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Uxinzelelo oluxhasayo

I-Back Clinic Oxidative Stress Chiropractic kunye neQela leMithi eliSebenzayo. Uxinzelelo lwe-oxidative luchazwa njengokuphazamiseka kwibhalansi phakathi kokuveliswa kwe-oxygen esebenzayo (i-radicals yamahhala) kunye nokukhusela i-antioxidant. Ngamanye amazwi, kukungalingani phakathi kokuveliswa kwee-radicals zamahhala kunye nokukwazi komzimba ukuchasana okanye ukukhupha imiphumo eyingozi ngokusebenzisa i-neutralization yi-antioxidants. Uxinzelelo lwe-oxidative lukhokelela kwiimeko ezininzi ze-pathophysiological emzimbeni. Ezi ziquka izifo ze-neurodeergenerative, oko kukuthi, isifo sika-Parkinson, isifo se-Alzheimer, ukuguqulwa kofuzo, i-cancer, i-syndrome engapheliyo, i-syndrome e-fragile X, intliziyo kunye nokuphazamiseka kwemithambo yegazi, i-atherosclerosis, ukungaphumeleli kwentliziyo, ukuhlaselwa yintliziyo kunye nezifo ezivuthayo. I-oxidation iyenzeka phantsi kweemeko ezininzi:

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 we-Endocrinology: ICortisol neMelatonin isingqi seRadiya

Umsebenzi we-Endocrinology: ICortisol neMelatonin isingqi seRadiya

Ngaba uziva:

  • Awukwazi ukulala ebusuku?
  • Unokuqala kancinci ekuseni?
  • Ukudinwa kwemini?
  • Ukuvuka ukhathale nasemva kokuba ulale iiyure ezintandathu okanye ngaphezulu?
  • Ngaba siphantsi koxinzelelo oluphezulu?

Ukuba ufumana naziphi na kwezi meko, ke kungabakho ngenxa ye-melatonin yakho kunye namanqanaba e-cortisol achaphazela umzimba kunye nesingqisho esijikelezayo.

Kwihlabathi liphela, izigidi zabantu zinengxaki yokulala. EUnited States, kukho malunga I-50-70 yezigidi zabantu abanobuthongo obungalunganga. Xa umntu elele ixesha elingaphantsi kweeyure ezisibhozo, bayadinwa, kwaye iingxaki ezininzi zinokufika kubo, ngakumbi ukuba ubomi babo buxakekile. Ngendlela yokuzixakekisa ngokulala kunye nokungalali kakuhle, kunokubangela ukuba umzimba ube namandla asezantsi ukwenza nawuphi na umsebenzi wenziwe, i-cortisol yoxinzelelo lwe-cortisol iya kuphakanyiswa, kwaye izifo ezifana noxinzelelo lwegazi oluphezulu kunye neswekile kunokubangela iingxaki ezinokubakhona xa zingalulanga. inyangwa.

Ingca

Kwi-endocrinology esebenzayo, i-melatonin kunye ne-cortisol ziihomoni ezenziwa ngumzimba ngokwendalo. Ihorton ye-cortisol okanye i-hormone yoxinzelelo inceda umzimba ukuba kwimeko "yokulwa okanye yokubaleka", enokuba yinto efanelekileyo kuye nabani na owenza iprojekthi okanye esiya kudliwanondlebe nomsebenzi. Nangona amanqanaba e-cortisol ephezulu, kunokubangela ukuba umzimba ube neengxaki ezifana nokuvuvukala, uxinzelelo lwe-oxidative olungapheliyo, kunye noxinzelelo lwegazi oluphezulu.

Isingqi seMelatonin seRadiyo

Ngehomoni ye-melatonin, le hormone ixelela umzimba xa ilixesha lokulala. Ngamanye amaxesha nangona kunjalo, abantu banobunzima bokulala, kwaye ukuthatha i-melatonin izongezo kunokuwuphumlisa umzimba loo nto yenze ukuba umntu alale. Kuba i-pineal gland ivelisa i-melatonin evela kwingqondo, inokufumaneka nasebusweni, kumongo wamathambo, kunye nesisu ukuze uphumze umzimba kwaye kumenze umntu abalele ngokwemvelo. Abanye zifundo zi bonisa ukuba isingqisho se-circadian ye-pineal gland evelisa i-melatonin. Ngokwenza oku, uphando lubonisa ukuba ulawulo lwe-melatonin:

  • inye: yenza ubuthongo kubantu abanengxaki yokulala.
  • Mbini: Inqanda umzimba ukuba uvuke ngokwendalo kwi-pacemaker yesekethe.
  • Ntathu: tshintsha iiwotshi zebhayoloji yecadiya ukonyusa umthamo wokulala xa umntu efuna ukulala kwangethuba ukuze ufumane izibonelelo zokulala iiyure ezisibhozo.

Xa umntu esebenza emsebenzini we-9 ukuya ku-5, bayakhula ngemizimba yabo kwaye baphumze imizimba yabo emva kosuku olunzima emsebenzini. Izifundo zifunyenwe ukuba iihomoni ze-melatonin kunye ne-cortisol zinceda ekumiseleni iphethini yeeyure ezingama-24 zomsebenzi womzimba kunye nokuphendula ngokumandla. Ngomjikelezo wokuveliswa kwehomoni yomzimba, unokuphazamiseka ukuba umntu uhlala ephaphame kakhulu ebusuku okanye ulale emini. Xa oku kusenzeka, umntu unokufumana ukuphazamiseka okuphazamisayo njengokutshintsha kwemozulu, isiyezi, ukuba nomsindo kunye nokudakumba, kwaye ube nokuphazamiseka kwemetabolism. Ayisiyiyo leya kuphela, kodwa amajoni omzimba kunye nenkqubo yayo ye-endocrine nayo inokonakala ngokunjalo, ibangele ukuba umzimba ube ngumngeneleli kusulelo nakwizifo.

Kufundwe ngaphezulu kwimigqi ye-circadian emzimbeni, njengoko Izifundo zibonisa indlela abantu abasebenza ngayo kutshintsho ebusuku banxulunyaniswe nenani elikhulu leengxaki zempilo ezihlaselayo kwinkqubo yentliziyo kunye nesisu kunye nokuphazamisa inkqubo yemetabolism. Nabani na osebenzise i -hift yasebusuku kufuneka atshintshe ishedyuli yabo yokulala kunye nokuziqhelanisa nohlengahlengiso olukhawulezileyo kucwangciso lwabo lokulala / lokuya emsebenzini ukuze basebenze. Kuba wonke umntu usebenza kwishedyuli yokutshintsha, inokuba noxinzelelo kwaye inokuthi ichaphazele ukusebenza komzimba womsebenzi kunye nokuchaphazela secretion ye-melatonin kunye ne-cortisol.

Iindlela zokuxhasa iCortisol neMelatonin

Kuyamangalisa nangona kunjalo, kukho iindlela zokunciphisa amanqanaba e-cortisol kwaye uqiniseke ukuba amanqanaba e-melatonin asebenza ngokuchanekileyo ukuze umzimba usebenze. Ukuze amanqanaba e-cortisol ahluthwe, umntu kufuneka enze imisebenzi yokucamngca, ufumane indawo ayithandayo, kwaye okona kubaluleke kakhulu, zama ukuzivocavoca ngokunzulu ukuze uphumze umzimba kuxinzelelo olungafunekiyo. Xa usenza imithambo yokuphefumla enzulu, unokunceda umzimba ukuba ukhulule nayiphi na ingxaki ebanjwe ngumntu, kwaye izihlunu emzimbeni ziqale ukuphumla, kwaye igazi liqalisa ukuphuma. Ngamanqanaba e-melatonin, asebenza kunye kunye nesigqi somzimba esijikeleze umzimba kwaye aqinisekise ukuba umzimba uyazi xa ilixesha lokuvuka, ukulala nokutya. I-melatonin hormone inokunceda ukulawula ubushushu bomzimba, ifuthe legazi, kunye namanqanaba amahomoni ukuqinisekisa ukuba asebenza ngokuchanekileyo. Xa kukho amanqanaba aphezulu ezi nkqubo, kunokubangela ukuba umzimba ube nezifo ezingapheliyo kwaye wenzakalise umzimba kwinkqubo.

Uphando lubonisa ukuba iihomoni ze-melatonin zinokubopha kwii-receptors zemithambo emzimbeni, ngaloo ndlela zikhuthaze ukuphumla. Kuba i-melatonin ibopha kwii-receptors ze-neurological, inokunciphisa nomsebenzi we-nerve kunye namanqanaba e-dopamine ukwenza amehlo abe nzima, ngaloo ndlela emenza umntu alale.

isiphelo

Ngomzimba ukukwazi ngokwendalo ukuvelisa amanqanaba e-melatonin kunye ne-cortisol ukuqinisekisa ukuba umzimba awubeki uxinzelelo olugqithisileyo imini yonke. Kuba i-melatonin idibene nomjikelezo womzimba ojikelezayo, umzimba uyazi ukuba kufuneka uhlale nini kwaye ulale. Njengoko wonke umntu eneshedyuli exakekileyo, kubalulekile ukuba uchithe ixesha kwaye uphumle kwaye ube neshedyuli yokulala esempilweni ukuze umzimba ube sempilweni kwaye usebenze. Abanye iimveliso Silapha ukuze uqiniseke ukuba inkqubo ye-endocrine isebenza kakuhle kwaye ixhasa i-adrenal gland kunye neswekile yemetabolism.

Ubungakanani bolwazi lwethu lukhawulelwe kwi-chiropractic, musculoskeletal, kunye nemicimbi yezempilo yovalo okanye amanqaku amayeza asebenzayo, izihloko kunye neengxoxo. Sisebenzisa iiprothokholi zempilo ezisebenzayo ukunyanga ukwenzakala okanye ukuphazamiseka kwenkqubo yemusculoskeletal. Iofisi yethu yenze umzamo oqinisekileyo wokubonelela ngezikhokelo ezixhasayo kwaye ichonge isifundo sophononongo esifanelekileyo okanye izifundo ezixhasa izithuba zethu. Sikwenza iikopi zezifundo zophando ezixhasayo ziya kufumaneka ebhodini okanye kuluntu xa luceliwe. Ukuqhubeka nokuxoxa ngomxholo ongentla, nceda ukhululeke ukubuza uGqirha Alex Jimenez okanye unxibelelane nathi apha 915-850-0900.


Iingxelo:

ICajochen, C, okqhubekayo. Indima ye-Melatonin kuMmiselo weeRekhodi zoLuntu kunye nokulala Ijenali yeNeuroendocrinology, I-US National Library of Medicine, ngo-Ep. 2003, www.ncbi.nlm.nih.gov/pubmed/12622846.

UJames, uFrancine O, et al. RhIiCircadian Rhythms zeMelatonin, iCortisol, kunye neClock Gene Expression ngexesha loLinganiso lweShift Work. ukulala, Umbutho oDibeneyo wokulala ngokulala, LLC, Novemba 2007, www.ncbi.nlm.nih.gov/pmc/articles/PMC2082093/.

UMonteleone, P, et al. Ubudlelwane beThutyana phakathi kweMelatonin kunye neempendulo zeCortisol kumaXesha asebusuku kuXinzelelo lwaBantu. Psychoneuroendocrinology, I-US National Library of Medicine, i-1992, www.ncbi.nlm.nih.gov/pubmed/1609019.

URaman, uRyan. INDLELA IMELatonin enokukunceda ngayo ukuba ulale kwaye uzive ungcono LwezeMpilo, Imithombo yeendaba yezeMpilo, nge-3 kaSeptemba ngo-2017, www.healthline.com/nutrition/melatonin-and- ukulala.

UZamanian, uZahra, et al. Umda woTshintsho eCortisol naseMelatonin Isangqa seSyadian kwiiGadi zoKhuseleko zeYunivesithi yaseShiraz yezoNyango. Ijenali yaMazwe ngaMazwe yoNyango, IMednow Publications kunye neMedia Pvt Ltd, ngoJulayi 2013, www.ncbi.nlm.nih.gov/pmc/articles/PMC3775223/.


Unyango oluDibeneyo nolusebenzayo- Esse How Videri

Ngokwazisa umntu malunga neDyunivesithi yeSizwe yezeNzululwazi yezeMpilo ibonelela ngolwazi kwizizukulwana ezizayo ezifuna ukwenza umohluko emhlabeni. IYunivesithi ibonelela ngeendlela ezahlukeneyo zobungcali bobuchwephesha bokusebenza kunye nokudibanisa amayeza.

Iindlela ze-5 Zenzakalisa iGut yakho El Paso, eTexas

Iindlela ze-5 Zenzakalisa iGut yakho El Paso, eTexas

Ngaba ukhe wazibuza ukuba kutheni uziva ulivila ukusuka kusuku olude? Okanye uzive ugula esiswini xa utya into embi okanye ugqithise ukutya okuthandayo? Ngaba kunokwenzeka ukuba amathumbu akho abonisa iimpawu zoxinzelelo kunye nokungonwabi ngenxa yemikhwa ethile onokuthi udibane nayo kwaye ube ungazi ngayo?

Kwinqaku lethu elingaphambili, sithethe ngaso Iintlobo ezintandathu zokutya ukuba amathumbu ethu kufuneka esempilweni. Oko esisisu sethu iqulethwe Izigidigidi zee-microbiomes, ezilungileyo nezingalunganga, ezi microbiomes zidlala indima ebalulekileyo kwimpilo yethu iphela. Intsholongwane esempilweni iphucula eyethu umthambo wezempilo, impilo yentliziyo, impilo yengqondo, ukulawula ubunzima bethu kwaye ilawula iswekile yethu yegazi. Ngeebhaktiriya ezilungileyo eziseziseleni zethu, iibacteria ziyasinceda ngenkqubo yokugaya ukutya kwaye sitshabalalisa intsholongwane eyingozi. Kodwa iindlela ezithile zokuphila kunye nokukhetha ukutya kunokunyusa iibhaktheriya ezimbi kwaye kunciphise iibhaktheriya ezilungileyo kunye nempilo ngokubanzi.

 

 

11860 Vista Del Sol, Ste. Iindlela ezili-128 ezi-5 owonakalisa ngayo ithumbu lakho e-El Paso, eTexas

 

Nazi iindlela ezintlanu ezimangalisayo zokhetho olukhathaza isisu sakho:

Ukungadli Uluhlu olubanzi lokutya

Amathumbu ethu adlala indima ebalulekileyo kwimpilo yethu iphela. Xa sitya ukutya okugcweleyo konke, isisu sethu sonwabile; sinamandla amaninzi okugqiba nawuphi na umsebenzi ophoswe kuthi kwaye siyafumana izakha mzimba zethu zegut. Nangona kunjalo, kule minyaka ingamashumi idlulileyo, besikhangeleka kakhulu kukutya okusekwe ngenxa yoxinzelelo lwezoqoqosho lokunyuka kwemveliso yokutya. I-FOA yachaza ukuba "i-75 pesenti yokutya kwehlabathi kuveliswa kuphela kwizityalo ezili-12 kunye neentlobo zezilwanyana ezintlanu" kwaye oko kubi kakhulu kwizityalo zethu zamathumbu.

Apha eKlinikhi yoNyango kunye neKliniki yeChiropractic, sazisa abaguli bethu ngokubaluleka kokutya okunesondlo, ukutya okupheleleyo ukukhuthaza kungekuphela nje amathumbu asempilweni kodwa nengqondo esempilweni. Xa umzimba uziswa kwifayile ye- iintlobo ezahlukeneyo zokutya okugcweleyo (enomxholo ophezulu wefibre), isisu sethu siqala ukulungisa umonakalo wokutya okuqhubekisiweyo osenokuba sikuchithile ngaphakathi.

 

11860 Vista Del Sol, Ste. Iindlela ezili-128 ezi-5 owonakalisa ngayo ithumbu lakho e-El Paso, eTexas

Ukusetyenziswa okungafanelekanga kwe-Prebiotic

Prebiotics ziintsinga ekungafunekiyo ukuba zetyiswe kwaye zinokudlula emathunjini ethu. Oko kunokubonakala ngathi yinkcitho, nangona kunjalo, i-prebiotics ikhuthaza iibacteria enobuhlobo ukuba ikhulele ezingubeni zethu. Nasiphi na isiqhamo esine-fiber ephezulu enje ngeeapile sinokunceda ekukhuleni siluncedo Iintsholongwane ezinjengeBifidobacteria.

Nangona kunjalo, xa ungayihoyi i-prebiotic kukutya kwakho, ukuyo eyonakalisa impilo yakho yokugaya ukutya. Ngaphandle kwentsholongwane, inkqubo yethu yokugaya ukutya iyacothisa ukukhula kunye nokwahlukana kweentaka zethu. Ke ukuze ube intsholongwane esempilweni Uphuhliso, kufuneka udibanise ukutya okuzele zizitya zombini kunye neentsinga zokutya ekutyeni kwakho. Ukutya okubandakanyiweyo kolu luhlu zii-oats, amandongomane, i-anyanisi, iigalikhi, iilekese, iiaparagus, iibhanana, iipere, amantshontsho kunye neembotyi.

Ukunamathela kukutya okuphezulu kwefiber kunokuba ngumceli mngeni nangona kunjalo, kukho ukhetho lokuthatha i-prebiotic supplements. Ukuba unayo i-allergen yokutya okanye iimvakalelo zokutya kuko nakuphi na ukutya okucebileyo okuphezulu kwefayibha, ukuthatha izongezelelo zonyango prebiotic inganceda ukukhulisa i-Bifidobacterium kunye ne-Faecalibacterium kwi-gut yakho kwaye ibe luncedo kwimpilo yakho ngaphandle kongaphumeleli.

 

Ukusetyenziswa kotywala kakhulu

Wonke umntu omdala uyabunandipha utywala kanye ngamaxesha athile. Ewe, sesinye seziselo ezikuncedayo ukuba uphumle kancinci emva kosuku olude, nangona kunjalo, ubuninzi bako bunokukhokelela ekusebenziseni kakubi utywala kunye nokuba likhoboka. Ngaba ubusazi ukuba ukusela utywala obuninzi akulunganga Intliziyo yakho, isibindi kunye nengqondo; ngaloo ndlela kubuhlungu impilo yakho yesisu kwaye kukunikeza idysbiosis?

Isifundo esisodwa yathi, izinxila ezine-dysbiosis zinemidi ephantsi ye-Bacteroidetes kunye nobuninzi beProteobacteria. Abo babengengawo amanxila abazange bachatshazelwe luphononongo.

Nangona kunjalo; kukho iindaba ezimnandi zokuzisikela umda kwisiselo esinxilisayo kwaye ukuba kunokuba luncedo kwiintsholongwane zakho ze-gut. Ukuba umodareyitha ngokufanelekileyo ubeka i-wayini ebomvu ngokufanelekileyo, polyphenols ewayini kunokunceda izibonelelo zakho zesisu. Ke, yonwabela iglasi ye wayini ngexesha elithile njengepilisi encinci engafanele ithathelwe ingqalelo.

Ukungalali ngokwaneleyo

Kwinqaku elinye elidlulileyo, besithetha ngendlela yokufikelela kwi ukulala kamnandi ebusuku ngokusebenzisa amayeza. Xa sifumana ukungalali ngokwaneleyo ngobomi bethu bobuchwephesha, oko kusichaphazela neengxaki zempilo ezahlukeneyo, kubandakanya isifo sentliziyo kwaye ukunyanya. Kwi Ucwaningo lwe-2016, abaphandi bafumanise ifuthe lokuncitshiswa kokulala kwexesha elifutshane kwi-gut micobiota emva kweentsuku ezimbini.

Xa umzimba wethu ungafumani iiyure ezisi-8 zokulala ezicetyiswayo, amathumbu ethu athatha umthwalo omkhulu njengoko siziva sidangele kwaye sidiniwe. Ke, ukuze siqinisekise ukuba wethu gut microbiome uya kukhathalelwa, sincoma ukuba ucime izixhobo zakho zombane ubuncinane imizuzu engama-30 phambi kokuba ulungele ukuhlala phantsi ebusuku. Cima zonke izibane, kwaye ungaseli naluphi na ulwelo ubuncinci kwiiyure ezimbini phambi kokulala, vala amehlo akho kwaye uthathe umoya onzulu kwimo yokucamngca, kwaye uphumle njengoko usiya kwidolophu eleleyo.

 

 

Umthambo ongafanelekanga

Ngokuphila kwethu okukhawulezileyo kunye nemisebenzi enoxinzelelo, kunzima ukufumana ixesha lokuzilolonga. Kodwa xa ngenene sifumana ixesha lokuzilolonga, ayipheleli nje ekuziveni kamnandi iingqondo zethu; kodwa umzimba wethu kunye namathumbu aziva kamnandi ngokunjalo. Nangona kunjalo, izinto zihlala zivela xa sikwindlela yokwenza umthambo kwaye kufuneka sitsibe imithambo ngokupheleleyo. Iyenzeka kuthi sonke kwaye kunzima ukuqhubeka apho besiyeke khona xa besizama ukuzilolonga.

Xa singazilolongi amatyeli aliqela evekini, imizimba yethu ithatha umthwalo omkhulu kuthi njengoko besisiya sisiba nobunzima. uxinzelelo yindlela ephezulu kakhulu, kwaye sinayo i-a ithuba eliphezulu ngokufumana isifo esinganyangekiyo. Xa oku kwenzeka Apha eklinikhi, sizabalazela ukwazisa abaguli bethu ngokubaluleka kokuzilolonga kunye nokuba ayitshintshi nje impilo yabo kodwa iyatshintsha imeko yabo ngokupheleleyo.

Nangona kunjalo, musa ukwenza umthambo onzima apho uya kuzenzakalisa. Qala ngokuzilolonga okuphantsi kwaye uyakhe njengoko usiya kuba i-flora yakho yamathumbu iya kukubulela ngayo.

Njengokugqibela, apha ku-Injury Medical sifuna ukukugcina unolwazi malunga nesondlo kunye neendlela zokukunceda ukuphucula izigulo zakho ngale mimangaliso ye-5. Kodwa ukukufundisa ngento enokuba iyonakalisa isisu sakho. Ngala mazwi othusayo kunye notshintsho elincinci kubomi bakho bemihla ngemihla, isisu sakho siya kukubulela ngokutsala ixesha elide.

 


 

Izibonelelo zeNCBI

Ngobu bungqina obuvela kuphando lwe-2016 yophando, inkqubo yomzimba yokuzikhusela ibalulekile ekuthinteleni iintlobo ngeentlobo zezifo kwaye idla ngokuba negalelo kukuphazamiseka kwemetabolism. Nangona kunjalo, inokunceda ekuboneleleni nenjongo yonyango xa kujongwa ukudumba kwenkqubo yokunganyangeki kwe-insulin. Ngaphezu koko, ukugonywa kwamathumbu okuguquguqukayo kuye kwadityaniswa notshintsho kwi-gut microbiota, umsebenzi wokuthintelwa kwamathumbu, iiseli ze-immune ezihlala emathunjini, kunye nokuchasana ne-antigens engena kwi-gastrointestinal, okanye i-GI, inkqubo. Nangona oku bekukholelwa ngaphambili ukuba kuphakamisa ingozi yezigulo ze-esophageal kubandakanya, usulelo lwe-pathogenic kunye nokudumba okungapheliyo, okunokuthi ekugqibeleni kukhokelele kwimicimbi yezempilo engapheliyo.

 

 

ImiSebenzi yeMidi-Dimensional yeeConone zeCetone

ImiSebenzi yeMidi-Dimensional yeeConone zeCetone

Imizimba yeKetone yenziwa sisibindi kwaye isetyenziswa njengomthombo wamandla xa i-glucose ingafumaneki lula emzimbeni womntu. Izidumbu ezimbini eziphambili ze-ketone ziyi-acetoacetate (i-AcAc) kunye ne-3-beta-hydroxybutyrate (3HB), ngelixa i-acetone yinto yesithathu kwaye incinci kakhulu, i-ketone body. IiKetones zihlala zikhona egazini kwaye amanqanaba azo anda ngexesha lokuzila ukutya kunye nokuzilolonga ixesha elide.�Ketogenesis yinkqubo ye-biochemical apho iilwanyana zivelisa izidumbu ze-ketone ngokuphuhla kwama-acid acids kunye ne-ketogenic amino acid.

Izidumbu ze-Ketone zenziwe ngokubanzi kwi i-mitochondria yeeseli zesibindi. I-Ketogenesis iyenzeka xa kunamazinga e-glucose aphantsi egazini, ngokukodwa emva kwezinye izityalo ze-carbohydrates stores, ezifana ne-glycogen, ziphelile. Le ndlela iyakwenzeka kwakhona xa kukho inani elaneleyo le-insulin. Ukuveliswa kwamagumbi e-ketone ekugqibeleni kuqaliswe ukwenza amandla atholakalayo agcinwe emzimbeni womntu njenge-fatty acids. I-Ketogenesis ivela kwi-mitochondria apho ilawulwa ngokuzimeleyo.

Abstract

I-ketone body metabolism yiyona node ephambili kwi-homeostasis yomzimba. Kule ngongoma, sixoxa ngendlela ietononi eziqhuba ngayo iindidi ezixubileyo zokucwangcisa ukulungelelanisa ukusebenza komzimba kunye nokusebenza komzimba ngokungafaniyo kwezondlo kunye nokukhusela ekuvukeleni nokulimala kwiinkqubo ezininzi zeenkonzo. Ngokuqhelekileyo kubonwa njengemigweba yezinto ezinomsocolo kuphela ekungqinisweni kwinqumbo ye-carbohydrate, ukuqwalaselwa kwangoko kubonakalisa ukubaluleka kwamagumbi e-ketone njengendlela ebalulekileyo yokuxilisa kunye nabalindi beempawu xa i-carbohydrates ininzi. Ukuzalisekisa kwakhona imifanekiso yonyango eyaziwayo yezifo zesistim se-nervous, iindima eziza kuba yimizimba ye-ketone emdlalweni, sele ikhethileyo inxaxheba kwintliziyo kunye nesibindi, ivula iindlela zokwelapha ezinxulumene nokugqithisa nesifo se-cardiovascular. Iingxabano kwi-ketone metabolism kunye nokubonakaliswa zixutyushwa ukudibanisa imfundiso yeklasi kunye nokuqwalaselwa kwangoku.

intshayelelo

Imizimba yeKetone yenye yezona zinto zibalulekileyo zomthombo wamafutha kuzo zonke iindawo zobomi, i-eukarya, ibhaktheriya, kunye ne-archaea (Aneja et al., 2002; Cahill GF Jr, 2006; Krishnakumar et al., 2008). I-Ketone umzimba wemetabolism ebantwini iye yaxhatshazwa ukuba ifuthe ingqondo ngexesha leepisodic lokunqongophala kwezondlo. Imizimba ye-ketone idityaniswe neendlela ezibalulekileyo zesondlo esanyisayo ezifana ne-?-oxidation (FAO), umjikelo we-tricarboxylic acid (TCA), i-gluconeogenesis, de novo lipogenesis (DNL), kunye ne-biosynthesis ye-sterols. Kwizilwanyana ezanyisayo, imizimba ye-ketone iveliswa kakhulu esibindini ukusuka kwi-FAO-derived acetyl-CoA, kwaye ithuthelwa kwizicubu ze-extrahepatic ze-terminal oxidation. Le physiology ibonelela ngesinye isibaso esongezwa ngamaxesha amafutshane okuzila ukutya, oko kwandisa ukufumaneka kwe-acid enamafutha kunye nokunciphisa ukufumaneka kwe-carbohydrate (Cahill GF Jr, 2006; McGarry and Foster, 1980; Robinson and Williamson, 1980). I-Ketone body oxidation iba ligalelo elibalulekileyo kumandla apheleleyo we-mammalian metabolism ngaphakathi kwezicubu ze-extrahepatic kwiindawo ezininzi ze-physiological, kubandakanywa ukuzila ukutya, indlala, ixesha lokuzala, emva kokuzivocavoca, ukukhulelwa, kunye nokubambelela kwi-carbohydrate ephantsi yokutya. Ukujikeleza i-ketone body concentrations kubantu abadala abasempilweni ngokuqhelekileyo ibonisa i-circadian oscillations phakathi kwe-100�250 �M, ukunyuka ukuya kwi ~ 1 mM emva kokuzivocavoca ixesha elide okanye i-24h yokuzila ukutya, kwaye inokuqokelela ukuya kwi-20 mM kwiimeko ze-pathological ezifana ne-diabetes ketoacidosis. Cahill GF Jr, 2006; Johnson et al., 1969b; Koeslag et al., 1980; Robinson and Williamson, 1980; Wildenhoff et al., 1974). Isibindi somntu sivelisa ukuya kuthi ga kwi-300 g yemizimba ye-ketone ngosuku (i-Balasse kunye ne-Fery, ngo-1989), enegalelo phakathi kwe-5-20% yenkcitho yamandla iyonke kwiindawo ezondlayo, ezizila ukutya, kunye nendlala (Balasse et al., 1978; Cox et al., 2016; Cox et al. al., XNUMX).

Izifundo zakutsha ngoku zibalaselise indima ebalulekileyo kwiimpawu ze-ketone kwi-mammalian cell metabolism, homeostasis, kunye nokubonakaliswa phantsi kweendawo ezahlukeneyo zezobugcisa kunye nezifo. Ngaphandle kokukhonza njengombane wamandla kwiimfucu ze-extrahepatic ezifana nobuchopho, intliziyo, okanye i-squelet muscular, izidumbu ze-ketone zidlala indima ebonakalayo njengokubonisa abalamlamli, abaqhubi beeprotheyini emva kokuguqulela (i-PTM), kunye nabaxhasi be-inflammation kunye nokuxinzezeleka kwengcinezelo. Kule ngongoma, sinika imibono yesibini kunye neyamhlanje yeendima ze-pleiotropic ze-ketone kunye ne-metabolism yazo.

Ubume be-Ketone Body Metabolism

Ireyithi ye-hepatic ketogenesis ilawulwa yi-orchestrated series of physiological and biochemical transformations of fat. Abalawuli abaphambili babandakanya i-lipolysis ye-fatty acids esuka kwi-triacylglycerols, ukuthuthwa ukuya kunye nokunqumla kwi-hepatocyte plasma membrane, ukuthuthwa kwi-mitochondria nge-carnitine palmitoyltransferase 1 (CPT1), i-? kwezi nkqubo, ikakhulu iglucagon kunye ne-insulin [ihlaziywe kwi (Arias et al., 1995; Ayte et al., 1993; Ehara et al., 2015; Ferre et al., 1983; Kahn et al., 2005; McGarry kunye noFoster) , 1980; Williamson et al., 1969)]. Ngokwesiqhelo i-ketogenesis ijongwa njengendlela echithekileyo, apho i-?-i-oxidation-derived acetyl-CoA idlula umsebenzi we-citrate synthase kunye/okanye ukufumaneka kwe-oxaloacetate ukwenzela ukujiyisa ukwenza i-citrate. Abaphakathi kwekhabhoni ezintathu babonisa umsebenzi we-anti-ketogenic, mhlawumbi ngenxa yokukwazi ukwandisa i-oxaloacetate pool yokusetyenziswa kwe-acetyl-CoA, kodwa i-hepatic acetyl-CoA yoxinaniso yodwa ayiqinisi izinga le-ketogenic (Foster, 1967; Rawat kunye neMenahan, 1975; Williamson kunye nabanye, ngo-1969). Ukulawulwa kwe-ketogenesis nge-hormonal, i-transcriptal, kunye neziganeko zasemva kokuguqulelwa kunye zixhasa ingcamango yokuba iindlela ze-molecular ukuba i-fine-tune ketogenic rate zihlala zingaqondwa ngokupheleleyo (jonga i-Regulation ye-HMGCS2 kunye ne-SCOT / OXCT1).

I-Ketogenesis yenzeka ngokuyinhloko kwi-matrix ye-mitochondrial ye-hepatic kumazinga ahambelana ne-oxidation yamafutha. Emva kokuthuthwa kwamatyathanga e-acyl ngaphaya kwe-membrane ye-mitochondrial kunye ne-?-oxidation, i-isoform ye-mitochondrial ye-3-hydroxymethylglutaryl-CoA synthase (HMGCS2) idala i-fate eyenza i-acetoacetyl-CoA (i-AcAc-CoA) kunye ne-acetyl-CoA ye-acetyl-CoA (Umfanekiso 1A). I-HMG-CoA lyase (HMGCL) iqhekeza i-HMG-CoA ukukhulula i-acetyl-CoA kunye ne-acetoacetate (i-AcAc), kwaye le yokugqibela iyancitshiswa ibe yi-d-?-hydroxybutyrate (d-?OHB) nge-phosphatidylcholine-dependent mitochondrial d-?OHB dehydrogenase (? I-BDH1) kwi-NAD +/NADH-idibene kufuphi ne-equilibrium reaction (Bock and Fleischer, 1975; LEHNINGER et al., 1960). I-equilibrium ye-BDH1 rhoqo ithanda ukuveliswa kwe-d-?OHB, kodwa umlinganiselo we-AcAc/d-?OHB imizimba yeketone ihambelana ngokuthe ngqo ne-mitochondrial NAD+/NADH ratio, kwaye ngaloo ndlela umsebenzi we-BDH1 oxidoreductase ulungelelanisa amandla e-mitochondrial redox (Krebs et al., 1969; 1967; Williamson et al., 1929). I-AcAc ingaphinda izenze ngokuzenzekelayo i-decarboxylate kwi-acetone (Pedersen, 7), umthombo wevumba elimnandi kubantu abaphethwe yi-ketoacidosis (oko kukuthi, imizimba ye-serum ketone iyonke> ~3.6 mM; AcAc pKa 4.7, ?OHB pKa 1). Iindlela apho imizimba ye-ketone ithuthwa ngayo kwi-membrane yangaphakathi ye-mitochondrial ayaziwa, kodwa i-AcAc/d-?OHB ikhutshwa kwiiseli ngokusebenzisa abathuthi be-monocarboxylate (kwizilwanyana ezincancisayo, i-MCT 2 kunye ne-16, eyaziwa ngokuba yi-solute carrier 1A amalungu osapho 7 kunye I-2011) kwaye ihanjiswe kwi-circulation kwii-tissue ze-extrahepatic ze-oxidation ye-terminal (Cotter et al., 2012; Halestrap noWilson, 2012; Halestrap, 2012; Hugo et al., 1940). Ukugxininiswa kwemizimba ye-ketone ejikelezayo iphezulu kunezo zikhoyo kwizicubu ze-extrahepatic (i-Harrison kunye ne-Long, i-1) ebonisa ukuba imizimba ye-ketone ihanjiswa phantsi kwe-concentration gradient. Ukulahleka komsebenzi wenguqu kwi-MCTXNUMX kuhambelana nokuvela ngokukhawuleza kwe-ketoacidosis, ebonisa indima ebalulekileyo ekungenisweni komzimba we-ketone.

� Ngaphandle kokuphazamiseka okunokwenzeka kwemizimba ye-ketone kwi-non-oxidative fates (jonga i-Non-oxidative metabolic fates yemizimba ye-ketone), i-hepatocytes ayinakho ukukwazi ukugaya imizimba ye-ketone abayivelisayo. Imizimba ye-Ketone eyenziwe nge-novo ngesibindi (i) i-catabolized kwi-mitochondria ye-extrahepatic tissues ukuya kwi-acetyl-CoA, ekhoyo kumjikelezo we-TCA we-terminal oxidation (Umfanekiso 1A), (ii) iguqulelwe kwi-lipogenesis okanye i-sterol synthesis pathways (ii) Umzobo 1B), okanye (iii) ukhutshelwe kumchamo. Njengolunye uphethiloli olunamandla, imizimba ye-ketone ixutywe ngokukhawuleza entliziyweni, imisipha yethambo kunye nengqondo (Balasse kunye neFery, 1989; Bentourkia et al., 2009; Owen et al., 1967; Reichard et al., 1974; Sultan, 1988 ). Extrahepatic mitochondrial BDH1 catalyzes the reaction first of ?OHB oxidation, iyiguqulela ngasemva AcAc (LEHNINGER et al., 1960; Sandermann et al., 1986). I-cytoplasmic d-?OHB-dehydrogenase (BDH2) ene-20% kuphela yolandelelwano lwesazisi kwi-BDH1 ine-Km ephakamileyo yemizimba ye-ketone, kwaye idlala indima kwi-homeostasis yensimbi (Davuluri et al., 2016; Guo et al., 2006) . Kwi-matrix ye-mitochondrial ye-extrahepatic, i-AcAc ivuliwe kwi-AcAc-CoA ngokutshintshiselana kwe-CoA-moiety esuka kwi-succinyl-CoA kwi-reaction catalyzed by unique mammalian CoA transferase, succinyl-CoA: 3-oxoacid-CoA transferase (SCOT, CoA transferase; ifakwe ngekhowudi yi-OXCT1), ngokusabela kolungelelwaniso olusondeleyo. Amandla asimahla akhutshwe yi-hydrolysis ye-AcAc-CoA inkulu kune-succinyl-CoA, ithanda ukwenziwa kwe-AcAc. Ngaloo ndlela i-ketone body oxidative flux ivela ngenxa yesenzo sobunzima: ukunikezelwa okukhulu kwe-AcAc kunye nokusetyenziswa ngokukhawuleza kwe-acetyl-CoA ngokusebenzisa i-citrate synthase i-AcAc-CoA (+ succinate) ukwakheka kwe-SCOT. Ngokucacileyo, ngokuchasene ne-glucose (i-hexokinase) kunye ne-fatty acids (i-acyl-CoA synthetases), ukusetyenziswa kwemizimba ye-ketone (i-SCOT) kwifom ye-oxidizable ayifuni utyalo-mali lwe-ATP. I-AcAc-CoA thiolase reaction ebuyiselwa umva [i-catalyzed yiyo nayiphi na i-thiolases ye-mitochondrial efakwe kwi-ACAA2 (i-encoding enzyme eyaziwa ngokuba yi-T1 okanye i-CT), i-ACAT1 (i-encoding T2), i-HADHA, okanye i-HADHB] ivelisa iimolekyuli ezimbini ze-acetyl-CoA, abangena kumjikelezo we-TCA (uHersh noJencks, i-1967; iStern et al., 1956; Williamson et al., 1971). Ngexesha le-ketotic states (oko kukuthi, i-serum ketones> 500 �M), imizimba ye-ketone iba negalelo elikhulu kwinkcitho yamandla-kwaye isetyenziswa kwiithishu ngokukhawuleza de kuthathwe okanye kufakwe i-oxidation yenzeke (Balasse et al., 1978; Balasse and Fery, 1989, 1987) ; Edmond et al., 1987). Inxalenye encinci kakhulu yemizimba ye-ketone ephuma kwisibindi inokulinganiswa ngokukhawuleza kumchamo, kwaye ukusetyenziswa kunye namazinga okubuyisela kwakhona yizintso zilingana noxinzelelo lokujikeleza (Goldstein, 1980; Robinson noWilliamson, 1). Ngexesha lee-ketotic states kakhulu (> 2013 mM kwi-plasma), i-ketonuria isebenza njengengxelo ye-semi-quantitative ye-ketosis, nangona ininzi yovavanyo lweklinikhi yemizimba ye-ketone yomchamo ibona i-AcAc kodwa kungekhona? OHB (Klocker et al., XNUMX).

Iziseko ze-Ketogenic kunye neMpembelelo yazo kwi-Hepatocyte Metabolism

I-substrates ze-Ketogenic ziquka i-fatty acids kunye nama-amino acids (umzobo 1B). I-catabolism yama-amino acids, ngakumbi i-leucine, ivelisa nge-4% yamalungu e-ketone kwi-post-absorption state (Thomas et al., 1982). Ngaloo ndlela i-acetyl-CoA i-substrate echibini yokuvelisa i-ketone imizimba iphuma kwi-acid acids, kuba ngexesha lamazwe anikezela nge-carbohydrates supply, i-pyruvate ingena kumjikelezo we-TCA we-hepatic ngokuyinhloko nge-aplerosis, oko kukuthi, i-ATP-dependence carboxylation kwi-oxaloacetate (OAA), okanye i-malate (I-MAL), kwaye ayikho i-decarboxylation ye-oxidative kwi-acetyl-CoA (i-Jeoung et al., I-2012; i-Magnusson et al., I-1991; i-Merritt et al., I-2011). Ngesibindi, i-glucose kunye ne-pyruvate inika isandla ngokungathandeki kwi ketogenesis, nangona i-pyruvate decarboxylation kwi-acetyl-CoA iphezulu (Jeoung et al., 2012).

I-Acetyl-CoA iqhubeka neendidi ezininzi ezibandakanya i-hepatic intermediary metabolism ngaphaya kwesizukulwane se-ATP ngokusebenzisa i-oxidation yesigxina (kwakhona ubone Ukuhlanganiswa kwe-ketone body metabolism, ukuguqulwa kwesithuba sokuguqulela emva, kunye ne-physiological cell). I-Acetyl-CoA isebenza ngokugqithiseleyo (i) i-pyruvate carboxylase (i-PC), ngaloo ndlela isebenzise indlela yokulawulwa kwemigodi eyenza i-intlerotic yokungena kweemetabolites kumjikelezo we-TCA (i-Owen et al., I-2002; i-Scrutton ne-Utter, i-1967) kunye (ii) ne-pyruvate dehydrogenase i-kinase, e-phosphorylates kwaye inqanda i-pyruvate dehydrogenase (PDH) (Cooper et al., i-1975), ngokuqinisekileyo ukuphucula ukuhamba kwe-pyruvate kumjikelezo we-TCA nge-aplerosis. Ngaphezu koko, i-cytoplasmic acetyl-CoA, enezixhobo ezinokuguqula i-acetyl-CoA kwi-metabolite ezithuthwayo, inqanda i-oxidation e-fatty acid: i-acetyl-CoA carboxylase (i-ACC) iguqula ukuguqulwa kwe-acetyl-CoA kwi-malonyl-CoA, i-lipogenic substrate kunye ne-allosteric inhibitor ye-CPT1 ye-mitochondrial [yahlaziywa ku (Kahn et al., 2005; McGarry noFoster, 1980)]. Ngaloo ndlela, i-mitochondrial-acetyl-CoA echibini ilawula kwaye ilawulwa yindlela ye-ketogenesis, eyenza iindawo eziphambili ze-metabolism eziphambili ze-hepatic.

Iifom zeMetabolic yeeMetoneli zeMetone

Ixesha eliphambili le-ketoni ezifumaneka kwi-fox-derivated oxidation. Nangona kunjalo, i-AcAc ingahanjiswa ngaphandle kwe-mitochondria kwaye isetyenziswe kwiindlela ze-anabolic ngokuguqulwa kwi-AcAc-CoA ngempendulo exhomekeke kwi-ATP eyenziwa yi-cytoplasmic acetoacetyl-CoA synthetase (AACS, Fig. 1B). Le ndlela isebenza ngexesha lokuphuculwa kwengqondo kunye nokukhwabanisa imilenze (Morris, 2005; uRobinson noWillion, 1978; Ohgami et al., 2003). I-AACS iphinda ichazwe kakhulu kwiisitives, kwaye i-osteoclasts esebenzayo (Aguilo et al., 2010; Yamasaki et al., 2016). I-Cytoplasmic AcAc-CoA inokuthi ibhekiswe yi-cytosolic HMGCS1 kwi-bioreynthesis ye-sterol, okanye ifakwe kwi-thietyses ye-acetyl-CoA (ACAA1 kunye ne-ACAT2), i-carboxylated kwi-malonyl-CoA, kwaye ifake isandla kwi-synthesis acid acids (i-Bergstrom et i-1984; u-Edmond, i-1974; i-Endemann et al., i-1982; i-Geelen et al., i-1983; i-Webber ne-Edmond, i-1977).

Nangona ukubaluleka kwe-physiological kuseza kusekwa, ii-ketones zinokusebenza njenge-anabolic substrates nakwisibindi. Kwimixholo yovavanyo eyenziweyo, i-AcAc inokuba negalelo ukuya kuthi ga kwisiqingatha se-lipid esandula ukwenziwa, kwaye ukuya kuthi ga kwi-75% ye-cholesterol entsha eyenziweyo (Endemann et al., 1982; Geelen et al., 1983; Freed et al., 1988). Ngenxa yokuba i-AcAc ivela kwi-oxidation ye-hepatic engaphelelanga, ukukwazi kwe-AcAc ukufaka isandla kwi-lipogenesis kwi-vivo kuya kuthetha ukukhwela ibhayisekile engenamsebenzi, apho ii-ketones ezithathwe ngamanqatha zingasetyenziselwa ukuveliswa kwe-lipid, ingcamango ebaluleke kakhulu kwi-physiological ifuna ukuqinisekiswa kovavanyo, kodwa inokusebenza. iindima eziguqukayo okanye ezingalunganga (uSolinas et al., 2015). I-AcAc ibonelela nge-cholesterogenesis, kunye ne-AACS ephantsi ye-Km-AcAc (~50 �M) ithanda ukusebenza kwe-AcAc nakwilizwe elondliwe (Bergstrom et al., 1984). Indima eguquguqukayo ye-cytoplasmic ketone metabolism iye yacetyiswa kwi-primary mouse embryonic neurons kunye ne-3T3-L1 ephuma kwi-adipocytes, njengoko i-AACS i-knockdown idityanisiwe yokwahlula kohlobo ngalunye lweseli (Hasegawa et al., 2012a; Hasegawa et al., 2012b). I-Knockdown ye-AACS kwiimpuku kwi-vivo iyancipha i-cholesterol ye-serum (Hasegawa et al., 2012c). I-SREBP-2, i-master transcriptional regulator ye-cholesterol biosynthesis, kunye ne-peroxisome proliferator activated receptor (PPAR)-? zi-activators ze-AACS zombhalo, kwaye zilawula ukubhaliswa kwayo ngexesha lophuhliso lwe-neurite kunye nesibindi (Aguilo et al., 2010; Hasegawa et al., 2012c). Kuthatyathwe kunye, i-cytoplasmic ketone body metabolism inokubaluleka kwiimeko ezikhethiweyo okanye kwimbali yendalo yesifo, kodwa akwanelanga ukulahla imizimba ye-ketone ephuma kwisibindi, njengoko i-hyperketonemia enkulu yenzeke kwisimo sokukhubazeka okukhethiweyo kweyona nto iphambili ye-oxidative ngokulahleka kokuguqulwa komsebenzi. ukuya eSCOT (Berry et al., 2001; Cotter et al., 2011).

Ummiselo we-HMGCS2 kunye ne-SCOT / OXCT1

Ukungafani kwe-mitochondrial kwi-gene encoding i-cytosolic HMGCS kwenzeka ekuqaleni kwe-vertebrate evolution ngenxa yentswelo yokuxhasa i-ketogenesis ye-hepatic kwiintlobo ezineengqondo eziphezulu ukuya kubunzima bomzimba (Boukaftane et al., 1994; iCunnane ne-Crawford, i-2003). I-HMGCS2 iinguqulelo ebantwini kubangela ukulahleka kwe-hypoglycemia (hypnetotic hypoglycemia) (Pitt et al., 2015; Thompson et al., 1997). I-Robust HMGCS2 ibinzana kuphela, kwaye i-epitlium ye-colonic, kunye ne-enzymatic activity iboniswe ngeendlela ezahlukeneyo (iMascaro et al., 1995; uMcGarry kunye noFoster, 1980; uRobinson noWillionon, i-1980). Nangona iimeko ezipheleleyo zezinto eziphilayo zichaphazela ukuba i-HMGCS2 idinga ukuhlengahlengiswa, ukubonakaliswa kwayo kunye / okanye umsebenzi ulawulwa ngexesha lokuzalwa emva kokubeleka, ukuguga, isifo sikashukela, indlala okanye ukungena kokutya kwe-ketogenic (i-Balasse ne-Fery, i-1989; i-Cahill GF Jr, i-2006 ; Girard et al., 1992; Hegardt, 1999; iSatapati et al., 2012; iSengupta et al., 2010). Kwi-fetus, i-methylation ye-5� ye-flanking ye-Hmgcs2 gene ihambelana ngokungafaniyo kunye nombhalo wayo, kwaye iguqulwa ngokuyinxenye emva kokuzalwa (Arias et al., 1995; Ayte et al., 1993; Ehara et al., 2015; Ferre et al., 1983; Ayte et al., XNUMX; Ehara et al., XNUMX; Ferre et al. ., XNUMX). Ngokufanayo, i-Bdh1 eneempembelelo ibonisa ipateni yokubonakalisa intuthuko, ikhula ukusuka ekuzaleni ukuya ekutheni, kwaye iqhutywe yindlela yokutya ye-ketogenic kwi-fibroblast yokukhula (FGF) -XXMUMX-dependence (Badman et al., 21; Zhang et al., 2007 ). I-Ketogenesis kwizilwanyana ezincelisayo ziphendula kakhulu kwi-insulin kunye ne-glucagon, ikhutshwe kwaye ivuselelwe, ngokulandelanayo (McGarry noFoster, 1977). I-insulin igxotha i-lipolysis ye-adipose yamathambo, ngaloo ndlela iyanqanda i-ketogenesis ye-substrate yayo, ngoxa i-glucagon ikwandisa i-ketogenic flux ngokuchaphazela ngqo isibindi (Hegardt, 1999). I-Hmgcs2 yoshicilelo ishukunyiswa yi-forkhead ye-transcriptional factor FOXA2, inqatshelwe nge-insulin-phosphatidylinositol-3-kinase / Akt, kwaye ibangelwa yi-glucagon-cAMP-p300 ukubonisa (Arias et al., 1995; Hegardt, 1999; , 1990; Thumelin et al., 1993; von Meyenn et al., 2013; Wolfrum et al., 2004; Wolfrum et al., 2003). PPAR? (Rodriguez et al., 1994) kunye nethagethi yayo, i-FGF21 (u-Badman et al., 2007) iphinda ifake i-Hmgcs2 ukubhalwa kwesibindi ngexesha lendlala okanye ulawulo lokutya kwe-ketogenic (Badman et al., 2007; Inagaki et al., 2007) ). Ukuqaliswa kwePPAR? inokuthi yenzeke ngaphambi kokuba utshintsho olusuka kwi-fetal ukuya kwi-physiology ye-neonatal, ngelixa i-FGF21 isebenze inokuthi ithandeke kwixesha lokuqala le-neonatal nge-?OHB-mediated inhibition ye-histone deacetylase (HDAC) -3 (Rando et al., 2016). i-mTORC1 (ithagethi ye-mammalian ye-rapamycin complex 1) ixhomekeke kwisithintelo se-PPAR? umsebenzi wokubhaliweyo kwakhona umlawuli ophambili we-Hmgcs2 gene expression (Sengupta et al., 2010), kunye nesibindi PER2, i-master circadian oscillator, ilawula ngokungathanga ngqo intetho ye-Hmgcs2 (Chavan et al., 2016). Ukuqwalaselwa kwamva nje kubonisa ukuba i-interleukin-6 ye-tumor ye-extrahepatic iphazamisa i-ketogenesis nge-PPAR? ukucinezelwa (Flint et al., 2016).

Umsebenzi we-HMGCS2 umsebenzi we-enzyme ulawulwa ngePTM ezininzi. I-HMGCS2 i-serine phosphorylation yandise umsebenzi wayo kwi-vitro (iGrimsrud et al., 2012). Umsebenzi we-HMGCS2 unqatshelwe ngokulandelana kwe-succinyl-CoA kunye ne-lysine asele ekutshintsheni (Arias et al., 1995; Hegardt, 1999; iLowe neTubbs, i1985; i-1990; i-RN et al., I-2013; iRed et al. 1975; Thumelin et al., 1993). Ukuphumelela kwe-HMGCS2, i-HMGCL kunye ne-BDH1 i-lysine i-litoine i-mitochondria ye-hepatic iinjongo ze-NAD + exhomekeke ku-deacylase sirtuin 5 (SIRT5) (Rardin et al., 2013). Umsebenzi we-HMGCS2 uphinde ukhutshwe yi-SIRT3 ye-diacetylation ye-lysine, kwaye kungenzeka ukuba i-crosstalk phakathi kwe-acetylation kunye ne-succinylation ilawula umsebenzi we-HMGCS2 (Rardin et al., 2013; Shimazu et al., 2013). Nangona ubuchule bee-PTM zilawula i-HMGCS2 Km kunye ne-Vmax, ukuguqulwa kwale PTM akukabikwa ngokukodwa kwaye akuzange kuqinisekiswe njengabaqhubi bemishini ye ketogenesis kwi vivo.

I-SCOT iboniswa kuzo zonke iiseli zamammalia eziphethe i-mitochondria, ngaphandle kweeypatocytes. Ukubaluleka komsebenzi we-SCOT kunye ne-ketolysis kuboniswe kwiimfucuza ze-SCOT-KO, ezibonakalise ukubulala okufanako ngenxa ye-hypoglycemia ye-hyperketonemic ngaphakathi kwe-48h emva kokuzalwa (iCotter et al., 2011). Ukulahleka kweTissue-ye-SCOT kwi-neurons okanye kwi-myocytes yamathambo kukhuthaza ukungonakali kwamandla ngexesha lendlala kodwa ayibulali (Cotter et al., 2013b). Kubantu, ukulahlekelwa kwe-SCOT kudala kwasekuqaleni ebomini kunye ne-ketoacidosis enzima, kubangele ukunyuka, ukuhlanza kunye ne-coma (i-Berry et al., I-2001; iFukao et al., I-2000; i-Kassovska-Bratinova et al., I-1996; i-Niezen-Koning et al. , I-1997; i-Saudubray et al., I-1987; i-Snyderman et al., I-1998; iTildon kunye ne-Cornblath, i-1972). Incinci encinci iyaziwa kwinqanaba leselula malunga ne-SCOT yegciwane kunye neeprotheyini zolawulo. I-Oxct1 imbonakalo ye-MRNA kunye neprotheni ye-SCOT kunye nomsebenzi wancipha kwiindawo ze-ketotic, mhlawumbi ngeendlela ezixhomekeke kwi-PPAR (iFenselau ne-Wallis, i1974; iFenselau kunye neWallis, i1976; i-1986; i-1991; i-2001; i-Turko et al ., 2010; Wentz et al., 1). Kwi-ketoacidosis yesifo sikashukela, ukungafani phakathi kwe-ketogenesis ye-hepatic kunye ne-oxidation ye-extrahepatic iyancipha ngakumbi ngumsebenzi we-SCOT. Ukugqithisa ngokugqithisileyo kwe-insulin-independent independent carporator (GLUT2 / SLC1A1) kwi-cardiomyocytes inqanda intetho ye-Oxct2009 kunye ne-downregulates i-ketoni ye-oxidation yesigxina kwi-non-ketotic state (Yan et al., 1). Esibindi, i-Oxct122 mRNA ininzi ixhaswa yi-microRNA-3 kunye ne-histone methylation i-H27K3me2011 ebonakalayo ngexesha lokutshintsha ukusuka kwintsholongwane ukuya kwixesha lokubeletha (Thorrez et al., 1). Nangona kunjalo, ukuxhaswa kwegama le-Oxct1 ye-hepatic kwixesha lokubeleka lixhomekeke ekuphumeni kwe-Oxct1-ebonisa i-hematopoietic progenitors esesibindi, kunokuba ilahlekelwe yintetho ye-Oxct1 esele ikhona kwi-hepatocytes eyahlukana. Enyanisweni, ukubonakaliswa kweprotheni ye-Oxct2008 mRNA kunye ne-SCOT kuma-hepatocytes ahluke kakhulu (Orii et al., XNUMX).

I-SCOT ikwalawulwa ziiPTMs. I-enzyme i-hyper-acetylated kwiingqondo ze-SIRT3 KO iigundane, ezibonisa kwakhona ukunciphisa imveliso ye-AcAc exhomekeke kwi-acetyl-CoA (Dittenhafer-Reed et al., 2015). I-nitrate engeyiyo-enzymatic yeentsalela ze-tyrosine ze-SCOT iphinda igxininise umsebenzi wayo, oye waxelwa kwiintliziyo zeemodeli ezahlukeneyo zesifo seswekile (Marcondes et al., 2001; Turko et al., 2001; Wang et al., 2010a). Ngokwahlukileyo, i-tryptophan residue nitration yongeza umsebenzi weSCOT (Br�g�re et al., 2010; Rebrin et al., 2007). Iinkqubo zeemolekyuli zentsalela-i-nitration ethile okanye i-de-nitration eyilelwe ukumodareyitha umsebenzi we-SCOT inokubakho kwaye ifuna ukucaciswa.

Iingxabano kwi-Extrahepatic Ketogenesis

Kwizilwanyana ezincancisayo i-primary organ ketogenic isibindi, kwaye kuphela i-hepatocytes kunye neeseli ze-gut epithelial zivakalisa kakhulu i-isoform ye-mitochondrial ye-HMGCS2 (Cotter et al., 2013a; Cotter et al., 2014; McGarry kunye noFoster, 1980; Robinson, Robinson noWilliamson) . I-Anaerobic bacterial fermentation ye-polysaccharides eyinkimbinkimbi ivelisa i-butyrate, efunnwe yi-colonocytes kwizilwanyana ezincelisayo kwi-terminal oxidation okanye i-ketogenesis (i-Cherbuy et al., 1980), enokuthi idlale indima ekuhlukeni kwekholonocyte (Wang et al., 1995). Ngaphandle kweeseli ze-epithelial ze-gut kunye ne-hepatocytes, i-HMGCS2016 iphantse ingekho phantse kuzo zonke ezinye iiseli ze-mammalian, kodwa ithemba le-ketogenesis ye-extrahepatic liye laphakanyiswa kwiiseli ze-tumor, i-astrocytes yenkqubo ye-nervous central, intso, i-pancreatic ? iiseli, i-retinal pigment epithelium (RPE), kunye nakwi-skeletal muscle (Adijanto et al., 2; Avogaro et al., 2014; El Azzouny et al., 1992; Grabacka et al., 2016; Kang et al., 2016) ; Le Foll et al., 2015; Nonaka et al., 2014; Takagi et al., 2016a; Thevenet et al., 2016; Zhang et al., 2016). I-Ectopic HMGCS2011 iye yabonwa kwizicubu ezingenayo amandla e-ketogenic (Cook et al., 2; Wentz et al., 2016), kunye ne-HMGCS2010 ibonisa imisebenzi ye-ketogenesis-ezimeleyo yokukhanya kwenyanga, kubandakanywa phakathi kwe-nucleus yeseli (Chen et al. , 2; Kostiuk et al., 2016; Meertens et al., 2010).

Naziphi na izicubu ze-extrahepatic ezikhupha imizimba ye-ketone nazo ziyakwazi ukuqokelela imizimba ye-ketone ngokusebenzisa iindlela ezizimeleyo ze-HMGCS2 (umzobo 2A). Nangona kunjalo, akukho zicubu ze-extrahepatic apho ugxininiso lomzimba we-ketone oluzinzileyo ludlula oko kumjikelezo (Cotter et al., 2011; Cotter et al., 2013b; Harrison and Long, 1940), egxininisa ukuba imizimba ye-ketone ihanjiswa phantsi. i-concentration gradient ngokusebenzisa iindlela ezixhomekeke kwi-MCT1/2. Enye indlela ye-extrahepatic ketogenesis ebonakalayo inokubonakalisa ukukhubazeka okuhambelana ne-ketone oxidation. Iinkcazo ezongezelelweyo ezinokubakho ziwela ngaphakathi kwendawo yokubunjwa komzimba we-ketone. Okokuqala, i-de novo ketogenesis inokuthi yenzeke ngomsebenzi oguqulwayo we-enzymatic we-thiolase kunye ne-SCOT (i-Weidemann kunye ne-Krebs, i-1969). Xa i-concentration ye-acetyl-CoA iphezulu kakhulu, iimpendulo eziqhelekileyo ezinoxanduva lwe-AcAc oxidation zisebenza kwicala elingasemva (GOLDMAN, 1954). Indlela yesibini yenzeka xa ?-i-oxidation-derived intermediates iqokelelana ngenxa yebhottleneck yomjikelo we-TCA, i-AcAc-CoA iguqulelwa kwi-l-?OHB-CoA nge-reaction catalyzed by mitochondrial 3-hydroxyacyl-CoA dehydrogenase, kwaye ngokuqhubekayo nge-3-hydroxybutyryl I-CoA deacylase ukuya kwi-l-?OHB, engaqondakaliyo nge-mass spectrometry okanye i-resonance spectroscopy evela kwi-physiological enantiomer d-?OHB (Reed kunye ne-Ozand, 1980). I-l-?OHB inokwahlulwa ngokwe-chromatographically okanye nge-enzymatic ukusuka kwi-d-?OHB, kwaye ikhona kwizicubu ze-extrahepatic, kodwa kungekhona kwisibindi okanye igazi (Hsu et al., 2011). I-Hepatic ketogenesis ivelisa kuphela i-d-?OHB, ekuphela kwe-enantiomer eyi-BDH substrate (Ito et al., 1984; uLincoln et al., 1987; Reed no-Ozand, 1980; Scofield et al., 1982; Scofield et al., 1982). Indlela yesithathu ezimeleyo ye-HMGCS2 yenza i-d-?OHB ngokusebenzisa i-amino acid catabolism, ngakumbi leyo ye-leucine kunye ne-lysine. Indlela yesine ibonakala kuphela ngenxa yokuba ingenxa ye-artifact yokulebula kwaye ibizwa ngokuba yipseudoketogenesis. Le nto ibangelwa ukuguqulwa kwe-SCOT kunye ne-thiolase reactions, kwaye inokubangela ukugqithisa kwe-ketone body turnover ngenxa ye-isotopic dilution ye-ketone body tracer kwi-extrahepatic tissue (Des Rosiers et al., 1990; Fink et al., 1988) . Nangona kunjalo, i-pseudoketogenesis isenokungahoywa kwiimeko ezininzi (Bailey et al., 1990; Keller et al., 1978). I-schematic (Umfanekiso we-2A) ubonisa indlela eluncedo yokufaka isicelo ngelixa uqwalasela i-tissue ephakamileyo yoxinaniso lwe-ketones.

� Izintso mva nje zifumene ingqwalasela njengelungu elinokubakho ketogenic. Kuninzi lwamazwe, intso ngumthengi onayo imizimba yeketone ephuma kwisibindi, ikhupha okanye iphinda ikhuphe imizimba yeketone egazini, kwaye izintso aziyiyo i-net ketone body generator okanye i-concentrator (Robinson noWilliamson, 1980). Ababhali bophononongo lweklasi baphetha ukuba i-ketogenesis encinci ye-renal elinganisiweyo kwinkqubo yovavanyo eyenziweyo yayingahambelani ne-physiologically (Weidemann kunye ne-Krebs, i-1969). Kutshanje, i-renal ketogenesis ifakwe kwi-diabetic kunye ne-autophagy yokunqongophala kwemouse yeemodeli, kodwa kunokwenzeka ukuba i-multi-organ shifts kwi-homeostasis ye-metabolic iguqule i-ketone metabolism edibeneyo ngamagalelo kumalungu amaninzi (Takagi et al., 2016a; Takagi et al., 2016b; Zhang et al., 2011). Olunye upapasho lwakutsha nje lucebise i-renal ketogenesis njengendlela ekhuselayo yokulimala kwe-ischemia-reperfusion kwizintso (Tran et al., 2016). Ugxininiso lwemeko oluzinzileyo lwe-?OHB olusuka kwizicatshulwa zeethishu zezintso zeempuku luxelwe ku ~4�12 mM. Ukuvavanya ukuba ingaba oku kuyabambeka na, silinganise ?Ugxininiso lwe-OHB kwiincindi zentso ezisuka kwi-feed kunye ne-24h ezila ukudla iimpuku. ISerum ?Uxinzelelo lwe-OHB lonyukile ukusuka ~100 �M ukuya kwi-2 mM ngokuzila ukudla okuyi-24h (Umfanekiso 2B), ngelixa uzinzo lwezintso ?Uxinzelelo lwe-OHB lumalunga ne-100 �M kwimeko yokutya, kwaye kuphela yi-1 mM kwimo yokuzila ye-24h (Fig. 2C�E), imigqaliselo ehambelana nogxininiso olubalwe kwiminyaka engama-45 eyadlulayo (Hems and Brosnan, 1970). Kuhlala kunokwenzeka ukuba kwi-ketotic states, imizimba ye-ketone ephuma kwisibindi ingaba yi-renoprotective, kodwa ubungqina be-renal ketogenesis bufuna ukuxhaswa okungakumbi. Ubungqina obubambekayo obuxhasa i-ketogenesis ye-extrahepatic yangempela yaboniswa kwi-RPE (Adijanto et al., 2014). Olu tshintsho lwemetabolism lunomdla lwacetyiswa ukuba luvumele iiketone ezivela kwi-RPE ukuba zihambe ziye kwi-photoreceptor okanye kwiiseli ze-Mller glia, ezinokunceda ekuhlaziyweni kwecandelo langaphandle le-photoreceptor.

?OHB njengoMqondiso woMqondiso

Nangona zizityebi ngamandla, imizimba ye-ketone yenza i-provocative �non-canonical� yokubonakalisa indima kwi-homeostasis yeselula (Umfanekiso 3) (uNewman noVerdin, i-2014; uRojas-Morales et al., 2016). Umzekelo, ?I-OHB inqanda i-HDACs yeKlasi I, eyonyusa i-histone acetylation kwaye ngaloo ndlela ikhuthaze ukubonakaliswa kofuzo olunciphisa uxinzelelo lwe-oxidative (Shimazu et al., 2013). ?OHB ngokwayo i-histone covalent modifier kwiintsalela ze-lysine kwizibindi zokuzila ukutya okanye i-streptozotocin eyenzelwe iimpuku zesifo seswekile (Xie et al., 2016) (kwakhona jonga ngezantsi, Ukudityaniswa kwe-ketone yomzimba we-metabolism, ukuguqulwa kwe-post-translation, kunye ne-cell physiology, kunye Imizimba yeKetone, uxinzelelo lwe-oxidative, kunye ne-neuroprotection).

?I-OHB ikwasebenza ngokusebenzisa i-G-protein coupled receptors. Ngeendlela ezingacacanga zeemolekyuli, icinezela umsebenzi wenkqubo ye-nervous enovelwano kwaye inciphisa inkcitho yamandla iyonke kunye nesantya sentliziyo ngokunqanda umqondiso omfutshane we-fatty acid nge-G protein edibene ne-receptor 41 (GPR41) (Kimura et al., 2011). Enye yezona ziphumo zifundiswayo zokubonisa i-?OHB iqhubeka nge-GPR109A (ekwaziwa ngokuba yi-HCAR2), ilungu le-hydrocarboxylic acid GPCR sub-family echazwe kwizicubu ze-adipose (ezimhlophe kunye ne-brown) (Tunaru et al., 2003), kunye iiseli zomzimba (u-Ahmed et al., 2009). ?OHB kuphela kwe-endogenous ligand eyaziwayo ye-GPR109A receptor (EC50 ~770 �M) eyenziwe yasebenza ngu-d-?OHB, l-?OHB, kunye ne-butyrate, kodwa hayi i-AcAc (Taggart et al., 2005). Umyinge wogxininiso ophezulu we-GPR109A usebenze ufezekiswa ngokuthotyelwa kokutya kwe-ketogenic, indlala, okanye ngexesha le-ketoacidosis, ekhokelela ekuvinjweni kwe-adipose tissue lipolysis. Impembelelo ye-anti-lipolytic ye-GPR109A iqhubela phambili ngokuvinjelwa kwe-adenylyl cyclase kunye nokuncipha kwe-cAMP, inhibiting i-hormone ebucayi ye-triglyceride lipase (Ahmed et al., 2009; Tunaru et al., 2003). Oku kudala i-loop yengxelo engalunganga apho i-ketosis ibeka i-modulatory brake kwi-ketogenesis ngokunciphisa ukukhutshwa kwe-fatty acids engabonakaliyo kwi-adipocytes (u-Ahmed et al., 2009; Taggart et al., 2005), umphumo onokuthi ulungelelaniswe ngu idrive enovelwano evuselela i-lipolysis. I-Niacin (i-vitamin B3, i-nicotinic acid) inamandla (EC50 ~ 0.1 �M) ligand ye-GRP109A, isetyenziswe ngokufanelekileyo amashumi eminyaka ye-dyslipidemias (Benyo et al., 2005; Benyo et al., 2006; Fabbrini et al., 2010; Lukasova et al., 2011; Tunaru et al., 2003). Nangona i-niacin iphucula ukuthuthwa kwe-cholesterol eguqukayo kwi-macrophages kwaye inciphisa izilonda ze-atherosclerotic (Lukasova et al., 2011), iziphumo ze-?OHB kwizilonda ze-atherosclerotic zihlala zingaziwa. Nangona i-GPR109A i-receptor yenza iindima zokukhusela, kwaye unxibelelwano oluthakazelisayo lukhona phakathi kokusetyenziswa kwe-ketogenic yokutya kwi-stroke kunye nezifo ze-neurodeergenerative (Fu et al., 2015; Rahman et al., 2014), indima yokukhusela ye-?OHB nge-GPR109A ayizange iboniswe kwi-vivo .

Okokugqibela, i-?OHB inokuchaphazela ukuthanda ukutya kunye nokuhlutha. Uhlalutyo lwe-meta lwezifundo ezilinganisa imiphumo ye-ketogenic kunye nokutya okuphantsi kakhulu kwamandla kwagqiba ukuba abathathi-nxaxheba abasebenzisa ezi zidlo babonisa ukuhlutha okuphezulu, xa kuthelekiswa nokulawula ukutya (Gibson et al., 2015). Nangona kunjalo, ingcaciso ebambekayo malunga nesi siphumo zezongezelelweyo zemetabolism okanye iihomoni ezinokuguqula umdla wokutya. Umzekelo, iimpuku ezigcinwe kwi-rodent ketogenic diet zibonise ukunyuka kwenkcitho yamandla xa kuthelekiswa neempuku ezityiswayo ezilawulwayo, nangona i-caloric intake efanayo, kunye ne-leptin ejikelezayo okanye i-peptides elawula ukuziphatha kokutyisa ayizange iguqulwe (Kennedy et al., 2007). Phakathi kweendlela ezicetywayo ezicebisa ukuthotywa kokutya yi-?OHB ibandakanya zombini umqondiso kunye ne-oxidation (Laeger et al., 2010). I-Hepatocyte ecacileyo yokususwa kwe-circadian gene gene (Per2) kunye ne-chromatin immunoprecipitation studies ibonise ukuba i-PER2 isebenze ngokuthe ngqo i-Cpt1a gene, kwaye ilawula ngokungathanga ngqo i-Hmgcs2, ekhokelela kwi-ketosis ephazamisekileyo kwiigundane ze-Per2 (Chavan et al., 2016). Ezi mpuku zibonise ulindelo lokutya olonakalisayo, oluye lwabuyiselwa ngokuyinxenye lulawulo lwenkqubo ye-?OHB. Izifundo zexesha elizayo ziya kufuneka ukuba ziqinisekise inkqubo ye-nervous central njengendlela echanekileyo ye-?OHB ekujoliswe kuyo, kwaye ingaba i-ketone oxidation iyadingeka kwimiphumo ebonwayo, okanye ingaba enye indlela yokubonakalisa ibonakaliso ibandakanyeka. Abanye abaphandi baye bacela ukuba kunokwenzeka kwi-astrocyte-derived ketogenesis ngaphakathi kwe-hypothalamus ye-ventromedial njengomlawuli wokutya okutyayo, kodwa olu qwalaselo lwangaphambili luya kuzuza kwiimvavanyo ezisekelwe kwimfuza kunye ne-flux (Le Foll et al., 2014). Ubudlelwane phakathi kwe-ketosis kunye nokunqongophala kwezondlo kuhlala kunomdla kuba indlala kunye nokuhlutha zizinto ezibalulekileyo kwiinzame zokulahlekelwa ubunzima.

Ukuhlanganiswa kweMetabolism ye-Ketone Body, i-Post-Translation, kunye ne-Cell Physiology

Izidumbu ze-Ketone zinegalelo kumachibi ase-acetyl-CoA, i-intermediate ephambili ebonisa imisebenzi ebonakalayo kwi-cell metabolism (Pietrocola et al., 2015). Inxaxheba enye ye-acetyl-CoA kukuba isebenze njenge-substrate ye-acetylation, i-histone covalent-modified enzymatically-catalyised histone (Choudhary et al., 2014; Dutta et al., 2016; Fan et al., 2015; Menzies et al., 2016 ). Ininzi enkulu yeeprotheni zamamithachondrial ezinamandla, ezininzi zazo ezinokuthi zenzeke ngeendlela ezingekho ze-enzymatic, ziye zavela kwizifundo ze-proteomics (i-Dittenhafer-Reed et al., I2015; i-Rbert et al., I-2013 ; Shimazu et al., 2013). I-liysine deacetylases zisebenzisa i-zinc cofactor (umz., I-nucleocytosolic HDACs) okanye i-NAD + njenge-co-substrate (i-sirtuins, i-SIRTs) (i-Choudhary et al., I-2010; i-Menzies et al., I-2014). I-acetylproteome isebenza njengombini kunye nomphathi we-aletyl-CoA yamanzi, njengokuba izixhobo zomzimba kunye nezofuzo ziza kubangela ukuhlukahluka kwe-acetylation engekho-enzymatic (Weinert et al., 2016). Njengoko i-metabolites ye-intracellular isebenza njengabalawuli be-lysine ase-acetylation asele, kubalulekile ukuqwalasela indima yamalungu e-ketone, ubuninzi bawo bunamandla.

?OHB sisilungisi se-epigenetic ngokusebenzisa ubuncinci iindlela ezimbini. Ukunyuka kwe-?Amanqanaba e-OHB abangelwa ukuzila ukutya, ukuthintela i-caloric, ulawulo oluthe ngqo okanye ukuzivocavoca ixesha elide kuvusa inhibition ye-HDAC okanye i-histone acetyltransferase activation (Marosi et al., 2016; Sleiman et al., 2016) okanye uxinzelelo lwe-oxidative (Shimazu et al.), . ?I-OHB inhibition ye-HDAC2013 inokulawula i-physiology ye-metabolic physiology (uRando et al., 3). Ngokuzimeleyo, ?OHB ngokwayo iguqula ngokuthe ngqo iintsalela ze-histone lysine (Xie et al., 2016). Ukuzila ukutya ixesha elide, okanye i-steptozotocin-induced diabetic ketoacidosis yandise i-histone ?-hydroxybutyrylation. Nangona inani le-lysine ?-hydroxybutyrylation kunye neendawo ze-acetylation zazithelekiseka, i-stoichiometrically enkulu i-histone ?-hydroxybutyrylation kune-acetylation yabonwa. Ufuzo olwahlukileyo lwachatshazelwa yi-histone lysine ?-hydroxybutyrylation, ngokuchasene ne-acetylation okanye i-methylation, ebonisa imisebenzi eyahlukeneyo yeselula. Nokuba i-?-hydroxybutyrylation izenzekela okanye i-enzymatic akwaziwa, kodwa yandisa uluhlu lweendlela ngokusebenzisa imizimba yeketone echaphazela ngokuguquguqukayo ukukhutshelwa.

Iziganeko ezibalulekileyo zokuhlengahlengiswa kweeseli ngexesha lokuthintelwa kwekhalori kunye nokunciphisa izondlo zingaxutywa kwi-SIRT3- kunye ne-SIRT5-exhomekeke kwi-mitochondrial deacetylation kunye ne-desuccinylation, ngokulandelanayo, ukulawula iiprotheni ze-ketogenic kunye ne-ketolytic kwinqanaba le-post-translation kwisibindi kunye nezicubu ze-extrahepatic (i-Dittenha-Reed e-Reed. 2015; Hebert et al., 2013; Rardin et al., 2013; Shimazu et al., 2010). Nangona uthelekiso lwe-stoichiometric lweendawo ezithathiweyo aludibanisi ngokuthe ngqo kwiinguqu kwi-metabolic flux, i-acetylation ye-mitochondrial iguquguqukayo kwaye inokuqhutywa yi-acetyl-CoA yoxinaniso okanye i-mitochondrial pH, kunokuba i-enzymatic acetyltransferases (Wagner no-Payne, i-2013). Ukuba i-SIRT3 kunye ne-SIRT5 imodareyitha imisebenzi ye-ketone umzimba we-metabolizing enzymes iphakamisa umbuzo wendima ehambelanayo yee-ketones ekufakeni i-acetylproteome, i-succinylproteome, kunye nezinye iithagethi zeselula ezinamandla. Ewe, njengoko ukwahluka kwe-ketogenesis kubonakalisa ukugxila kwe-NAD +, ukuveliswa kwe-ketone kunye nobuninzi kunokulawula umsebenzi we-sirtuin, ngaloo ndlela kuphembelela amachibi e-acetyl-CoA/succinyl-CoA ewonke, i-acylproteome, kwaye ke i-mitochondrial kunye ne-cell physiology. ?-i-hydroxybutyrylation yeentsalela ze-enzyme ye-lysine inokongeza omnye umaleko kwi-reprogramming yeselula. Kwizicubu ze-extrahepatic, i-ketone body oxidation inokuvuselela utshintsho olufanayo kwi-cell homeostasis. Ngelixa i-compartmentation yamachibi e-acetyl-CoA ilawulwa kakhulu kwaye ilungelelanisa uluhlu olubanzi lweenguqu zeselula, ukukwazi kwemizimba ye-ketone ukubumba ngokuthe ngqo zombini i-mitochondrial kunye ne-cytoplasmic acetyl-CoA i-concentrations ifuna ukucaciswa (Chen et al., 2012; Corbet et al., 2016; Pougovkina et al., 2014; Schwer et al., 2009; Wellen noThompson, 2012). Ngenxa yokuba i-acetyl-CoA igxininisekile ilawulwa ngokuqinileyo, kwaye i-acetyl-CoA i-membrane impermeant, kubalulekile ukuqwalasela iindlela zomqhubi zokulungelelanisa i-acetyl-CoA homeostasis, kubandakanywa amazinga emveliso kunye ne-oxidation ye-terminal kumjikelo we-TCA, ukuguqulwa kwimizimba ye-ketone, i-mitochondrial. i-efflux nge-carnitine acetyltransferase (i-CrAT), okanye i-acetyl-CoA ukuthumela ngaphandle kwe-cytosol emva kokuguqulwa kwi-citrate kunye nokukhululwa nge-ATP citrate lyase (ACLY). Iindima eziphambili zezi ndlela zokugqibela kwi-cell acetylproteome kunye ne-homeostasis zifuna ukuqonda okufanayo kweendima ze-ketogenesis kunye ne-ketone oxidation (Das et al., 2015; McDonnell et al., 2016; Moussaieff et al., 2015; Overmyer et al. 2015; Seiler et al., 2014; Seiler et al., 2015; Wellen et al., 2009; Wellen and Thompson, 2012). Ubuchwephesha obuguquguqukayo kwi-metabolomics kunye ne-acylproteomics ekusekweni kweemodeli eziguquguqukayo zofuzo ziya kufuneka ukuba zichaze iithagethi kunye neziphumo.

Iimpendulo ze-Anti-and Pro-Inflammatory Responses to Ketone Bodies

I-Ketosis kunye nemizimba ye-ketone imodareyitha ukuvuvukala kunye nokusebenza kweeseli zomzimba, kodwa iindlela ezahlukeneyo kunye nezingahambelaniyo ziye zacetywa. Ukunciphisa izondlo ixesha elide kunciphisa ukuvuvukala (Youm et al., 2015), kodwa i-ketosis engapheliyo yohlobo lwe-1 yeswekile yimeko ye-pro-inflammatory (Jain et al., 2002; Kanikarla-Marie noJain, 2015; Kurepa et al., 2012) ). Iindima ze-Mechanism-based signaling roles ze-?OHB ekudumbeni zivela ngenxa yokuba iiseli ezininzi ze-immune system, kuquka i-macrophages okanye i-monocytes, zivakalisa kakhulu i-GPR109A. Ngelixa i-?OHB isebenzisa impendulo echasene nokuvuvukala (Fu et al., 2014; Gambhir et al., 2012; Rahman et al., 2014; Youm et al., 2015), ukugxilwa okuphezulu kwemizimba ye-ketone, ngakumbi i-AcAc, qalisa impendulo ye-pro-inflammatory (uJain et al., 2002; Kanikarla-Marie noJain, 2015; Kurepa et al., 2012).

Iindima ezichasene nokuvuvukala kwe-GPR109A ligands kwi-atherosclerosis, ukukhuluphala, isifo sesibindi esivuthayo, isifo se-neurological, kunye nomhlaza ziye zahlaziywa (Graff et al., 2016). Inkcazo ye-GPR109A yongezwa kwiiseli ze-RPE zeemodeli zesifo sikashukela, izigulane zesifo seswekile (Gambhir et al., 2012), kunye ne-microglia ngexesha le-neurodegeneration (Fu et al., 2014). Iimpembelelo ezichasayo ze-?OHB ziphuculwe yi-GPR109A yokugqithisa kakhulu kwiiseli ze-RPE, kwaye ichithwe yi-pharmacological inhibition okanye i-genetic knockout ye-GPR109A (Gambhir et al., 2012). ?OHB kunye ne-nicotinic acid engaphandle (i-Taggart et al., 2005), zombini zinikela iziphumo ezichasayo kwi-TNF? okanye ukuvuvukala okubangelwa yi-LPS ngokunciphisa amanqanaba eprotheyini ye-pro-inflammatory (iNOS, COX-2), okanye i-cytokines efihliweyo (TNF?, IL-1?, IL-6, CCL2 / MCP-1), ngokuyinxalenye ngokuthintela i-NF -?B translocation (Fu et al., 2014; Gambhir et al., 2012). ?OHB inciphisa uxinzelelo lwe-ER kunye ne-NLRP3 inflammasome, isebenze impendulo yoxinzelelo lwe-antioxidative (Bae et al., 2016; Youm et al., 2015). Nangona kunjalo, kwi-neurodeergenerative inflammation, i-GPR109A-exhomekeke ?Ukukhuselwa kwe-OHB-mediated ayibandakanyi abalamli abavuthayo njenge-MAPK indlela yokubonisa indlela (umz., ERK, JNK, p38) (Fu et al., 2014), kodwa inokufuna i-PGD1 exhomekeke kwi-COX-2 imveliso (Rahman et al., 2014). Kuyathakazelisa ukuba i-macrophage GPR109A iyadingeka ukuba isebenzise umphumo we-neuroprotective kwimodeli ye-ischemic stroke (Rahman et al., 2014), kodwa ukukwazi kwe-?OHB ukuvimbela i-NLRP3 inflammasome kwi-bone macrophages ephuma kwi-macrophages yi-GPR109A ezimeleyo (Youm et al. ., 2015). Nangona uphando oluninzi ludibanisa? I-OHB kwimiphumo echasayo, i-? I-Anti- versus pro-inflammatory effects of ?OHB ke ngoko inokuxhomekeka kudidi lweeseli, ?OHB concentration, ixesha lokuba sesichengeni, kunye nobukho okanye ukungabikho kweemodyuli ezisebenzisanayo.

Ngokungafaniyo ne-?OHB, i-AcAc inokuvula umqondiso obonisa ukudumba. I-AcAc ephakamileyo, ngokukodwa nge-concentration ye-glucose ephezulu, iqinisa ukulimala kweeseli ze-endothelial ngokusebenzisa i-NADPH oxidase / i-oxidative stress dependent mechanism (Kanikarla-Marie noJain, 2015). Uxinzelelo oluphezulu lwe-AcAc kwintambo ye-umbilical yoomama abanesifo seswekile yadityaniswa nesantya esiphezulu se-protein oxidation kunye ne-MCP-1 yoxinaniso (Kurepa et al., 2012). I-AcAc ephezulu kwizigulane ezinesifo seswekile yayinxulunyaniswa ne-TNF? intetho (i-Jain et al., 2002), kunye ne-AcAc, kodwa hayi ., 1).

Iziganeko ze-Ketone ezixhomekeke kumzimba we-ketone zivame ukuqhutyelwa kuphela ngokugxininiswa komzimba we-ketone (> 5 mM), kwaye kwimeko yezifundo ezininzi ezidibanisa i-ketones kwi-pro- okanye i-anti-inflammatory effects, ngokusebenzisa iindlela ezingacacanga. Ukongezelela, ngenxa yemiphumo ephikisanayo ye-?OHB ngokumelene ne-AcAc ekudumbeni, kunye nokukwazi kwe-AcAc /? I-OHB ngokwemilinganiselo eyahluka-hlukeneyo, kunye nokwahluka koxinaniso olongezelekayo [umzekelo, (Saito et al., 2016)]. Ekugqibeleni, i-AcAc inokuthengwa ngokuthengisa kuphela njengetyuwa ye-lithium okanye njenge-ethyl ester efuna isiseko se-hydrolysis ngaphambi kokusetyenziswa. I-Lithium cation ngokuzimeleyo ibangela ukuhanjiswa kwe-signal cascades (Manji et al., 1995), kunye ne-AcAc anion i-labile. Okokugqibela, izifundo zisebenzisa i-racemic d/l-?OHB zinokubhidaniswa, njengoko kuphela i-d-?OHB stereoisomer inokudityaniswa kwi-AcAc, kodwa i-d-?OHB kunye ne-l-?OHB inomqondiso ngamnye nge-GPR109A, inhibit i-NLRP3 inflammasome, kwaye zisebenza njenge-lipogenic substrates.

Amathunjini e-Ketone, uxinzelelo lwe-Oxidative, kunye ne-neuroprotection

Uxinzelelo lwe-oxidative luchazwa njengemeko apho i-ROS ibonakaliswe ngokugqithisileyo, ngenxa yemveliso egqithisileyo kunye / okanye ukupheliswa kokuphazamiseka. I-Antioxidant kunye ne-oxidative yokunciphisa uxinzelelo lweendima zemizimba ye-ketone zichazwe ngokubanzi zombini kwi-vitro nakwi-vivo, ngakumbi kumxholo we-neuroprotection. Njengoko uninzi lwe-neurons lungenzi ngokufanelekileyo i-phosphates yamandla aphezulu ukusuka kwi-acids enamafutha-kodwa i-oxidize imizimba ye-ketone xa i-carbohydrates inqabile, iziphumo ze-neuroprotective zemizimba ye-ketone zibaluleke kakhulu (Cahill GF Jr, 2006; u-Edmond et al., 1987; Yang kunye nabanye, ngo-1987). Kwiimodeli zoxinzelelo lwe-oxidative, i-BDH1 induction kunye nokunyanzeliswa kwe-SCOT iphakamisa ukuba i-ketone body metabolism inokuphinda ihlelwe kwakhona ukuze igcine ukubonakaliswa kweeseli ezahlukeneyo, amandla e-redox, okanye iimfuno ze-metabolic (Nagao et al., 2016; Tieu et al., 2003).

Imizimba yeKetone inciphisa amabakala omonakalo weselula, ukulimala, ukufa kunye ne-apoptosis ephantsi kwi-neurons kunye ne-cardiomyocytes (iHaces et al., 2008; Maalouf et al., 2007; Nagao et al., 2016; Tieu et al., 2003). Iindlela eziceliweyo ziyahluka kwaye azisoloko zihambelana noxinaniso. Uxinzelelo lwe-millimolar ephantsi ye-(d okanye i-l)-?OHB ihlamba i-ROS (i-hydroxyl anion), ngelixa i-AcAc icoca iintlobo ezininzi ze-ROS, kodwa kuphela kugxininiso oludlula uluhlu lwe-physiological (IC50 20�67 mM) (Haces et al., 2008) . Ngokuchaseneyo, impembelelo enenzuzo phezu kwekhonkco lothutho lwe-electron's redox enokubakho yindlela eqhele ukunxulunyaniswa ne-d-?OHB. Ngelixa zonke imizimba emithathu ye-ketone (d/l-?OHB kunye ne-AcAc) yanciphisa ukufa kweeseli ze-neuronal kunye nokuqokelela kwe-ROS okubangelwa yi-chemical inhibition ye-glycolysis, kuphela i-d-?OHB kunye ne-AcAc ithintele ukuhla kwe-neuronal ATP. Ngokwahlukileyo, kwi-hypoglycemic kwimodeli ye-vivo, (d okanye i-l) -? ; Tieu et al., 2008). Izifundo ze-vivo zeempuku zondliwe ukutya kwe-ketogenic (i-2007% kcal fat kunye ne-2016% yeprotheni) ibonise ukuhluka kwe-neuroanatomical ye-antioxidant umthamo (Ziegler et al., 2009), apho utshintsho olunzulu lwabonwa kwi-hippocampus, ngokunyuka kwe-glutathione peroxidase kunye nenani lilonke. amandla antioxidant.

Ukutya kwe-Ketogenic, i-ketone esters (kwakhona ubone Ukusetyenziswa koNyango lokutya kwe-ketogenic kunye nemizimba ye-ketone yangaphandle), okanye ? isifo sikaParkinson (Tieu et al., 2014); inkqubo ye-nervous central ne-oxygen toxicity seizure (D'Agostino et al., 2003); i-epileptic spasms (Yum et al., 2013); i-encephalomyopathy ye-mitochondrial, i-lactic acidosis kunye ne-stroke-like (MELAS) i-episodes syndrome (uFrey et al., 2015) kunye nesifo se-Alzheimer (uCunnane noCrawford, i-2016; i-Yin et al., 2003). Ngokwahlukileyo, ingxelo yamva nje ibonise ubungqina be-histopathological yenkqubela phambili ye-neurodeergenerative ngokutya kwe-ketogenic kwimodeli yemouse ye-transgenic yokulungiswa kwe-DNA ye-mitochondrial engaqhelekanga, ngaphandle kokunyuka kwe-mitochondrial biogenesis kunye ne-antioxidant signatures (Lauritzen et al., 2016). Ezinye iingxelo eziphikisanayo zibonisa ukuba ukuvezwa kwimizimba ye-ketone ephezulu kubangela uxinzelelo lwe-oxidative. I-high ?I-OHB okanye i-AcAc doses eyenza i-nitric oxide secretion, i-lipid peroxidation, ukunciphisa ukubonakaliswa kwe-SOD, i-glutathione peroxidase kunye ne-catalase kwi-hepatocytes yethole, ngelixa i-hepatocytes ye-rat i-MAPK indlela yokungeniswa kweendlela yayibizwa ngokuba yi-AcAc kodwa kungekhona? ; Shi et al., 2016; Shi et al., 2004).

Kuthatyathwe kunye, iingxelo ezininzi zidibanisa? I-OHB ekunciphiseni uxinzelelo lwe-oxidative, njengoko ulawulo lwayo luvimbela i-ROS / imveliso ye-superoxide, ikhusela i-lipid peroxidation kunye ne-protein oxidation, inyusa amanqanaba eprotheni ye-antioxidant, kunye nokuphucula ukuphefumula kwe-mitochondrial kunye nokuveliswa kwe-ATP (Abdelmegeed et al., 2004; Haces et al., 2008; Jain et al., 1998; Jain et al., 2002; Kanikarla-Marie kunye noJain, 2015; Maalouf et al., 2007; Maalouf kunye noRho, 2008; Marosi et al., Tieu2016, 2003 et al., 2016; Yin et al., 2003; Ziegler et al., 2002). Ngelixa i-AcAc idityaniswe ngokuthe ngqo ngakumbi kune-?OHB kunye nokungeniswa koxinzelelo lwe-oxidative, ezi ziphumo azisoloko zichithwa ngokulula kwiimpendulo ezilindelekileyo zokuvuvukala (uJain et al., 2015; Kanikarla-Marie noJain, 2016; Kanikarla-Marie kunye UJain, ngo-2016). Ngaphezu koko, kubalulekile ukuqwalasela ukuba inzuzo ebonakalayo ye-antioxidative eyenziwa yi-pleiotropic ye-ketogenic yokutya ayinako ukudluliselwa yimizimba ye-ketone ngokwazo, kwaye i-neuroprotection enikezelwa yimizimba ye-ketone ayinakubangelwa ngokupheleleyo kuxinzelelo lwe-oxidative. Ngokomzekelo ngexesha lokunciphisa i-glucose, kwimodeli yokunciphisa i-glucose kwi-cortical neurons, i-? d-?OHB induces kwakhona i-canonical antioxidant proteins FOXO3a, SOD, MnSOD, kunye ne-catalase, ngokubonakalayo nge-HDAC inhibition (Nagao et al., 2016; Shimazu et al., 2013).

Izifo ezingenalo utywala (ii-NAFLD) kunye neCetone Body Metabolism

Ukutyeba okunxulunyaniswa ne-NAFLD kunye ne-nonalcoholic steatohepatitis (NASH) zezona zinto zibangela isifo sesibindi kumazwe aseNtshona (i-Rinella kunye ne-Sanyal, 2016), kunye nokusilela kwesibindi okubangelwa yi-NASH sesinye sezizathu eziqhelekileyo zokufakwa kwesibindi. Ngelixa ukugcinwa okungaphezulu kwe-triacylglycerols kwii-hepatocytes> i-5% yesisindo sesibindi (i-NAFL) iyodwa ayibangeli ukusebenza kwesibindi okuguqulwayo, ukuqhubela phambili kwi-NAFLD ebantwini kuhambelana nenkqubo ye-insulin yokumelana kunye nokwanda komngcipheko wohlobo lweswekile 2, kwaye kunokuba negalelo kwi-pathogenesis isifo sentliziyo kunye nesifo sezintso esinganyangekiyo (UFabbrini et al., 2009; UTargher et al., 2010; UTargher kunye noByrne, 2013). Iinkqubo ze-pathogenic ze-NAFLD kunye ne-NASH aziqondwa kakuhle kodwa zibandakanya ukungahambi kakuhle kwesifo se-hepatocyte metabolism, i-hepatocyte autophagy kunye noxinzelelo lwe-endoplasmic reticulum, ukusebenza kweeseli zomzimba, i-adipose ukudumba kwezicubu, kunye nabalamli abanoxinano lwenkqubo (UFabbrini et al., 2009; Masuoka kunye neChalasani, 2013 ; UTargher et al., 2010; UYang et al., 2010). Ukutshintshwa kwe-carbohydrate, lipid, kunye ne-amino acid metabolism kunye negalelo kukutyeba, isifo seswekile, kunye ne-NAFLD ebantwini nakwimodeli yezinto eziphilayo [ezihlaziyiweyo ku (UFarese et al., 2012; iLin kunye neAccili, 2011; INewgard, 2012; USamuel no UShulman, 2012; Ilanga kunye noLazaro, 2013)]. Ngelixa i-hepatocyte yokungaqhelekanga kwi-cytoplasmic lipid metabolism ibonwa rhoqo kwi-NAFLD (UFabbrini et al., 2010b), indima ye-mitochondrial metabolism, elawula ukulahlwa kwamafutha kwe-oxidative ayicacanga ncam kwi-NAFLD pathogenesis. Ukungaqheleki kwemetabolondrial metabolism kwenzeka kwaye kunegalelo kwi-NAFLD / NASH pathogenesis (IHyotylainen et al., 2016; Serviddio et al., 2011; Serviddio et al., 2008; Wei et al., 2008). Kukho ngokubanzi (Felig et al., 1974; Iozzo et al., 2010; Koliaki et al., 2015; Satapati et al., 2015; Satapati et al., 2012; Ilanga et al., 2011) kodwa ayifani ( UKoliaki noRoden, 2013; Perry et al., 2016; Rector et al., 2010) isivumelwano sokuba, ngaphambi kokuphuhliswa kwe-NASH ye-bona fide, i-hepatic mitochondrial oxidation, ngakumbi i-oxydation ye-fat, yongezwa ekutyebeni kakhulu, , kunye neNAFLD. Kusenokwenzeka ukuba njengoko i-NAFLD iqhubeka, amandla e-oxidative heterogenity, nditsho naphakathi kwemitochondria nganye, iyavela, kwaye ekugqibeleni umsebenzi we-oxidative uye ungasebenzi (UKoliaki et al., 2015; Ngqonyela et al., 2010; ISatapati et al., 2008; ISatapati okqhubekayo. ., 2012).

I-Ketogenesis isoloko isetyenziswa njenge-proxy ye-hepatic fat oxidation. Ukukhubazeka kwe-ketogenesis kuvela njengoko i-NAFLD iqhubela phambili kwiimodeli zezilwanyana, kwaye mhlawumbi kubantu. Ngeendlela ezingachazwanga ngokupheleleyo, i-hyperinsulinemia icinezela i-ketogenesis, enokuba negalelo kwi-hypoketonemia xa kuthelekiswa nolawulo oluthambileyo (Bergman et al., 2007; Bickerton et al., 2008; Satapati et al., 2012; Soeters et al., 2009; 2011; , 2005; Vice et al., 2015). Nangona kunjalo, ukukwazi ukujikeleza i-ketone body concentrations ukuqikelela i-NAFLD iphikisana (M'nnist et al., 2001; Sanyal et al., 2012). Iindlela eziqinileyo zobungakanani bemagnethi ye-resonance spectroscopic kwiimodeli zezilwanyana zibonakalise ukwanda kwereyithi ye-ketone yokunganyangeki kwe-insulin, kodwa amaxabiso anciphileyo abonakala ngoxhathiso oluqatha lwe-insulin (Satapati et al., 2010; Sunny et al., 2008). Kubantu abatyebe ngokugqithiseleyo abanesibindi esinamafutha, izinga le-ketogenic liqhelekileyo (Bickerton et al., 2011; Sunny et al., 4), kwaye ngoko, amazinga e-ketogenesis ayancipha ngokumalunga nokunyuka kwe-fatty acid load ngaphakathi kwe-hepatocytes. Ngenxa yoko, i-acetyl-CoA ephuma kwi-oxidation inokubhekiswa kwi-terminal oxidation kumjikelo we-TCA, ukwandisa i-terminal oxidation, i-phosphoenolpyruvate-driven gluconeogenesis nge-anaplerosis/cataplerosis, kunye noxinzelelo lwe-oxidative. I-Acetyl-CoA nayo inokuthi ihambe ngaphandle kwe-mitochondria njenge-citrate, i-precursor substrate ye-lipogenesis (Umfanekiso we-2015) (i-Satapati et al., 2012; Satapati et al., 2015; Solinas et al., 2012). Ngelixa i-ketogenesis iba yimpendulo encinci kwi-insulin okanye ukuzila ukutya ngokukhuluphala ixesha elide (i-Satapati et al., 1), iindlela ezisezantsi kunye neziphumo ezisezantsi zoku zihlala zingaqondwa ngokupheleleyo. Ubungqina bamva nje bubonisa ukuba i-mTORC2016 icinezela i-ketogenesis ngendlela enokuthi ibe phantsi kwe-insulin yokubonisa (Kucejova et al., 1), ehambelana nokuqwalaselwa kwe-mTORC2 inqanda i-PPAR?-mediated Hmgcs2010 induction (Sengupta et al., 2). kwakhona ubone ukuLawulwa kwe-HMGCS1 kunye ne-SCOT / OXCTXNUMX).

Ukuqwalaselwa kwangaphambili kwiqela lethu kubonisa imiphumo emibi ye-hepatic yokungaphumeleli kwe-ketogenic (Cotter et al., 2014). Ukuvavanya i-hypothesis ephazamisa i-ketogenesis, nakwi-carbohydrate-replete kwaye ngoko ke "non-ketogenic" ithi, igalelo kwi-metabolism ye-glucose engaqhelekanga kwaye ibangele i-steatohepatitis, senze imodeli yempuku yokungaphumeleli kwe-ketogenic ngokulawulwa kwe-oligonucleotides ye-antisense (ASO) ejoliswe kuyo. Hmgcs2. Ukulahleka kwe-HMGCS2 kwimicebe yabantu abadala ephantsi kwamafutha aphantsi kubangele i-hyperglycemia ethambileyo kwaye inyuse ngokuphawulekayo imveliso yamakhulu ee-metabolites ze-hepatic, i-suite ephakamisa ngamandla i-lipogenesis activation. Ukutya okunamafutha aphezulu kwiigundane kunye ne-ketogenesis eyaneleyo kubangele ukulimala okukhulu kwe-hepatocyte kunye nokuvuvukala. Ezi ziphumo zixhasa i-hypotheses ephakathi ukuba (i) i-ketogenesis ayiyona indlela yokuphuphuma kwe-passive kodwa kunokuba i-node eguquguqukayo kwi-hepatic kunye ne-homeostasis edibeneyo ye-physiological, kunye (ii) nolwandiso olulumkileyo lwe-ketogenic ukunciphisa i-NAFLD / NASH kunye ne-disordered hepatic glucose metabolism ifanele ukuphononongwa. .

Ngaba i-ketogenesis ephazamisekileyo inokuba negalelo njani kumonzakalo we-hepatic kunye nokuguqulwa kwe-glucose homeostasis? Ingqwalasela yokuqala kukuba ngaba umtyholi unqongophala kwe-ketogenic flux, okanye i-ketones ngokwabo. Ingxelo yakutshanje ibonisa ukuba imizimba ye-ketone inokunciphisa uxinzelelo lwe-oxidative olubangelwa ukulimala kwe-hepatic ekuphenduleni i-n-3 polyunsaturated fatty acids (Pawlak et al., 2015). Khumbula ukuba ngenxa yokungabikho kokubonakaliswa kwe-SCOT kwi-hepatocytes, imizimba ye-ketone ayinayo i-oxidized, kodwa inokuba negalelo kwi-lipogenesis, kwaye isebenze kwiindidi ezahlukeneyo zokubonisa ngokuzimeleyo kwi-oxidation yazo (kwakhona ubone i-Non-oxidative metabolic fates of ketone bodies and ?OHB as umlamli obonisa umqondiso). Kwakhona kunokwenzeka ukuba imizimba ye-ketone ephuma kwi-hepatocyte ingasebenza njengomqondiso kunye / okanye i-metabolite kwiintlobo zeeseli ezingabamelwane ngaphakathi kwe-hepatic acinus, kubandakanywa iiseli ze-stellate kunye ne-Kupffer cell macrophages. Ngelixa uncwadi olunyiniweyo olukhoyo lucebisa ukuba ii-macrophages azikwazi ukwenza i-oxidize imizimba ye-ketone, oku kulinganiswe kuphela kusetyenziswa iindlela zakudala, kwaye kuphela kwi-peritoneal macrophages (Newsholme et al., 1986; Newsholme et al., 1987), ebonisa ukuba ukuphinda- Uvavanyo lufanelekile lunikezwe ukubonakaliswa kwe-SCOT eninzi kwi-macrophages eyenziwe ngamathambo (Youm et al., 2015).

I-Hepatocyte ketogenic flux ingaba yi-cytoprotective. Nangona iindlela zobuncwane zingaxhomekekanga kwi-ketogenesis nganye, ukutya okuphantsi kwe-carbohydrate ketogenic kuye kwadibaniswa nokuphucula i-NAFLD (Browning et al., 2011; Foster et al., 2010; Kani et al., 2014; Schugar noCrawford, 2012) . Ukuqwalasela kwethu kubonisa ukuba i-hepatocyte ketogenesis inokuphendula kwaye ilawule i-TCA cycle flux, i-anaplerotic flux, i-phosphoenolpyruvate-derived gluconeogenesis (Cotter et al., 2014), kunye nokuguqulwa kwe-glycogen. I-Ketogenic impairment iqondisa i-acetyl-CoA yokwandisa i-TCA flux, esibindi idibaniswe nokunyuka kokulimala kwe-ROS (Satapati et al., 2015; Satapati et al., 2012); inyanzelisa ukuphambukiswa kwekhabhoni ibe ziintlobo zelipid ezidityanisiweyo ezinobungqina be-cytotoxic; kwaye inqanda i-NADH i-oxidation kwakhona kwi-NAD + (Cotter et al., 2014) (Umfanekiso 4). Kuthatyathwe kunye, iimvavanyo zexesha elizayo ziyafuneka ukujongana neendlela apho ukusilela kwe-ketogenic kunokuthi kube yi-maladaptive, igalelo kwi-hyperglycemia, ikhuphe i-steatohepatitis, nokuba ezi ndlela zisebenza kwi-NAFLD/NASH yabantu. Njengoko ubungqina be-epidemiological bubonisa ukukhubazeka kwe-ketogenesis ngexesha lokuqhubeka kwe-steatohepatitis (Embade et al., 2016; Marinou et al., 2011; Mnist et al., 2015; Pramfalk et al., 2015; Safaei 2016, unyango olwandisa i-ketogenesis ye-hepatic inobungqina obunobuncwane (i-Degirolamo et al., 2016; Honda et al., 2016).

Iimpawu zeCetone kunye nokungaphumeleli kwentliziyo (HF)

Ngesantya semetabolism esingaphezulu kwe-400 kcal/kg/ngosuku, kunye nenguquko ye-6�35 kg ye-ATP/ngosuku, intliziyo lilungu elineyona nkcitho iphezulu yamandla kunye nemfuno ene-oxidative (Ashrafian et al., 2007; Wang et al., 2010b). Uninzi lwenguqu yamandla e-myocardial ihlala ngaphakathi kwe-mitochondria, kwaye i-70% yolu nikezelo lusuka kwi-FAO. Intliziyo i-omnivorous kwaye ibhetyebhetye phantsi kweemeko eziqhelekileyo, kodwa intliziyo ehlaziya i-pathologically (umzekelo, ngenxa ye-hypertension okanye i-myocardial infarction) kunye nentliziyo yesifo seswekile nganye iyancipha i-metabolically inflexible (Balasse kunye noFery, 1989; BING, 1954; Fukao et al., 2004) ; Lopaschuk et al., 2010; Taegtmeyer et al., 1980; Taegtmeyer et al., 2002; Young et al., 2002). Enyanisweni, ukungahambi kakuhle kwemfuzo ye-cardiac fuel metabolism kwiimodeli zemouse kuvusa i-cardiomyopathy (uCarley et al., 2014; Neubauer, 2007). Ngaphantsi kweemeko ze-physiological hearts eziqhelekileyo zikhupha imizimba ye-ketone ngokulingana nokuhanjiswa kwazo, ngeendleko ze-fatty acid kunye ne-glucose oxidation, kwaye i-myocardium yeyona nto iphezulu yomthengi we-ketone yomzimba ngeyunithi yobunzima (BING, 1954; Crawford et al., 2009; GARLAND et al. ., 1962; Hasselbaink et al., 2003; Jeffrey et al., 1995; Pelletier et al., 2007; Tardif et al., 2001; Yan et al., 2009). Xa kuthelekiswa ne-oxidation ye-asidi enamafutha, imizimba ye-ketone isebenza ngamandla, inika amandla amaninzi akhoyo kwi-ATP synthesis nge-molecule ye-oksijini etyalwe (i-P / O ratio) (Kashiwaya et al., 2010; Sato et al., 1995; Veech, 2004) . I-Ketone body oxidation iphinda ivelise amandla angaphezulu kunokuba i-FAO, igcina i-ubiquinone oxidized, ephakamisa i-redox span kwikhonkco lokuthutha i-electron kwaye yenza amandla amaninzi afumaneke ukuze enze i-ATP (Sato et al., 1995; Veech, 2004). I-oxidation yemizimba ye-ketone inokunciphisa imveliso ye-ROS, kwaye ngoko ke uxinzelelo lwe-oxidative (Veech, 2004).

Izifundo zokuqala nokungenelela kunye nokuhlola okubonisa ukubonisisa zibonisa indima enokuyilungisa yamalungu e-ketone entliziyweni. Kwimizamo yokuzama ukutshatyalaliswa kwe-ischemia / i-reperfusion, izidumbu ze-ketone ezithe zenziwa yimiphumo ye-cardioprotective (Al-Zaid et al., 2007; i-Wang et al., I-2008), mhlawumbi ngenxa yokwanda kwe-mitochondrial in intliziyo okanye ukulawulwa kwe-phosphorylation ebalulekileyo abalamlamli (uSorek et al., 2012; Zou et al., 2002). Uphando olutshanje lubonisa ukuba ukusetyenziswa komzimba we-ketone kunyuke ekuphelelweni kweentlanzi (Aubert et al., 2016) kunye nabantu (Bedi et al., 2016), ukuxhasa ukubonwa kwangaphambili kubantu (BING, 1954; Fukao et al., 2000; Janardhan et al., 2011; Longo et al., 2004; Rudolph kunye neSchinz, 1973; iTildon kunye neConblath, i-1972). Ukwandiswa kwamanani emzimbeni we-ketone kunyuselwa kwintsholongwane yokukhubazeka kwentliziyo, ngokubhekiselele ekuzaliseni izixinzelelo, ukuqwalaselwa okubalulekileyo kunye nokubaluleka kwayo (Kupari et al., 1995; Lommi et al., 1996; Lommi et al., 1997; Neely et al ., I-1972), kodwa iigundane ezineenkcukacha ze-SCOT ezingabonakaliyo kwi-cardiomyocytes zibonisa ukulungiswa kwe-ventricular ventricular kunye ne-ROS zisayineli ekuphenduleni ukunyanzeliswa kwengcinezelo yokuxinzelela ingozi (Schugar et al., 2014).

Ukuqwalaselwa okwangoku okwangoku kukhangeleka kwindlela yesifo sikashukela kuye kwabonisa ukuba unxibelelwano olukhoyo phakathi kwe-myocardial ketone metabolism kunye ne-pathological ventricular remodeling (i-Fig. 5). Inhibition ye-renal proximal nebular tubular sodium / i-glucose co-transporter I-2 (SGLT2i) yandisa ukujikeleza komzimba we-ketone kubantu (Ferrannini et al., 2016a; Inagaki et al., 2015) kunye namagundane (Suzuki et al., 2014) ngokunyuka i-hepatic ketogenesis (iFerrannini et al., i-2014; i-Ferrannini et al., i-2016a; i-Katz kunye ne-Leiter, i-2015; i-Mudaliar et al., i-2015). Ngokukrakra, ubuncinane enye yee-arhente zanciphisa izibhedlele ze-HF (umz., Njengoko kuboniswe nguvavanyo lwe-EMPA-REG OUTCOME), kunye nokufelwa komzimba (Fitchett et al., 2016; Sonesson et al., 2016; Wu et al., 2016a : Zinman et al., 2015). Nangona umqhubi weendlela ezixhamlayo kwiziphumo ze-HF ezixhunyiwe kwi-SGLT2i zihlala zixubushe ngokuxubusha, inzuzo yokuphila isenokuthi iyenze i-ketosis kodwa ibuye iphumelele ekuthini isisindo, uxinzelelo lwegazi, i-glucose kunye namazinga e-uric acid, ukuqina kobunzima, inkqubo ye-nervous sympathetic, osmotic i-diuresis / umthamo we-plasm wehlisiwe, kunye ne-hematocrit eyanda (uRaz noCahn, i-2016; i-Vallon ne-Thomson, i-2016). Kuthatyathwa ndawonye, ​​ingcamango yokuba ukhenkethemia yokwandisa i-ketonemia kwii-HF izigulane, okanye abo basemngciphekweni omkhulu wokuhlakulela i-HF, ihlala ingquzulwano kodwa iphantsi kophando olusebenzayo kwizifundo zangaphambi kweklinikhi kunye neklinikhi (uFranran et al., 2016b; Kolwicz et al., 2016; Lopaschuk kunye neVerma, 2016; Mudaliar et al., 2016; iTeegtmeyer, 2016).

Amathambo e-Ketone kwi-Biology Cancer

Ukuqhagamshelana phakathi kweempawu ze-ketone kunye nomhlaza kukhula ngokukhawuleza, kodwa izifundo kwizifundo zezilwanyana kunye nabantu ziye zaveza izigqibo ezihlukahlukeneyo. Ngenxa yokuba i-ketone metabolism inamandla kunye nesimo sezondlo esiphendulayo, siyayilinganisa ukuqhubela phambili ukuxhamla kwi-biological kunye nomhlaza ngenxa yezinto ezinokuthathwa ngokuchanekileyo. Iiseli zomhlaza zingaphantsi kwe-reprogramming reprogramming ukwenzela ukuba kugcinwe ukukhula kweseli ngokukhawuleza nokukhula (iDeNicola kunye noCanley, i-2015; i-Pavlova kunye no-Thompson, i-2016). I-classic yaseWarburg eyenziwa ngumhlaza wesifo se-metabolism ibangelwa yinxaxheba ebalulekileyo ye-glycolysis kunye ne-lactic acid fermentation ukudlulisela amandla kwaye ihlawulise ukuxhomekeka okuphantsi kwe-phosphorylation ye-oxidative kunye nokuphefumula kwe-mitochondrial (De Feyter et al., 2016; Grabacka et al., 2016; Kang et al., 2015; Poff et al., 2014; Shukla et al., 2014). I-glucose carbon ilawulwa ngokuglycolysis, i-pentose phosphate pathway, kunye ne-lipogenesis, ezidibeneyo zibonelela ngezixhobo ezifunekayo ukwenyuka kwe-tumor biomass (i-Grabacka et al., I-2016; i-Shukla et al., I-2014; i-Yoshii et al., I-2015). Ukutshintshwa kweeseli zomhlaza kwi-glucose inyanzeliso kwenzeka ngokukwazi ukusebenzisa izixhobo zamanye amafutha, kuquka i-acetate, glutamine, kunye ne-aspartate (Jaworski et al., 2016; Sullivan et al., 2015). Ngokomzekelo, ukufikelela okuvumelekileyo kwi-pyruvate kubonisa amandla omhlaza weseli ukuguqula i-glutamine kwi-acetyl-CoA nge-carboxylation, ukugcina iimfuno zombini kunye ne-anabolic (uYang et al., 2014). Ukutshintshisiswa kokutshintshwa kweeseli zomhlaza kukusetyenziswa kwe-acetate njengamafutha (i-Comerford et al., I-2014; i-Jaworski et al., I-2016; i-Mashimo et al., I-2014; i-Wright ne-Simone, i- 2016; i-Yoshii et al., I-2015). I-Acetate iphinde ibe yintsika ye-lipogenesis, eyona nto ibaluleke kakhulu kwi-cell proliferation, kwaye inzuzo yalo mzila we-lipogenic ihambelana nesigulo esinesigxina sokusinda kunye nomthwalo omkhulu we-tumor (i-Comerford et al., I-2014; i-Mashimo et al., I-2014; i-Yoshii et al ., 2015).

Iiseli ezingezonomhlaza zitshintsha ngokulula umthombo wazo wamandla ukusuka kwi-glucose ukuya kwimizimba ye-ketone ngexesha lokungabikho kweglucose. Le plasticity inokuthi iguquguquke ngakumbi phakathi kweentlobo zeeseli zomhlaza, kodwa kwi-vivo efakwe kwi-brain tumors oxidized [2,4-13C2] -? �Ukubuyisela umva isiphumo se-Warburg� okanye �iimodeli ezimbini ze-tumor metabolism� ziqikelela ukuba iiseli zomhlaza zibangela ?Imveliso ye-OHB kwi-fibroblasts ekufutshane, ibonelela ngeemfuno zamandla zeseli yethumba (Bonuccelli et al., 2016; Martinez-Outschoorn et al., 2010) . Kwisibindi, utshintsho kwi-hepatocytes ukusuka kwi-ketogenesis ukuya kwi-ketone oxidation kwi-hepatocellular carcinoma (i-hepatoma) iiseli zihambelana nokusebenza kwe-BDH2012 kunye nemisebenzi ye-SCOT ebonwa kwimigca yeseli ye-hepatoma (Zhang et al., 1). Enyanisweni, iiseli ze-hepatoma zibonisa i-OXCT1989 kunye ne-BDH1 kunye ne-oxidize ketones, kodwa kuphela xa i-serum ilambile (Huang et al., 1). Kungenjalo, kuye kwacetywa i-tumor cell ketogenesis. Ukutshintsha okunamandla kwi-ketogenic gene expression kuboniswa ngexesha lokuguqulwa komhlaza we-colonic epithelium, uhlobo lweseli oluhlala lubonisa i-HMGCS2016, kwaye ingxelo yakutshanje iphakamisa ukuba i-HMGCS2 ingaba ngumqondiso we-prognosis ye-prognosis embi kwi-colorectal kunye ne-squamous cell carcinomas (Camarero et al., 2; Chen et al., 2006). Ingaba lo mbutho ufuna okanye ubandakanya i-ketogenesis, okanye umsebenzi wokukhanya kwenyanga we-HMGCS2016, uhlala uzimisele. Ngokuchaseneyo, kuyabonakala ?Imveliso ye-OHB ngemelanoma kunye neeseli ze-glioblastoma, ezivuselelwe yi-PPAR? I-agonist fenofibrate, yayinxulumene nokubanjwa kokukhula (Grabacka et al., 2). Uphononongo olongezelelweyo luyafuneka ukuba lubonise iindima ze-HMGCS2016 / SCOT expression, i-ketogenesis, kunye ne-ketone oxidation kwiiseli zomhlaza.

Ngaphandle kwendawo ye-fuel metabolism, ii-ketones zisandula ukubandakanyeka kwibhayoloji yeseli yomhlaza ngendlela yokubonisa. Uhlalutyo lwe-BRAF-V600E + i-melanoma ibonise i-OCT1-exhomekeke kwi-HMGCL exhomekeke kwi-oncogenic ye-BRAF exhomekeke kwindlela (Kang et al., 2015). Ukwandiswa kwe-HMGCL kwanxulunyaniswa noxinzelelo oluphezulu lwe-AcAc yeselula, eyathi yaphucula ukusebenzisana kwe-BRAFV600E-MEK1, ikhulisa umqondiso we-MEK-ERK kwi-feed-forward loop eqhuba ukwanda kwe-tumor cell kunye nokukhula. Olu qwalaselo luphakamisa umbuzo othakazelisayo we-extrahepatic ketogenesis enokuthi emva koko ixhase indlela yokubonisa (kwakhona ubone ?OHB njengomlamli womqondiso kunye neeNgxaki kwi-ketogenesis ye-extrahepatic). Kwakhona kubalulekile ukuqwalasela iziphumo ezizimeleyo ze-AcAc, d-?OHB, kunye ne-l-?OHB kwi-metabolism yomhlaza, kwaye xa uqwalasela i-HMGCL, i-leucine catabolism inokuthi iphazamiseke.

Imiphumo yokutya kwe-ketogenic (kwakhona jonga Ukusetyenziswa koNyango lokutya kwe-ketogenic kunye nemizimba ye-ketone yangaphandle) kwiimodeli zezilwanyana ezinomhlaza ziyahluka (De Feyter et al., 2016; Klement et al., 2016; Meidenbauer et al., 2015; Poff et al., 2014; Klement et al., 2011; Meidenbauer et al., 2014; Poff et al. ., 2016; Seyfried et al., 2016; Shukla et al., 2016). Ngelixa imibutho ye-epidemiological phakathi kokutyeba, umhlaza, kunye nokutya kwe-ketogenic kuxoxwa ngayo (Liskiewicz et al., 2016; Wright noSimone, 81), uhlalutyo lwe-meta olusebenzisa ukutya kwe-ketogenic kwimodeli yezilwanyana nakwizifundo zabantu lucebise impembelelo ephilileyo ekusindeni, kunye inzuzo enokuthi idibaniswe nobukhulu be-ketosis, ixesha lokuqalisa ukutya, kunye nendawo ye-tumor (Klement et al., 18; Woolf et al., 1). Unyango lweeseli zomhlaza we-pancreatic kunye nemizimba ye-ketone (d-?OHB okanye i-AcAc) inqanda ukukhula, ukwanda kunye ne-glycolysis, kunye nokutya kwe-ketogenic (i-2014% kcal fat, i-2014% yeprotheni, i-91% ye-carbohydrate) iyancipha kwi-vivo tumor weight, i-glycemia, kunye ukwanda kwemisipha kunye nobunzima bomzimba kwizilwanyana ezinomhlaza wokufakelwa (Shukla et al., 9). Iziphumo ezifanayo zabonwa kusetyenziswa imodeli yeseli ye-metastatic glioblastoma kwiigundane ezifumene i-ketone supplementation ekudleni (Poff et al., 2016). Ngokuchasene noko, ukutya kwe-ketogenic (i-2015% kcal fat, i-XNUMX% yeprotheyini) yanda ukujikeleza ?I-concentration ye-OHB kunye ne-glycemia eyanciphayo kodwa ayinayo impembelelo kwi-tumor volume okanye ubude bokuphila kwiigundane ezithwala i-glioma (De Feyter et al., XNUMX). Isalathisi se-glucose ketone sicetywayo njengesalathisi seklinikhi esiphucula ukulawulwa kwe-metabolic ye-ketogenic-induced brain cancer therapy kubantu kunye neegundane (Meidenbauer et al., XNUMX). Ithatyathwe kunye, iindima ze-ketone body metabolism kunye nemizimba ye-ketone kwibhayoloji yomhlaza iyathandeka kuba nganye ibeka iinketho zonyango ezithathekayo, kodwa imiba esisiseko isacaciswa, kunye neempembelelo ezicacileyo ezivela kwi-matrix yezinto eziguquguqukayo, kubandakanywa (i) umahluko phakathi kwe-ketone yangaphandle. imizimba echasene nokutya kwe-ketogenic, (ii) uhlobo lweseli yomhlaza, i-polymorphisms ye-genomic, ibakala, kunye nenqanaba; kunye (iii) nexesha kunye nobude bokuchanabeka kwi-ketotic state.

UDkt Jimenez White Coat
I-Ketogenesis yenziwe ngamalungu e-ketone ngokuphuhla kwama-acids acids kunye ne-ketogenic amino acid. Le nkqubo ye-biochemical inikeza amandla kumalungu athile, ngokukodwa ingqondo, phantsi kweemeko zokuzila ukutya njengendlela yokuphendula ukungabi khona kwegazi kwi-glucose. Izidumbu ze-ketone ziveliswa ikakhulu kwi-mitochondria yeselintshi yesibindi. Nangona ezinye iiseli ziyakwazi ukwenza i-ketogenesis, azinako ukwenza ngokufanelekileyo njengeseli zesibindi. Ngenxa yokuba i-ketogenesis ivela kwimitochondria, iinkqubo zayo zilawulwa ngokuzimela. UDkt Alex Jimenez DC, i-CCST Insight

Ukusetyenziswa kwezifo zeTetogenic Diet kunye namaBhunga aKonone aqhelekileyo

Ukusetyenziswa kwezidlo ze-ketogenic kunye nemizimba ye-ketone njengezixhobo zonyango ziye zavela nakwiimeko ezingenalo umhlaza ezibandakanya ukukhuluphala kunye ne-NAFLD / NASH (Browning et al., 2011; Foster et al., 2010; Schugar and Crawford, 2012); ukungaphumeleli kwentliziyo (Huynh, 2016; Kolwicz et al., 2016; Taegtmeyer, 2016); isifo se-neurological and neurodegenerative (uMartin et al., 2016; McNally kunye noHartman, 2012; Rho, 2015; Rogawski et al., 2016; Yang and Cheng, 2010; Yao et al., 2011); iimpazamo ezizalwayo zemetabolism (Scholl-B�rgi et al, 2015); kunye nokusebenza komthambo (Cox et al., 2016). Ukusebenza kokutya kwe-ketogenic kuye kwaxatyiswa ngakumbi kunyango lokuxhuzula, ngakumbi kwizigulana ezinganyangekiyo ngamachiza. Uninzi lwezifundo ziye zavavanya ukutya kwe-ketogenic kwizigulana zabantwana, kwaye zityhila ukuya kuthi ga kwi- ~ 50% yokunciphisa imvamisa yokubamba emva kweenyanga ze-3, ngokusebenza okuphuculweyo kwii-syndromes ezikhethiweyo (Wu et al., 2016b). Amava anqongophele ngakumbi kwisifo sokuxhuzula kwabantu abadala, kodwa ukuncitshiswa okufanayo kubonakala, kunye nempendulo engcono kwizigulana zokuxhuzula eziqhelekileyo (Nei et al., 2014). Iindlela ezingaphantsi kwe-anti-convulsant zihlala zingacacanga, nangona ii-hypotheses ezithunyelweyo ziquka ukunciphisa ukusetyenziswa kwe-glucose / glycolysis, i-reprogrammed glutamate transport, impembelelo engathanga ngqo kwi-ATP-sensitive potassium channel okanye i-adenosine A1 receptor, ukuguqulwa kwenkcazo ye-sodium ye-isoform, okanye imiphumo kwi-hormone ejikelezayo kuquka i-leptin. Lambrechts et al., 2016; Lin et al., 2017; Lutas noYellen, 2013). Kuhlala kungacacanga ukuba isiphumo sokuchasana nokuxhuzula sibangelwa ikakhulu kwimizimba ye-ketone, okanye ngenxa yemiphumo ye-cascade ye-metabolic yokutya okuphantsi kwe-carbohydrate. Nangona kunjalo, i-ketone esters (jonga ngezantsi) ibonakala iphakamisa umda wokubamba kwiimodeli zezilwanyana zokuhlutha okucaphukisayo (Ciarlone et al., 2016; D'Agostino et al., 2013; Viggiano et al., 2015).

I-Atkins-style kunye ne-ketogenic, i-low-carbohydrates diet zidlalwa njengento engathandekiyo, kwaye ingabangela ukumbumba, i-hyperuricemia, i-hypocalcemia, i-hypomagnesemia, ibangela i-nephrolithiasis, i-ketoacidosis, ibangele i-hyperglycemia, kwaye iphakame i-cholesterol kunye namafutha ase-fatty acid (Bisschop et al., 2001 ; IKossoff kunye neHartman, i-2012; i-Kwiterovich et al., I-2003; i-Suzuki et al., I-2002). Ngenxa yezi zizathu, ukubambelela kwexesha elide kubangela iingxaki. Izifundo zogqithiso zixhaphaza ngokubanzi ukusabalalisa ngokubanzi (i-94% kcal fat, i-1% kcal carbohydrate, i-5% kcal protein, i-Bio-Serv F3666), eyenza i-ketosis enamandla. Nangona kunjalo, ukwandisa umxholo weprotheni, nokuba i-10% kcal iyanciphisa kakhulu i-ketosis, kwaye i-5% kcal protein restriction ibangela ukuphazamiseka kwemiphumo ye-metabolic and physiological. Ukuqulunqwa kwesondlo kuphelile, enye intsingiselo echaphazela ukulimala kwesibindi, kunye ne-ketogenesis (Garbow et al., 2011; Jornayvaz et al., 2010; i-Kennedy et al., 2007; i-2013; i-Schugar kunye al., 2013). Iziphumo zokusetyenziswa kwexesha elide kwizidlo ze-ketogenic kwiimicebe zihlala zingachazwanga ngokucacileyo, kodwa uphando olutshanje kwiimicebe lubonakalisile ukusinda okuqhelekileyo kunye nokungabikho kwezimbonakaliso zokulimala kwesibindi kwiimfucu kwizidlo ze-ketogen ngaphezu kobomi babo, nangona i-amino acid metabolism, inkcitho yamandla kunye nokubonakaliswa kwe-insulin zachazwa ngokukhawuleza (Douris et al., 2015).

Iinkqubo zokwandisa i-ketosis ngeendlela ezingezinye iindlela zokutya zetokenjini ziquka ukusetyenziswa kwezinto zokugcoba umzimba ze-ketone. Ukulawulwa kweempawu ze-ketone ezingenakukwazi ukudala isimo semvelo esingafani naso kwi-physiology eqhelekileyo, kuba ukujikeleza i-glucose kunye namaqondo e-insulin aqhelekileyo, ngelixa iiseli zingasindisa i-glucose ukusetyenziswa kunye nokusetyenziswa. Imizimba yeKetone ngokwazo inobomi obufutshane obufutshane, kwaye ukungeniswa okanye ukufakwa kwesodium ?OHB ityuwa ukufezekisa i-ketosis yonyango ixhokonxa umthwalo wesodium engathandekiyo. I-R/S-1,3-butanediol yi-dialcohol engeyona inetyhefu ekhawuleza i-oxidized kwisibindi ukuze ivelise i-d/l-?OHB (Desrochers et al., 1992). Kwimixholo yovavanyo eyahlukeneyo, eli thamo lilawulwa yonke imihla kwiimpuku okanye iimpuku kangangeeveki ezisixhenxe, inika ukujikeleza ?OHB yoxinaniso ukuya kuthi ga kwi-5 mM ngaphakathi kwe-2 h yolawulo, ezinzile ubuncinane i-3h eyongezelelweyo (D') Agostino et al., 2013). Ukuncitshiswa okukodwa kokutya okuye kwabonwa kwiigorantshi zanikwa uR / S-1,3-butanediol (Umchweli kunye neGrossman, 1983). Ukongezelela, ezintathu zeekhemikhali ze-ketone esters (KEs), (i) i-monoester ye-R-1,3-butanediol kunye ne-d-?OHB (R-3-hydroxybutyl R-?OHB); (ii) i-glyceryl-tris-?OHB; kunye (iii) ne-R, S-1,3-butanediol acetoacetate diester, nayo ifundwe ngokubanzi (Brunengraber, 1997; Clarke et al., 2012a; Clarke et al., 2012b; Desrochers et al., 1995a; Desrochers et al., 1995a; Clarke et al., 2010b; Desrochers et al., XNUMXa; Desrochers et al. ., XNUMXb; Kashiwaya et al., XNUMX). I-advanteji yendalo yangaphambili kukuba ii-moles ezi-2 ze-physiological d-?OHB ziveliswa nge-mole ye-KE, kulandela i-esterase hydrolysis emathunjini okanye esibindini. Ukhuseleko, i-pharmacokinetics, kunye nokunyamezela kuye kwafundiswa ngokubanzi kubantu abasebenzisa i-R-3-hydroxybutyl R-? 714a; Cox et al., 6; Kemper et al., 2012; Shivva et al., 2016). Kwiingcongolo, oku ke kunciphisa i-caloric intake kunye ne-plasma ye-cholesterol iyonke, ikhuthaza i-brown adipose tissue, kwaye iphucula ukuxhathisa kwe-insulin (i-Kashiwaya et al., I-2010; i-Kemper et al., I-2015; i-Veech, i-2013). Iziphumo zakutshanje zibonisa ukuba ngexesha lokuzivocavoca kubadlali abaqeqeshiweyo, i-R-3-hydroxybutyl R-?OHB iyancipha i-skeletal muscle glycolysis kunye ne-plasma lactate concentrations, i-intramuscular triacylglycerol oxidation, kunye nokugcinwa kwe-muscle glycogen content, nangona xa i-carbohydrate edibeneyo ivuselela ukukhuselwa kwe-insulin. Cox et al., 2016). Ukuphuhliswa okuqhubekayo kwezi ziphumo ezikhangayo kuyadingeka, kuba ukuphucula ukunyamezela ukuqhuba ukusebenza kwakuqhutywe kakhulu yimpendulo enamandla kwi-KE kwizifundo ze-2 / 8. Nangona kunjalo, ezi ziphumo zixhasa ukufundiswa kweklasi ezibonisa ukhetho lwe-ketone oxidation ngaphezu kwamanye amacwecwe (GARLAND et al., 1962; Hasselbaink et al., 2003; Stanley et al., 2003; Valente-Silva et al., 2015), kubandakanywa ngexesha lokuzivocavoca, kwaye abadlali abaqeqeshiwe banokubongwa ukuba basebenzise ietone (Johnson et al., 1969a; uJohnson noWalton, 1972; Winder et al., 1974; Winder et al., 1975). Ekugqibeleni, iindlela ezinokuxhasa ukuqhuba umsebenzi ophuculweyo emva kokudla okulinganayo kwe-caloric (ukusabalaliswa ngokwahlukileyo phakathi kwama-macronutrients) kunye nokulingana kwamazinga okusetyenziswa kwe-oksijini kuya kuhlala kuchongwa.

Ngethuba elizayo

Yakuba ibekwe ibala kakhulu njengendlela ephuphumayo ekwaziyo ukuqokelela ukukhutshwa okuyityhefu okuphuma ekutshisweni kwamafutha kwiindawo ezithintelweyo zecarbohydrate (i-�ketotoxic� paradigm), uqwalaselo lwakutsha nje luxhasa uluvo lokuba i-ketone body metabolism isebenza iindima eziluncedo nakwimimandla enecarbohydrates, ivula i-ketohormetic. � ingcamango. Ngelixa iindlela ezilula zokondla kunye ne-pharmacological zokulawula i-ketone metabolism zenza ukuba kube yinjongo ekhangayo yonyango, i-aggressive ibekwe kodwa iimvavanyo ezinobulumko zihlala kuzo zombini iilebhu zophando ezisisiseko kunye nokuguqulela. Iimfuno ezingafezekanga ziye zavela kwimimandla yokuchaza indima ye-leveraging ketone metabolism kwintliziyo, ukukhuluphala, i-NAFLD / NASH, uhlobo lwe-2 yeswekile, kunye nomhlaza. Umda kunye nefuthe leendima 'ezingezo-canonical' zomqondiso wemizimba ye-ketone, kubandakanywa nolawulo lwee-PTM ezinokuthi zibuyele emva nangaphambili kwiindlela zemetabolism kunye nezibonakaliso, zifuna uphononongo olunzulu. Ekugqibeleni, i-ketogenesis ye-extrahepatic inokuvula i-paracrine enomdla kunye neendlela zokubonisa i-autocrine kunye namathuba okuchaphazela i-co-metabolism ngaphakathi kwenkqubo ye-nervous kunye ne-tumor ukuphumeza iziphelo zonyango.

Imibulelo

Ncbi.nlm.nih.gov/pmc/articles/PMC5313038/

Imihlathi

Ncbi.nlm.nih.gov

Ukuqukumbela, imizimba ye-ketone idalwe sisibindi ukuze isetyenziswe njengomthombo wamandla xa kungekho glucose eyaneleyo efumanekayo kumzimba womntu. I-Ketogenesis yenzeka xa kukho amanqanaba eglucose ephantsi egazini, ngakumbi emva kokuba ezinye iivenkile ze-carbohydrate zeselula ziphelile. Injongo yale nqaku ingentla yayikuxoxa ngeendima ezininzi-dimensional zemizimba ye-ketone kwi-fuel metabolism, ukubonakaliswa, kunye nonyango. 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: Ncbi.nlm.nih.gov/pmc/articles/PMC5313038/

Ikholi ye-Green Call Now Button H .png

Ingxoxo yesihloko esongezelelweyo: cBuhlungu obuBuhlungu

Umqolo obuhlunguSesinye sezona zinto zixhaphakileyo zokukhubazeka kunye neentsuku eziphosiweyo emsebenzini kwihlabathi liphela. Iimpawu ezibuhlungu zangasemva kwisizathu sesibini esiqhelekileyo sokutyelelwa kweofisi kagqirha, ngaphezulu kwenani losulelo oluphezulu lokuphefumla. Ngokumalunga neepesenti ezingama-80 zabemi baya kuba neentlungu zentlungu emva kanye ebomini babo. Umqolo sisakhiwo esintsonkothileyo esenziwe ngamathambo, amalungu, iigaments, kunye nezihlunu, phakathi kwezinye izicwili ezithambileyo. Ukwenzakala kunye / okanye iimeko ezixhonyiweyo, 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. �

umfanekiso weblogi wekratshi yephepha

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

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Ziziphi izingozi ze-Nrf2 Exverendression?

Ziziphi izingozi ze-Nrf2 Exverendression?

The i-nyukliya erythroid I-2 enxulumene ne-2 yokubonisa indlela, eyaziwa ngokuba ngu-Nrf2, yindlela yokukhusela esebenza "njengomlawuli oyintloko" wempendulo yomzimba womntu olwa ne-antioxidant response. I-Nrf2 ivala amanqanaba okuxinwa kwe-oxidative ngaphakathi kweeseli kwaye ibangela iindlela ezikhuselayo zokukhusela i-antioxidant. Nangona i-Nrf2 isebenze inokufumana inzuzo eninzi, i-Nrf2 "ukugqithiseleka" inokuba nemingcipheko emininzi. Kubonakala ukuba i-NRF2 ibaluleke kakhulu ekuthintela ukuphuhliswa jikelele kwezifo ezahlukeneyo ngaphezu kokuphucula ngokubanzi le micimbi yezempilo. Nangona kunjalo, i-NRF2 inokubangela iingxaki. Isizathu esibangeleyo emva kwe-NRF2 "ukugqithisa kakhulu" ngenxa yokuguquka komzimba okanye ukuqhubela phambili okungapheliyo kwimizi yeciksi okanye ukuxinzezeleka kwengcinezelo, phakathi kwabanye. Ngezantsi, siza kuxubusha ukuhlaselwa kwe-Nrf2 ngokugqithiseleyo nokubonisa iindlela zayo zokusebenza ngaphakathi komzimba womntu.

Cancer

Izifundo zophando zifumanise ukuba iimpuku ezingachazi i-NRF2 zithambekele ngakumbi ekuphuhliseni umhlaza ekuphenduleni ukuvuselela komzimba kunye neekhemikhali. Izifundo ezifanayo zophando, nangona kunjalo, zibonise ukuba ukusebenza kwe-NRF2 ngaphezulu, okanye ukungasebenzi kwe-KEAP1, kunokubangela ukonyuka komhlaza othile, ngakumbi ukuba ezo ndlela ziphazamisekile. I-NRF2 egqithisileyo inokubakho ngokutshaya, apho ukusebenza okuqhubekayo kwe-NRF2 kukholelwa ukuba kungunobangela womhlaza wemiphunga kubantu abatshayayo. I-Nrf2 overexpression inokubangela ukuba iiseli ezinomhlaza zingazonakalisi, ngelixa ukusebenza kwe-NRF2 okwethutyana kunokuthintela iiseli ezinomhlaza ekuvuseleleni ukwenziwa kwe-toxin. Ukongeza, ngenxa yokuba i-NRF2 overexpression inyusa amandla e-antioxidant omzimba womntu okusebenza ngaphaya kwe-redox homeostasis, oku kukonyusa ukwahlulwa kweseli kwaye kuvelise ipateni engaqhelekanga ye-DNA kunye ne-histone methylation. Oku ekugqibeleni kunokwenza i -chemotherapy kunye ne-radiotherapy zingasebenzi kakuhle kumhlaza. Ke ngoko, ukunciphisa umda ekusebenzeni kwe-NRF2 ngezinto ezinjenge-DIM, iLuteolin, i-Zi Cao, okanye i-salinomycin inokuba zilungele izigulana ezinomhlaza nangona i-Nrf2 yokunyanzeliswa kokusebenza kungathathwa njengeyona nto ibangela umhlaza. Ukusilela kwesondlo kunokuchaphazela ii-genes, kubandakanya i-NRF2. Oku kunokuba yindlela enye yokuba ukusilela kunegalelo njani kwizidumbu.

Ibindi

Ukugqithiswa kwe-Nrf2, kunokuchaphazela nokusebenza kwamalungu athile emzimbeni womntu. Ukugqithiswa kwe-NRF2 kunokukhawulela ekugqibeleni ukuveliswa kwe-insulin-efana nokukhula kwe1, okanye i-IGF-1, esesibindi, esibalulekileyo ekuhlaziyweni kwesibindi.

intliziyo

Nangona i-Nrf2 ingenakuncedo, ukugqithisa okuqhubekayo kwe-NRF2 kunokudala iziphumo ezinobungozi kwixesha elide entliziyweni, njenge-cardiomyopathy. Inkulumo ye-NRF2 inganyuswa ngamazinga aphezulu e-cholesterol, okanye ukusetyenziswa kwe-HO-1. Oku kukholelwa ukuba yisona isizathu sokuba amazinga aphezulu angama-cholesterol angabangela iimeko zempilo yengqondo.

Vitiligo

Ukugqithiswa kwe-NRF2 kuye kwabonakaliswa ukuba kuvimbele ukukwazi ukuguqulwa kwi-vitiligo njengoko kunokuthintela iTyrosinase, okanye i-TYR, isenzo esibalulekileyo ekuguqulweni kwe-melaninogenesis. Ucwaningo luye lwabonisa ukuba le nkqubo ingaba esinye sezizathu eziphambili zokuba kutheni abantu abane-vitiligo bengabonakali ukuvuselela i-Nrf2 ngokufanelekileyo njengabantu abangenayo i-vitiligo.

Kutheni i-NRF2 ingaSebenzi kakuhle

EHormesis

I-NRF2 kufuneka ivulwe ngokwe-hormetically ukuze ikwazi ukuthatha inzuzo yayo. Ngamanye amazwi, i-Nrf2 akufuneki iqalise yonke imzuzu okanye yonke imihla, ngoko ke, luluvo olukhulu ukuthatha ikhefu kuyo, ngokomzekelo, iintsuku ezi-5 ngeentsuku ezi-5 zokuphumla okanye yonke enye imini. I-NRF2 kufuneka kwakhona ifezekise umda othile wokuqalisa impendulo yayo ye-hormetic, apho i-stressor encinci ingenako ngokwaneleyo ukuyiqalisa.

I-DJ-1 Oxidation

Iprotheni deglycase DJ-1, okanye nje i-DJ-1, ebizwa ngokuba yi-protein ye-Parkinson, okanye i-PARK7, ngumlawuli oyintloko kunye nomtshina we-redox kwisimo somzimba. I-DJ-1 ibalulekile ekulawuleni indlela i-NRF2 enokuyenza ngayo umsebenzi wayo kwaye ivelise impendulo ye-antioxidant. Kwimeko apho i-DJ-1 iba ngaphezulu, iiseli ziya kwenza iprotheni ye-DJ-1 ingafinyeleleki. Le nkqubo yenza ukuba ukusebenza kwe-NRF2 kuphelelwe ngokukhawuleza njengoko i-DJ-1 ibaluleke kakhulu ukugcina amanqanaba alinganiselayo we-NRF2 kwaye ikhusela ukuba iphulwe phantsi kwiseli. Ukuba ngaba iprotheni ye-DJ-1 ayikho okanye ingaphezulu, i-NRF2 ibonakaliso iya kuba yinto encinci, mhlawumbi isebenzise i-DIM okanye ezinye i-activation NRF2. I-DJ-1 ibonakaliso imele ukubuyisela isenzo se-NRF2 esingakwaziyo.

Ukugula okungapheliyo

Ukuba unesifo esingapheliyo, kuquka i-CIRS, izifo ezingapheliyo / i-dysbiosis / i-SIBO, okanye i-heavy metal build up, efana ne-mercury kunye / okanye ukusuka kwiingcambu zeengcambu, ezi zinokuthintela iinkqubo ze-NRF2 kunye nesigaba sesibini sokutshatyalaliswa. Kunokuba uxinzelelo lwe-oxidative luguqule i-NRF2 ibe yi-antioxidant, i-NRF2 ayiyi kubangela kwaye uxinzelelo lwe-oxidative lunokuhlala kwiseli kwaye lubangele umonakalo, oku kuthetha ukuba akukho mpendulo ye-antioxidant. Esi sisizathu esibalulekileyo sokuba kutheni abantu abaninzi abane-CIRS benovelwano oluninzi kwaye bafikelele kwizinto ezininzi. Abanye abantu bakholelwa ukuba banokuba nempendulo ye-herx, nangona kunjalo, le ndlela yokusabela inokuba yonakalisa iiseli kude. Ukunyanga izifo ezingapheliyo, nangona kunjalo, kuya kuvumela isibindi ukuba sikhuphe i-toxins kwi-bile, ngokuthe ngcembe siphuhlise impendulo ye-hormetic ye-activation ye-NRF2. Ukuba i-bile ihlala inetyhefu kwaye ayikhutshwanga emzimbeni womntu, iya kuphinda ivuselele uxinzelelo lwe-oxidative ye-NRF2 kwaye ibangele ukuba uzive ubi nakakhulu xa iphinda ihlanjululwe kwi-gastrointestinal, okanye i-GI, iphecana. Ngokomzekelo, i-ochratoxin A inokuvala i-NRF2. Ngaphandle kokunyanga ingxaki, i-histone deacetylase inhibitors inokuthintela ukusabela kwe-oxidative ukusuka kwizinto ezininzi ezibangela ukusebenza kwe-NRF2 kodwa kunokuthintela i-NRF2 ekubeni ibangele - ngokuqhelekileyo, enokuthi ekugqibeleni isilele ukukhonza injongo yayo.

I-Fish Oil Dysregulation

I-Cholinergics yizinto ezikhuthaza i-acetylcholine, okanye i-ACh, kwaye i-choline ebuchosheni ngokunyuka kwe-ACh, ngokukodwa xa ikhubaza ukuwa kwe-ACh. Izigulane ezine-CIRS zihlala zifumana iingxaki ngokuchithwa kwamanqanaba e-acetylcholine emzimbeni womntu, ingakumbi kwingqondo. Ioli yeentlanzi ivuselela i-NRF2, isebenzise indlela yayo yokukhusela i-antioxidant ngaphakathi kweeseli. Abantu abanezigulo ezinganyangekiyo banokuba neengxaki zoxinzelelo lwengqondo kunye ne-acetylcholine excitotoxicity, ukusuka ekuqokelelekeni kwe-organophosphate, enokubangela ukuba i-oyile yeentlanzi idale ukudumba emzimbeni womntu. Ukusilela kweCholine ukongeza ukusebenza kwe-NRF2. Kubandakanya i-choline kwisidlo sakho, (i-polyphenols, amaqanda, njl. Njl.) Inokunceda ekuphuculeni iimpembelelo ze-cholinergic dysregulation.

Yintoni eyehlisa i-NRF2?

Ukunciphisa i-NRF2 ukugqithisa kakhulu kukulungele abantu abanomhlaza, nangona kunokuba luncedo kwiintlobo zeminye imiba yempilo.

Ukutya, iziNcediso, kunye namayeza aqhelekileyo:

  • Apigenin (amanani aphezulu)
  • Brucea javanica
  • Chestnuts
  • I-EGCG (iindleko eziphezulu zanda iNRF2)
  • Fenugreek (Trigonelline)
  • UHiba (Hinokitiol / ?-thujaplicin)
  • Isidlo seTyuwa esiphezulu
  • I-Luteolin (i-Celery, i-pepper eluhlaza, i-parsley, i-perilla leaf, kunye ne-chamomile tea - i-dose ephezulu iyakwandisa i-NRF2-40 mg / kg luteolin kathathu ngeveki)
  • I-Metformin (ukungadliyo okungapheliyo)
  • I-N-Acetyl-L-Cysteine ​​(i-NAC, ngokuthintela impendulo ye-oxidative, i-doses ephezulu)
  • I-Orange Peel (i-polymethoxylated flavonoids)
  • I-Quercetin (amanani aphezulu anganyusa iNRF2 - 50 mg / kg / d quercetin)
  • Salinomycin (iziyobisi)
  • I-retinol (yonke i-ac retinoic acid)
  • I-Vitamin C xa idibene neQuercetin
  • I-Zi Cao (i-Purple Gromwel i-Shikonin / i-Alkannin)

Iindlela kunye nezinye:

  • Bach1
  • ukubheja
  • Biofilms
  • Brusatol
  • Camptothecin
  • DNMT
  • DPP-23
  • EZH2
  • I-Glucocorticoid I-Receptor ukusayinwa (i-Dexamethasone ne-Betamethasone kunye)
  • I-GSK-3? (ingxelo elawulayo)
  • Kusebenze kwe-HDAC?
  • Halofuginone
  • I-Homocysteine ​​(i-ALCAR ingakwazi ukuguqula le homocysteine ​​yenza amazinga aphantsi a-NRF2)
  • IL-24
  • Keap1
  • MDA-7
  • I-NF? B.
  • I-Ochratoxin A (i-aspergillus neepeniciclium species)
  • Leprothemia ye-Promyelocytic
  • p38
  • p53
  • p97
  • I-alpha receptor alpha
  • Selenite
  • SYVN1 (Hrd1)
  • STAT3 inhibition (njenge-Cryptotanshinone)
  • I-Testosterone (kunye ne-Testosterone propionate, nangona i-TP intranasally inokunyusa iNRF2)
  • Trecator (Ethionamide)
  • I-Trx1 (ngokunciphisa iCys151 eKeep1 okanye kwiCys506 kwingingqi ye-NLS yeNrf2)
  • Trolox
  • Vorinostat
  • Ukunqongophala kweZinc (kwenza kube nzima nakubungqondo)

Indlela ye-Nrf2 yeNtsebenzo

Uxinzelelo lwe-oxidative lubangela i-CUL3 apho i-NRF2 esuka ku-KEAP1, inhibitor engafanelekanga, ingena kwinucleus yale seli, ivuselela ukubhalwa kwe-ARE, ijika i-sulfuridi ibe yi-disulfide, ibe iguqula ibe yi-geneticidants genes, ekhokelela ekuphuculweni kwe-antioxidants, njenge-GSH, i-GPX, i-GST, i-SOD, njl. Ezinye ezinye ziyakubonwa kwiluhlu olungezantsi:
  • Ukwandisa i-AKR
  • U kwandisa
  • Ukwandisa i-ATF4
  • Ukwandisa iBcl-xL
  • Ukwandisa iBcl-2
  • Ukwandisa iBDNF
  • Ukwandisa i-BRCA1
  • Ukwandisa c-Juni
  • Ukwandisa iCAT
  • Ukwandisa iCGMP
  • Ukwandisa i-CKIP-1
  • Ukwandisa i-CYP450
  • Ukwandisa iCul3
  • Ukwandisa i-GCL
  • Ukwandisa i-GCLC
  • Ukwandisa i-GCLM
  • Ukwandisa i-GCS
  • Ukwandisa i-GPx
  • Ukwandisa i-GR
  • Ukwandisa i-GSH
  • Ukwandisa i-GST
  • Ukwandisa iHIF1
  • Ukwandisa i-HO-1
  • Ukwandisa iHQO1
  • Ukwandisa i-HSP70
  • Ukwandisa i-IL-4
  • Ukwandisa i-IL-5
  • Ukwandisa i-IL-10
  • Ukwandisa i-IL-13
  • Ukwandisa i-K6
  • Ukwandisa i-K16
  • Ukwandisa i-K17
  • Ukwandisa iMEH
  • Ukwandisa uMnup2-5
  • Ukwandisa iNADPH
  • Ukwandisa i-Notch 1
  • Ukwandisa iNQO1
  • Ukwandisa iPARAR-alpha
  • Ukwandisa iPrx
  • Ukwandisa i-p62
  • Ukwandisa i-Sesn2
  • Ukwandisa i-Slco1b2
  • Ukwandisa i-sMafs
  • Ukwandisa i-SOD
  • Ukwandisa iTrx
  • Ukwandisa iTxn (d)
  • Ukwandisa UGT1 (A1 / 6)
  • Ukwandisa iVEGF
  • Iyanciphisa i-ADAMTS (4 / 5)
  • Iyancipha i-alpha-SMA
  • Iyancipha i-ALT
  • Iyancipha i-AP1
  • Iyanciphisa i-AST
  • Iyanciphisa iBach1
  • Iyancipha i-COX-2
  • Iyanciphisa i-DNMT
  • Iyancipha iFASN
  • Iyancipha iFGF
  • Iyanciphisa i-HDAC
  • Yehlisa i-IFN-?
  • Iyanciphisa i-IgE
  • Iyanciphisa i-IGF-1
  • Iyancipha i-IL-1b
  • Iyancipha i-IL-2
  • Iyancipha i-IL-6
  • Iyancipha i-IL-8
  • Iyancipha i-IL-25
  • Iyancipha i-IL-33
  • Iyancipha iNOS
  • Iyancipha i-LT
  • Iyanciphisa i-Keap1
  • Iyanciphisa i-MCP-1
  • Iyanciphisa iMIP-2
  • Iyanciphisa i-MMP-1
  • Iyanciphisa i-MMP-2
  • Iyanciphisa i-MMP-3
  • Iyanciphisa i-MMP-9
  • Iyanciphisa i-MMP-13
  • Iyanciphisa iNfkB
  • Iyancipha NO
  • Iyanciphisa i-SIRT1
  • Iyanciphisa i-TGF-b1
  • Iyanciphisa i-TNF-alpha
  • Iyanciphisa iTyr
  • Iyancipha i-VCAM-1
  • I-encoded kwi-gene NFE2L2, i-NRF2, okanye i-2 enxulumene ne-2 yenkampani ye-nerythroid, iyinqobo ye-leucine, okanye i-bZIP, i-superfamily esebenzisa iKap'n'Collar, okanye i-CNC isakhiwo.
  • Ikhuthaza ama-enzymes e-nitric, i-biotransformation enzymes, kunye ne-xenobiotic abathumeli bezithuthi.
  • Ngumlawuli obalulekileyo xa kusenziwa isigaba sesibini se-antioxidant kunye ne-detoxification enzyme genes, ekhusela iiseli kumonakalo obangelwe yi-oxidative stress kunye ne-electrophilic attack.
  • Ngeemeko ze-homeostatic, i-Nrf2 isetyenziswe kwi-cytosol ngokuqhotyoshelweyo komzimba we-N-terminal domain ye-Nrf2, okanye iprotheni ehlobene ne-Kelch-e-ECH okanye i-Keap1, ebizwa ngokuba yi-INrf2 okanye i-Inhibitor ye-Nrf2, yokuvimbela ukusetyenziswa kwe-Nrf2.
  • Inokuphinda ilawulwe yi-mammalian selenoprotein thioredoxin ukunciphisa i-1, okanye i-TrxR1, esebenza njengomlawuli ongekho.
  • Xa bexhatshazwa kwi-electrophilic stressors, i-Nrf2 idibanisa ne-Keap1, idlulisela kwinucleus, apho i-heterodidize idilesi yeprotheni elawulayo.
  • Ukusebenzisana rhoqo kunokubandakanya kunye nalawo asemagunyeni okubhalwa kwirejista uJun noFos, ezinokuba ngamalungu eproduct yentsapho yeprotini yezinto ezibhaliweyo.
  • Emva kokunciphisa, ezi zinkimbinkimbi zibophezela kwizinto eziphendulayo ze-antioxidant / electrophile / ARE / EPRE kwaye zisebenzise ukubhalwa kwephepha, njengoko kunjalo kwiinkomfa zakwaJun-Nrf2, okanye ukucima umbhalo, kufana ne-Fos-Nrf2.
  • Ukumiswa kwe-ARE, ekhutshwe okanye evinjelwe, iya kugqiba ukuba yeyiphi i-gene elawulwa ngodluliselo ngolu hlobo.
  • NINI ikhutshwa:
  1. Ukusebenza kwe-thesynthesis ye-antioxidants iyakwazi ukukhupha i-ROS njenge-catalase, superoxide-dismutase, okanye i-SOD, GSH-peroxidases, GSH-reductase, GSH-transferase, NADPH-quinone oxidoreductase, okanye i-NQO1, inkqubo yeCytochrome P450 monooxygenase, thioredoxin, reductase, kunye ne-HSP70.
  2. Ukusetyenziswa kwale synthase ye-GSH kuvumela ukukhula okuqaphelekayo kwenqanaba le-intracellular ye-GSH, ekhuselayo.
  3. Ukongezwa kwale nxalenye kunye namazinga e-phase II enzymes efana ne-UDP-glucuronosyltransferase, i-N-acetyltransferases kunye ne-sulfotransferase.
  4. Ukugqitywa kwe-HO-1, eyona mvume yokukhusela ekhuselekileyo yokukhula kwe CO, ngokubambisana ne-NO ivumela ukuba i-vasodilation yamaseli esicchem.
  5. Ukunciphisa i-iron overload ngokusebenzisa i-ferritin ephakamileyo kunye ne-bilirubin njenge-lipophilic antioxidant. Zombili iiprotheni zesigaba II kunye ne-antioxidants ziyakwazi ukulungisa uxinzelelo olungapheliyo lwe-oxidative kunye nokuvuselela inkqubo eqhelekileyo ye-redox.
  • I-GSK3? phantsi kolawulo lwe-AKT kunye ne-PI3K, i-phosphorylates Fyn ekhokelela kulwakhiwo lwenyukliya lwe-Fyn, ethi i-Fyn phosphorylates i-Nrf2Y568 ikhokelele kuthumelo lwenyukliya kunye nokonakaliswa kwe-Nrf2.
  • I-NRF2 iphinda inciphise impendulo ye-TH1 / TH17 kwaye ivuselele impendulo ye-TH2.
  • Ii-inhibitors ze-HDAC zenze indlela yokubonakalisa iNrf2 kwaye ilawulwa phezulu ukuba i-Nrf2 iinjongo eziphantsi kwe-HO-1, i-NQO1, kunye ne-glutamate-cysteine ​​ligase i-catalytic subunit, okanye i-GCLC, ngokukhupha i-Keap1 nokukhuthaza ukuhlukana kwe-Keap1 ukusuka kwi-Nrf2, i-Nrf2 i-transplant nuclear, ne-Nrf2 -AHA ebophayo.
  • I-Nrf2 ibandakanya isigxina-ubomi malunga nemizuzu ye-20 phantsi kweemeko ezisisiseko.
  • Ukunciphisa i-IKK? ichibi ngeKeap1 yokubopha kunciphisa I? B? Ukuthotywa isidima kwaye kunokuba yindlela engafunekiyo apho ukwenziwa kwe-Nrf2 kungqineke kuthintela ukwenziwa kwe-NF?
  • I-Keap1 ayisoloko idityaniswe ukuba i-NRF2 isebenze, njenge-chlorophyllin, blueberry, ellagic acid, i-astaxanthin kunye ne-tea polyphenols inokukhuthaza i-NRF2 kunye ne-KEAP1 kwi-400 ipesenti.
  • I-Nrf2 ilawula kakubi ngekota ye-stearoyl CoA desaturase, okanye i-SCD, ne-citrate lyase, okanye i-CL.

Genetics

KEAP1

Rs1048290

  • I-C allele - ibonakalise umngcipheko omkhulu kunye nefuthe elikhuselekileyo lokulwa nesifo sokuxhatshazwa kwezilwanyana (DRE)

rs11085735 (Ndiyi-AC)

  • idibene nenqanaba lokunciphisa ukusebenza komphunga kwi-LHS

MAPT

Rs242561

  • I-Tlele - ukukhusela i-Parkinsonian disorders-yayinamandla ngakumbi kwi-NRF2 / sMAF yokubopha kwaye yahlanganiswa namazinga aphezulu e-MAPT mRNA kwimimandla eyahlukeneyo ye-MAPT, kubandakanya i-cerebellar cortex (CRBL), i-cortex ye-tempte (i-TTX), into ebomvu ye-intralobula (i-WHMT)

NFE2L2 (NRF2)

rs10183914 (Ndiyi-CT)

  • T allele - ukwandiswa kwamanqanaba eprotheni ka-Nrf2 kunye nokulibazisa iminyaka yokuqalisa kweParkinson ngeminyaka emine

rs16865105 (Ndiyi-AC)

  • I-C allele - yayinobungozi obukhulu beZifo ze-Parkinson

rs1806649 (Ndiyi-CT)

  • I-C allele - sele ichongiwe kwaye ingaba ifanelekile kwi-etiology yomhlaza webele.
  • edibene nomngcipheko ophezulu wokwamkelwa esibhedlele ngexesha lamazinga aphezulu e-PM10

rs1962142 (NdingumGG)

  • I-allele - yayinxulumene nenqanaba eliphantsi le-cytoplasmic NRF2 ibinzana (P = 0.036) kunye ne-negative sulfiredoxin ibinzana (P = 0.042)
  • I-protected-left-protected from blood circulation (FEV) yokunciphisa (ukunyanzeliswa komthamo wokuphefumula kwesibini) ngokumalunga nesimo sokubhema ugwayi (p = 0.004)

rs2001350 (ndingumTT)

  • I-Tlele-protected-protected from FEV decline (ukunyanzeliswa komthamo wokuphefumula ngomzuzwana omnye) ngokumalunga nesimo sokubhema ugwayi (p = 0.004)

rs2364722 (NdingumAA)

  • Ikhuseleke ngokukhawuleza ukusuka kwi-FEV yokunciphisa (ukunyanzeliswa kwevolumu yokuphefumula kwesibini) ngokumalunga nesimo sokubhema ugwayi (p = 0.004)

Rs2364723

  • I-C iphela-inxulumene nokunciphisa kakhulu i-FEV kubantu baseJapan abanomdlavuza wamaphaphu

Rs2706110

  • G allele - ubonise umngcipheko omkhulu kunye nesiphumo esikhuselekileyo sokulwa nesifo sokuxhatshazwa kwezidakamizwa (DRE)
  • I-AA alleles - ibonise kakhulu incitshiso ye-KEAP1
  • I-AA alleles - idibene nomngcipheko wokwanda komhlaza wesibeleko (P = 0.011)

rs2886161 (ndingumTT)

  • I-allele - ehambelana neZifo ze-Parkinson

Rs2886162

  • I-allele-yayinxulunyaniswa nentetho ephantsi ye-NRF2 (P = 0.011; OKANYE, 1.988; CI, 1.162-3.400) kunye ne-AA genotype yayinxulumene nokuphila okungalunganga (P = 0.032; HR, 1.687; CI, 1.047 2.748)

rs35652124 (ndingumTT)

  • I-allele-ehambelana nephezulu ehambelana nobudala ekuqaleni kweSifo se-Parkinson vs G allele
  • I-C allele - inyuse iprotheni ye-NRF2
  • I-allele - yayineeprotheni ezingaphantsi kwe-NRF2 kunye nomngcipheko omkhulu wesifo senhliziyo kunye noxinzelelo lwegazi

rs6706649 (Ndiyi CC)

  • I-C allele - yayineeprotheni ezisezantsi ze-NRF2 kwaye yandisa ingozi yeZifo ze-Parkinson

rs6721961 (NdingumGG)

  • I-allele - yayineprotheni ephantsi yeNRF2
  • I-TT ithobela - umbutho phakathi kokubhema ugwayi kwi-smoking smokers kunye nokunciphisa izinga lomzimba
  • I-TT allele - yayinxulumene nomngcipheko wokwanda komhlaza webele [P = 0.008; OKANYE, 4.656; ixesha lokuzithemba (CI), 1.350�16.063] kunye ne-T allele idibaniswe nomlinganiselo ophantsi we-NRF2 inkcazo yeprotheni (P = 0.0003; OKANYE, 2.420; CI, 1.491�3.926) kunye ne-SRXN1 ibonakaliso (P = 0.047; 1.867; CI = 1.002�3.478)
  • I-allele - allele yadibaniswa ngokuchanekileyo ne-ALI ehlobene ne-28-day-mortality emva kwe-syicrome
  • I-Tlele-protected-protected from FEV decline (ukunyanzeliswa komthamo wokuphefumula ngomzuzwana omnye) ngokumalunga nesimo sokubhema ugwayi (p = 0.004)
  • G allele - enxulumene nomngcipheko ophezulu we-ALI olandela ingxaki enkulu kwi-Yurophu nase-Afrika-yaseMelika (umlinganiselo we-OR, X ORUMX; 6.44%
  • I-AA alleles - ehambelana nesifo sesifuba esisisifo
  • I-AA alleles - ibonakaliswe kakhulu ekunciphiseni imbonakalo ye-NRF2 yesimo somzimba kwaye ngenxa yoko, ingozi enkulu yomdlavuza wamaphaphu, ngakumbi abo babesolo
  • I-AA alleles - inomngcipheko ophezulu kakhulu wokuphuhlisa i-T2DM (OKANYE 1.77; 95% CI 1.26, 2.49; p = 0.011) ngokumalunga nalabo abane-CC genotype
  • I-AA ixhomekeke-inxulumano oluqilileyo phakathi kokulungiswa kwelinxeba kunye nobutshanje obunokutsha kweemitha-mlilo (ezinxulumene nomngcipheko ophezulu kakhulu wokuphuhlisa imiphumo emfutshane kwi-Afrika-baseMerika ngokuhamba kwiCaucasians)
  • ezinxulumene nomlomo we-estrogen unyango kunye nomngcipheko we-thromboembolism eneengqungquthela kubasetyhini abasemva

rs6726395 (Ndingum AG)

  • Ukhuselo olukhuselekileyo ukusuka kwi-FEV1 ukwehla (ukunyanzela umthamo wokuphefumula kwesibini) ngokumalunga nesimo sokubhema ugwayi (p = 0.004)
  • I-allele-ehambelana nokunciphisa kakhulu i-FEV1 kubantu baseJapan abanomdlavuza womphunga
  • I-GG alleles - yayinezinga eliphezulu leNRF2 kwaye iyancipha umngcipheko wokuhlaselwa kwe-macular
  • I-GG alleles - yayinomdla ophezulu kunye neCholangiocarcinoma

rs7557529 (Ndiyi-CT)

  • I-C iphela-ehambelana nezifo ze-Parkinson
UDkt Jimenez White Coat
Uxinzelelo lwe-oxidative kunye nezinye izixinzelelo zingabangela umonakalo weseli ekugqibeleni ekukhokelela kwimibandela yezempilo. Uphando luye lwabonisa ukuba ukusebenza kwe-Nrf2 kunokukhuthaza umzimba wokhuselo lomzimba wokukhusela i-antioxidant, nangona kunjalo, abaphandi baye baxubusha ukuba i-Nrf2 ukugqithisa ingxaki inokuba neyona mngcipheko omkhulu kwimpilo kunye nokuphila kakuhle. Iindidi ezahlukahlukeneyo zomhlaza zingenzeka kwakhona nge-Nrf2 yokuqhekeza. 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:
  • 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.
Ngokwezifundo zophando, i-Nrf2, yeyona nto ibalulekileyo ekhutshelweyo eyenza ukuba iiseli zikhusele iindlela zokulwa ne-antioxidant ukuze zikhuphe ubuthi emzimbeni womntu. Ukugqithiswa kwe-Nrf2, nangona kunjalo, kunokubangela 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
Ikholi ye-Green Call Now Button H .png

Ingxoxo yesihloko esongezelelweyo: cBuhlungu obuBuhlungu

Umqolo obuhlunguSesinye sezona zinto zixhaphakileyo zokukhubazeka kunye neentsuku eziphosiweyo emsebenzini kwihlabathi liphela. Iimpawu ezibuhlungu zangasemva kwisizathu sesibini esiqhelekileyo sokutyelelwa kweofisi kagqirha, ngaphezulu kwenani losulelo oluphezulu lokuphefumla. Ngokumalunga neepesenti ezingama-80 zabemi baya kuba neentlungu zentlungu emva kanye ebomini babo. Umqolo sisakhiwo esintsonkothileyo esenziwe ngamathambo, amalungu, iigaments, kunye nezihlunu, phakathi kwezinye izicwili ezithambileyo. Ukwenzakala kunye / okanye iimeko ezixhonyiweyo, ezinje ngedisni, 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.  
umfanekiso weblogi wekratshi yephepha

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

***
Umsebenzi we-Nrf2 Ukuqalisa

Umsebenzi we-Nrf2 Ukuqalisa

Uninzi lweengxelo zophando ngokuphathelele umdlavuza ziye zavumela ootitshala bezempilo ukuba baqonde indlela umzimba uchithe ngayo. Ngokuhlalutya izakhi zofuzo ezisemgangathweni kwiiseli ezixhamlayo, abaphandi bafumene i-nyukliya erythroid I-2 enxulumene ne-2 yokubonisa indlela, eyaziwayo njengeNrf2. I-NRF2 yinto ebalulekileyo yenguqu ebhaliweyo eyenza umzimba womzimba iindlela zokukhusela i-antioxidant ukuze kulawulwe i-oxidation kwizinto zombini zangaphakathi kunye zangaphakathi ukukhusela amanqanaba okwandisa uxinzelelo.

Iimigaqo zeNrf2

I-NRF2 ibalulekile ekugcineni impilo yonke nokuba sempilweni kwayo kuba iyayisebenzisa eyona njongo iphambili yokulawula indlela esilawula ngayo yonke into esijongana nayo yonke imihla kwaye singaguli. Ukusebenza kwe-NRF2 kudlala indima kwinkqubo yesixokelelwano sokuxutywa kwentsholongwane. Kwinqanaba I.

Ukusebenza kwe-NRF2 kuncitshisa i-oxidation jikelele kunye nokuvuvukala komzimba womntu ngefuthe elibi. Ukubangela i-NRF2, ukuphendula okuvuthayo ngenxa ye-oxidation kufuneka kwenzeke ukwenzela ukuba iiseli zivelise impendulo eguquguqukayo kwaye zenze i-antioxidants, njenge glutathione. Ukuphula umgaqo we-Nrf2, ngokukodwa, ukunyanzeliswa kwengcinezelo kusebenze i-NRF2 leyo leyo isebenzayo impendulo ye-antioxidant emzimbeni womntu. Imisebenzi ye-NRF2 ukulinganisela ukubonakaliswa kwe-redox, okanye ukulingana kwamanqanaba akhuphayo kunye ne-antioxidant kwiseli.

Umzekeliso omkhulu wendlela le nkqubo isebenza ngayo ingabonakaliswa ngokwenza umthambo. Kuwo wonke umsebenzi, umsipha uhlengahlengiso ukuze ukwazi ukufumana enye iseshoni yokuzilolonga. Ukuba i-NRF2 iba ngaphantsi okanye ichazwe ngaphezulu ngenxa yosulelo olunganyangekiyo okanye ukonyuka kokuvezwa kwetyhefu, enokuthi iqatshelwe kwizigulana ezinesifo esinganyangekiyo sokuphendula ngokudumba, okanye i-CIRS, imiba yezempilo inokuba mandundu - ngokulandela ukusebenza kwe-NRF2. Ngaphezu kwako konke, ukuba i-DJ-1 iba ne-oxidized engaphezulu, ukusebenza kwe-NRF2 kuya kuphela ngokukhawuleza.

Iimpembelelo ze-NRF2 Ukuqalisa

Ukusebenza kwe-NRF2 kubonakaliswe kakhulu kwimiphunga, isibindi kunye neentso. I-nuclear erythroid i-2 enxulumene ne-2, okanye i-NRF2, ngokuqhelekileyo isebenza ngokunciphisa amanqanaba okwanda kwe-oxidation emzimbeni womntu onokubangela uxinzelelo lwe-oxidative. Ukuqalisa ukusebenza kwe-Nrf2 kunokunceda ukuphatha iinkalo ezahlukeneyo zempilo, nangona kunjalo, ukusetyenziswa ngokugqithiseleyo kwe-Nrf2 kunokudambisa iingxaki ezahlukeneyo, eziboniswa ngezantsi.

Ukusebenza kwesikhashana kweNrf2 kunokukunceda:

  • Ukuguga (oko kukuthi ubude)
  • Ukuzimela ngokuzenzekelayo kunye nokuvutha okubanzi (oko kukuthi iArthritis, Autism)
  • I-Cancer kunye ne-Chemoprotection (oko kukuthi i-EMF Exposure)
  • Ukuxinezeleka kunye nokuxhalabisa (oko kukuthi i-PTSD)
  • Ukuboniswa kweziyobisi (i-Alcohol, i-NSAID)
  • Ukuzivocavoca nokuSebenza koMonde
  • Izifo ze-Gut (ie i-SIBO, iDysbiosis, Ulcerative Colitis)
  • Izifo Zeengso (oko kukuthi Kukho ukulimala kweentso, i-Lupus Nephritis)
  • Izifo zesibindi (oko kukuthi isifo soTywala, i-Acute hepatitis, i-Nonalcoholic Fatty Liver Disease, i-Nonalcoholic Steatohepatitis, i-Cirrhosis)
  • Izifo eziLungile (okt Asthma, Fibrosis)
  • I-Metabolic and Vascular Disease (ie Atherosclerosis, Hypertension, Stroke, Isifo sikashukela)
  • I-neurodegeneration (okt i-Alzheimer's, i-Parkinson, i-Huntington kunye ne-ALS)
  • Ubuhlungu (oko kukuthi i-Neuropathy)
  • Izifo zesikhumba (okt Psoriasis, UVB / Sun Protection)
  • I-Toxin Exposure (Arsenic, Asbestos, Cadmium, i-Fluoride, i-Glyphosate, i-Mercury, i-Sepsis, i-smoke)
  • Umbono (oko kukuthi ukukhanya okuKhanya, ukuKhathazeka, iiCataracts, iCorneal Dystrophy)

Ukucatshulwa kwe-Nrf2 kunokugqithisa:

  • Atherosclerosis
  • I-Cancer (oko kukuthi ubuchopho, isisu, intloko, i-neck Pancreatic, iprostate, intsholongwane, i-Thyroid)
  • Isifo Sengqondo Esiphefumulayo Sempendulo (CIRS)
  • Ukufakelwa kwenhliziyo (ngelixa i-NRF2 evulekile ingaba yingozi, i-NRF2 inokukunceda ukulungisa)
  • hepatitis C
  • I-Nephritis (iimeko ezinzima)
  • Vitiligo

Ngaphaya koko, i-NRF2 inokunceda ekwenzeni izongezo ezithile zesondlo, iziyobisi, kunye nomsebenzi wamayeza. Izixhobo ezininzi zendalo zinokunceda ukubangela i-NRF2. Ngophando lwangoku lophando, abaphandi babonakalisile ukuba inani elikhulu leekhompawundi ekwakukholelwa ukuba zii-antioxidants zazizezinyani ngokwenene. Kungenxa yokuba phantse zonke zifuna i-NRF2 ukuze isebenze, nokuba zincedisa njenge-curcumin kunye neoyile yeentlanzi. I-cocoa, umzekelo, ibonakalisiwe ukuvelisa iziphumo ze-antioxidant kwiimpuku ezine-NRF2 gene.

Iindlela zokuqalisa i-NRF2

Kwimeko yezifo ezingenayo i-neurodeergenerative njenge-Alzheimer's disease, isifo sika-Parkinson, isifo okanye isifo se-autoimmune, mhlawumbi kungcono ukuba ne-Nrf2 iphakanyiswe, kodwa ngeendlela ezivuthayo. Ukuxuba i-activators ye-NRF2 ingaba nesiphumo esongezelelweyo okanye isistim, njengokuba ngezinye izihlandlo sinokuxhomekeka kwimizi. Izindlela eziphezulu zokunyusa iNrf2 ibonakaliso zidweliswe ngezantsi:

  • I-HIST (Ukuzivocavoca) + CoQ10 + Ilanga (le synergize kakuhle)
  • I-Broccoli ihluma + i-LLLT entlokweni nasemathambo
  • Butyrate + Super Coffee + Morning Sun
  • Ukwenziwa kwe-Acupuncture (le ndlela yindlela enye, i-laser acupuncture ingasetyenziswa kwakhona)
  • Ukuzila
  • Cannabidiol (CBD)
  • I-Lion's Mane + i-Melatonin
  • I-Alpha-lipoic acid + DIM
  • Umhlonyane
  • Ukuqaliswa kwe-PPAR-gamma

Uluhlu olulandelayo olupheleleyo oluqulethe ezinye iindlela ze-350 zokuqalisa i-Nrf2 ngokutya, indlela yokuphila kunye nezixhobo, iiprobitics, izongezo, iifrimbi kunye namafutha, ama-hormone kunye ne-neurotransmitters, izidakamizwa / imichiza kunye neekhemikhali, iindlela kunye neendlela zokubhala, kunye nezinye iindlela isikhokelo esifutshane malunga noko kunokubangela iNrf2. Ngenxa yokukhawuleza kweli nqaku, siye sishiya ngaphezu kwe-500 nezinye ukutya, izongezelelo zondlo kunye nezixhobo ezinokunceda ukuvula iNrf2. Ezi zilandelayo zidweliswe ngezantsi:

Ukutya:

  • Acai Berries
  • Utywala (iwayini elibomvu lungcono, ngakumbi ukuba kukho ikhoksi kuyo, njengokuba iprotocatechuic aldehyde kwi-coorks inokuphinda isebenze i-NRF2. Ngokuqhelekileyo, utywala alunyanzelwanga, nangona ukunyusa okuninzi kukunyusa i-NRF2. Ukutya okungapheliyo kunokunciphisa i-NRF2.
  • Algae (kelp)
  • IiApile
  • Ihoyi emnyama
  • Nutshontsho zaseBrazil
  • I-Broccoli Ihluma (kunye nezinye i-isothiocyanates, i-sulforaphane kwakunye nemifuno e-cruciferous efana ne-bok choy ene-D3T)
  • I-Blueberries (0.6-10 g / imini)
  • Iidroth (falcarinone)
  • I-Cayenne Pepper (iCapsaicin)
  • I-Celery (i-Butylphthalide)
  • Chaga (Betulin)
  • I-Chamomile Tea
  • Chia
  • Potato yaseTshayina
  • Chokeberries (Aronia)
  • Icoleta (Ubumnyama okanye iCocoa)
  • Cinnamon
  • Ikhofi (njenge-chlorogenic acid, iCafestol neKahweol)
  • Cordyceps
  • Intlanzi (kunye neShellfish)
  • I-Flaxseed
  • Garlic
  • Ghee (mhlawumbi)
  • I-Ginger (neKaramonin)
  • Gojiberries
  • I-Grapefruit (Naringenin - 50 mg / kg / d naringenin)
  • Amagilebhisi
  • Iti eluhlaza
  • guava
  • Intliziyo yePalm
  • Hijiki / Wakame
  • I-honeycomb
  • ikiwi
  • Imifuno
  • I-Lion's Mane
  • Mahuwa
  • Mangos (Mangiferin)
  • Mangosteen
  • Ubisi (ibhokhwe, inkomo - ngokusebenzisa umgaqo we-microbiome)
  • I-Mulberries
  • Ioli yeOlive (ipomace - hydroxytyrosol kunye ne-Oleanolic acid)
  • I-Omega 6 Fatty Acids (i-Lipoxin A4)
  • Osange Oranges (Morin)
  • Amashroom Oyster
  • Ipapaya
  • Amanqatha
  • IiPigeon Peas
  • Igromegranate (iPunicalagin, iAlilagic Acid)
  • IPolisi (iPinocembrin)
  • AmaPatates aMnandi
  • IRambutan (iGeraniin)
  • Anyanisi
  • Reishi
  • Rhodiola Rosea (Salidroside)
  • I-Bran Bran (i-cycloartenyl ferulate)
  • Riceberry
  • IRooibos Tea
  • IRosemary
  • umba-
  • Umgcini
  • I-Sesame yeOyile
  • I-Soy (kunye neeoflavones, Daidzein, Genistein)
  • I-squash
  • Ierberberries
  • I-Tartary buckwheat
  • Thyme
  • iitumato
  • Ubhontshisi be Tonka
  • nethamarikhi
  • Wasabi
  • Ujodo

Indlela yokuphila kunye namadivayisi:

  • Ukwenziwa kwe-Acupuncture kunye ne-Electroacupuncture (nge-collagen i-ECM)
  • Isibane esiluhlaza
  • Imidlalo yeBongo (yandisa i-NRF2 kwi-hippocampus)
  • Ukukhawulwa kweCaloric
  • Ubunzima (imvula, i-plunges, ibhanti ye-ice, igesi, i-cryotheraphy)
  • EMFs (i-frequency ephantsi, njenge-PEMF)
  • Ukuzivocavoca umzimba (Ukuzivocavoca okunamandla njenge-HIST okanye i-HIIT kubonakala kuluncedo ekuphembeleleni i-NRF2, ngelixa umthambo omde ungayenzi i-NRF2, kodwa inyusa amanqanaba e-glutathione)
  • Ukutya okuphezulu okutya (ukutya)
  • Ukushisa okuphakamileyo (iSauna)
  • Hydrogen Inhalation kunye ne-Hydrogen Water
  • Unyango lwe-Oxygen Hyperbaric
  • Utyholongwane olwenziwe kakubi (njengoJovvv)
  • Intravenous Vitamin C
  • Isidlo seKetogenic
  • Ozone
  • Ukubhema (akunyanzelwanga - ukwanda kokutshaya kwe-NRF2, ukutshaya okungapheliyo kunciphisa i-NRF2. Ukuba ukhetha ukutshaya, i-Holy Basil inokukunceda ukukhusela ukuhlaselwa kwe-NRF2)
  • Ilanga (UVB kunye ne-Infrared)

Probiotics:

  • Bacillus subtilis (fmbJ)
  • I-Clostridium butyricum (MIYAIRI 588)
  • Lactobacillus brevis
  • I-Lactobacillus casei (i-SC4 ne-114001)
  • Lactobacillus collinoides
  • I-Lactobacillus gasseri (OLL2809, L13-Ia, kunye neSBT2055)
  • I-Lactobacillus helveticus (NS8)
  • I-Lactobacillus paracasei (NTU 101)
  • I-Lactobacillus plantarum (C88, CAI6, FC225, SC4)
  • I-Lactobacillus rhamnosus (GG)

Izibonelelo, iiHerbs, namafutha:

  • I-Acetyl-L-Carnitine (ALCAR) neCarnitine
  • Allicin
  • I-Alpha-lipoic acid
  • Amentoflavone
  • Andrographis paniculata
  • Agmatine
  • Apigenin
  • Arginine
  • I-Artichoke (i-Cyanropicrin)
  • Ashwaganda
  • Astragalus
  • Bacopa
  • Beefsteak (Isogemaketone)
  • Berberine
  • I-Beta-caryophyllene
  • UBidiens Pilosa
  • I-Black Cumin Imbewu ye-Oil (Thymoquinone)
  • Boswellia
  • Butein
  • Bhoxisa
  • Cannabidiol (CBD)
  • I-Carotenioids (njenge-Beta-carotene [i-synergy ne-Lycopene – 2 � 15 mg/d lycopene], i-Fucoxanthin, i-Zeaxanthin, i-Astaxanthin, ne-Lutein)
  • Chitrak
  • Chlorella
  • Chlorophyll
  • Chrysanthemum zawadskii
  • Cinnamomea
  • Common Sundew
  • ubhedu
  • ECoptis
  • CoQ10
  • Curcumin
  • Damiana
  • UDan Shen / uSage obomvu (iMiltirone)
  • DIM
  • Dioscin
  • Dong Ling Cao
  • I-Dong Quai (i-female ginseng)
  • Ecklonia Cava
  • EGCG
  • Elecampane / Inula
  • Eucommia Bark
  • Feric acid Acid
  • Fisetin
  • Ioyile yeentlanzi (i-DHA / i-EPA-3 1 g / d yeoyile yentlanzi ene-1098 mg EPA kunye ne-549 mg DHA)
  • Galangal
  • Gastrodin (Tian Ma)
  • Gentiana
  • IGeranium
  • UGinkgo Biloba (Gink gold B)
  • Glasswort
  • Gotu Kola
  • Imbewu yeMbewu yeMbewu
  • Agrimony enoboya
  • Haritaki (Triphala)
  • Hawthorn
  • Helichrysum
  • IHenna (iJuglone)
  • Hibiscus
  • Higenamine
  • I-Basil engcwele / iTulsi (i-Ursolic Acid)
  • Hops
  • I-Horny Goat Weed (Icariin / Icariside)
  • Indigo Naturalis
  • Intsimbi (ayikhuthazwa ngaphandle kokuba ibalulekile)
  • I3C
  • Iinyembezi zikaYobhi
  • UMoringa Oleifera (njengoKafferol)
  • Inchinkoto (i-combo yeZhi Zi kunye ne-Wormwood)
  • I-Kudzu Root
  • Rootice Root
  • I-Lindera Root
  • I-Luteolin (amanani aphezulu ekusebenziseni, amanani aphantsi awanqanda i-NRF2 kumhlaza nangona kunjalo)
  • Magnolia
  • Manjistha
  • Maximowiczianum (i-Acerogenin A)
  • Arnica waseMexico
  • Ingxube Yamanzi
  • MitoQ
  • Mu Xiang
  • Mucuna Pruriens
  • Nicotinamide kunye neNAD +
  • Panax Ginseng
  • I-Passionflower (njenge-Chrysin, kodwa i-chyrisin inganciphisa iNRF2 nge-dysregulation ye-PI3K / Akt ukubonisa)
  • I-Pau dcoarco (Lapacho)
  • Phloretin
  • Piceatannol
  • PQQ
  • Procyanidin
  • Pterostilbene
  • Pueraria
  • I-Quercetin (amanani aphezulu kuphela, amanani aphantsi awanqanda i-NRF2)
  • Qiang Huo
  • Red Clover
  • I-Resveratrol (i-Piceid kunye nezinye i-phytoestrogens ngokwenene, i-Knotweed)
  • Rose Hips
  • Rosewood
  • Rutin
  • Sappanwood
  • Sarsaparilla
  • Saururus chinensis
  • I-SC-E1 (iGypsum, Jasmine, i-Licorice, iKudzu, kunye neBhalon Flower)
  • Schisandra
  • UkuPhilisa (i-prunella)
  • Skullcap (Baicalin noWogonin)
  • Inkunzi yeSerrel
  • Si Wu Tang
  • Sideritis
  • ISpikenard (Aralia)
  • Spirulina
  • ISt John's Wort
  • ISulfrafa
  • Sutherlandia
  • Tao Hong Si Wu
  • Taurine
  • Iindudumo zikaThixo iVine (i-Triptolide)
  • I-Tocopherols (njenge-Vitamin E okanye i-Linalool)
  • Tribulus R
  • Tu Si Zi
  • TUDCA
  • I-Vitamin A (nangona ezinye i-retinoids zivimbela i-NRF2)
  • I-Vitamin C (idosi ephezulu kuphela, idosi ephantsi iyanqanda�NRF2)
  • I-Vitex / Umthi ococekileyo
  • I-White Peony (i-Paeoniflorin esuka ePaeonia lactiflora)
  • Umhlonyane (Hispidulin noArtemisinin)
  • Xiao Yao Wan (I-Free and Easy Wanderer)
  • Yerba Santa (uEliodictyol)
  • Yuan Zhi (Tenuigenin)
  • I-Zi Cao (iya kunciphisa i-NRF2 emdlalweni)
  • Izinki
  • Ziziphus Jujube

IiHormones kunye namaNeurotransmitters:

  • Adiponectin
  • Adropin
  • I-Estrogen (kodwa inganciphisa i-NRF2 kwiisisu zebele)
  • Melatonin
  • Progesterone
  • I-Quinolinic Acid (ekuphenduleni ukukhusela i-excitotoxicity)
  • Serotonin
  • IiHormone zeTyroid ezifana ne-T3 (inokwandisa i-NRF2 kwiiseli ezinempilo, kodwa iyancipha ngomhlaza)
  • Vitamin D

Iziyobisi / iMichiza kunye neekhemikhali:

  • Acetaminophen
  • Acetazolamide
  • Amlodipine
  • I-Auranofin
  • Bardoxolone methyl (BARD)
  • Benznidazole
  • bha
  • CDDO-imidazolide
  • I-Ceftriaxone (kunye ne-beta-lactam antibiotics)
  • Cialis
  • Dexamethasone
  • IDiprivan (Propofol)
  • UEliodictyol
  • Exendin-4
  • Ezetimibe
  • Fluoride
  • Fumarate
  • HNE (oxidized)
  • Idazoxan
  • I-arsenic engaqhelekanga kunye ne-sodium arsenite
  • I-JQ1 (inokuvimbela i-NRF2 kwakhona, engaziwa)
  • Governmentiris
  • UMelphalan
  • Methazolamide
  • I-Methylene Blue
  • Nifedipine
  • NSAID
  • Oltipraz
  • Ii-PPIs (njenge-Omeprazole kunye neLansoprazole)
  • Iiprotandim - iziphumo ezinkulu kwi vivo, kodwa zibuthathaka / azikhoyo ekusebenziseni i-NRF2 kubantu
  • Probucol
  • Rapamycin
  • Reserpine
  • IRuthhenium
  • Sitaxentan
  • Izitatimende (ezifana ne-Lipitor neSimvastatin)
  • Tamoxifen
  • Tang Luo Ning
  • tBHQ
  • I-Tecfidera (i-Dimethyl fumarate)
  • I-THC (engaqiniseki njenge-CBD)
  • Theophylline
  • Umbelliferone
  • Ursodeoxycholic Acid (UDCA)
  • IVerapamil
  • Viagra
  • 4-Acetoxyphenol

Iindlela / Izinto zokuTshintshe:

  • ?7 NAChR isebenze
  • AMPK
  • Bilirubin
  • CDK20
  • CKIP-1
  • CYP2E1
  • EAATs
  • Gankyrin
  • Gremlin
  • GJA1
  • H-ferritin ferroxidase
  • I-HDAC inhibitors (njenge-valproic acid kunye ne-TSA, kodwa ingabangela ukungazinzi kwe-NRF2)
  • Iiprotheni ezithusayo
  • IL-17
  • IL-22
  • IKlotho
  • mvumele-7 (uyakhonkca phantsi i-BX1 RNA)
  • MAPK
  • Abamkeleki bakaMichael (abaninzi)
  • miR-141
  • miR-153
  • i-miR-155 (idibanisa i-MBach1 RNA kwakhona)
  • i-miR-7 (ebuchosheni, inceda umdlavuza kunye ne-schizophrenia)
  • Notch1
  • Uxinzelelo lwe-Oxyidative (njengeROS, RNS, H2O2) kunye ne-Electrophiles
  • I-PGC-1?
  • I-PKC-delta
  • I-PPAR-gamma (iziphumo zentsebenziswano)
  • I-Sigma-1 receptor inhibition
  • I-SIRT1 (yandisa i-NRF2 ebuchosheni nasemiphungeni kodwa inganciphisa yonke)
  • SIRT2
  • ISIRT6 (kwisibindi kunye nengqondo)
  • SRXN1
  • I-TrxR1 inhibition (ukucinywa okanye ukuchithwa kwakhona)
  • Zinc protoporphyrin
  • 4-HHE

Okunye:

  • Ankaflavin
  • Asbestos
  • Avicins
  • Bacillus amyloliquefaciens (esetyenziswe kwezolimo)
  • ICarbon Monoxide
  • Daphnetin
  • Ukuncipha kweGlutathione (ukuncipha kwe80%�90% kunokwenzeka)
  • Gymnaster koraiensis
  • hepatitis C
  • Herpes (HSV)
  • Umthi womlotha waseNdiya
  • Indigowoad Root
  • Isosalipurposide
  • Isorhamentin
  • I-Monascin
  • I-Omaveloxolone (eqinile, aka RTA-408)
  • PDTC
  • Ukwehla kweSelenium (ukusilela kwe-selenium kunokunyusa iNRF2)
  • Luberia waseLiberia
  • Sophoraflavanone G
  • Tadehagi triquetrum
  • Ukubona sinensis (7-DGD)
  • ICilongo Flower
  • 63171 kunye ne63179 (eqinile)
UDkt Jimenez White Coat
I-nyukliya ye-erythroid i-2 ehambelana ne-2 indlela yokubonisa, eyaziwa ngokuba ngu-Nrf2, yinto ebhaliweyo eyenza indima enkulu yokulawula iindlela zokukhusela i-antioxidant body body, ngokukodwa ukwenzela ukulawula uxinzelelo lwe-oxidative. Nangona amazinga okwandisa uxinzelelo lwe-oxidative angasebenzisa i-Nrf2, iimpembelelo zalo ziphakanyiswa ngokugqithiseleyo ngokufumaneka kwamacandelo athile. Ukutya okunye kunye nezongezelelo kukunceda kusebenze iNrf2 emzimbeni womntu, kubandakanywa isothiocyanate sulforaphane zivela kwi-broccoli. 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:

  • 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.

Ngokophando oluninzi lwangoku, inyukliya erythroid 2-enxulumene ne-2 indlela yokubonisa, eyaziwa ngokuba yi-Nrf2, yinto ebalulekileyo ekhutshelweyo eyenza ukuba iiseli zikhusele iindlela zokulwa nokukhusela umzimba womntu kwizinto zangaphandle nangaphakathi kunye nokuthintela ukwanda amanqanaba oxinzelelo lwe-oxidative. 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

Ikholi ye-Green Call Now Button H .png

Ingxoxo yesihloko esongezelelweyo: cBuhlungu obuBuhlungu

Umqolo obuhlunguSesinye sezona zinto zixhaphakileyo zokukhubazeka kunye neentsuku eziphosiweyo emsebenzini kwihlabathi liphela. Iimpawu ezibuhlungu zangasemva kwisizathu sesibini esiqhelekileyo sokutyelelwa kweofisi kagqirha, ngaphezulu kwenani losulelo oluphezulu lokuphefumla. Ngokumalunga neepesenti ezingama-80 zabemi baya kuba neentlungu zentlungu emva kanye ebomini babo. Umqolo sisakhiwo esintsonkothileyo esenziwe ngamathambo, amalungu, iigaments, kunye nezihlunu, phakathi kwezinye izicwili ezithambileyo. Ukwenzakala kunye / okanye iimeko ezixhonyiweyo, 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. �

umfanekiso weblogi wekratshi yephepha

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

***

Ziziphi iinzuzo zeNrf2?

Ziziphi iinzuzo zeNrf2?

Uxinzelelo oluxhamlayo luyinxaxheba enkulu ekuphuhlisweni kwemiba yezempilo eyahlukeneyo, kuquka nomhlaza, isifo senhliziyo, isifo sikashukela, ukuguga ngokukhawuleza kunye ne-neurodegeneneration. Ukutya okucebileyo, iitrob kunye nezongezelelo zingasetyenziselwa ukukhusela umzimba womntu ukusuka kumanqanaba aphakamileyo oxinzelelo. Uphando olutsha luye lwabonisa ukuba Indlela yokuguqula i-Nrf2 unokunceda ukukhulisa imiphumo ye-antioxidants. I iinzuzo zeNrf2 zichazwe ngezantsi.

Ukhusela iBhunga malunga neTyxin

I-NRF2 yinto yangaphakathi enokukhusela iiseli kwizinto ezinobungozi, zangaphakathi nangaphandle. I-NRF2 inokunceda ekuphuculeni indlela umzimba womntu osabela ngayo kwiziyobisi / kumayeza kunye ne-toxins, ukuphucula ukuveliswa kweeprotheyini ezinceda ukuphelisa i-compounds kwiseli, eyaziwa ngokuba yi-multidrug resistance-associated proteins, okanye i-MRPs. Ukuphefumla umsi wecuba ukuvumela imiphunga ukuba ikhuphe ubutyhefu.

Ukongeza, kubalulekile ukuba imiphunga izikhusele ngokuchasene nezinto ezinokuthi zenzeke, izifo zentsholongwane, i-endotoxins yebhaktiriya, i-hyperoxia, kunye nezinto ezahlukeneyo ezingcolisa indalo. I-trigger eqhubekayo ye-Nrf2 nangona kunjalo, inokunciphisa amanqanaba ento eyaziwa ngokuba yi-glutathione kuwo wonke umzimba womntu. I-NRF2 inokukhusela isibindi kwityhefu kwaye inokukhusela isibindi kwi-arsenic hepatotoxicity. Ngaphezu koko, i-NRF2 ikhusela isibindi kunye nengqondo ekusetyenzisweni kotywala. Ngokomzekelo, i-Nrf2 inokukhusela ngokuchasene ne-acetaminophen toxicity.

Ukulwa nokuvuvukala kunye nokuxinezeleka koxinzelelo

Ukuqalisa ukusebenza kwe-NRF2 kunokunceda ukulwa nokuvuvukala ngokunciphisa ama-cytokines avuzayo, afana nalawo akhona kwi-psoriasis. I-NRF2 inokunciphisa ukutshaya okunxulumene neentlobo zempilo ezinjenge-arthritis kunye ne-fibrosis yesibindi, izintso kunye nemiphunga. I-NRF2 inokukunceda ukulawula i-allergies ngokunciphisa i-Th1 / iT17 cytokines nokuphakamisa i-cytokines ye-TH2. Oku kunokuba luncedo kwizifo ezinjenge-asthma.

I-NRF2 ikwakhusela kumonakalo weselula ukusuka ekukhanyeni okuluhlaza �kunye nakwi-UVA/UVB� efumaneka ekukhanyeni kwelanga. Ukusilela kwe-Nrf2 kunokwenza ukuba kube lula kakhulu ukufumana ukutshiswa lilanga. Enye ingqiqo emva koku kukuba i-NRF2 iyakwazi ukulawula i-collagen ekuphenduleni imisebe ye-UV. I-Advanced Glycation End-Products, okanye i-AGEs, igalelo ekuphuhliseni imiba emininzi yezempilo, kuquka isifo sikashukela kunye nezifo ze-neurodeergenerative. I-NRF2 inokunciphisa uxinzelelo lwe-oxidative ye-AGEs ngaphakathi komzimba. I-NRF2 inokukhusela umzimba womntu kumanqanaba aphezulu oxinzelelo olusekelwe kubushushu.

Uphucula iMitochondria kunye nokuSebenza koMsebenzi

I-NRF2 yi-booster ye-mitochondrial. Ukusebenza kwe-NRF2 kunegalelo ekunyukeni kwamandla e-ATP kwi-mitochondria, ngaphezu kokusetyenziswa okuphuculweyo kwe-oksijini, okanye i-citrate, kunye namafutha. Ngaphandle kwe-NRF2, i-mitochondria iya kuba namandla okusebenza kunye noshukela, okanye i-glucose, kunamafutha. I-NRF2 ikwabalulekile kwimitochondria ukuba iphuhle ngenkqubo eyaziwa ngokuba yi-biogenesis. Ukusebenza kwe-NRF2 kubalulekile ukuze �ukuxhamla kwiinzuzo zokuzilolonga.

Ngenxa yomsebenzi we-Nrf2, umthambo uphakamisa umsebenzi we-mitochondrial, apho esi siphumo sinokunyuswa nge-CoQ10, iCordyceps, kunye neCaloric Restriction. Ukuzivocavoca okuphakathi okanye ukuzivocavoca ngokukhawuleza kubangela i-mitochondrial biogenesis kunye ne-synthesis ephakamileyo ye-superoxide dismutase, okanye i-SOD, kunye ne-heme-oxygenase-1, okanye i-HO-1, ngokusebenzisa i-NRF2 activation. I-Alpha-Lipoic Acid, � okanye i-ALA, kunye noDan Shen banokunyusa i-NRF2 mediated mitochondrial biogenesis. Ngapha koko, i-NRF2 inokuphucula ukunyamezelana komthambo apho ukususwa kwe-NRF2 kwenza umthambo ube yingozi.

Khusela i Hypoxia

I-NRF2 inceda ekukhuseleni umzimba womntu kwi-cellular oxygen loss / dection, umcimbi wezempilo obizwa ngokuba yi-hypoxia. Abantu ngabanye abane-CIRS banciphise amazinga oksijeni ekubeni i-NRF2 yabo ivinjelwe, oku kuphumela kumanqanaba amancinci we-VEGF, i-HIF1 kunye ne-HO-1. Ngokuqhelekileyo, kubantu abanezempilo abane-hypoxia, i-miR-101, efunekayo ekudalweni kweeseli ze-stem, zixhalabele kwaye zikhulise inani lee-NRF2 / HO-1 kunye ne-VEGF / iNOS, ngoko ukukhusela umonakalo wengqondo, kodwa oko kungabonakali ukuba kwenzeke kwiiCIRS.

I-Hypoxia, ebonakaliswe yi-HIF1 ephantsi, kwii-CIRS nayo ingakhokelela ekukhuseleni kwegazi yengqondo ngenxa ye-NRF2 ukungalingani. I-Salidroside, e-Rhodiola, imisebenzi kwi-NRF2 isebenze kwaye incedisa nge-hypoxia ngokunyusa amazinga e-VEGF kunye ne-HIF1 ngaphakathi komzimba womntu. I-NRF2 nayo iyakhusela ekugqibeleni isakhiwo se-lactate entliziyweni. Ukusebenziswa kwe-NRF2 kunokumisa nokunyuka kwe-hypoxia-kukhutshwe kwi-Altitude Motion Ukugula, okanye i-AMS.

Uguqula Ukuguga Ukuguga

Iikhompawundi ezininzi ezinokubulala ngobuninzi obukhulu zinokwandisa ixesha elide kumanani amancinci ngenxa ye-xenohormesis nge-NRF2, i-PPAR-gamma, kunye ne-FOXO. Ubungakanani obuncinci beetyhefu bunyusa amandla eseli ukuze ixhotyiswe ngcono kwixesha elizayo xa icelwa umngeni nge-toxin, nangona kunjalo, oku ayisosiqinisekiso sokutya iikhemikhali ezinetyhefu.

Umzekeliso olungileyo wale nkqubo kukuthintelwa kwekhalori. I-NRF2 inokuphucula ubomi beeseli ngokuphakamisa amanqanaba e-mitochondria kunye ne-antioxidants kunye nokunciphisa amandla okufa kweeseli. I-NRF2 iyancipha ngokuguga kuba i-NRF2 ikhusela iiseli ze-stem ukuba zingafi kwaye zibancede ukuba bahlaziye. I-NRF2 idlala indima ekuphuculeni ukuphiliswa kwesilonda.

Ikhuthaza iNkqubo yeMascular

Ukwenziwe ngokuchanekileyo ngemveliso ye-sulforfane, ukusetyenziswa kwe-NRF2 kunokukhusela kwizifo zentliziyo ezifana nokunyuka kwengcinezelo yegazi, okanye uxinzelelo lwegazi, kunye nobunzima beetriyiti, okanye i-atherosclerosis. I-NRF2 inokuphucula u-Acetylcholine, okanye i-ACh, umsebenzi ophumayo kwisistim ye-vascular ngeli xesha ukunciphisa uxinzelelo lwe-cholesterol. Ukusebenza kwe-Nrf2 kunokuqinisa intliziyo, nangona kunjalo, i-Nrf2 ingaphumelelwanga inokuphakamisa amathuba okuba nesifo senhliziyo.

Iitatimins zinokuthintela okanye zikhokele kwisifo senhliziyo. I-NRF2 nayo inendima enkulu ekulinganiseni i-iron kunye ne-calcium enokukhusela umzimba womntu ekubeni unamanqanaba ensimbi ephakamileyo. Ngokomzekelo, i-Sirtuin 2, okanye i-SIRT2, inokulawula i-homeostasis yesinyithi kwiiseli ngokusebenza kwe-NRF2 ekholelwa ukuba iyafuneka kwimilinganiselo enempilo yesinyithi. I-NRF2 inokunceda kwakhona ngeSickle Cell Disease, okanye i-SCD. Ukungasebenzi kakubi kwe-NRF2 kusenokuba sisisemva kwe-endotoxemia efana ne-dysbiosis okanye i-lectins eyenze ingozi yomshukela. I-Nrf2 inokukhusela umzimba womntu ngokumelene ne-amphetamine eyonakalisa umonakalo kwinkqubo yesistim.

Ukulwa Neuroinflammation

I-NRF2 inokukhusela kunye nokuncedisa ukuvuvukala kwengqondo, ebizwa ngokuba yi-neuroinflammation. Ukongezelela, i-NRF2 inokukunceda ngeNkqubo yokuThuthukiswa kweNkqubo yeNervous Central, okanye i-CNS, ukuphazamiseka, kuquka:

  • Izifo ze-Alzheimer (AD) - kunciphisa uxinzelelo lwe-betyloid beta kwi-mitochondria
  • I-Amyotrophic Lateral Sclerosis (ALS)
  • Izifo zeHuntington (HD)
  • Multiple Sclerosis (MS)
  • Ukuvuselelwa Kwamanzi
  • Isifo se-Parkinson (PD) - sikhusela i-dopamine
  • Ukulimala kweNtsholongwane yokuCala (SCI)
  • I-stroke (ischemic and hemorrhagic) - inceda i-hypoxia
  • Ukulimala kweBrain Injury

I-NRF2 ibonakalise ukuhla kwe-neuroinflammation kulutsha olune-Autism Spectrum Disorders okanye i-ASD. I-Idebenone idibanisa ngokufanelekileyo kunye ne-NRF2 activators ngokuchasene neuroinflammation. I-NRF2 inokuphucula i-Blood Brain Barrier, okanye i-BBB. Ngokomzekelo, ukusetyenziswa kwe-NRF2 kunye ne-carnosic acid efunyenwe kwi-rosemary kunye ne-sage inokuwela i-BBB kwaye ibangele i-neurogenesis. I-NRF2 iye yaboniswa ukuba iphakamise i-Brain Derived Neurotrophic Factor, okanye i-BDNF.

I-NRF2 iphinda imodareyithe amandla okutya okunesondlo ukuze kubangele iNerve Growth Factor, okanye i-NGF njengoko inokunceda kwakhona ngenkungu yengqondo kunye nemiba ebangelwa yi-glutamate ngokumodareyitha i-N-Methyl-D-Aspartate, okanye i-NMDA receptors. Inokunciphisa uxinzelelo lwe-oxidative kwi-quinolinic acid, ebizwa ngokuba yi-QUIN. Ukusebenza kwe-NRF2 kunokukhusela ekubanjweni kwaye iidosi ezinkulu zinokunciphisa umda wokubamba. Kwiidosi eziqhelekileyo zokuvuselela, i-NRF2 inokuphucula amandla okuqonda emva kokubanjwa ngokunciphisa i-glutamate ye-extracellular kwingqondo kunye nokukwazi ukutsala i-cysteine ​​​​kwi-glutamate kunye ne-glutathione.

Ukhulula uxinzelelo

Kwixinzelelo, kuqhelekile ukuqaphela ukuvuvukala kwengqondo, ingakumbi ukusuka kwi-prefrontal cortex kunye ne-hippocampus, kunye nokuhla kwe-BDNF. Kwezinye iinguqulelo zokudakumba, i-NRF2 inokuphucula iimpawu zokudandatheka ngokunciphisa ukuvuvukala ngaphakathi kwengqondo kunye nokwandisa amazinga e-BDNF. Ukwazi u-Agmatine ukunciphisa uxinzelelo ngokuphakamisa i-noradrenaline, i-dopamine, i-serotonin kunye ne-BDNF kwi-hippocampus incike kusebenziso lwe-NRF2.

Iqulethe iipropati zeNtsholongwane

I-NRF2 inokulingana nomxhasi we-tumor njengokuba umgqugquzeli we-tumor ukuba angayilawulwa ngokufanelekileyo. I-NRF2 inokukhusela kumdlavuza obangelwa yi-radicals yamahhala kunye noxinzelelo lwe-oxidative, nangona kunjalo, ukugqithiswa kwe-NRF2 kunokufumaneka kwiseli yomhlaza. Ukusebenza ngokubanzi kwe-NRF2 kunokunceda ngeendlela ezahlukeneyo zeekhensi. Ngokomzekelo, ukuncedisa i-Protandim kunokunciphisa umdlavuza wesikhumba ngo-activation NRF2.

Uxolela ubuhlungu

I-Gulf War Illness, okanye i-GWI, isifo esichaphazelekayo esichaphazela kwiMfazwe yeMfazwe yaseGulf, iqoqo leempawu ezingapheliyo, ezinokuthi zibandakanye ukhathala, iintloko, intlungu edibeneyo, ukunyanzelisa, ukulala, ukusila, ukugula, kunye nokukhunjulwa kwemiba. I-NRF2 inokuphucula iimpawu ze-GWI ngokunciphisa i-hippocampal kunye nokuvuvukala ngokubanzi, ngaphezu kokunciphisa intlungu. I-NRF2 inokunceda ukuncedisa intlungu ebuhlungu besifo somzimba kunye nokuphucula umonakalo weentambo kwi-neuropathy ye-diabetes.

Uphucula isifo sikashukela

Amanqanaba aphezulu e-glucose, okubhetele ngokubhekiselele kwi-hyperglycemia, ibangela umonakalo ochaphazelekayo kwiiseli ngenxa yokuphazamiseka komsebenzi we-mitochondrial. Ukuqalisa ukusebenza kwe-NRF2 kunokukhusela umzimba womntu ngokumalunga nokulimala kwe-hyperglycemia kwiseli, oko kukuthintela ukufa kwesisele. Ukusetyenziswa kwe-NRF2 kunokukhusela ngokuphindaphindiweyo, ukubuyisela, nokuphucula umsebenzi we-beta-cell we-pancreatic, ngelixa kunciphisa ukunyanzelwa kwe-insulin.

Ukhusela Umbono Nokuva

I-NRF2 iyakhusela ukulimala kwiso kwi-retinopathy yesifo sikashukela. Inokuthi iphinde iphephe ukubunjwa kwe-cataracts nokukhusela i-photoreceptors enxamnye nokufa okubangelwa kukukhanya. I-NRF2 yongeza ukhusela indlebe, okanye i-cochlea, kwi-stress kunye nokulahlekelwa kwindlebe.

Unokukunceda ukunyaniseka

I-NRF2 inokunceda ngokukhuluphala ngokuyinhloko ngenxa yokukwazi ukulawula ukuguqulwa kwezinto ezisebenzisayo kwi-fat accumulation emzimbeni womntu. Ukusebenza kwe-NRF2 kunye ne-sulforaphane kunokuphakamisa ukukhutshwa kwe-Acat Acid Synthesis, okanye i-FAS, kunye ne-Uncoupling Proteins, okanye i-UCP, okubangelwa ukuqokelela kwamafutha amaninzi kunye namafutha amaninzi amaninzi, ebonakala njengamafutha afaka i-mitochondria.

Ukhusela i-Gut

I-NRF2 inceda ukukhusela umthamo ngokukhusela i-intestine microbiome homeostasis. Ngokomzekelo, i-lactobacillus probiotics izokubangela iNRF2 ukulondoloza umthamo kwixinzelelo loxinzelelo. I-NRF2 inokukunceda ukunqanda i-Ulcerative Colitis, okanye i-UC.

Ukhusela amaLungu eSondo

I-NRF2 inokukhusela amasende kwaye igcine inani lamadlozi kwingozi kubantu abanesifo seswekile. Inokunceda kwakhona nge-Erectile Dysfunction, okanye i-ED. Ezinye izongezo zokunyusa i-libido njenge-Mucuna, i-Tribulus, kunye ne-Ashwaganda-zinokuphucula umsebenzi wesondo ngokuvula i-NRF2. Ezinye izinto eziphakamisa i-NRF2, ezifana nokukhanya kwelanga okanye i-broccoli ihluma, inokunceda ukuphucula i-libido.

Ulawula iiBones kunye neMiscle

Uxinzelelo lwe-oxidative lungabangela ukuxinwa kwethambo nokunciphisa amandla, okuqhelekileyo kwi-osteoporosis. Ukuqalisa ukusebenza kwe-NRF2 kunokukwazi ukuphucula ama-antioxidants amathambo nokukhusela ekugugeni kwethambo. I-NRF2 inokukhusela ukulahlekelwa kwemisipha kunye nokuphucula i-Duchenne Muscular Dystrophy, okanye i-DMD.

Iqulethe iipropati zeNtsholongwane

Okokugqibela kodwa kuncinci, ukusebenza kwe-NRF2 kunokunceda ekugqibeleni ukukhusela umzimba womntu kwiintsholongwane ezininzi. Kwizigulane ezine-virus ye-dengue, iimpawu zazingekho kakhulu kubantu ababenamanqanaba amakhulu e-NRF2 xa kuthelekiswa nabantu abanamadigri angaphantsi kwe-NRF2. I-NRF2 inokunceda abantu abane-Human Immunodeficiency-1 Virus,� okanye i-HIV. I-NRF2 inokukhusela uxinzelelo lwe-oxidative kwi-Adeno-Associated Virus, okanye i-AAV, kunye ne-H. Pylori. Ekugqibeleni, i-Lindera Root inokucinezela i-virus ye-Hepatitis C kunye nokusebenza kwe-NRF2.

UDkt Jimenez White Coat
I-Nrf2, okanye i-NF-E2 enxulumene ne-2, iyinto ebonakalayo ebhalweni kubantu abalawula ukuthetha kwetadi ethile ye-antioxidant kunye ne-detoxifying gene. Le ndlela yokubonisa iyasebenza ngenxa yoxinzelelo lwe-oxidative njengoko iphakamisa amaninzi e-antioxidant kunye nesigaba se-II se-detoxification detective enzymes yokubuyisela i-homeostasis emzimbeni womntu. Abantu bachitshiyelwa ukuba basebenze kuwo wonke umhlaba we-homeostasis okanye ibhalansi. Xa umzimba ubhekene noxinzelelo lwe-oxidative, i-Nrf2 isebenza ukulawula i-oxidation kunye nokulawula uxinzelelo. I-Nrf2 ibalulekile ekukhuseleni imiba yempilo enxulumene noxinzelelo lwe-oxidative. 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:

  • 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.

Xa umzimba womntu ujongene nezinto eziyingozi zangaphakathi nangaphandle njenge-toxin, iiseli kufuneka zikhawuleze zibangele amandla azo e-antioxidant ukulwa noxinzelelo lwe-oxidative. Ngenxa yokuba amanqanaba aphezulu oxinzelelo lwe-oxidative azimisele ukubangela imiba eyahlukeneyo yezempilo, kubalulekile ukusebenzisa i-Nrf2 isebenze ukuthatha inzuzo yayo. 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

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

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Yintoni iSulforfane?

Yintoni iSulforfane?

ISulfrafa i-phytochemical, into ephakathi kwe-isothiocyanate iqela le-organosulfur, iifrifu, i-klafusili, iklabishi, i-cauliflower kunye ne-Brussels ihluma. Ikwafumaneka kwakhona kwi-bok choy, i-kale, iikholeji, imifuno yesardard kunye ne-watercress. Uphando luye lwabonisa ukuba i-sulforfane inokukunceda ukukhusela iintlobo ezahlukeneyo zomhlaza kusebenze imveliso yeNrf2, okanye into yenyukliya erythroid 2 ehambelana nayo, into ekhutshelweyo elawula iindlela zokukhusela i-antioxidant ezilawula impendulo yeseli kwii-oxidants. Injongo yenqaku elilandelayo kukuchaza umsebenzi wesulforaphane.

Abstract

I-KEAP1-Nrf2-I-system ye-antioxidant inkqubo yindlela enqununu eyenziwa yiiseli kwizixinzelelo ze-oxidative kunye ne-xenobiotic. I-Sulforfane (SFN), i-isothiocyanate ye-electrophilic ephuma kwimifuno e-cruciferous, ivuselela i-KEAP1-Nrf2-ARE yindlela kwaye iyenze i-molecule-of-interest ekwenzeni izifo apho ukunyamezela okuxhamlayo kwimiba ebaluleke kakhulu. Siyabonisa apha ukuba i-mitochondria yenkqubela, i-red retinal pigment epithelial (i-RPE-1) iiseli eziphathwe nge-SFN zixhomekeke kwi-hyperfusion ezizimeleyo ze-Nrf2 kunye ne-inhibitor yayo ye-cytoplasmic KEAP1. I-fusion yama-mitochondrial ibikwa ngokuba yi-cytoprotective ngokuvimbela ukubunjwa kwepore kwi-mitochondria ngethuba le-apoptosis, kwaye ngokuhambelana nale nto, sibonisa i-Nrf2-ezizimeleyo, i-cytoprotection yeeseli eziphathwe nge-SFN eziboniswe kwi-apducto-inducer, staurosporine. Ngokuchanekileyo, i-SFN inciphisa ukuqeshwa kunye / okanye ukugcinwa kwe-fission factor factor Drp1 kwi-mitochondria kunye ne-peroxisomes kodwa ayichaphazeli ubuninzi be-Drp1. Ezi nkcukacha zibonisa ukuba iipropati ezixhamlayo ze-SFN zandisa ngaphaya komsebenzi we-KEAP1-Nrf2-ARE kunye nokuqinisekisa ukuba uphando olongezelelweyo olwenziwe ngokusetyenziswa kweli arhente kwiimvavanyo ezininzi zeklinikhi.

Internet: I-Sulforfane, i-Nrf2, i-Drp1, i-Mitochondria, i-Fission, i-Fusion, i-Apoptosis

intshayelelo

I-Sulforfane yi-Nrf2-Independent Inhibitor ye-Mitochondrial Fission

I-Sulforfane (i-SFN) i-isothiocyanate isakhi esivela ekudleni ngokuqhelekileyo ukusuka kwimifuno ye-cruciferous [56]. Iveliswa kwizityalo njengempendulo ye-xenobiotic kwixesha elidlulileyo ngokukhutshwa kwe-enzyme ye-myrosinase yamaseli awonakele; le enzyme iguqula i-glucosinolates kwi-isothiocyantes [42]. Kwiminyaka emibini edlulileyo, i-SFN ibonakaliswe ngokubanzi kwi-antiticancer, i-antioxidant, kunye ne-antimicrobial properties [57]. Uninzi lwale mpu melelo luye lwaxelwa kumandla we-SFN ukulungelelanisa i-KEAP1-Nrf2-antioxidant element element (ARE) indlela yokubonisa, nangona imisebenzi eyongeziweyo yekhampani sele ichongiwe, kubandakanya ukuvinjelwa komsebenzi we-histone deacetylase kunye nokuqhubela phambili kweseli [ 29]. I-Nrf2 iyinhloko ye-antioxidant transcription factor kwaye phantsi kweemeko ze-homeostasis, ukuzinza kwayo kugxothwa ngokusebenza kwe-cytoplasmic Cullin3KEAP1 ubiquitin ligase complex [20]. Ngokukodwa, i-Nrf2 ibhalwa kwiCullin3KEAP1 ligase ngokuzibophezela kumxhasi we-substrate substrate KEAP1 kwaye yatshintshwa kwakhona ngeetyunithi ze-polyUb ezijolise kwinto yokubhalwa kwe-proteasome-mediated degradation. Lo mgangatho wokubuyisela umyinge we-Nrf2 kwiiseli ezixinezelekile ~ ~ 15 min [30], [33], [46], [55]. Ukuphendula iintlobo ezininzi uxinezeleko, neziqapheleka ntshikilelo oxidative, KEAP1, iproteni cysteine-sisityebi, wenza njengoko zincwadi Womenzi redox, kunye oxidative loyamano cysteines ezibalulekileyo, ingakumbi C151, ka KEAP1 dissociates Nrf2-KEAP1 ukusuka CUL3 ngaleyo Nrf2 ukuthotywa [ 8], [20], [55]. Ngokuphawulekayo, i-SFN, kwaye mhlawumbi nezinye izisebenzisi ze-Nrf2, zifanisa uxinzelelo lwe-oxidative ngokuguqula i-C151 ye-KEAP1 umzekelo [21]. Ukuzinza kwe-Nrf2 kuvumela ukuthunyelwa kwayo kwi-nucleus apho kukhuthaza ukubonakalisa ibhetri yeSigaba II se-antioxidant kunye ne-genetic detection. I-Nrf2 ibophezela kumacandelo okukhuthaza abaphendulela i-antioxidant (ARE) yeengqungquthela zayo zokujoliswa kwe-gene ngokusebenzisa i-heterodidizeri kunye neeprotheni ezincinci ze-Maf [19]. Le nkqubo ibonisa impendulo enamandla kunye nefuthe kuma-antioxidants angqalileyo afana ne-SFN, ama-radicals amahhala aveliswa yi-mitochondria [16], okanye enye imithombo ye-physiologic yoxinzelelo lwe-oxidative [41].

I-Mitochondria yinto enamandla, i-subcellular organels elawula imisebenzi enkulu yamaselula ukusuka kuveliso lwe-ATP kunye ne-intracellular calcium buffering to regulation redox kunye ne-apoptosis [13], [49]. I-Mitochondria nayo ibonisa umthombo oyintloko wendalo ye-oxygen (ROS) ngaphakathi kweseli. Ulawulo olufanelekileyo lomsebenzi we-mitochondrial ngoko ke luyimfuneko ekuphuculiseni ukuveliswa kwe-ATP ukuhlangabezana neemfuno zeselula ngeli xesha kunye nokunciphisa iziphumo ezinobungozi bokuveliswa kwemveliso ekhululekile. Imfuneko ebalulekileyo yokumodareyitha eyiyo yomsebenzi we-mitochondrial yindlela yokwenza i-mitochondria ukuba isebenze ngokuzimeleyo njengomatshini we-biochemical kwaye njengenxalenye yomnatha omkhulu.

I-minochondrial network morphology kunye nomsebenzi zixhaswa ngumlinganiselo olawulwayo phakathi kwe-fission kunye ne-fusion. Ukufunwa kwe-mitochondrial kuyadingeka kwintombi yeseli yelifa le-mitochondria ngexesha lokuhlukana kweeseli [28] kunye nokuchithwa okukhethiweyo, okuzimeleyo kweemitochondria, ezibizwa ngokuba yi-1]. Ngokwahlukileyo, ukuxubusha kuyadingeka ukuzaliswa kwamagciwane e-mitochondrial kunye nokwabelana ngamacandelo eketoni yokuthutha i-electron phakathi kwe-mitochondria engumakhelwane [i-54]. Kwinqanaba le-molecular, fission mitochondrial kunye ne-fusion zilawulwa yi-GTPases enkulu, njenge-dynamin-like. enzyme ezintathu ngokuyintloko nokulawula fusion: Mitofusins ​​1 kunye 2 (Mfn1 / 2) ziya ezimbini-kudlula iiproteni outer inwebu ukuba ukulamla engaphandle inwebu fusion nge intsebenziswano heterotypic phakathi mitochondria ezikufutshane [15], [25], [37], ngelixa OPA1 i kwangaphakathi iprotheni ye membrane eqinisekisa ngokufanayo ukulawula ukudibanisa kweembrane zangaphakathi [5]. Umsebenzi GTPase zonke zontathu iiprothini iyafuneka ukuze fusion robust [5], [18], kunye OPA1 kwenziwa kulawulwa proteolysis ezimbaxa phakathi inwebu ayo ephakathi proteases OMA1 [14], PARL [6], kunye YME1L [45 ]. Okubalulekileyo, i-membrane ye-mitochondrial ekhoyo ifunekayo ukwenzela ukuxuba ngokufanelekileyo ukuze kupheliswe ukuhlanganiswa kwe-mitochondria eyonakele [26].

I-fission ye-Mitochondrial ixhaswa ngokuyinxalenye yiprotheni ye-cytosolic ebizwa ngokuba yiproteinyini ehlobene ne-Dynamin 1 (Drp1 / DNM1L). I-Drp1 isetyenziswe kwi-cytosol ukuya kwiindawo eziza kubakho kwi-membrane yangaphandle ye-mitochondrial [43]. Iimpendulo ezinkulu zeDrk1 kwi-membrane yangaphandle ziyi-mitochondrial fission factor (Mff) [32] kwaye, ngaphantsi kwe-Fission 1 (Fis1) [51]. Ukongezwa koko, i-receyor receptor, i-MIEF1 / MiD51, yafunyaniswa ukuba yenza umlinganiselo wokunciphisa umsebenzi weproktro ye-Drp1 kwiindawo ezinokungeniswa kwe-fission [58]. Emva kokufakwa kwimbumba ye-mitochondrial yangaphandle, i-Drp1 i-oligomerizes kwizakhiwo ezinjenge-spiral ezijikelezayo emzimbeni we-mitochondrion ize isebenzise amandla avela kwi-GTP hydrolysis ukudibanisa ukuxhatshazwa kwenyama yangaphandle kunye ne-inner membranes [17]. Iipululeri ezivela kwi-Endoplasmic reticulum zisebenza njengendlela yokuqala ye-mitochondria phambi kwe-Drp1 oligomerization, igxininisa isityhilelo sokuba imitochondria engagqithwanga ibanzi ngaphezu kwe-permissive circumference ye-Drp1 spiral [12]. I-actin i-dynamics nayo ibalulekile ekusebenzisaneni kwe-ER-mitochondria ehamba phambili kwe-fission mitochondrial [24]. Ukongeza kwendima yayo kwi-fission mitochondrial, i-Drp1 ivuselela i-fission ye-peroxisomes [40].

I-Drp1 ifana kakhulu neprotein ye-dynamin ephawulekayo kuba iiprotheni ziqulethe i-N-terminal domain GTPase, i-Middle middle ebaluleke kakhulu kwi-self-oligomerization, kunye ne-C-terminal ye-GTPase ifree domain [31]. I-Drp1 ifikelela ekukhetheni kwimimbritri ye-mitochondrial ngokudibanisa nokusebenzisana kunye neeprotheni zayo ze-receptor Mff kunye neFis1 kunye nokudityaniswa kwayo kwe-cardiolipin ye-phospholipid ethile ye-mitochondria nge-B-ins domain domain. I-Drp1 ihlala ikhona njenge-homotetramer kwi-cytoplasm, kwaye i-assembly order ephezulu kwiindawo ze-fission zendawo zixutyushwa nguMmandla ophakathi we-Drp2 [1].

Ukunikezelwa kwekhonkco phakathi komsebenzi we-mitochondrial kunye ne-KEAP1-Nrf2-ARE endleleni, saphanda ngemiphumo yokusebenza kwe-Nrf2 kwisakhiwo somsebenzi kunye nemisebenzi. Siyabonisa apha ukuba i-SFN inciphisa i-hyperfusion ye-mitochondrial, engalindelekanga, i-Independent ye-Nrf2 kunye ne-KEAP1. Esi siphumo se-SFN sisinqanda umsebenzi we-Drp1. Siyaqhubeka sibonisa ukuba i-SFN inika ukuxhathisa kwi-apoptosis e-Nrf2-ezizimeleyo kunye nezimilo eziye zabonwa kwiiseli eziphelile yi-Drp1. Ezi nkcukacha ngokubanzi zibonisa ukuba ngaphezu kokuzinzisa nokuvuselela i-Nrf2, i-SFN imodareyitha ye-mitochondrial dynamics kwaye igcina ukuqina kwamaselula kunye nokuphila.

iziphumo

I-Sulforfane Ikhupha i-Nrf2 / KEAP1-Ukuzimela ngokuzimeleyo kweMitochondria

Ngexesha lokufunda ngefuthe lokuvula kwe-Nrf2 kwi-dynamics ye-mitochondrial dynamics, safumanisa ukuba unyango lweeseli ezingafakwanga, i-retinal pigment epithelial (RPE-1) yeeseli ezine-sulforaphane (SFN), isilumli esinamandla sokubonisa i-Nrf2, senza ukuba kube nokuhlangana okunamandla uthungelwano lwe-mitochondrial xa kuthelekiswa neeseli ezinyangwa ngolawulo lwezithuthi (Ikhiwane. 1A kunye no-B). I-morphology ye-mitochondria kwezi seli ifana kakhulu naleyo ye-mitochondria kwiiseli ezigqitywe yi-siRNA ye-endo native Drp1, eyona nto iphambili kwimissionchondrial fission factor (Ikhiwane. 1A). Esi siphumo siphakamise umbono onomdla wokuba i-mitochondrial fission kunye ne-fusion status iphendula ngokuthe ngqo kumanqanaba e-Nrf2 kwiseli. Nangona kunjalo, ukukhuthazwa kweeseli kunye nezinye i-Nrf2 stabilizers kunye ne-activators ezifana ne-proteasome inhibitor MG132, i-pro-oxidant tBHQ, okanye i-knockdown ye-Nrf2 inhibitor KEAP1 ayizange ifake i-mitochondrial fusion (Ikhiwane. 1A kunye ne-B). Ukuzinza kwe-Nrf2 ngezi zinto kuqinisekisiweyo kukucima kwentshona kwe-Nrf2 engapheliyo (Ikhiwane. 1C). Ngaphaya koko, ukubonakaliswa kwe-Nrf2 yayinokuhanjiswa ngenxa ye-SFN-induction mitochondrial fusion, njengokugoqoza kwe-Nrf2 engapheliyo kunye ne-siRNA yehlulekile ukumelana nale phenotype (Umzobo 1D F). Ngenxa yokuba i-SFN ivuselela umgaqo we-KEAP1-Nrf2-ARE ngokuguqula ngokungagungqiyo intsalela ye-cysteine ​​ye-KEAP1 [21], sankqonkqoza i-KEAP1 ukujongana nokuba ngaba i-SFN-eyenziwe yimitochondrial hyperfusion ivuselelwa ngokuxhomekeka kwe-KEAP1, kodwa indlela ezimeleyo yeNrf2. Nangona kunjalo, ukupheliswa kwe-KEAP1 nako akuphumelelanga ukuphelisa i-SFN-induction mitochondrial fusion (Ikhiwane. 1G I). Ngapha koko, i-SFN ibuyisele umva i-pro-fission morphology ebangelwa kukususwa kwe-KEAP1 (Ikhiwane. 1G, iphaneli b ngokuchasene nepaneli d). Ezi ziphumo zibonisa ukuba unyango lwe-SFN lubangela i-mitochondrial fusion ezimeleyo kwi-canonical KEAP1-Nrf2-ARE kwaye ikhokelele ekubeni sibuze ukuba ngaba i-SFN ichaphazela ngokuthe ngqo izinto ze-mitochondrial fission okanye i-fusion machinery.

Umzobo we-1 SFN ukhuthaza i-Nrf2 / i-KEAP1-emele i-mitochondrial fusion. (A) Iiseli ze-RPE-1 zatshintshelwa kwii-siRNAs kunye neentsuku ezi-3 kamva zaphathwa nge-DMSO okanye i-Nrf2 activators SFN (50? M), MG132 (10? M), okanye tBHQ (100? M) ye-4 h. IMitochondria (ebomvu) ifakwe iilebheli nge-anti-Tom20 antibody, kwaye i-nuclei (eluhlaza okwesibhakabhaka) iphikisiwe ne-DAPI. (B) Igrafu ebonisa ubungakanani be-mitochondrial morphology yokufumana amanqaku ukusuka (A). > Iiseli ezingama-50 kwimeko nganye zavavanywa ngendlela engaboniyo. (C) Ummeli wasentshona blots o (A). (D) I-RPE-1 iiseli zatshintshelwa nge-10 nM siRNA kunye neentsuku ezi-3 kamva zaphathwa nge-SFN ye-4 h ngaphambi kokuba zilungiswe kwaye zingcoliswe njengakwi (A). (E) Igrafu ebonisa ubungakanani be-mitochondrial phenotype yokufumana amanqaku ukusuka (D). > Iiseli ezili-100 kwimeko nganye zavavanywa ngendlela engaboniyo. (F) Ummeli wasentshona blots ukusuka (D). (G) Iiseli zadluliselwa zaza zaphathwa njenge (D) nge-siCON okanye i-siKEAP1. (H) Iiseli ezivela (G) zafumana amanqaku (B) kunye (E) ngesiseko se-mitochondrial morphology. (I) Ummeli weendawo ezisentshona ezivela (G). Idatha kwi (B), (E), kunye (H) yaqulunqwa ukusuka kuvavanyo oluzimeleyo lwe-3 nganye kunye nokubaluleka kweenkcukacha-manani kwagqitywa luvavanyo lomfundi olunemisila emibini. Iimpazamo zibonakalisa +/- SD (Ukutolikwa kwesalathiso sombala kulo mfanekiso, umfundi ubhekiswa kuhlobo lwewebhu lweli nqaku).

I-Sulforfane Impairs Association of Mitochondrial Association of Drp1

Ngokusekelwe ekufumaneni ukuba unyango lwe-SFN luthintela imfucuza yemithachondrial, sasiqiqa ukuba le nkohlakalo yayingumphumo wokusebenza ngokugqithisileyo okanye ukukhutshwa komsebenzi wefission. Ukucalula phakathi kwezi zimbini, sinokufanisa i-morphology ye-peroxisomes ekukho nasekhokho kwe-SFN. I-Peroxisomes ifana ne-mitochondria ngokuthi ziyi-organelles ezinamandla ukuma kunye nobude balo buhlala buhamba [44]. I-Peroxisomes iqulethe zombini iFis1 ne-Mff kwimbumba yayo yangaphandle kwaye, ngenxa yoko, iinjongo ze-fission ye-Drp1-mediated fission [22], [23]. Nangona kunjalo, i-peroxisomes ayisebenzisi imishini yefusion yomnatha we-mitochondrial kwaye ngenxa yoko, musa ukuhlanganiswa [39]. Kunoko, i-peroxisomal fission iyachasiswa ngokunyusa i-peroxisomes ekhoyo nge-novo kwongezwa kweembrane kunye neeprotheni [44]. Ngenxa yokuba i-peroxisomes ayinayo i-Mfn1 / 2 kunye ne-OPA1, saqiqa ukuba ukuba i-SFN isebenzise imishini yokuxuba kunokuba ivimbele umshishini we-fission, ubude be-peroxisome abuyi kuchaphazeleka. Kwiiseli eziphathwe ngezithuthi, i-peroxisomes igcinwa njengefutshane, ijikelezi, i-punctiform organelles (umzobo 2, iipaneli b no-d). Nangona kunjalo, unyango lwe-SFN lwandise ubude be-peroxisome nge ~ 2 ngokuthelekiswa nokulawulwa kweeseli (umzobo 2, ipaneli f no h). Ukongezelela, ezininzi ze-peroxisomes zazingqineka kufuphi neziko, ezibonisa isithuba esingenakucala (umzobo 2, ipaneli h, iifolothi). Ngokufanayo, i-peroxisomes kwiiseli ezihanjiswe nge-Drp1 siRNA zazide zide (umzobo 2, ipaneli j kunye n), eqinisekisa ukuba iDkt1 iyadingeka ukuba i-feroxisomal fission kwaye icetyise ukuba unyango lwe-SFN lubangela i-mitochondrial kunye ne-peroxisomal phenotypes ngokuphazamisa umatshini we-fission.

Umzobo we-2 SFN ukhuthaza ukwandisa i-peroxisomal. (A) Iiseli ze-RPE-1 zahanjiswa nge-10 nM ye-siRNA ebonisiweyo kunye neentsuku ezi-3 kamva zaphathwa nge-DMSO okanye i-50? M SFN ye-4 h. Iiperoxisomes (eziluhlaza) zibhalwe i-anti-PMP70 antibody, mitochondria eneMitoTracker (ebomvu), kunye ne-DNA edibene ne-DAPI. Ii-insets ezandisiweyo ze-peroxisomes zibonisiwe ngasekunene (iiphaneli d, h, kunye ne-l) ukulungiselela ukubonwa kweenguqu kwi-morphology ebangelwa yi-SFN kunye ne-Drp1 depletion. Iintloko zentloko zikhankanya amanqaku okuxinana. (Ukutolikwa kwesalathiso sombala kulo mfanekiso, umfundi uthunyelwa kuhlobo lwewebhu lweli nqaku).

Ngokulandelayo sagqiba ukuba i-SFN inqanda njani umsebenzi we-Drp1. Amathuba abandakanya ukunciphisa amanqanaba okuvakalisa, ukufunwa / ukugcinwa kwi-mitochondria, i-oligomerization, okanye umsebenzi we-enzymatic we-GTPase. Ukusilela kuyo nayiphi na enye yezi kungakhokelela ekunciphiseni i-mitochondrial fission kunye ne-hyperfusion. Asizange sibone utshintsho olunokuveliswa kwakhona kumanqanaba eprotheni ye-Drp1 emva konyango lwe-SFN (iFig. 1C kunye ne-3A), kwaye ngoko ke iqukumbele ukuba i-SFN ayitshintshi i-Drp1 ukuzinza okanye inkcazo, ehambelana ne-Drp1 enesiqingatha sobomi> 10 h [50] kwaye unyango lwethu lwe-SFN lube lolwexesha elifutshane. Emva koko, siphande ukuba i-SFN ichaphazele ukuqeshwa okanye ukugcinwa kwe-Drp1 kwi-mitochondria. Uphando lwe-Fractionation lubonise ukuba i-SFN yenza ukulahlekelwa kwe-Drp1 kwi-fraction ye-mitochondrial (Umfanekiso we-3A, imizila ye-7�8 kunye ne-Fig. 3B). Njengoko kuchazwe ngaphambili [43], kuphela iqhezu elincinci le-Drp1 (~ 3%) lidibaniswa nenethiwekhi ye-mitochondrial nangaliphi na ixesha ngexesha leemeko ezizinzileyo kunye neninzi ye-enzyme ehlala kwi-cytoplasm (Umfanekiso 3A, imizila ye-5�8) ). Ezi nkcukacha zokwahlula ziqinisekiswa ngokusebenzisa uhlalutyo lwe-co-localization olubonisa i- ~ 40% yokunciphisa i-mitochondria-localized, i-punctate Drp1 foci emva kwe-SFN-unyango (Umfanekiso 3C kunye no-D). Ngokudibeneyo, ezi datha zibonisa ukuba i-mitochondrial fusion eyenziwa yi-SFN, ubuncinane inxalenye, ngenxa yobudlelwane obuncitshisiweyo be-Drp1 kunye ne-mitochondria. Idatha yethu ayihlukanisi phakathi kokuba i-SFN iphazamisa ukuqeshwa kwe-mitochondrial ngokubhekiselele kukugcinwa kwe-mitochondrial ye-Drp1, okanye zombini, njengoko uhlalutyo lwe-Drp1 engapheliyo aluzange lukwazi ukujonga i-GTPase nge-microscopy yeseli ephilayo.

Umzobo we-3 SFN ubangela ukulahlekelwa kweDktXXUMUM kwiMitochondria. (A) Inxalenye ye-subcellular ye-RPE-1 iiseli ezilandelayo kwi-4 h ye-DMSO okanye i-SFN. I-cell-lysates (i-WCL), i-nyukliya (i-Nuc), i-cytosolic (i-Cyto), kunye namaqhezu angama-mitochondrial (Mito) ahlambulukanga aphendululwa yi-SDS-PAGE kwaye iqhutyelwa ukutshintshwa kwentshona kunye nama-antibodies ebonisiweyo. Ukufuduka kwamanqaku esisindo se-molecular kuboniswe ngakwesobunxele. (B) Iigrafu ezibonisa i-quantification ye-densitometric ye-Drp1 kumaqhezu achaziweyo ukusuka kwi-A). (C) Ii-RPE-1 zeeseli zatshintshelwe nge-10 nM siCON okanye i-siDrp1 kunye ne-3 iintsuku kamva ziphathwa nge-DMSO okanye i-SFN ye-4 h. I-Drp1 (eluhlaza) iboniswe ngophawu lolwa-Drp1, i-mitochondria kunye ne-MitoTracker (obomvu) kunye ne-nuclei ene-DAPI (eluhlaza okwesibhakabhaka). (D) Ulungelelaniso lwentsebenziswano lwengingqi ye Drp1 kunye neMitoTracker uphawu ukusuka (C). Iinkcukacha kwi (B) kunye (D) zaqulunqwa ukusuka kwi-3 kunye ne-5 yokuzimela ezizimeleyo, ngokulandelanayo, kunye nokubaluleka kwenani labekwe nguvavanyo lwe-Tailed Student t-test. Iimpazamo eziphosakeleyo zibonisa +/- SD kunye ne-asterisks ibonisa ukubaluleka kwamanani. (Ukuchazwa kweembonakalo zemibala kulo mfanekiso wesiganeko, umfundi uhanjiswa kwiphepha lewebhu le nqaku).

I-Sulforfane iqinisekisa ukukhuselwa kwe-Staurosportine-i-apoptosis eyimfuneko ngokuzimela kwi-Nrf2

Umsebenzi wangaphambili ubonise ukuba i-mitochondrial fission ivumela ukubunjwa kwe-pores kwi-membrane ye-mitochondrial yangaphandle eyenziwa yi-Bax / Bak ngexesha le-apoptosis [11]. I-Drp1 ibonakaliswe ukuba ikhethwe ngokukhethiweyo kwi-mitochondria ngexesha le-apoptosis [11] kwaye, ngokuhambelana nale nto, i-mitochondria eqhekezayo iye yabonwa kwangoko kwinkqubo [27]. Ngakolunye uhlangothi, ukuvimbela i-mitochondrial fission kucingelwa ukuba inqanda i-apoptosis ngokuthintela ukubunjwa kwe-membrane pores yangaphandle evumela ukukhululwa kwe-cytochrome c [53]. Ngokuhambelanayo, ukuvuselela ukudibanisa kwe-mitochondrial kulibazisa ukuqhubela phambili kwe-apoptosis eyenziwa yi-compounds kuquka i-staurosporine (STS) [14]. Ukugqiba ukuba i-SFN ikhusela iiseli ze-RPE-1 ukusuka kwi-apoptosis ye-STS-mediated kwaye ukuba kunjalo, nokuba oku kufuna i-Nrf2, siseke i-assay ukuze senze ngokukhawuleza i-poly ADP ribose polymerase (PARP) cleavage, i-substrate ye-caspase-3 esebenzayo kunye ne-marker ecacileyo ye i-apoptosis. Ukunyangwa kweeseli ze-RPE-1 nge-1 �M STS ye-6 h kuphela kubangele ukuchithwa okuthobekileyo kwe-PARP kodwa oku kuthintelwe yi-SFN yonyango yokubambisana (umzekelo, i-Fig. 4A, i-lane 3 ngokubhekiselele kwi-4). Ukonyusa ukomelela kolu vavanyo, siye sazisa ngakumbi iiseli kwi-STS-induced apoptosis ngokuyinyanga kwangaphambili nge-siRNA ejolise kwi-anti-apoptotic factor, i-Bcl-XL. Le pretreatment yanciphisa ukubonakaliswa kwe-Bcl-XL kwaye yakhuthaza ngokuphawulekayo i-PARP cleavage njengomsebenzi wexesha elivezwe kwi-STS (Umfanekiso we-4B, thelekisa umgca we-2 ukuya kwiindlela ze-4�10). Okubalulekileyo, i-2 h yonyango lwangaphambili kunye ne-SFN yanciphisa i-PARP yokuqhawula kwiiseli ezivezwe kwi-STS (umzobo we-4C, umzila we-3 ngokumelene ne-4 kunye ne-lane 5 ngokuchasene ne-6). Ngokufanayo, iiseli ezichithwe ngokuzinzileyo ze-Nrf2 nge-CRISPR / Cas9 zikhuselwe ngokulinganayo kwi-STS ubuthi nge-SFN yonyango lwangaphambili (Umfanekiso we-4C, umzila we-11 ngokubhekiselele kwi-12 kunye nomzila we-13 ngokubhekiselele kwi-14 kunye ne-Fig. 4D). Olu khuselo lwabonwa kusetyenziswa zombini i-PARP cleavage (Umfanekiso we-4C kunye no-D) kunye ne-morphology yeselula (umzobo 4E) njengokufunda. Ukusebenza kokuchithwa kwe-Nrf2 yi-CRISPR/Cas9 kwaqinisekiswa ngokuchithwa kwentshona (umzobo 4C, i-Nrf2 blot). Njengoko kuqikelelwe, ukuphelisa iiseli ze-Drp1, eziphinda zivelise i-hyperfusion phenotype (Umfanekiso 1A), iphinde ivalwe i-PARP cleavage ekuphenduleni kwi-STS xa kuthelekiswa nokulawula iiseli ezifakwe kwi-SFN (Fig. 4F kunye ne-G). Ngokudibeneyo, ezi ziphumo zihambelana ne-SFN enikezela ukhuseleko kwi-apoptosis ngokusebenzisa amandla ayo okukhawulela umsebenzi we-Drp1, ozimeleyo ekuzinziseni nasekusebenzeni kwe-Nrf2.

Umzobo 4 Iziphumo ze-cytoprotective ze-SFN zizimele kwintetho ye-Nrf2 (A) Iiseli ze-RPE-1 zanyangwa kwangaphambili nge-DMSO okanye i-50? M SFN ye-2 h ngaphambi konyango nge-DMSO, 1? M staurosporine (STS), okanye 50? M etoposide ye-6 h kwaye yaqwalaselwa ngokuchasene ne-PARP yasentshona. (B) Iiseli ze-RPE-1 zadluliselwa nge-2.5 nM siCON, 1 nM siBcl-XL, okanye i-2.5 nM siBcl-XL kunye neentsuku ezi-3 kamva baphathwa nge-DMSO okanye i-1? M STS ye-2, 4, okanye i-6 h. Ummeli wamabala asentshona abonisiwe kwaye ukufuduka kwamakishi obunzima beemolekyuli kubonisiwe ngasekhohlo. (C) I-CRISPR / i-Cas9 eyenziwe ngohlobo lwasendle (Nrf2WT) kunye ne-Nrf2 knockout (Nrf2KO) Iiseli ze-RPE-1 zahanjiswa nge-1 nM siBcl-XL kunye neentsuku ezi-3 kamva zanyangwa kwangaphambili nge-DMSO okanye i-50? M SFN ye-2 h . Emva koko, iiseli zazinyangwa nge-1? M STS ye-2, 4, okanye i-6 h. Ummeli weendawo ezisentshona kunye nee-antibodies ezibonisiweyo zibonisiwe. (D) Ukulinganiswa kwePARP ecandiweyo njengepesenti ye-PARP iyonke (icacisiwe + ayicaciswanga) ukusuka kuvavanyo oluzimeleyo oluyi-3. Ngokubalulekileyo, amanqanaba e-PARP acacisiweyo ayathelekiswa nokuba iiseli zichaze i-Nrf2 okanye hayi, zibonisa ukuba ukhuseleko lwe-SFN kwi-STS luzimele kwinto ebhaliweyo. (E) Imifanekiso engama-20X eyahlukileyo ethathwe kwangoko ngaphambi kokuvuna i-lysates ukusuka (C). Ibha yesikali = 65 m. (F) Ummeli wasentshona blots obonisa ukuba ukupheliswa kwe-Drp1 kunika ukhuselo olusondeleyo kufana ne-STS njengonyango lwe-SFN. Iiseli ze-RPE-1 zigqithiselwe nge-1 nM siBcl-XL kwaye zongezwa zatshintshwa nge-10 nM siCON okanye i-10 nM siDrp1. Kwiintsuku ezi-3 kamva, iiseli ze-siCON zanyangwa kwangaphambili nge-SFN njengakwi (A) kunye (C) emva koko zavezwa kwi-STS ye-4 h ngaphambi kokuba ivunwe kwaye iqhutyelwe ukucinywa kwentshona kunye neentsholongwane ezichaziweyo. (G) Kuyafana (D) kwidatha ebhalwe ku (F) equlunqwe ukusuka kwiimvavanyo ezi-3 ezizimeleyo. Iimpazamo zibonakalisa +/- SEM

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Sifumene ukuba i-SFN imodareyitha yefitochondrial fission / fusion dynamics ezizimeleyo kwimiphumo ye-KEAP1-Nrf2-ARE. Oku kuyamangalisa ngenxa yekhonkco esicatshulwayo phakathi kwe-mitochondrial ukungasebenzi kunye nokuveliswa kweROS kunye nokufuneka kwe-radicals yama-free-derived-derived by activation of Nrf2. Le mpembelelo eyongezelelweyo yempembelelo ye-SFN yinto ebaluleke kakhulu kunikezelwa ngaphezu kwezilingo zeclini ze-30 ukuqhubeka nokuvavanya i-SFN ekwenzeni unyango lwezifo ezahlukahlukeneyo kuquka nomhlaza wesifo seprotate, isifo se-pulmary disease, kunye nesifo segciwane lesigane [7], [10], [ 47].

Ngenxa SFN yi isothiocyanate [56] kwaye usebenze Nrf2 kweesiginali ngokuthi acylating ngqo cysteines ezibalulekileyo KEAP1 ukucinezela Nrf2 ukuthotywa [21], kulandela ukuba SFN abonakalisa imiphumo pro-fusion ngokuthi modulating umsebenzi a ngokucandeka okanye fusion factor nge cysteine ​​ukulungiswa . Idatha yethu ixhasa kakhulu i-Drp1 elawulwa kakubi yi-SFN nangona ukuba i-GTPase ijolise ngqo kwi-acylation ihlala ingacacisiwe. Nangona le gap ilwazi, umsebenzi we-Drp1 ubonakaliswe ngokukhatyiswa yi-SFN njengoko zombini i-mitochondria kunye ne-peroxisomes zixhatshazwa ekuphenduleni ukwelashwa kwe-SFN kwaye la maqumrhu asebenzisana noDktXXUMUM ngenxa yeziganeko zabo zokungabikho [1]. Ukongeza, i-SFN iyanciphisa inani le-Drp1 elinika indawo kwaye liqokelele kwi-mitochondria (Fig. 3). Ngenxa yokuba zethu iimvavanyo zenziwa nazo zonke iiprotheyini ezinokuphela, ukufumana kwethu i-Drp1 kwiindawo ze-fission fito ziphantsi kweemeko zeemeko zemeko, kwaye ngenxa yoko, asikwazi ukwahlula phakathi kokuqeshiswa ngokubhekiselele kwisiphene sokugcinwa kwe-enzyme ebangelwa yi-SFN. Ukongeza, asikwazi ukuphelisa ithuba lokuba i-SFN ifake i-receptor kwi-mitochondria (i-Fis1 okanye i-Mff) ukuvimbela ukuqashwa kwe-Drp1 kodwa, sikhankanya ukuba iDktp1 iguqulwe ngqo. I-Drp1 inee-cysteines ezilisithoba, ezisibhozo zazo zihlala ngaphakathi kwi-Middle Domain ezifunekayo kwi-oligomerization [3], kwaye enye yazo ihlala kwiGTPase Effector Domain (GED) kwi-C-terminus ye-Drp1. I-acylation ecacileyo yeyiphi ya ma-cysteines inokubangela ukukhubazeka komsebenzi kwi-Drp1 kwaye ke ixhomekeke kwimpembelelo ye-SFN kwi-dynamic mitochondrial dynamics. Ngokuphawulekayo, umsebenzi ongaphambili uphakamise ukuba iziphene kwi-oligomeri kunye nomsebenzi onokwenza umsebenzi unokuphelisa ukugcinwa kweDkt1 kwi-mitochondria [52]. I-Cys644 kwinqanaba leGED lijoliswe ngokukodwa kumsebenzi wangaphambili obonisa ukuba utshintsho lwe-cysteine ​​phenocopies uguquko oluchaphazela umsebenzi we-Drp1 GTPase [4] kwaye ukuba le cysteine ​​ethile iguqulwa yi-electrophiles esebenzayo (9]. Isigqibo salo mbuzo obalaseleyo siza kufuna ukuqinisekiswa kwe-spectrometric.Ngokusisishwankathelo, siye sachonga inombolo, umsebenzi we-cytoprotective kwi-SFN yeklinikhi echaphazelekayo. Ukongezelela ekusebenziseni inkosi ye-anti-oxidant transcription factor Nrf2, i-SFN ikhuthaza ukufutha kwe-mitochondrial kunye ne-peroxisomal fusion, kwaye le mphumela ilawulwa yi-Nrf2. Indlela ejongene nale nto ibandakanya ukunciphisa umsebenzi we-GTPase Drp1, umlamli oyintloko we-mitochondrial kunye ne-peroxisomal fission. Umphumo omkhulu we-fusion-matedchondrial fusion e-SFN yilapho iiseli zithintela kwimiphumo enobungozi be-apoptosis inducer staurosporine. Isenzo esongezelelweyo se-cytoprotective se-SFN sinokusetyenziswa kweeklinikhi ezithile kwizifo ezininzi ezibangelwa yi-neurodeergenerative izifo ezithathayo ingozi (umz., Izifo ze-Parkinson, i-Alzheimer's disease, i-Alzheimer's Disease's Age), njengoko ezi zifo zidibene ne-apoptosis kwaye zancitshiswa amanqanaba kunye / okanye ukudityaniswa kwe-Nrf2 [35], [36], [48].

Impahla nenkqubo

IApoptosis Assays

Iiseli zahlwayelwa zaza zatshintshelwa kwi-siRNA njengoko kubonisiwe ngezantsi. Iiseli zanyangwa kwangaphambili nge-50? M sulforaphane ye-2 h yokunyusa i-mitochondrial fusion emva koko baphathwa nge-1? M staurosporine yokwenza i-apoptosis. Ngexesha lokuvuna, imithombo yeendaba yaqokelelwa kwiityhubhu ezizodwa kwaye yafakwa kwisantya esiphezulu kwi-centrifugation kwiiseli zepoptotic cell. Le pellet yeseli yayihlanganiswe neeseli ezinamatheleyo kwaye inyibilikiswa kumaxesha e-2-egxile kwiLammli buffer. Iisampulu zaziphantsi kokucinywa kwe-PARP yasentshona.

I-CRISPR / i-Cas9 Yakha i-Generation

Ukudala i-LentiCRISPR / eCas9 1.1, i-LentiCRISPR v2 (i-addgene #52961) yahlulwa kuqala nge-Age1 kunye ne-BamH1. Ngokulandelayo, i-SpCas9 esuka eSpCas9 1.1 (i-addgene #71814) i-PCR yenziwe nge-Age1 kunye ne-BamH1 ngaphezulu kokusebenzisa oku kulandelayo: (Phuma AGCGCACCGGTTCTAGAGCGCTGCCACCATGGACTATAAGGACCACGAC, Phindela i-AAGCGCGGATCCCTTTTTCTTTTTGCCTGGCCGG) kwaye igxinwe kumvini osiweyo ngasentla. Ukulandelelana kwe-sgRNA kwachongwa ngokusebenzisa iBenchling.com. Iiparameters zabekwa ukujolisa ngokulandelelana kwekhowudi kunye neyona ndawo ephezulu ekujoliswe kuyo kunye nakwizinga eliphantsi. Oku kulungisiweyo ilandelayo (ulandelelwano kujoliswe umgca ngaphantsi, HS sgNFE2L2 # 1 ingqiqo CACCGCGACGGAAAGAGTATGAGC, antisense AAACGCTCATACTCTTTCCGTCGC; HS sgNFE2L2 # 2 kengoku CACCGGTTTCTGACTGGATGTGCT, antisense AAACAGCACATCCAGTCAGAAACC; HS sgNFE2L2 # 3 kengoku CACCGGAGTAGTTGGCAGATCCAC, antisense AAACGTGGATCTGCCAACTACTCC) ziye annealed kwaye ligated kwi BsmB1 kunqunyulwa LentiCRISPR / eCas9 1.1. I-RPE-1 iiseli ezikhethwe nge-Lentivirally zikhethwe nge-puromycin kwaye zigcinwe njengabantu abahlanganisiwe. Ukunyunyuzwa kwaqinisekiswa nge-immunofluorescence nasentshonalanga yokucima.

INkcubeko yeNkcubeko kunye noTshintsho

Iiseli ze-epithelial pigment epithelial cell eziguqulwe nge-telomerase (RPE-1) (ATCC) zakhuliswa kwi-Dulbecco's Modified Eagle Medium (DMEM) equlathe i-1 g / L iswekile eyongezwe nge-penicillin, i-streptomycin, i-1X engabalulekanga i-amino acid cocktail (Life Technologies), kunye ne-10% Serum Bovine Serum (iTekhnoloji yoBomi). Ukuhanjiswa kwe-siRNA, iiseli ezingama-30,000 35,000 / mL zahlwayelwa ngobusuku bonke. Iiseli zifumene i-10 nM siRNA exutywe kwi-serum-free DMEM kwaye idityaniswe ne-0.3% ye-Interferin transfection reagent (PolyPlus). Kukhuthazo lwe-apoptosis, iiseli zafumana i-1 nM Bcl-XL siRNA. Iiseli zavunwa emva kweentsuku ezi-2 3.

Iikhemikhali, ii-Antibodies, kunye ne-irRNA i-Oligos

Ama-antibodies ngokuchasene? -Tubulin (Ukutyikitywa kweseli),? -Tubulin (Sigma), Drp1 (BD Biosciences), KEAP1 (Proteintech), Lamin B1 (Abcam), PARP (Cell Signaling), PMP70 (Abcam), kunye neTom20 (BD Biosciences ) zazisetyenziswa kwi-1: 1000 yokuxolelwa kwintshona yokucima kunye ne-immunofluorescence. Ngaphakathi endlwini, anti-Nrf2 umvundla womzimba wasetyenziswa kwi-1: 2000 yokucima kwentshona [34], [59]. I-Sulforaphane (Sigma) kunye ne-staurosporine (Tocris) zazisetyenziswa kwi-50? M kunye ne-1? M ngokwahlukeneyo. I-siRNAs ngokuchasene ne-Drp1 (Dharmacon), Nrf2 (Dharmacon), KEAP1 (Ukutyikitywa kweSeli), kunye ne-Bcl-XL (ukutyikitywa kweSeli) zisetyenziswe kwi-10 nM ngaphandle kokuba kuchazwe ngenye indlela.

I-immunofluorescence kunye ne-Vivo Labeling

Iiseli ezihlwayelwe kwimbombozi yeglasi eyi-18 mm zaphathwa ngesithuthi okanye iziyobisi, zalungiswa kwi-3.7% ye-formaldehyde zaze zagqitywa kwi-0.2% Triton X-100 / PBS kumkhenkce kangange-10 min. Iintsholongwane zokuqala zafakwa kwi-3% ye-albin serum albumin (BSA) kwi-PBS ngobusuku nge-4 C. Ukulandela ukuhlamba kwe-PBS, iiseli zafakwa i-1 h kwizilwanyana ezifanelekileyo, i-Alexa488- okanye i-Alexa546-, ii-antibodies zesibini ezitshatileyo (ezixutywe i-1: 1000) kunye ne-0.1? G / mL DAPI (Sigma) kwi-3% BSA / PBS. IMitochondria iboniswe nokuba yi-anti-Tom20 immunofluorescence okanye ngokufaka iiseli kwi-200 nM MitoTracker Red CMXRos (Molecular Probes, Inc.) kwi-DMEM engenaserum ye-30 min kwi-37 C ngaphambi kokulungiswa.

I-Microscopy kunye noHlolo lokuHlaziya

Iisampulu ze-Immunofluorescence zajongwa kwimicroscope ye-LSM710 Confocal (Carl Zeiss). IiMicrographs zafakwa kusetyenziswa i-63X okanye i-100X yeenjongo zokuntywiliselwa kweoyile kunye nemifanekiso ehlengahlengisiweyo yaphuculwa kusetyenziswa iAdobe Photoshop CS6. Uhlalutyo lwasekhaya lwenziwa kusetyenziswa uCarl Zeiss LSM710 intsebenzo yolungelelwaniso lwasekhaya kunye nemingcele ebekwe ngesandla ngelixa limfanyekisiwe ekuchazeni iisampulu. Imilinganiselo yesikali kuyo yonke indawo, ngaphandle kokuba kuboniswe ngenye indlela, zii-10 .m. I-Mitochondrial morphology yavavanywa ngamanqaku angaboniyo. Ukuba i-mitochondria yeseli igcinwe njenge-puncta emininzi, ejikelezayo, ekhethiweyo, iseli lafumana amanqaku njenge-'fission '. Ukuba i-mitochondria nganye ibingafani kwaye inethiwekhi yonke ye-mitochondrial ibonakale iqhubeka, iseli lafumana amanqaku njenge- fusion . Zonke ezinye iiseli, kubandakanya nezo zihlanganisa i-mitochondria, zafumana amanqaku njenge-'Intermediate '.

Izihlomelo zeSellular

Iiseli ze-RPE-1 zikhule zadibana. Ukulandela ukuhlanjwa kwe-PBS, iiseli zathotyelwa kwi-centrifugation kwi-600 g ye-10 min kwaye yaphinda yafakwa kwakhona kwi-600? Ukunqunyanyiswa kwaxhonywa amaxesha angama-210 kwi-homogenizer yokuDumisa. Iqhekeza le-homogenate ligcinwe njenge-lysate yeseli yonke Intsalela yafakwa kwi-centrifugation kwi-70 g ye-5 min kwi-pellet nuclei. Ii-supernatants ziphantsi kwe-centrifugation kwi-1 g ye-7.4 min ukucoca i-nuclei eseleyo kunye neeseli ezingafakwanga. Le supernatant iphantsi kwe-centrifugation kwi-1 g ye-30 min kwi-pellet mitochondria. I-supernatant yagcinwa njengecandelo le- cytosolic fraction . I-pellet yahlanjwa ngobunono nge-PBS yaza yaphinda yaxhonywa kwindawo yokuma yodwa. Ukuxinana kweprotein yeqhekeza ngalinye kwakulinganiswa nge-bicinchoninic acid (BCA) yeesayidi kunye nexabiso elilinganayo leeprotein zisonjululwe yi-SDS-PAGE.

Blotting Western

Iiseli zahlanjwa kwi-PBS kwaye zahlanjululwa ngamaxesha e-2 agxininiswe i-Laemmli solubilizing buffer (100 mM Tris [pH 6.8], 2% SDS, 0.008% bromophenol blue, 2% 2-mercaptoethanol, 26.3% glycerol, kunye ne-Yrinin0.001% Pyrinin5). I-Lysates ibilisiwe kwi-1 min ngaphambi kokulayisha kwi-sodium dodecyl sulfate (SDS) i-polyacrylamide gels. Iiprotheyini zidluliselwe kwi-nitrocellulose membranes kwaye i-membrane ivalwe kwi-5 h kwi-5% Ubisi / TBST. Izilwa-buhlungu zokuqala zixutywe kwi-4% yobisi/TBST zaza zaqatywa ngeblothi ngobusuku obuyi-5 �C. I-Horseradish peroxidase (HRP) -i-antibodies zesibini ezidibeneyo zixutywe kwi-XNUMX% yobisi / i-TBST. Amabhulothi acutshungulwa nge-chemiluminescence ephuculweyo kunye ne-densitometric quantifications zenziwa kusetyenziswa isoftware ye-ImageJ.

UDkt Jimenez White Coat

I-Sulforfane yikhemikhali evela kwiqoqo ye-isothiocyanate yezinto ze-organosulfur ezifunyenwe kwimifuno ye-cruciferous, kuquka i-broccoli, iklabishi, i-cauliflower, i-kale, kunye ne-collards, phakathi kwezinye. I-sulforfane ikhiqizwa xa i-enzyme i-myrosinase iguqula i-glucoraphanin, i-glucosinolate, ibe yi-sulforfane, eyaziwa nangokuthi i-sulforaphane-glucosinolate. Izihluma ze-Broccoli kunye ne-cauliflower zinokuxinwa okuphezulu kwe-glucoraphanin okanye i-precursor ukuba i-sulforaphane. Uphando luye lwabonisa ukuba i-sulforfane ikwandisa amandla omzimba womntu wokukhusela i-antioxidant ukukhusela imiba eyahlukeneyo yempilo. 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:

  • 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

Sciencedirect.com/science/article/pii/S2213231716302750

I-Sulforfane iveliswa njani?

Ukutshaya kunciphisa i-Epithiospecifier iProtein Activity kunye nokwandisa iSulfrafom Ifom e-Broccoli

Abstract

I-Sulforaphane, i-isothiocyanate esuka kwi-broccoli, yenye yezona zinto zinamandla eziphuma kwi-anticarcinogens yokutya. Le ngqungquthela ayikho kwimifuno engaguqukiyo, kunokuba yenziwe kwi-precursor yayo ye-glucosinolate, i-glucoraphanin, ngesenzo se-myrosinase, i-enzyme ye-thioglucosidase, xa izicubu ze-broccoli zichithwa okanye zihlafunwa. Nangona kunjalo, inani lophononongo lubonise ukuba isivuno se-sulforaphane esivela kwi-glucoraphanin siphantsi, kwaye i-analog ye-nitrile engeyona i-bioactive, i-sulforaphane nitrile, imveliso yokuqala ye-hydrolysis xa izicubu zezityalo zityunyuzwa kwiqondo lokushisa. Ubungqina bamva nje bubonisa ukuba kwi-Arabidopsis, ukubunjwa kwe-nitrile kwi-glucosinolates ilawulwa yiprotheyini ye-heat-sensitive protein, i-epithiospecifier protein (ESP), i-non-catalytic cofactor ye-myrosinase. Iinjongo zethu yayikukuvavanya iziphumo zokufudumeza i-broccoli florets kunye nehlumela kwi-sulforaphane kunye ne-sulforaphane nitrile formation, ukufumanisa ukuba i-broccoli inomsebenzi we-ESP, emva koko ilungelelanise utshintsho oluxhomekeke kubushushu kumsebenzi we-ESP, umxholo we-sulforaphane kunye ne-bioactivity, njengoko kulinganiswe ngokungeniswa kwe-ESP. isigaba II sokukhupha i-enzyme quinone reductase (QR) kwinkcubeko yeeseli. Ukufudumeza i-broccoli florets entsha okanye i-broccoli ihluma ukuya kwi-60 �C ngaphambi kokuba i-homogenization inyuke ngaxeshanye inyuse ukubunjwa kwe-sulforaphane kunye nokunciphisa ukubunjwa kwe-sulforaphane nitrile. Ilahleko enkulu yomsebenzi we-ESP ihambelana nokuhla kwe-sulforaphane nitrile formation. Ukufudumeza ukuya kwi-70 �C nangaphezulu kunciphisa ukwakheka kweemveliso zombini kwi-broccoli florets, kodwa hayi kwihlumelo le-broccoli. Ukungeniswa kwe-QR kwimouse ye-hepatoma ye-Hepa lclc7 iiseli ezihambelana nokunyuka kwi-sulforaphane formation.

 

Ukufudumeza kwangaphambili i-broccoli florets kunye nehlumelo ukuya kwi-60 C inyuse kakhulu ukwenziwa kwe-myrosinase-catalyzed form of sulforaphane (SF) kwizicubu zemifuno emva kokutyumza. Oku kunxulunyaniswa nokwehla kwe-sulforaphane nitrile (SF Nitrile) kunye nomsebenzi we-epithiospecifier protein (ESP).

Internet: I-Broccoli, i-Brassica oleracea, i-Cruciferae, i-Cancer, i-Anticarcinogen, i-Sulforfane, i-Sulforfane nitrile, iprotheniospecifier protein, i- Quinone reductase

Ukuqukumbela, i-sulforaphane yi-phytochemical efumaneka kwi-broccoli, kunye neminye imifuno ye-cruciferous. Umthamo ongalawulwayo we-oxidants obangelwa zizinto zombini zangaphakathi nangaphandle zingabangela uxinzelelo lwe-oxidative emzimbeni womntu onokuthi ekugqibeleni ukhokele kwimiba eyahlukeneyo yezempilo. I-Sulforaphane inokuvula ukuveliswa kwe-Nrf2, into ekhutshelweyo enceda ukulawula iindlela ezikhuselayo ze-antioxidant ezilawula impendulo yeseli kwii-oxidants. 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

Ikholi ye-Green Call Now Button H .png

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 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.

umfanekiso weblogi wekratshi yephepha

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

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