Methylene blue na progeria: amasomo ava ku cyitegererezo cyo gusaza kw’uturemangingo

Guhinduka kw’inyuguti imwe muri gene imwe bituma abana basaza ku muvuduko uteye ubwoba. Umusatsi uratakara, ingingo zikagagara, imiyoboro y’amaraso ikagabanuka ubugari, kandi igihe cyo kubaho giteganyijwe kikagarukira mu myaka y’ubugimbi. Iyo ndwara ni Hutchinson-Gilford progeria syndrome, kandi ubushakashatsi kuri yo bwamaze imyaka bwibanda ku ntima y’akaremangingo, aho poroteyine yahindutse yangiza. Ubushakashatsi bwo muri 2016 bwa University of Maryland bwabajije ikindi kibazo: mitokondiriya zo muri utwo turemangingo zimeze zite? Igisubizo cyahuje ibice bibiri by’akaremangingo, kandi irangi ry’ubururu rimaze ikinyejana ryagize icyo rihindura kuri byombi.

Ubwo bushakashatsi ni ubwa Xiong na bagenzi be, bwasohotse muri Aging Cell muri 2016. Bwakoresheje gusa uturemangingo twororewe muri laboratwari. Ibyo ni byo bigena uko ibikurikira byose bigomba kumvikana. Ibyabonetse ni nyakuri kandi birasobanutse. Intera iri hagati yabyo n’uburyo ubwo ari bwo bwose bwo kuvura na yo irasobanutse.

Icyitegererezo: ihinduka rimwe, poroteyine imwe ifatira

Progeria itangirana n’isimburwa rya C na T ku mwanya wa 1824 muri gene ya LMNA. Iryo hinduka ntirihindura aside amine. Rikoresha ahantu hari hihishe ho gukata no guteranya RNA, bigatuma aside amine 50 zikurwa muri poroteyine ya lamin A. Iyo poroteyine ngufi, yitwa progerin, ibura ahantu yagombaga gukatirwa, ubusanzwe hakaba ari ho hatuma akaremangingo gakuraho itsinda rya farnesyl riyifata. Bityo, progerin igumana farnesyl ubuziraherezo, igafatira ku gice cy’imbere cy’agahu k’intima, aho lamin A isanzwe yagombye kujya ifatira ikanahava.

Ingaruka zabyo ku ntima zaranditswe neza kandi ziragaragara kuri mikorosikopi. Intima zigira ibibyimba n’iminkanyari aho kugumana ishusho y’igi yorohereye. Heterochromatin, DNA yegeranye cyane idakora ubusanzwe iba ku nkengero z’intima, iragabanuka. Uburyo gene ibihumbi zikora burahinduka. Tekereza kuri lamina y’intima nk’urusobekerane rushyigikira urukuta ruri inyuma y’impapuro zirutaka: iyo igice kimwe cy’urwo rusobekerane gisudiriwe ahantu hatari ho, urukuta rurabyimba, n’imitako yo ku mpapuro igatakaza ishusho mu cyumba cyose.

Ubushakashatsi bwakoresheje uturemangingo twa fibroblast two mu ruhu rw’abarwayi ba progeria, hamwe n’uturemangingo two kugereranyaho twari twarimuriwe mu bikoresho bishya byo kororerwamo inshuro zingana. Bwakoresheje kandi irindi tsinda ryahinduwe kugira ngo uturemangingo twa fibroblast dusanzwe dukore progerin mu buryo butaziguye. Uturemangingo twahinduwe twagize inenge zimwe n’izindi, bikerekana ko progerin ari yo yabiteye, aho kuba amateka y’abarwayi cyangwa igihe uturemangingo twamaze twororwa. Ubukana bw’inenge bwakurikiraga ingano ya progerin: itsinda ryakoraga progerin nyinshi ryagaragaje inenge zikomeye kurushaho muri byose.

Uko mitokondiriya zari zimeze

Mitokondiriya zo mu turemangingo twa fibroblast tuzima zikora urusobekerane rufite amashami ruzengurutse intima, rugizwe n’udutembo tureture tugenda ku nzira z’urwego rushyigikira akaremangingo. Mu matsinda y’uturemangingo twa progeria, urwo rusobekerane ntirwari rukiriho. Umugabane munini kurushaho wa mitokondiriya wari waracitsemo ibice, nyinshi zari zabyimbye, kandi mikorosikopi ikoresha electron yagaragaje ko utugingo duto twangiritse bikabije twari twiyongereye hafi inshuro ebyiri. Amafoto yafashwe akurikirana uko ibintu bihinduka mu gihe yagaragaje ko zagendaga intera ngufi kandi ku muvuduko muto kurusha izo mu turemangingo two kugereranyaho.

Imikorere yakurikiye imiterere. Superoxide yo muri mitokondiriya n’ingano y’ibintu bitera okisidasiyo mu karemangingo kose byariyongereye. Uturemangingo twinshi kurushaho twagaragaje ihungabana ry’itandukaniro ry’ingufu z’amashanyarazi hagati y’impande z’agahu ka mitokondiriya. Ikorwa rya ATP ryaragabanutse. Nta na kimwe muri ibyo gitangaje gifashwe ukwacyo, kuko mitokondiriya zangiritse zisohora ibintu birimo ogisijeni bikora cyane mu myitwarire ya shimi kandi zigakora ingufu nke. Igishya cyari impamvu yatanzwe. PGC-1alpha, poroteyine ifasha iyandukurwa rya gene kandi igateza imbere ikorwa rya mitokondiriya binyuze mu bindi biyikurikira nka NRF1, TFAM, n’ibigenga uguhuza no gutandukanya mitokondiriya MFN1, MFN2, OPA1, FIS1 na DRP1, yari yagabanutse hafi inshuro umunani ku rwego rwa mRNA mu turemangingo twa progeria, kandi poroteyine yayo na yo yagabanutse mu buryo buhuye na byo. Progerin yasaga n’ibuza gukora igenzura rikuru ry’ikorwa no kubungabungwa bya mitokondiriya. Iryo sano hagati yo kwangirika kwa lamina y’intima n’imikorere ijyanye n’ingufu ni igice cy’ibisobanuro byagutse ku ikorwa ry’ingufu muri mitokondiriya, naho uruhande rw’ibintu bitera okisidasiyo muri iyo mikorere rusobanurwa mu bijyanye n’umutwaro wa okisidasiyo no kugenzura ROS.

Ibyo methylene blue yahinduye

Abashakashatsi bashyize uturemangingo muri methylene blue ifite ubucucike buke bwa 100 nanomolar, ubudahagarara mu gihe cy’ibyumweru. Mu bijyanye no korora uturemangingo, ibyo ni ukubimaramo igihe kirekire ku bucucike buke, si uguhabwa umuti mu gihe gito. Methylene blue ihinduranya hagati y’imiterere ya okisidasiyo n’iy’igabanyuka rya okisidasiyo kandi ishobora gutwara electron muri mitokondiriya. Ni yo mpamvu isobanurwa nk’ikinyabutabire cya redox kigira icyo gikora kuri mitokondiriya, aho kuba ikinyabutabire gisanzwe kirwanya okisidasiyo gikoreshwa kikarangira igihe gikuyemo ubushobozi bw’ikintu kimwe gitera okisidasiyo.

Mitokondiriya zahindutse mu turemangingo dusanzwe no mu twa progeria. ATP yariyongereye, ingano y’ibintu bitera okisidasiyo iragabanuka, kandi umugabane wa mitokondiriya zifite inenge zikomeye uragabanuka. Ikorwa rya PGC-1alpha ryaragarutse igice, hamwe na bimwe mu byo igenga biyikurikira. Kugeza aho, ibyo byari ingaruka rusange zo gufasha imikorere ya mitokondiriya, zitihariye kuri progeria.

Ibyabonetse ku ntima ni byo byatunguranye, kandi byari byihariye ku turemangingo turwaye. Ibibyimba byo ku ntima byaragabanutse, nk’uko isesengura ryapimaga imiterere ryabigaragaje. Ingano zose za lamin A na C zariyongereye. Icyagaragaye cyane kurusha ibindi, progerin yahinduye aho iba: mu turemangingo twa progeria tutahawe methylene blue, hafi 30 ku ijana gusa bya progerin ni byo byari mu gice gishonga cyo mu mazi yo mu ntima, ibindi bifatiye ku gahu. Nyuma yo guhabwa methylene blue, umugabane ushonga wazamutse ugera hafi kuri 65 ku ijana, wegereye uko lamin isanzwe yitwara. Iyo ivuye ku gahu, progerin ikururana poroteyine nke ziyegereye, kandi ibice bishonga bya lamin A na C na byo byarasubiranye.

Nyuma y’uko progerin ivuye ku gahu, imiterere ibiri igaragara ku ntima yarushijeho kuba myiza. Heterochromatin yo ku nkengero z’intima, yasuzumwe hakoreshejwe mikorosikopi ya electron no gusiga ibara ryerekana poroteyine ya heterochromatin HP1-alpha, yagaragaye ko yasubiranye. Kandi isesengura ry’uruhererekane rwa RNA ryagaragaje ko urusobe rwose rwa RNA rwari rwegereye imiterere isanzwe: uturemangingo twa progeria tutahawe methylene blue twari dutandukanye n’uturemangingo two kugereranyaho kuri gene zirenga 3,200, mu gihe utwayahawe twari dutandukanye na two kuri gene hafi 1,670. Mu turemangingo dusanzwe, ubwo buryo bumwe bwahinduye gene nke gusa zibarirwa mu macumi, bikaba bishyigikira ko ingaruka ku ntima zifitanye isano na progerin aho kuba uguhungabanya muri rusange iyandukurwa rya gene. Ihame ry’uko ibyitegererezo by’uturemangingo n’inyamaswa bisubiza ibibazo bifunganye kurusha uko imitwe y’inkuru ibivugaho ishobora kubyumvikanisha risobanurwa mu nyandiko uko wasoma ubushakashatsi kuri methylene blue.

Impamvu ubu atari uburyo bwo kuvura

Imipaka ine ituma ubu bushakashatsi buguma aho bugomba kuba: muri laboratwari.

Icya mbere, byose byabereye mu bikoresho byo kororeramo uturemangingo. Uturemangingo twa fibroblast twororewe muri laboratwari ntitugira amaraso atugeraho, imiterere y’ubwirinzi bw’umubiri, imiterere y’ingirangingo, cyangwa uburyo umubiri wose wakira ukanatunganya ikinyabutabire, ari byo bigena niba kigera ku cyo kigomba gukoraho. Muri iyi nyandiko nta nyamaswa yahawe icyo kinyabutabire kandi nta murwayi wavuwe.

Icya kabiri, uturemangingo twa fibroblast twa progeria ni icyitegererezo cy’ubwoko bumwe bw’uturemangingo. Iyo ndwara yica cyane cyane binyuze mu ngaruka igira ku mitsi itwara amaraso ava ku mutima, ku magufa no ku binure, kandi ubushakashatsi bwasuzumye gusa fibroblast n’icyitegererezo kimwe cy’imikaya ikora itagengwa n’ubushake. Izindi ngirangingo zishobora kwitwara ukundi.

Icya gatatu, gusubirana kw’intima kwaturutse ku byumweru byo kumara ubudahagarara mu mazi yo kororeramo arimo ubucucike buri ku rwego rwa nanomolar. Ubucucike bwo mu gikoresho cyo kororeramo si ingano y’umuti uhabwa umuntu, kandi nta na kimwe muri iyi nyandiko gihindura 100 nanomolar zo muri ayo mazi mo gahunda yo guha umuntu umuti. Methylene blue ifite uburyo bwayo bwo kugira ingaruka bitewe n’ingano yakoreshejwe ndetse n’umwirondoro wayo w’umutekano mu zindi mikoreshereze y’ubuvuzi, kandi ubu bushakashatsi ntibutanga ishingiro ryo kuyikoresha mu rugo. Amakuru rusange ajyanye n’umutekano aboneka mu nyandiko umutekano wa methylene blue n’ingaruka zayo mbi.

Icya kane, progeria si ugusaza gusanzwe. Ni indwara idakunze kuboneka iterwa n’ihinduka rimwe muri gene, aho urwego rushyigikira intima rwangirika mu buryo bwihariye. Kuba ikinyabutabire kigabanya uko kwangirika kwihariye mu turemangingo twororewe muri laboratwari bivuga bike ku gusaza kw’abantu badafite iryo hinduka. Imiterere igaragara y’uturemangingo itanga uburyo bwo gusobanukirwa imikoranire hagati y’intima na mitokondiriya, si igisubizo cyerekana kuramba.

Bityo, incamake itabogamye igomba kugengwa n’aho ibyo byagaragariye. Mu turemangingo twa fibroblast twa progeria, progerin igabanya PGC-1alpha, bigatuma mitokondiriya zicikamo ibice, zigenda buhoro, zigira ibintu byinshi bitera okisidasiyo kandi zigakora ingufu nke. Methylene blue ku bucucike buke yagaruye ibipimo by’imikorere ya mitokondiriya mu turemangingo twose, kandi inatuma progerin iva ku gahu k’intima mu turemangingo turwaye, hamwe no gusubirana igice kw’imiterere y’intima, heterochromatin n’imikorere ya gene. Icyo gikorwa ku bice byombi gituma ubu bushakashatsi bukwiye kumenywa. Ntigituma methylene blue iba uburyo bwo kuvura progeria cyangwa gusaza.