Indlela i-methylene blue esebenza ngayo: ukudluliselwa kwama-electron, nalapho ama-electron egcina khona

Iflaski evalwe ngesivalo esebhentshini iyisingeniso esifushane kunazo zonke kodwa esithembekile sendlela i-methylene blue esebenza ngayo. Amanzi, i-glucose, ingcosana ye-sodium hydroxide, nodayi owanele ukwenza uketshezi lube luhlaza okwesibhakabhaka olujulile nolungadidaniseki. Linda imizuzu embalwa bese umbala oluhlaza okwesibhakabhaka uyanyamalala kuze kube iflaski ibukeka njengeflaski yamanzi. Yinyakazise, umbala ubuye ngokushesha. Bese uyafiphala futhi, futhi uzoqhubeka nokwenza kanjalo inqobo nje uma kukhona i-glucose ezimisele ukudedela ama-electron kanye ne-oxygen ezimisele ukuwamukela.

Akukho okushintshile ngodayi ngaphandle kwenani lama-electron awuphethe. Uma use-oxidised, uluhlaza okwesibhakabhaka. Uma use-reduced, awunjalo. Cishe konke okunye okubhalwe ezincwadini zokwelapha nezocwaningo ngaleli molekyuli kuvela kuleso sinyathelo esisodwa esibuyiseleka emuva, ngoba imolekyuli engathatha ama-electron komunye umlingani bese iwanikeza omunye iyisidlulisi, futhi isidlulisi asenzi lutho sisodwa. Esikwenzayo kuncike ngokuphelele kulokho okusekupheleni ngakunye kwaso.

Izinhlobo ezimbili, nokuthi kungani leli pheya libalulekile

Uhlobo oluyi-oxidised luwuhlelo lwamasongo oluyisicaba, olushajwe kahle. Leso simo esiyisicaba nesishajwe kahle yisona esenza lunamathele kuma-nucleic acid, lubophe ezakhiweni ezine-sialylated kulwelwesi lwamaseli, futhi lumunce ukukhanya okubonakalayo ngamandla phakathi cishe kuka-600 no-700 nanometres, okuyingxenye ye-spectrum iso lomuntu eliyibona njengoluhlaza okwesibhakabhaka.

Uhlobo oluyi-reduced luhluke kakhulu. Alunawo umthwalo kagesi, luncibilika emafutheni kunasemanzini, futhi alunambala. I-ionisation yalo iphansi kakhulu ku-pH engaphakathi komzimba, cishe ngamaphesenti ambalwa. Ngakho imolekyuli eyi-reduced iwela ulwelwesi lweseli kalula nge-diffusion, futhi uma isingaphakathi, lapho indawo ine-oxidising kakhulu, ingaphinde ibe yi-oxidised bese empeleni ivaleleka khona. Uhlelo lwamasongo oluyi-oxidised luyisicaba; oluyi-reduced lungasonteka. Leyo miphumela yesakhiwo, kanye nokushintsha kombala uqobo, kuyingxenye yendaba yalezi zinhlobo ezimbili ngokwazo, futhi kuchazwe kabanzi ekuqhathanisweni kwe-methylene blue ne-leucomethylene blue.

Ukwamukela ama-electron

Udayi oyi-oxidised uzokwamukela ama-electron kubanikelayo abaningi abahlukene. I-glucose eseflaskini yokubonisa ingenye yabo. Ngaphakathi kweseli, ama-pyridine nucleotide ayi-reduced kanye nezingxenye ze-mitochondrial electron transport chain ezinye zazo. Lapho i-methylene blue iba yi-reduced esicutshini esine-oxygen, umjikelezo ewumisayo usebenzisa kokubili i-reducing agent ne-oxygen, bese ukhiqiza ama-reactive oxygen species, ikakhulukazi i-hydrogen peroxide. Udayi uphuma emjikelezweni ungashintshile, usulungele ukuwuphinda futhi.

Lelo phuzu lokugcina lichaza ukuphikisana okungase kubonakale kuwukunganaki. Ezincwadini i-methylene blue ichazwa kokubili njenge-pro-oxidant nanjenge-antioxidant, futhi zombili izincazelo zingasekelwa. Inganciphisa ukukhiqizwa kwe-superoxide ngokusebenza njenge-electron acceptor yokwenziwa, iphambukise ukugeleza kwama-electron kude nezindawo zama-enzyme lapho i-oxygen ibingaguqulwa khona ibe ama-superoxide radical. Emasikweni amaseli esibindi kuboniswe ukuthi ikhuthaza ama-enzyme okuvikela e-antioxidant esigaba 2, okuhlanganisa i-thioredoxin reductase 1 ne-NADPH quinone oxidoreductase. Ukuthi yiluphi uhlangothi kulezi ezimbili olubonayo kuncike ekutheni iluphi uhlangothi lwesidlulisi olushoda ngama-electron ngaleso sikhathi. Umbuzo ofana nokuthi "ingabe i-methylene blue iyi-antioxidant" awuphelele kuze kube usho ukuthi ukusiphi isistimu, ikuphi ukugxila, nokuthi yini enye ekhona.

Ukudlulisa ama-electron

Uma udayi usuphethe i-electron eyengeziwe, kungalandela izinto ezintathu ezihluke kakhulu, futhi ngokuvamile zichazwa ngaphansi kwesihloko esisodwa. Akufanele kube njalo.

Ingadlulisela i-electron esikhungweni sensimbi. Isibonelo esicace kakhulu yi-haemoglobin esenziwe i-oxidised kusukela esimweni se-ferrous saya esimweni se-ferric. Kuleso simo ayikwazi ukuthwala i-oxygen. Emaselini abomvu, i-enzyme yenza udayi ube yi-reduced, bese udayi oyi-reduced udlulisela ama-electron ku-haem iron eyi-oxidised ngaphandle kokusebenzisa i-enzyme, ubuyisele i-haemoglobin esebenzayo bese udayi ubuyela esimweni sawo esiyi-oxidised. Udayi awupheli ngenxa yalokhu; uyajikeleza. Isimo somtholampilo esisekelwe kulokhu kusabela siyindaba yasesibhedlela, futhi incazelo ye-methylene blue ku-methemoglobinemia ichaza ukuthi isetshenziswa kanjani nokuthi kungani igadwa ngokucophelela kangaka.

Inothi elithembekile mayelana nokufundwayo: ukubuyekezwa okubili lesi sihloko esisekelwe kukho akusho i-reducing cofactor efanayo esinyathelweni se-enzyme, okukodwa kusho i-NADH kanti okunye kusho i-NADPH. Lokhu kungavumelani kukhona ngempela futhi akukaxazululwa emithonjeni etholakalayo lapha, ngakho incazelo ephephile iwukuchaza indima edlalwa yingxenye ngayinye kunokubeka igama le-cofactor eyodwa.

Ingadlulisela amandla, noma i-electron, ku-oxygen, uma kukhona ukukhanya. Le ndlela ikhona kuphela ngaphansi kokukhanya. Udayi ovuselelwe ufinyelela esimweni se-triplet, futhi kusukela lapho kunezindlela ezimbili ezingase zenzeke. Kweyokuqala, udayi ovuselelwe usebenzisana ngokuqondile nemolekyuli eseduze, uthathe i-hydrogen noma udlulisele i-electron, okukhiqiza ama-radical; ukusabela ngale ndlela namanzi kukhiqiza ama-hydroxyl radical. Kweyesibili, amandla okuvuselelwa adluliselwa ku-oxygen uqobo, kukhiqize i-singlet oxygen, uhlobo olune-electrophilic kakhulu olubola phakathi kwama-microseconds futhi ngokuvamile olwamukelwa njengendlela eyinhloko i-methylene blue ekhanyisiwe elimaza ngayo amaseli amagciwane. Ukusabela namalipid nama-peptide emvilophini yeseli, kanye nama-guanine base ku-DNA, kuphakathi kwemiphumela ebhaliwe.

Umphumela ongokoqobo wale ndlela ukuthi ukukhanyisa kushintsha izinombolo ngama-order of magnitude. Emininingwaneni eqoqwe ngu-Wainwright no-Crossley, i-methylene blue ngokumelene ne-Pseudomonas aeruginosa ine-minimum bactericidal concentration cishe engu-500 micromolar ebumnyameni, futhi cishe engu-25 micromolar ngaphansi komthamo wokukhanya ongu-12 joules per square centimetre. Ngokumelene nohlobo olulodwa lwe-Staphylococcus aureus, amanani ebumnyameni nangaphansi kokukhanya womabili angu-5 micromolar. Ngamanye amazwi, ukuthi imolekyuli ibalwa njenge-antimicrobial nhlobo akusona isici semolekyuli kuphela; kuyisici semolekyuli kanye nokukhanya.

Ingasebenza ngokuqondile endaweni ye-enzyme, ngaphandle kwesidlulisi. I-methylene blue yenza i-oxidise i-ferrous iron eboshelwe ku-nitric oxide synthase, okwenza i-enzyme ingasebenzi. Ivimbela i-soluble guanylate cyclase, futhi phakathi kuka-1 no-10 micromolar kuwukugxila okuvamile kwaselabhorethri okusetshenziselwa leyo njongo. Ivimbela i-monoamine oxidase type A nge-IC50 ephakathi kuka-27 no-180 nanomolar, okuyindlela esekela ukusebenzisana okubhalwe kahle nama-serotonin reuptake inhibitor kanye nesizathu sokuthi ukusebenzisana kwe-methylene blue nemithi kube isigaba esizimele.

Lezi zindlela ezintathu zihlukile ngokwekhemistri. Ukuzihlanganisa kube isimangalo esisodwa sokuthi i-methylene blue isebenza nge-redox cycling yisona sizathu esikhulu esenza okuningi okubhalwe ngayo kufundeke sengathi kuqinisekile kakhulu kodwa ngesikhathi esifanayo kungacacile.

Umehluko omine onquma ukuthi isitatimende sendlela yokusebenza sisho okuthile yini

Iluphi uhlobo. Udayi oyi-reduced awushintshaniswa ngokuqondile nodayi oyi-oxidised. Ukuvinjelwa kwe-acetylcholinesterase kukhombisa ugibe: ngesikhathi eside sokufukanyelwa kwe-in vitro, i-methylene blue iya ngokuya iba yi-reduced ibe uhlobo lwayo olungenambala, bese ukuvinjelwa kwehla, ngoba imolekyuli eyi-reduced ayiyivimbeli leyo enzyme. Ukuhlolwa okuqhubeka isikhathi esanele ukuze kushintshe uhlobo kuzobika umphumela obuthakathaka futhi kukhuthaze incazelo engalungile.

Ikuphi ukugxila. Ibanga laselabhorethri lokuvimbela i-soluble guanylate cyclase lingu-1 kuya ku-10 micromolar. Ukuqeda ukudluliswa okuqhutshwa yi-glutamate ezingxenyeni ze-hippocampus yegundane kwadinga 5 kuya ku-50 micromolar. Imiphumela enobuthi emasikweni amaseli ibikwa ngaphezu kuka-100 micromolar. Lokhu akusikho ukuhlolwa okufanayo, futhi indlela yokusebenza eqinisekiswe ku-50 micromolar ayitholakali ngokuzenzakalela esigulini esine-plasma concentration eyingxenye encane yalokho.

Iyiphi indlela yokunikezwa. I-absolute oral bioavailability icishe ibe ngu-72 per cent, kanti i-terminal plasma half-life ingu-5 kuya ku-7 hours. Ukunikezwa ngomlomo kukhiqiza ukugxila okuphezulu emathunjini nasesibindini; ukunikezwa nge-intravenous kukhiqiza ukugxila okuphezulu ebuchosheni. Indlela yokunikezwa inquma ukuthi yisiphi isicubu esihlangana nama-electron.

Iyiphi imodeli, nokuthi izibani zazikhanyisiwe yini. Ingxenye enkulu yezincwadi eziphathelene nezindlela zokusebenza isekelwe emasikweni amaseli nasemsebenzini wamagundane, futhi imiphumela ye-in vitro ngale molekyuli incike ekuvezweni ekukhanyeni, ku-membrane potential nasesimweni se-redox samaseli, ngoba isibani se-microscope sisodwa sanele ukuyenza i-photosensitise. Phakathi kuka-65 no-85 per cent womthamo onikeziwe wenziwa i-reduced ube uhlobo olungenambala emaselini abomvu nasezicutshini ezisezindaweni ezikude nomgogodla womzimba. Zonke lezo zinto zimi phakathi kwendlela yokusebenza ecacile esitsheni sokuhlola nesimangalo ngomuntu.

Kungani umbuzo wobumsulwa ungumbuzo wekhemistri

Ukukhanyisa kwenza i-demethylate i-methylene blue. Umkhiqizo wokuqala yi-Azure B, bese kuba yi-Azure A, bese kuba yi-thionin, futhi ukukhanya okunamandla kakhulu kukhiqiza ukubola okuningi kunokukhanya okubuthakathaka. Ngakho imolekyuli okuwusizo kwayo kuncike ekukwazini ukwamukela nokunikela ngama-electron iyimolekyuli okungenzeka imikhiqizo yayo yokubola ibe yizihlobo zekhemistri eziseduze ezihlala kuleso sixazululo esifanayo. Ukwakheka kwalokho okusesitsheni akuyona imininingwane yobuhle.

Yingakho ukuhambisana nencazelo ye-USP kuyisivivinyo esinencazelo kumthengi. Umkhiqizo ongayifinyeleli ungudayi, futhi udayi uphethe ukungcola, okuhlanganisa i-Azure B, izinsimbi ezisindayo nezincibilikisi ezisalile, umuntu owugwinyayo angazifuni. Olunye ugibe ngumthengisi ohlola izinsimbi ezisindayo kuphela bese wethula lowo mphumela njengokuhambisana okuphelele. Blupreme isebenzisana nomkhiqizi wemithi we-methylene blue futhi ihlola yonke incazelo: ubunikazi, ubumsulwa, ukungcola kwe-organic, izincibilikisi ezisalile, ukungcola kwezinto, insalela ngemva kokushiswa, imikhawulo yamagciwane nama-bacterial endotoxins. Idokhumenti yokuhlolwa kwaselabhorethri esekela iqoqo ngalinye iyashicilelwa, futhi ukukhetha umphakeli ikakhulukazi kuwudaba lokuhlola ukuthi leyo dokhumenti ikhona yini nokuthi ihlanganisani.

Ipheya elilodwa elibuyiseleka emuva. Izindlela eziningana eziphuma kulo. Indlela iyona enquma ukuthi isimangalo singasho ukuthini.