I-Nrf2 icacisiwe: I-Keap1-Nrf2 Pathway

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).

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).

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.

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

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:

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Umgca wexesha elipheleleyo

• 00: 00: 34 - Ukuqaliswa kwe-sulforaphane, ingqwalasela ephambili yevidiyo.
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• 00: 04: 38 - Sulforfane nomhlaza.
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• I-00: 09: 16 - I-Sulforfane ikhono lokuphucula ukwanda kwe-carcinogen (benzene, acrolein).
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• 00: 19: 04 - Ukuqala kwecandelo lokuguga.
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• 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.
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• 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.
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• I-00: 34: I-13 - I-Sulforfane iphakamisa ama-proteins.
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• 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.
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• 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.
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• 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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