Uko ubururu bwa metilene butandukanye n'ibirwanya okisidasiyo bisanzwe

Ikirwanya okisidasiyo gisanzwe gihura na radikali yigenga rimwe gusa. Gitanga elekitironi, kigakuraho ubukana bw'iyo radikali, maze kikaba kirangiye. Mu mibare, ni kimwe kuri kimwe, kandi uburinzi burahagarara iyo ibihari bishize.

Ubururu bwa metilene ntibukora gutyo. Bwakira elekitironi, bukazishyikiriza ahandi, hanyuma bugasubira mu miterere yabwo ya mbere bwiteguye kongera gukora urwo ruziga. Molekile imwe ishobora gukora inshuro ibihumbi. Iryo tandukaniro risobanura imbaraga zabwo ku ngano nto n'aho kutagira icyo bukora bitanga amasomo y'ingenzi. Ibikurikira bigereranya iyo mikorere yombi binyuze mu bushakashatsi butatu bwatangajwe, bitirengagije ibisubizo byagaragaje ko nta ngaruka zabonetse.

Ni uguhanahana, si ugukora nka siponji

Mu rwego rwa shimi, buba mu miterere ibiri ishobora gusimburana. Ubururu bwa metilene bwatakaje elekitironi buba ari ubururu, bufite umuriro w'amashanyarazi, kandi bushonga mu mazi. Ubururu bwa metilene bwakiriye elekitironi, bwitwa leuco-methylene blue, ntibugira ibara cyangwa umuriro w'amashanyarazi, kandi bushonga mu mavuta bihagije ku buryo bwambuka utwugara tw'ingirabuzimafatizo nta nkomyi. Imbere muri mitokondiriya, iryo bara ryatakaje elekitironi rizakira ku bizitwara bifitanye isano na NADH mu ntangiriro z'inzira, rikazishyikiriza sitokorome c na kompelegisi IV ku mpera zayo. Ribikora ritanyuze muri kompelegisi I kugeza kuri III, ari na ho elekitironi zikunze gutorokera kuri ogisijeni zigakora superoxide. Iryo bara risigara ryongeye gutakaza elekitironi, maze rigasubiramo uruziga. Imikorere y'iyo miterere yombi ubwayo isobanurwa mu nyandiko ivuga uko ubururu bwa metilene bukora.

Ikintu gikuraho radikali mu buryo butaziguye gikora nyuma y'aho elekitironi zatorokeye. Gitegereza ko superoxide cyangwa perokiside bibaho, hanyuma kikabikuraho ubukana, molekile imwe kuri radikali imwe. Ikintu gikora mu ruziga rwa redox gikora mbere y'uko ibyo biba, kigahindura inzira elekitironi zinyuramo kugira ngo hakorwe superoxide nkeya, kitashize. Imibare y'ingano ikoreshwa ikurikira iyo mikorere: mu bushakashatsi buri hasi, ubururu bwa metilene bukora hafi ya 100 nanomolar, mu gihe ikintu gisanzwe gikuraho radikali gikenera 100 micromolar.

Ariko icyo guhanahana ntigikora cyonyine. Icyo gikora giterwa n'ibitanga elekitironi n'ibizakira kuri buri mpera. Iyo uhinduye uburyo gikoreramo, molekile imwe ishobora kurinda, kutagira icyo imara, cyangwa kutagira uruhare ku byo ushaka kugeraho.

Ingirabuzimafatizo z'imyakura: uburinzi busaba mitokondiriya zikora

Isesengura risobanutse kurusha ayandi riva mu bushakashatsi ku isano iri hagati y'imiterere ya molekile n'imikorere yayo, bwakorewe ku ngirabuzimafatizo z'imyakura za HT-22 zo muri hipokampe. Bwagerageje ubururu bwa metilene n'ibindi bintu bitandatu bifitanye isano na bwo ku bintu bine byangiza ingirabuzimafatizo (Poteet n'abandi, 2012). Iryo bara ryarinze ingirabuzimafatizo ku ngano zo ku rwego rwa nanomolar igihe zangizwaga na glutamate, rotenone (ikumira kompelegisi I), na iodoacetate. Ku glucose oxidase, itanga perokiside ya hidurojeni mu buryo butaziguye mu mvange ingirabuzimafatizo zikuriramo, nta cyo ryakoze kuva kuri 10 nanomolar kugeza kuri 10 micromolar, mu gihe pyruvate, ikuraho radikali mu buryo bworoshye, yazirinze. Iyo ikibazo ari urunigi rwo gutwara elekitironi rudakora neza, guhanahana elekitironi birafasha. Iyo perokiside yamaze kuboneka hanze y'ingirabuzimafatizo, nta cyo iba ifite cyo gutwara.

Ubwo bushakashatsi bwanagaragaje impamvu. Mu igerageza ryakoresheje ibiva muri mitokondiriya zasenywe, ibintu bibiri bifitanye isano n'iryo bara ariko bidafite iminyururu yo ku ruhande ku myanya 3 na 7, phenothiazine na 2-chlorophenothiazine, byarwanyaga okisidasiyo mu buryo butaziguye byonyine. Ubururu bwa metilene bwo ntibwabikoze. Bwahagarikaga okisidasiyo gusa iyo NADH n'ibice bya mitokondiriya bitangiritse byombi byabaga bihari. Mu yandi magambo, ntabwo bwakuragaho radikali na gato. Bwatwaraga elekitironi, kandi icyo kuzitwara gikenera aho kizifatira n'aho kizishyikiriza.

Ibintu bibiri birushaho gusobanura iyo mikorere. Kongera umunyururu wo ku ruhande kuri azote yo mu mpeta iri ku mwanya 10 byagabanyije imbaraga zo kurinda hafi inshuro igihumbi, bigaragaza ko azote itageretseho uwo munyururu ari ingenzi mu mikorere ya shimi y'urwo ruziga. Kandi gukoresha iryo bara igihe kirekire byongereye ikorwa n'imikorere bya kompelegisi IV, ari ihinduka ibyo bindi bintu bikuraho radikali mu buryo butaziguye bitateje. Ibisobanuro bifitanye isano n'itwarwa rya elekitironi muri mitokondiriya bitanga amakuru y'ibanze yo gusuzuma ibivugwa ku birwanya okisidasiyo.

Ingirabuzimafatizo z'uruhu: igereranya ritaziguye ubururu bwa metilene bwatsinzemo

Ubundi bushakashatsi bwagereranyije ubururu bwa metilene n'ibintu bitatu bizwi birwanya okisidasiyo mu ngirabuzimafatizo za fibroblaste z'uruhu rw'abantu, zafashwe ku bantu bazitanze bafite ubuzima bwiza, abarwayi ba progeria, n'abazitanze bafite imyaka irenga 80 (Xiong n'abandi, 2017). Mu byumweru bine, ubururu bwa metilene bwakoreshejwe kuri 100 nanomolar, N-acetylcysteine kuri 100 micromolar, naho MitoQ na mito-TEMPO buri kimwe kuri 100 nanomolar.

Ibisubizo byari bitandukanye cyane. Ubururu bwa metilene bwagabanyije superoxide yo muri mitokondiriya kandi bushyigikira ukwiyongera kw'ingirabuzimafatizo mu matsinda yose yazo. N-acetylcysteine ntiyagabanyije ROS yo muri mitokondiriya kandi yasaga n'itinza ukwiyongera kw'ingirabuzimafatizo. MitoQ, ku ngano yari isanzwe ikoreshwa mu bushakashatsi bwatangajwe, yongereye cyane ROS yo muri mitokondiriya kandi ikumira ukwiyongera kw'ingirabuzimafatizo. Mito-TEMPO yagaragaje inyungu ziringaniye mu matsinda amwe. Muri ibyo bine, icyakoraga mu ruziga nk'umusemburo ni cyo cyagize umusaruro munini, naho ikirwanya okisidasiyo cyerekezwaga ahantu runaka kandi kigashira mu kigero cy'ingano cyakoreshwaga cyateje ingaruka mbi kurusha kutagira igikoreshwa, nibura muri ubu buryo bw'igerageza bwamaze ukwezi.

Abanditsi bagaragaje ko igihe cyakoreshejwe gishobora gusobanura ibyo bisubizo, kuko ahandi MitoQ yakoreshejwe igihe kigufi yagaragazaga ibisubizo byiza kurushaho. Icyo cyitonderwa kireba n'ibindi: ibirwanya okisidasiyo bishira uko bikora biragabanuka, kandi ibikomoka ku gusenyuka kwabyo bishobora kugira imyitwarire idakwiye iyo bimaze igihe kirekire mu igerageza. Umusemburo wo ntushira uko ukora.

Iyo gahunda y'ubushakashatsi yanakomereje ku ruhu rw'umuntu rwubatswe mu buryo bwa 3D, aho ubururu bwa metilene ku ngano nto bwatumye igice cy'uruhu cya derme kirushaho kubyimba, bwongera ubuhehere, bwongera elastine na kolajene 2A1, bugabanya MMP9, kandi bwihutisha ugufunga kw'ibikomere. Ibyo biratanga icyizere, ariko bireba uruhu, kandi uruhu si igufa.

Amagufa: icyizere cyabonetse mu ngirabuzimafatizo zo mu igerageza cyaburiwe mu nyamaswa

Ubushakashatsi ku gusaza kw'amagufa bugaragaza urundi ruhande rw'ibisubizo (Poudel n'abandi, 2024). Mu ngirabuzimafatizo zororewe mu igerageza, ubururu bwa metilene na MitoQ byombi byakumiriye ikorwa rya osteokilasite, ingirabuzimafatizo zisenya amagufa, uko ingano yakoreshwaga yiyongeraga hejuru ya 0.25 micromolar. Ntibyabangamiye ubushobozi bw'ingirabuzimafatizo fatizo bwo gukomeza kubaho cyangwa ikorwa rya osteobulasite, ingirabuzimafatizo zubaka amagufa. Umushakashatsi usomye gusa ibyo bishushanyo by'ibisubizo yateganya ko inyamaswa byakoreshejweho zagira amagufa akomeye kurushaho.

Ibisubizo byo mu nyamaswa ntibyabihamije. Imbeba z'ingore zishaje zo mu bwoko bwa C57BL/6J zahawe ubururu bwa metilene kuri 250 micromolar mu mazi yo kunywa mu gihe cy'amezi 6 cyangwa 12. Imbeba za UM-HET3 zifite inkomoko zitandukanye zahawe ubururu bwa metilene kuri 28 ppm mu biryo kuva ku mezi 7 kugeza kuri 22, cyangwa MitoQ kuri 100 ppm kuva ku mezi 4 kugeza kuri 22. Isuzuma rya Micro-CT ry'igice cyo hanze gikomeye n'igice cy'imbere gifite utwenge by'igufa ry'ikibero, hamwe n'amagufa y'uruti rw'umugongo yo mu rukenyerero, ryagaragaje ko igabanuka ry'amagufa rijyana no gusaza ryakomezaga kimwe mu matsinda yahawe ibyo bintu no mu yo kugereranya. Amoko abiri y'imbeba, inzira ebyiri zo gutanga ibyo bintu, ibirwanya okisidasiyo bibiri, amezi byakoreshejwe, ariko nta ngaruka ku magufa.

Umwanzuro w'abanditsi urasobanutse: kugabanya igitutu cya okisidasiyo ukoresheje gusa ikirwanya okisidasiyo bisa n'ibidahagije kugira ngo bitinde gusaza kw'amagufa. Gutakaza amagufa biterwa n'imisemburo, imbaraga amagufa yikorera, ububyimbirwe, no gukuraho ingirabuzimafatizo zashaje. Gukosora itoroka rya elekitironi bikemura kimwe gusa mu bintu byinshi bibigiramo uruhare, kandi hano ibindi ni byo byagize imbaraga kurushaho. Amakuru ku uko ingamba zo kurwanya okisidasiyo zitwaye ku biranga gusaza afasha gusobanura ibyo bisubizo bitagaragaje ingaruka.

Gusoma ubwo bushakashatsi butatu hamwe

Ibintu bitatu bigaragara bikomeza guhura n'ibyabonetse muri izo nyandiko zose uko ari eshatu.

Icya mbere, imikorere ituma hamenyekana aho igarukira. Ubururu bwa metilene burafasha aho elekitironi ziyobywa imbere muri mitokondiriya kandi igitwara elekitironi gishobora kuzisubiza mu nzira ikwiye. Ntibukora aho ibitera okisidasiyo byamaze kuboneka kandi biri kure y'urwo runigi. Kutagira ingaruka ku glucose oxidase no ku magufa si ibisubizo biteye isoni bigomba gushakirwa ibisobanuro byo kubihakana. Ni ihame ry'imikorere rigaragara uko ryasobanuwe.

Icya kabiri, mu gukoresha igihe kirekire, imibare y'imikorere y'umusemburo irusha iyo gukoresha molekile zishira uko zikora. Molekile idashira ikomeza gukora ku ngano zo ku rwego rwa nanomolar mu gihe cy'ibyumweru, mu gihe ibikuraho radikali rimwe gusa bikenera ingano zo ku rwego rwa micromolar zibarirwa mu magana, kandi bishobora guhinduka ibyangiza iyo bimaze igihe kirekire mu igerageza.

Ibisobanuro ku ngano ikoreshwa, inzira inyuramo, n'uko ikwirakwira mu ngingo bisobanura igice cy'impamvu ikintu cyatsinze ku rwego rwa nanomolar mu ngirabuzimafatizo zororewe mu igerageza gishobora kutagira ingaruka mu kinyabuzima kizima.

Ku baganga n'abashakashatsi, umwanzuro ufite aho ugarukira ariko urahamye. Ubururu bwa metilene si ikirwanya okisidasiyo kirushijeho kugira imbaraga, ahubwo ni icyiciro gitandukanye: igitwara elekitironi gishobora kwiyuburura, gikenera mitokondiriya zitangiritse, ibitanga elekitironi bihari, n'ikizakira ku mpera y'inzira. Suzuma uburyo ubwo ari bwo bwose buteganywa bwo kubukoresha ubaza niba urwo ruziga ruhari mu ngingo bugenewe, kandi usabe igerageza ryo kugenzura nk'iryakozwe mu bushakashatsi bwa Poteet: gushyira ingirabuzimafatizo imbere ya perokiside mu buryo butaziguye, ari igerageza ikintu gikuraho radikali koko gitsinda, ariko igitwara elekitironi cyagombye gutsindwamo. Ni yo mpamvu kandi amagereranya y'ibinyabutabire bikora muri redox ayobowe n'abashakashatsi akomeza kwifashisha uburyo bwo kubigereranya mu buryo butaziguye.

Inkomoko

Amagereranya atatu yavuzwe haruguru ava mu bushakashatsi ku isano iri hagati y'imiterere n'imikorere y'ubururu bwa metilene n'ibindi bintu bitandatu bibukomokaho mu ngirabuzimafatizo z'imyakura, igereranya ry'ibirwanya okisidasiyo bine muri fibroblaste z'uruhu rw'umuntu no mu buryo bw'igerageza bw'uruhu bwa 3D, no mu bushakashatsi bw'igihe kirekire ku bururu bwa metilene na MitoQ mu gusaza kw'amagufa mu moko abiri y'imbeba. Iyi nyandiko itangaza ibyabonetse muri ubwo bushakashatsi kandi ntitanga inama zo kuvura.