselula ukuvelisa iiradicals zasimahla, ezinje nge-thiol radicals, okanye zenze iindlela zokubonisa iiseli. Ezi radicals zinokusabela kunye nezinye iimolekyuli ze-thiol ukuvelisa i-O22.. O22. iguqulwa ibe yi-H2O2, ebangela ukuveliswa kwe-oxygen eyongezelelweyo. Ezinye izinyithi, ezifana ne-arsenite, zenza i-ROS ibunjwe ngokungathanga ngqo ngokusebenza kweenkqubo zokuvelisa ngokugqithisileyo kwiiseli.56

I-Arsenic yinto enetyhefu kakhulu eyenza iindidi zeROS, kubandakanywa i-superoxide (O2 2), i-oxygen singlet (1O2), i-peroxyl radical (ROO), i-nitric oxide (NO), i-hydrogen peroxide (H2O2), kunye ne-dimethylarsinic peroxyl radicals [( CH3)2AsOO ].57�59 Arsenic (III) iikhompawundi zinokunqanda i-antioxidant enzymes, ngakumbi i-enzymes exhomekeke kwi-GSH, njenge-glutathione-S-transferases (GSTs), i-glutathione peroxidase (GSH-Px), kunye ne-GSH reductase, ngokubopha. - kumaqela abo e-sulfhydryl (�SH).60,61

Isikhokelo kwandisa i-lipid peroxidation.62 Ukuncipha okuphawulekayo kumsebenzi we-tissue SOD kunye nobuchopho be-GPx kuye kwabikwa emva kokuvezwa kwe-lead.63,64 Ukutshintshwa kwe-zinc, esebenza njenge-cofactor ye-enzymes ezininzi nge-lead, ikhokelela ekubeni i-enzyme ingasebenzi. Ukuvezwa kwelothe kunokubangela ukuvinjwa kwe-GST ngokuchaphazela i-thiols yezicubu.

I-ROS eyenziwa yi-metal-catalyzed reactions inokuguqula iziseko ze-DNA. Ukutshintshwa kwesiseko ezintathu, i-G / C, i-G / T, kunye ne-C / T, inokuthi yenzeke ngenxa yomonakalo we-oxidative nge-ion zetsimbi, ezifana ne-Fe21, Cu21, kunye ne-Ni21. U-Reid et al65 ubonise ukuba i-G / C yaveliswa kakhulu yi-Fe21 ngelixa indawo ye-C / T yayiyi-Cu21 kunye ne-Ni21.

IZINTO EZOKUXHUMA

Umzimba womntu uxhotyiswe ngeendidi ze-antioxidants ezisebenza ukulungelelanisa umphumo wee-oxidants. Kuzo zonke iinjongo ezisebenzayo, ezi zinokwahlulwa zibe ziindidi ezi-2: i-enzymatic (iThebhile 2) kunye ne-nonenzymatic (iThebhile 3).

Ii-Antioxidants ze-Enzymatic

Ii-antioxidants ezinkulu ze-enzymatic zemiphunga zi-SOD (EC 1.15.1.11), i-catalase (EC 1.11.1.6), kunye ne-GSH-Px (EC 1.11.1.9). Ukongeza kwezi enzymes ezinkulu, ezinye i-antioxidants, ezibandakanya i-heme oxygenase-1 (EC 1.14.99.3), kunye neeprotheni ze-redox, ezifana ne-thioredoxins (TRXs, EC 1.8.4.10), i-peroxiredoxins (PRXs, EC 1.11.1.15), kunye ne-glutaredoxins, kunye ne-glutaredoxins , zikwafunyaniswa ukuba zidlala indima ebalulekileyo kukhuselo lwe-pulmonary antioxidant.

Ekubeni i-superoxide yi-ROS ephambili eveliswa kwimithombo eyahlukeneyo, ukuchithwa kwayo yi-SOD kubaluleke kakhulu kwiseli nganye. Zonke iifom ezi-3 ze-SOD, oko kukuthi, i-CuZn-SOD, i-Mn-SOD, kunye ne-EC-SOD, zibonakaliswa ngokubanzi kwimiphunga yomntu. I-Mn-SOD ibekwe kwindawo ye-mitochondria matrix. I-EC-SOD ngokuyinhloko ibekwe kwindawo ye-matrix engaphandle, ngokukodwa kwiindawo eziqulethe ixabiso eliphezulu lohlobo lwe-collagen fibers kunye ne-pulmonary and systemic vessels. Kwakhona kuye kwafunyanwa kwi-epithelium ye-bronchial, i-alveolar epithelium, kunye ne-alveolar macrophages. Inqanaba eliphezulu le-EC-SOD kwimiphunga kunye nokubopha ngokuthe ngqo kumacandelo e-matrix e-extracellular inokumela icandelo elisisiseko lokukhusela i-matrix ye-lung.66,67

I-H2O2 eveliswa yisenzo se-SOD okanye isenzo se-oxidases, njenge-xanthine oxidase, iyancitshiswa emanzini nge-catalase kunye ne-GSH-Px. ICatalase ikhona njengetetramer eyenziwe ngeemonomer ezi-4 ezifanayo, nganye kuzo ineqela le-heme kwindawo esebenzayo. Ukuthotywa kwe-H2O2 kufezekiswa ngoguqulo phakathi kwe-2 conformations ye-catalase-ferricatalase (intsimbi edityaniswe namanzi) kunye ne-compound I (intsimbi ehlanganiswe ne-athomu ye-oxygen). I-Catalase iphinda ibophe i-NADPH njengokunciphisa ukulinganisa ukuthintela ukungasebenzi kwe-oxidative ye-enzyme (ukwenziwa kwe-compound II) nge-H2O2 njengoko iyancipha emanzini.69

I-Enzymes kumjikelezo we-redox ojongene nokunciphisa i-H2O2 kunye ne-lipid hydroperoxides (eyenziwe ngenxa ye-membrane lipid peroxidation) iquka i-GSH-Pxs.70 I-GSH-Pxs yintsapho ye-tetrameric enzymes equkethe i-amino acid eyodwa selenocysteine ngaphakathi iindawo ezisebenzayo kunye nokusebenzisa i-thiols ephantsi-molekyuli-ubunzima, njenge-GSH, ukunciphisa i-H2O2 kunye ne-lipid peroxides kwii-alcohols ezihambelanayo. I-GSH-Pxs ezine zichazwe, zifakwe kwii-genes ezahlukeneyo: I-GSH-Px-1 (i-cellular GSH-Px) iyindawo yonke kwaye iyanciphisa i-H2O2 kunye ne-peroxides ye-fatty acid, kodwa i-peroxyl lipids engabonakaliyo. -Px-71 (i-phospholipid hydroperoxide GSH-Px), enokusebenzisa i-thiols ezininzi ezahlukeneyo ezinobunzima obuphantsi bemolekyuli njengokunciphisa ukulingana. I-GSH-Px-4 (i-GSH-Px ye-gastrointestinal) ifumaneka kwiiseli ze-epithelial zesisu apho isebenza ukunciphisa i-peroxides yokutya. i-extracellular compartment kwaye kukholelwa ukuba yeyona enzyme ibalulekileyo kwi-antioxidant kwizilwanyana ezanyisayo. Kuzo, i-extracellular GSH-Px iphandwa kakhulu kwimiphunga yomntu.2

Ukongezelela, ukulahlwa kwe-H2O2 kuhambelana ngokusondeleyo kunye nee-enzyme ezininzi ezine-thiol, ezizezi, i-TRXs (TRX1 kunye ne-TRX2), i-thioredoxin reductases (EC 1.8.1.9) (TRRs), i-PRXs (eyi-thioredoxin peroxidases), kunye ne-glutaredoxin.

IiTRX ezimbini kunye ne-TRR zibonakaliswe kwiiseli zomntu, ezikhoyo kwi-cytosol kunye ne-mitochondria. Kwimiphunga, i-TRX kunye ne-TRR zibonakaliswa kwi-epithelium ye-bronchial kunye ne-alveolar kunye ne-macrophages. Ii-PRX ezintandathu ezahlukeneyo zifunyenwe kwiiseli zomntu, ezahlukileyo kwi-ultrastructural compartmentalization. Izifundo zovavanyo zibonakalise ukubaluleka kwe-PRX VI ekukhuseleni i-alveolar epithelium. Umphunga womntu uvakalisa zonke ii-PRXs kwi-epithelium ye-bronchial, i-alveolar epithelium, kunye ne-macrophages.75 I-PRX V isanda kufunyaniswa ukuba isebenze njenge-peroxynitrite reductase, i-76 ithetha ukuba inokusebenza njengento ekhuselekileyo yokukhusela ekuphuhlisweni kokulimala kwe-ROS-mediated lung .77

Okuqhelekileyo kwezi antioxidants yimfuneko ye-NADPH njengokunciphisa okufanayo. I-NADPH igcina i-catalase kwifom esebenzayo kwaye isetyenziswe njenge-cofactor nge-TRX kunye ne-GSH reductase (EC 1.6.4.2), eguqula i-GSSG kwi-GSH, i-co-substrate ye-GSH-Pxs. I-Intracellular NADPH, ngokuphindaphindiweyo, iveliswa ngokunciphisa i-NADP1 nge-glucose-6-phosphate dehydrogenase, i-enzyme yokuqala kunye ne-rate-limiting enzyme ye-pentose phosphate pathway, ngexesha lokuguqulwa kwe-glucose-6-phosphate kwi-6-phosphogluconolactone. Ngokuvelisa i-NADPH, i-glucose-6-phosphate dehydrogenase yinto ebalulekileyo yokumisela i-cytosolic GSH buffering capacity (GSH / GSSG) kwaye, ngoko ke, inokuthathwa njengento ebalulekileyo, elawula i-enzyme ye-antioxidant.78,79

I-GSTs (EC 2.5.1.18), enye intsapho ye-enzyme ye-antioxidant, yenza i-metabolites yesibini ingasebenzi, njenge-aldehydes engaxutywanga, i-epoxides, kunye ne-hydroperoxides. Iintsapho ezintathu ezinkulu ze-GST zichazwe: i-cytosolic GST, i-GST ye-mitochondrial, i-80,81 kunye ne-membrane ehambelana ne-microsomal GST enendima ye-eicosanoid kunye ne-GSH metabolism. I-Pi, i-Sigma, i-Theta, i-Omega, kunye ne-Zeta.82�83 Ngexesha leemeko ezingagxininiswanga, iklasi ye-Mu kunye ne-Pi GSTs isebenzisana ne-kinases Ask86 kunye ne-JNK, ngokulandelanayo, kwaye inhibit le kinases.1�87 Kuye kwaboniswa ukuba i-GSTP89 iyahlukana nayo I-JNK ekuphenduleni uxinzelelo lwe-oxidative.1 GSTP89 iphinda isebenze ngokomzimba kunye ne-PRX VI kwaye ikhokelela ekubuyiseleni umsebenzi we-enzyme ye-PRX nge-glutathionylation yeprotheni ene-oxidized.1

Nonenzymatic Antioxidants

I-Nonenzymatic antioxidants iquka iikhompawundi ezinobunzima obuphantsi be-molecular-weight, ezifana neevithamini (i-vitamin C kunye ne-E), i-b-carotene, i-uric acid, kunye ne-GSH, i-tripeptide (Lg-glutamyl-L-cysteynyl-L- glycine) equka i-thiol (i-thiol) sulfhydryl) iqela.

I-Vitamin C (i-Ascorbic Acid)

Ivithamin C enyibilikayo emanzini (i-ascorbic acid) ibonelela nge-intracellular kunye ne-extracellular aqueous-phase i-antioxidant umthamo we-antioxidant ngokuyinhloko ngokukhupha i-oxygen free radicals. Iguqula i-vitamin E ye-radicals yamahhala ibuyele kwi-vitamin E. Amanqanaba ayo e-plasma abonakaliswe ukuba ayancipha ngeminyaka.91,92

IVithamin E (a-Tocopherol)

I-Lipid-soluble vitamin E igxininiswe kwindawo yangaphakathi ye-hydrophobic ye-membrane yeseli kwaye iyona nto yokukhusela i-oxidant-induced membrane i-membrane. I-Vitamin E inikela nge-electron kwi-peroxyl radical, eveliswa ngexesha le-lipid peroxidation. I-a-Tocopherol yeyona ndlela isebenzayo ye-vitamin E kunye ne-membrane enkulu ebophe i-antioxidant kwiseli. I-Vitamin E ibangela i-apoptosis yeeseli zomhlaza kwaye inqanda ukubunjwa kwamahhala.93

Glutathione

I-GSH ininzi kakhulu kuzo zonke iikhompatimenti zeeseli kwaye yeyona nto iphambili ekunyibilikeni kwe-antioxidant. Umlinganiselo we-GSH/GSSG sisona sigqibo siphambili soxinzelelo lwe-oxidative. I-GSH ibonisa imiphumo ye-antioxidant ngeendlela ezininzi.94 Ikhupha i-hydrogen peroxide kunye ne-lipid peroxides ngesenzo se-GSH-Px. I-GSH inika i-electron yayo kwi-H2O2 ukuyinciphisa ibe yi-H2O kunye ne-O2. I-GSSG iphinda ithotywe ibe yi-GSH nge-GSH reductase esebenzisa i-NAD(P)H njengomnikeli we-electron. Ii-GSH-Pxs zikwabalulekile ekukhuselweni kwenwebu yeseli kwi-lipid peroxidation. Ukunciphisa i-glutathione inika iiprotons kwi-membrane lipids kwaye ikhusela ekuhlaselweni kwe-oxidant.95

I-GSH yicofactor yee-enzyme ezininzi ezikhupha ubutyhefu, ezifana ne-GSH-Px kunye nokudluliselwa. Inendima ekuguquleni i-vitamin C kunye ne-E kwiifom zabo ezisebenzayo. I-GSH ikhusela iiseli ezichasene ne-apoptosis ngokusebenzisana neproapoptotic kunye ne-antiapoptotic indlela yokubonisa indlela.94 Ikwalawula kwaye isebenze izinto ezininzi zokubhala, ezifana ne-AP-1, NF-kB, kunye ne-Sp-1.

IiCarotenoids (b-Carotene)

I-Carotenoids zimibala yemibala efumaneka kwizityalo. Ngokuyintloko, i-b-carotene ifunyenwe ukuba iphendule nge-peroxyl (ROO), i-hydroxyl (OH), kunye ne-superoxide (O22.) i-radicals.96 I-Carotenoids ibonisa iziphumo zabo ze-antioxidant kwi-oxygen ephantsi yoxinzelelo oluyingxenye kodwa ingaba nemiphumo ye-pro-oxidant kwi-oxygen ephezulu. i-concentrations.97 Zombini i-carotenoids kunye ne-retinoic acids (i-RAs) ziyakwazi ukulawula izinto ezibhaliweyo.98 b-Carotene inqanda i-oxidant-induced NF-kB activation kunye ne-interleukin (IL) -6 kunye ne-tumor necrosis factor-a production. I-carotenoids nayo ichaphazela i-apoptosis yeeseli. Imiphumo ye-Antiproliferative ye-RA ibonakaliswe kwizifundo ezininzi. Esi siphumo se-RA sixutyushwa ikakhulu ngama-retinoic acid receptors kwaye ayahluka phakathi kweentlobo zeeseli. Kwiiseli ze-mammary carcinoma, i-retinoic acid receptor yaboniswa ukuba iqalise ukuvinjelwa kokukhula ngokubangela ukubanjwa komjikelezo weseli, i-apoptosis, okanye zombini.99,100

IZIPHUMO ZOXINEZELEKO LWE-OXIDATIVE: GENETIC, PHYSIOLOGICAL, & BIOCHEMICAL MECHANISMS

Uxinzelelo lwe-oxidative lwenzeka xa ibhalansi phakathi kwe-antioxidants kunye ne-ROS iphazamiseka ngenxa yokuncipha kwe-antioxidants okanye ukuqokelela kwe-ROS. Xa uxinzelelo lwe-oxidative lwenzeka, iiseli zizama ukuchasana nemiphumo ye-oxidant kunye nokubuyisela ibhalansi ye-redox ngokusebenza okanye ukuthuliswa kwejene-encoding enzymes ezikhuselayo, izinto ezibhaliweyo, kunye neeprotheni zesakhiwo.101,102 Umlinganiselo phakathi kwe-glutathione oxidized kunye nokunciphisa (2GSH / GSSG) enye izinto ezibalulekileyo zokumisela uxinzelelo lwe-oxidative emzimbeni. Ukuveliswa okuphezulu kwe-ROS emzimbeni kunokutshintsha isakhiwo se-DNA, kubangele ukuguqulwa kweeprotheni kunye ne-lipids, ukusetyenziswa kwezinto ezininzi ezibangelwa uxinzelelo, kunye nokuveliswa kwe-cytokines e-pro-inflammatory and anti-inflammatory.

Iziphumo zoxinzelelo lwe-Oxidative kwi-DNA

I-ROS inokukhokelela ekuguqulweni kwe-DNA ngeendlela ezininzi, ezibandakanya ukuthotywa kweziseko, i-DNA eyodwa okanye i-double-stranded breaks, i-purine, i-pyrimidine okanye i-sugar-bound modifications, ukuguqulwa, ukucinywa okanye ukuhanjiswa, kunye nokudibanisa kunye neeprotheni. Uninzi lwezi nguqulelo ze-DNA (umzobo 1) zibaluleke kakhulu kwi-carcinogenesis, ukuguga, kunye ne-neurodeergenerative, i-cardiovascular, kunye nezifo ezizimele. Umsi wecuba, isinyithi esine-redox, kunye neentsimbi ezi-nonredox, ezifana ne-iron, i-cadmium, i-chrome, kunye ne-arsenic, zikwabandakanyeka kwi-carcinogenesis kunye nokuguga ngokuvelisa ii-radicals zamahhala okanye ukubopha kunye namaqela e-thiol. Ukwenziwa kwe-8-OH-G ngowona monakalo waziwa kakhulu we-DNA owenzeka ngoxinzelelo lwe-oxidative kwaye yinto enokubakho i-biomarker ye-carcinogenesis.

Imimandla yabakhuthazi bemizila yemfuza iqulathe ulandelelwano lwemvumelwano kwizinto ezikhutshelweyo. Ezi sayithi zibophelelayo ziqulathe ulandelelwano olutyebileyo lwe-GC olusesichengeni sohlaselo lwe-oxidant. Ukuqulunqwa kwe-8-OH-G DNA kwiindawo ezibophelelayo ze-transcription factor inokuguqula ukubophelela kwezinto ezibhaliweyo kwaye ngaloo ndlela iguqule ukubonakaliswa kweejene ezihambelanayo njengoko kuboniswe kwi-AP-1 kunye ne-Sp-1 yokulandelelana okujoliswe kuyo.103 Ngaphandle kwe-8-OH-G, I-8,59 -cyclo-29 -deoxyadenosine (i-cyclo-dA) nayo ibonakaliswe ukuba inqanda ukubhalwa kwi-generator gene kwi-cell system ukuba ifakwe kwibhokisi ye-TATA. . Ukubotshwa kweprotheni ye-TATA-ibophelelo kunokuphazamiseka ngenxa yobukho be-cyclo-dA.

Uxinzelelo lwe-oxidative lubangela ukungazinzi kwemimandla ye-microsatellite (i-tandem emfutshane ephindaphindayo). I-Redox yensimbi esebenzayo i-ion, i-hydroxyl radicals yandisa ukungazinzi kwe-microsatellite.105 Nangona i-DNA edibeneyo ikhefu ebangelwa ukulimala kwe-oxidant inokunyamezela ngokulula ngamaseli, i-DNA ephindwe kabini ikhefu eyenziwa yi-ionizing radiation ingaba yingozi enkulu kwi-cell survival.106

I-Methylation kwiziqithi ze-CpG kwi-DNA yindlela ebalulekileyo ye-epigenetic enokubangela ukuthuliswa kofuzo. I-Oxidation ye-5-MeCyt ukuya kwi-5-hydroxymethyl uracil (i-5-OHMeUra) ingenzeka ngokusebenzisa i-deamination / oxidation reactions ye-thymine okanye i-5-hydroxymethyl cytosine intermediates.107 Ukongeza kwi-modulating gene expression, i-DNA methylation ibonakala ichaphazela intlangano ye-chromatin.108 Iipateni ze-Aberrant DNA methylation ezibangelwa ukuhlaselwa kwe-oxidative nazo zichaphazela umsebenzi wokulungisa i-DNA.

Iziphumo zoxinzelelo lweOxidative kwiLipids

I-ROS inokubangela i-lipid peroxidation kwaye iphazamise ilungiselelo le-membrane ye-lipid bilayer enokuthi ingasebenzi i-membrane-bound bound receptors kunye ne-enzymes kunye nokwandisa i-tissue permeability. -linkages.109�110 I-112-Hydroxy-4-nonenal ibangela ukuchithwa kwe-GSH ye-intracellular kunye ne-induces yokuveliswa kwe-peroxide, i-2 isebenze i-epidermal growth factor receptor, i-113,114 kwaye ibangele ukuveliswa kwe-fibronectin.115 Imveliso ye-Lipid peroxidation, njenge-isoproactive substances kunye ne-asidi ye-isoprostabisturic , zisetyenziswe njenge-biomarkers ezingathanga ngqo zoxinzelelo lwe-oxidative, kunye namanqanaba okwandisa abonakaliswe kwi-exhaled breath condensate okanye i-bronchoalveolar lavage fluid okanye imiphunga yezigulane ezingapheliyo ze-pulmonary disease okanye ababhemayo.116�117

Iziphumo zoxinzelelo lwe-Oxidative kwiiProtheyini

I-ROS inokubangela ukuhlukana kwekhonkco le-peptide, ukuguqulwa kwentlawulo yombane yeeprotheni, ukudibanisa kweeprotheni, kunye ne-oxidation ye-amino acids ethile kwaye ngoko ke kukhokelela ekunyukeni kwe-proteolysis ngokuchithwa ngamaproteases athile. ngakumbi ichaphazeleka ngakumbi kwi-oxidation.120 I-Oxidation yamaqela e-sulfhydryl okanye iintsalela ze-methionine zeeprotheni zibangela utshintsho lwe-conformational, i-protein eqhubekayo, kunye nokuhla. Ukuguqulwa kwe-oxidative ye-enzymes kuboniswe ukuvimbela imisebenzi yabo.121

Kwezinye iimeko, i-oxidation ethile yeeprotheni inokuthi yenzeke. Ngokomzekelo, i-methionine ingaba yi-oxidized methionine sulfoxide126 kunye ne-phenylalanine kwi-o-tyrosine127; Amaqela e-sulfhydryl anokuthi afakwe i-oxidized ukuze enze iibhondi ze-disulfide;I-128 kunye namaqela e-carbonyl anokuthi afakwe kumatyathanga asecaleni amaprotheni. Imitha ye-Gamma, i-metal-catalyzed oxidation, i-HOCl, kunye ne-ozone inokubangela ukubunjwa kwamaqela e-carbonyl.129

Iziphumo zoxinzelelo lwe-Oxidative kuTshintsho lweSignali

I-ROS inokubangela ukubonakaliswa kweentlobo ezininzi zofuzo ezibandakanyekayo kwi-transduction ye-signal.1,130 Umlinganiselo ophezulu we-GSH / GSSG ubalulekile ekukhuselweni kweseli kumonakalo we-oxidative. Ukuphazamiseka kwesi silinganiselo kubangela ukusetyenziswa kwezinto ezithintekayo ze-redox, ezifana ne-NF-kB, i-AP-1, i-nuclear factor ye-activated T cells kunye ne-hypoxia-inducible factor 1, ezibandakanyekayo kwimpendulo yokuvuvukala. Ukusetyenziswa kwezinto ezikhutshelweyo nge-ROS kuphunyezwa ngokugqithiswa komqondiso we-cascades ohambisa ulwazi ukusuka ngaphandle ukuya ngaphakathi kwiseli. I-Tyrosine kinase i-receptors, ininzi ye-receptors factor receptor, njenge-epidermal growth factor receptor, i-vascular endothelial growth factor receptor, kunye ne-receptor ye-platelet-derived factor factor, i-protein tyrosine phosphatases, kunye ne-serine / threonine kinases ziithagethi ze-ROS.131�133 I-extra-cellular signal-regulated kinases, i-JNK, kunye ne-p38, engamalungu e-mitogen-activated protein kinase family kwaye abandakanyeka kwiinkqubo ezininzi kwiseli kuquka ukwanda, ukuhlukana, kunye ne-apoptosis, nayo inokulawulwa yi-oxidants.

Ngaphantsi kweemeko zokuxinzezeleka kwe-oxidative, i-cysteine intsalela kwindawo ye-DNA-binding ye-c-Jun, ezinye i-AP-1 subunits, kunye ne-inhibitory kB kinase i-S-glutathiolation eguqulwayo. I-Glutaredoxin kunye ne-TRX ziye zabikwa ukuba zidlala indima ebalulekileyo ekulawuleni iindlela zokubonisa i-redox-sensitive, ezifana ne-NF-kB kunye ne-AP-1, i-p38 mitogen-activated protein kinase, kunye ne-JNK.134�137

I-NF-kB inokuthi isebenze ekuphenduleni iimeko zokuxinzezeleka kwe-oxidative, njenge-ROS, i-radicals yamahhala, kunye ne-UV irradiation.138 I-Phosphorylation ye-IkB ikhulula i-NF-kB kwaye ivumela ukuba ingene kwi-nucleus ukuze isebenze i-gene transcription.139 Inani le-kinases kuxelwe kwi-phosphorylate IkBs kwiintsalela ze-serine. Ezi kinases zijoliswe kwiimpawu ze-oxidative ukuze kusebenze i-NF-kB.140 ii-agent zokunciphisa ziphucula i-NF-kB DNA yokubopha, ngelixa i-oxidizing agents zivimbela i-DNA yokubopha i-NF-kB. I-TRX inokusebenzisa izenzo ezi-2 ezichaseneyo kulawulo lwe-NF-kB: kwi-cytoplasm, ivimba ukuthotywa kwe-IkB kwaye inqanda ukusebenza kwe-NF-kB kodwa iphucula i-NF-kB DNA ebophelelayo kwi-nucleus.141 Ukusetyenziswa kwe-NF-kB ngokuchithwa kwe-oxidation-related degradation. ye-IkB iphumela ekubeni kusebenze iijini ezininzi ezinxulumene nokhuselo lwe-antioxidant. I-NF-kB ilawula ukubonakaliswa kwezakhi zofuzo ezininzi ezithatha inxaxheba ekuphenduleni komzimba, njenge-IL-1b, i-IL-6, i-tumor necrosis factor-a, i-IL-8, kunye neemolekyuli ezininzi zokubambelela. ukwahlukana kweeseli.

I-AP-1 nayo ilawulwa yi-redox state. Phambi kwe-H2O2, ezinye ii-ion zetsimbi zingenza ukuba kusebenze i-AP-1. Ukonyuka komlinganiselo we-GSH/GSSG kuphucula ukubophelela kwe-AP-1 ngelixa i-GSSG inqanda ukubophelela kwe-DNA ye-AP-1.144 DNA yokubopha i-Fos/Jun heterodimer yonyuka ngokunciphisa i-cysteine eyodwa egciniweyo kwi-domain ebopha i-DNA nganye iiprotheyini, i-145 ngelixa i-DNA ibophelela i-AP-1 inokuvinjelwa yi-GSSG kwiintlobo ezininzi zeeseli, ebonisa ukuba ukubunjwa kwebhondi ye-disulphide ngama-cysteine i-residues inqanda i-AP-1 DNA yokubopha.146,147 Ukutshintshwa kweSignali ngokusebenzisa uxinzelelo lwe-oxidative lushwankathelwe kwi-Figure 2.

IMISEBENZI

Uxinzelelo lwe-oxidative lunokuvela kwimveliso egqithisileyo ye-ROS ngokuphendula kwemetabolism esebenzisa ioksijini kunye nokutshintsha ibhalansi phakathi i-oxidant/antioxidant iimeko ezixhasa i-oxidants. I-ROS iveliswa yimisebenzi ye-metabolic yeselula kunye nezinto ezisingqongileyo, ezinje ngongcoliseko lomoya okanye umsi wecuba. I-ROS ziamolekyu ezisebenzayo kakhulu ngenxa yee-electron ezingasebenziyo kwisakhiwo sazo kwaye zisabela kunye ne-biological macromolecules ezininzi kwiseli, njenge-carbohydrates, i-nucleic acids, i-lipids, kunye neeprotheni, kwaye ziguqule imisebenzi yazo. I-ROS ikwachaphazela ukubonakaliswa kofuzo oluninzi ngokunyusa izinto ezikhutshelweyo ezibuthathaka kwi-redox kunye nohlengahlengiso lwechromatin ngotshintsho kwi-histone acetylation/deacetylation. Ukulawulwa kwemeko ye-redox ibalulekile ekusebenzeni kweeseli, ukusebenza, ukwanda, kunye nokusebenza kwamalungu.

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