I-Nrf2 Inkqubo yokuBonisa: Iimbopheleleko eziphambili kwi-Inflammation

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].

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).

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).

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].

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

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.

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

***