I-methylene blue ne-NAD+/NADH: ukuhumusha ibhalansi ye-redox yamaseli

Imibiko ephathelene ne-methylene blue ne-NAD+ ivame ukuhlanganisa izimangalo ezintathu ezihlukene zibe sinye. Esokuqala sithi isilinganiso se-NAD+ ne-NADH sishintshele esimweni esine-oxidation eyengeziwe. Esesibili sithi iseli line-NAD eningi iyonke. Esesithathu sithi ukukhiqizwa kwamandla kubuyele esimweni sangaphambili. Lokhu kuzwakala kuyindaba eyodwa yokubuyisela imetabolism. Ezivivinyweni lezi zinto zivame ukuhlukana, futhi imiphumela ethakazelisayo iyona kanye lapho zingahambisani khona.

Lokhu kudideka kuyaqondakala ngoba lezi zilinganiso ezintathu zisebenzisa amagama afanayo. I-NAD+ yamukela ama-electron ekuphendulaneni kwamakhemikhali kwemetabolism bese iba yi-NADH; ama-mitochondria abe esenza i-oxidation ye-NADH ayibuyisele ku-NAD+ ku-complex I futhi asebenzise amandla akhululiwe ukukhiqiza i-ATP. Incazelo egcwele yalowo mzila wama-electron itholakala encazelweni yokuthuthwa kwama-electron kuma-mitochondria, kanti uhlangothi lwamandla lutholakala kokuthi i-ATP nemetabolism yamandla. Kodwa isilinganiso neqoqo kuyizinto ezihlukene. Isilinganiso sibonisa ukuthi ama-molecule akhona athutha ama-electron ahlukaniswe kanjani phakathi kwesimo sokuthwala umthwalo nesokungawuthwali. Iqoqo libonisa ukuthi mangaki lawo ma-molecule akhona esewonke. Isilinganiso esingcono lapho iqoqo lingashintshile sisho ukwabiwa kabusha, hhayi ukukhiqizwa.

Izingxenye ezimbili, izinkomba ezimbili

Kunomunye umehluko obangela ukuhunyushwa okunganembile okungaqashelwa. Amaqoqo e-NAD aku-cytosol nakuma-mitochondria ahlukaniswa kakhulu ulwelwesi lwangaphakathi lwama-mitochondria, ngakho ingxenye ngayinye ingaba sesimweni esine-oxidation noma i-reduction ethe xaxa ngokuzimela. Inombolo eyodwa yeseli lonke iyakufihla lokhu.

Ucwaningo lwesibindi lwenza kwenzeka ukukala lo mehluko phakathi kwezingxenye. Ukulingana kokuphendulana kwe-lactate ne-pyruvate kubonisa isilinganiso se-NAD+ ne-NADH ku-cytosol, ngoba i-lactate dehydrogenase ixhumanisa lawo mapheya amabili. Ukulingana kokuphendulana kwe-3-hydroxybutyrate ne-acetoacetate kubonisa isilinganiso kuma-mitochondria ngokuxhumana okufanayo. Lapho womabili la mapheya ekalwa ezicutshini ezifriziwe ngokushesha ngokucindezelwa phakathi kwezinto ezibandayo, njengakucwaningo lwamagundane ondliwa nge-ethanol isikhathi eside, umphumela uba yizilinganiso ezimbili ze-redox ezivela esibindini esisodwa, futhi into ethile ingashintsha esinye ngaphezu kwesinye.

I-methylene blue isebenza kulolu hlelo njengomthuthi wama-electron kunokuba ibe yisibaseli. Yamukela ama-electron avela ku-NADH eduze kwe-complex I, ngaleyo ndlela ibe sesimweni se-reduction, bese iwadlulisela kubathwali abasezinyathelweni ezilandelayo, njenge-cytochrome c. Umphumela uba yi-oxidation ye-NADH ngaphandle kokudlula kuwo wonke umzila ovamile. Le ndlela yokusebenza ichaza kokubili ukuthi kungani iheha nokuthi kungani inomkhawulo: ingakhulula ukuvinjwa okubangelwa ukunqwabelana kwesimo se-reduction, kodwa ayakhi kabusha i-complex eyonakele noma ikhiqize ama-molecule amasha e-NAD.

Izifundo ezinhlanu, iphethini eyodwa yemiphumela ehlukene

Ithebula elingezansi lihlela lezi zifundo ezinhlanu ngokwezicubu, umphumela okaliwe we-redox, umphumela okaliwe wamandla, nalokho okwabuyela esimweni sangaphambili ngempela. Funda amakholomu amabili okugcina ndawonye. Lokho kuqhathanisa kuyiyona ngqikithi yalesi sihloko.

Lapho ukulungiswa kwe-redox kungazange kusindise izicubu

Ucwaningo oludala kunazo zonke kuleli qoqo luseyisixwayiso esicace kunazo zonke. Amagundane athola u-36 percent wamandla ekudleni kwawo nge-ethanol aba nezilinganiso eziphansi ze-NAD+/NADH ku-cytosol nakuma-mitochondria, ezakalwa ngawo womabili amapheya ezinkomba, futhi i-methylene blue engaba ngu-42 mg nge-kg ngosuku ekudleni yakuvimbela kakhulu lokho kushintsha. Nokho, i-triacylglycerol esibindini yacishe yaphindeka kathathu ngesikhathi sokukala sakamuva kungakhathaliseki ukuthi udayi wawukhona yini, futhi ukuhlolwa kwezicubu kwabonisa amafutha afanayo azungeze inkaba yezigaxa zesibindi. Ababhali bafinyelela ngokuqondile esiphethweni esingakhululekile: ukushintsha kwe-redox okuhambisana ne-oxidation ye-ethanol akukona ngokwakho okubangela ukunqwabelana kwamafutha esibindini. Umfundi othatha ukulungiswa kwesilinganiso njengokulungiswa kwesitho somzimba angabika lolu cwaningo ngokunganembile. Uhlelo oluphelele locwaningo, kuhlanganise namaqembu okuqhathanisa anikwe ukudla okulinganayo kanye nokuthathwa kwamasampula phakathi kwamabili lapho ukudakwa kuphezulu kakhulu, luchazwe kucwaningo lwe-ethanol nesibindi.

Qhathanisa lokho nocwaningo lwesibindi ekudleni okunamafutha amaningi, lapho ukushintsha okufanayo kwesilinganiso kwahambisana nokuthuthuka kwangempela kwezicubu. Emaselini esibindi nasesibindini segundane elincane ngemva kokunikezwa ngomlomo, i-methylene blue yandisa isilinganiso se-NAD+/NADH, futhi uchungechunge lokudluliswa kwezimpawu lwalandelelwa isinyathelo ngesinyathelo: i-SIRT1 yenyuka, kwasuswa amaqembu e-acetyl ku-PGC-1alpha, izinkomba zokwakheka kwama-mitochondria nokusetshenziswa komoya-mpilo kwenyuka, kwabe sekusebenza i-AMPK, i-CPT-1 ne-PPARalpha, kwaboniswa nokuthi ukuvuselelwa kwe-AMPK kuncike ku-SIRT1. Amagundane amancane adla ukudla okunamafutha amaningi anqwabelana namafutha ambalwa esibindini. Incazelo ehlongozwayo ithi ukushintsha kwe-redox lapha kwavulela indlela yokulawulwa kwezakhi zofuzo kunokuba kumane kulinganise kabusha isimo samakhemikhali, njengoba kuchazwe kucwaningo lwe-SIRT1 ne-AMPK esibindini. Uhlobo lwezilinganiso luyafana nolocwaningo lwe-ethanol, kodwa umphumela wezicubu uyaphambana. Umehluko usendleleni esebenza ezinyathelweni ezilandelayo, hhayi esilinganisweni sodwa.

Inhliziyo ne-retina: ama-sirtuin, ukwengezwa kwamaqembu e-acetyl, nokusindiswa ngaphandle kokubuyiselwa kwe-ATP

Ucwaningo lwenhliziyo enesifo sikashukela luxhumanisa ukushintsha kwe-redox nokwengezwa kwamaqembu e-acetyl kumaprotheni kusetshenziswa i-sirtuin ehlukile. Ama-mitochondria asesimweni sesifo sikashukela anamaqembu e-acetyl amaningi ngokweqile ku-lysine kuma-enzyme emetabolism, okuhambisana nokungakwazi ukushintsha kalula izinto ezisetshenziselwa ukukhiqiza amandla. I-methylene blue engu-10 mg nge-kg ngosuku yasiza i-oxidation ye-NADH ngendlela encike kumthamo, kumazinga asuka ku-6 kuya ku-18 micromolar kuma-mitochondria ahlukanisiwe, yandisa ukusebenza kwe-SIRT3 futhi yehlisa ukwengezwa kwamaqembu e-acetyl kabanzi, kuyilapho imithamo yezikhala zenhliziyo nengxenye yegazi ekhishwa inhliziyo kwathuthuka nakuba ukungasebenzi kahle kwe-complex I okuyisisekelo kwahlala kukhona. Lolu cwaningo lucacisa ukuziphatha kwemithamo okubikwe kweminye imibhalo: amazinga aphansi avuna indima yokuthutha ama-electron ngendlela ye-reduction, kuyilapho aphezulu engaphambukisa ama-electron ngendlela engakhiqizi inzuzo, ngakho umphumela uyahlukahluka ngokomthamo kunokuba uqhubeke ukhula njalo ngendlela efanayo. Ukuhlolwa kwamaprotheni nezilinganiso zenhliziyo kubikwe kucwaningo lokwengezwa kwamaqembu e-acetyl enhliziyweni enesifo sikashukela. Umongo wengcindezi ye-oxidation walokhu utholakala engcindezini ye-oxidation nasekulawulweni kwama-ROS.

Ucwaningo lwe-retina luwuqhubekisela phambili kakhulu lo mehluko. Kumagundane amancane ohlobo lwe-Harlequin antula i-AIF, anokungasebenzi kahle kokuhlanganiswa kwe-complex I, i-methylene blue yagcina ukujiya kwe-retina, izingxenye zangaphandle zamaseli amukela ukukhanya, kanye nezinkomba zamaseli ama-rod, ama-cone, ama-Muller nama-ganglion. Emaselini amukela ukukhanya ohlobo lwe-661W afakwe i-rotenone, udayi wabuyisela isilinganiso se-NADH ne-NAD+ kokujwayelekile futhi wehlisa izinhlobo zomoya-mpilo ezisebenza kakhulu ekuphendulaneni kwamakhemikhali ezingeni elingu-15 micromolar, kodwa i-ATP yahlala iphansi emazingeni ayesiza ukusinda kwamaseli. Ukwakheka nokusinda kwagcinwa ngaphandle kokubuyiselwa kwamandla, kanye nokwehliswa kokusabela kwama-mitochondria kumaprotheni angasongwanga kahle kanye ne-mitophagy. Lo mphumela ubeka udayi njengento enciphisa ingcindezi ye-reduction neye-oxidation kunokuba ibuyisele amandla, njengoba kubhalwe kucwaningo lokuvikelwa kwamaseli amukela ukukhanya e-retina.

Ithenda: isivivinyo lapho isimo samakhemikhali sashintsha khona kodwa izicubu zangathuthuki

Ucwaningo lwethenda le-Achilles luqukethe womabili la maphethini embhalweni owodwa futhi kufanelekile ukulufunda ngokucophelela. Ukuhlaziywa okuphelele kwegatsha ngalinye kutholakala ekuhlaziyweni kuka-2026 kocwaningo lokuphazamiseka kwethenda le-Achilles. Ithenda eligulayo labonisa ukuncipha kwe-NAD+, isilinganiso esiphansi se-NAD+ ne-NADH, izinkomba ezibuthakathaka ze-complex I, i-ATP ephansi, kanye ne-collagen engahlelekile. I-methylene blue yabuyisela isimo samakhemikhali se-NAD ne-ATP futhi yathuthukisa izinkomba ze-matrix kumalungiselelo amagundane, ezicubu zabantu ezikhishwe emzimbeni, nawamaseli.

Kwabe sekulandela izinguquko ezimbili ezazenziwe ngenhloso yokuhlola. Lapho i-complex I ivinjwe nge-rotenone, udayi waqhubeka nokuvikela isimo samakhemikhali se-NAD+ nezilinganiso ezihlobene ne-ATP kodwa wehluleka ukunciphisa umthwalo wezinto ezenza i-oxidation, ukubuyisela ibhalansi ye-collagen, noma ukugcina ukuphila kwamaseli. Lapho ukukhiqizwa kwe-AIF kwehlisiwe, lapho uhlelo lwe-complex I lwalungakhiwanga ngokwanele kunokuba luvinjwe ngomuthi, udayi wabuyisela izinto eziningi: ibhalansi ye-NAD, ingcindezi ye-oxidation, umehluko kagesi phakathi kwezinhlangothi zolwelwesi, nezinkomba ze-collagen. Isifundo sicacile. Isilinganiso esingcono se-NAD singagcinwa ngisho noma i-complex I ivinjiwe, kodwa ukusindiswa kwezicubu kulokhu kulungiselelwa kwakuncike endleleni ye-complex I ekwazi ukusebenza. Ukushintsha kwesilinganiso kuyadingeka kule ndaba kodwa akwanele, okuyiphuzu elichazwa ngokwengeziwe kucwaningo lwe-redox yethenda.

Indlela yokufunda isimangalo esilandelayo se-redox

Ukuhlola izinto ezintathu kusiza ukugwema ukuhumusha okuningi okunganembile. Okokuqala, buza ukuthi isilinganiso ngesayiphi ingxenye nokuthi yiliphi ipheya lezinkomba elisetshenzisiwe ukusithola. Umphumela we-lactate ne-pyruvate ku-cytosol awusho lutho ngokuqondile nge-matrix yama-mitochondria. Okwesibili, buza ukuthi ucwaningo lubika ukushintsha kwesilinganiso, iqoqo elikhulu le-NAD iyonke, noma ukubuyiselwa kwe-ATP, futhi uphathe ngakunye njengomphumela ohlukile. Okwesithathu, buza ukuthi yini ehlale ingalungisiwe: amafutha angancishisiwe, ukungasebenzi kahle kwe-complex I okungalungisiwe, noma ukushoda kwe-ATP okungalungisiwe konke kuyavela kulezi zifundo kuhambisana nokuthuthuka kwangempela kwe-redox.

Akukho kulokhu okuyisiqondiso semithamo. Zonke lezi zifundo ezinhlanu zisebenzisa izilwane, amaseli, noma izicubu ezilungiselelwe ucwaningo, nomonakalo odalwe ngaphansi kwezimo ezilawulwayo: ukudla okuwuketshezi okune-ethanol, isifo sikashukela esidalwe yi-streptozotocin, ukungasebenzi kahle kwe-complex I okubangelwa izakhi zofuzo, i-rotenone, i-peroxide, ne-collagenase. Amazinga ezitsheni zocwaningo awakwazi ukuguqulwa abe imithamo ephuzwa ngomlomo ngokumane uwabheke, futhi akukho muntu kulezi zifundo owathatha i-methylene blue ukuze alinganise i-redox. Ingqikithi yokusebenza kwemithi ku-redox nemithamo inomkhawulo ocacile futhi iwusizo ngaphezu kwanoma yiluphi uhlelo lokusetshenziswa: i-methylene blue yenza i-oxidation ye-NADH futhi ishintshe isilinganiso esikaliwe, ama-sirtuin aguqula lolo shintsho lube ukususwa kwamaqembu e-acetyl nokuhlelwa kabusha kwemetabolism kwezinye izicubu, futhi ukuthi izicubu ziyalandela yini kuncike ohlelweni lokusebenza udayi ongeke waluthatha indawo.