Methylene blue, tau na amyloid: impamvu uburyo bwo gukuraho poroteyine butandukanye

Baza icyo methylene blue ikora kuri poroteyine zo mu ndwara ya Alzheimer, maze wumve igisubizo kimwe gitangwa nta gushidikanya, kandi wagombye kumva bitatu buri kimwe gifite imipaka yacyo. Mu gahombo k'igerageza, ibuza tau kwifatanya na yo ubwayo. Mu cyitegererezo kimwe cy'imbeba, igabanya amyloid ishonga ariko tau ntihinduke. Mu kindi, igabanya imikorere ya anzime ituma amyloid ikorwa. Ibi byose byaragaragaye. Nta na kimwe muri byo gisobanura byose, kandi ntibibera byose mu nyamaswa imwe icyarimwe. Iyi nyandiko itandukanya ibi bitatu kugira ngo ibyavuye mu igerageza rimwe bitazongera gutangwa nk'ikimenyetso cy'ibyavuye mu rindi.

Abasomyi bashaka ibisobanuro byagutse ku buryo methylene blue ikora imbere mu ngirabuzimafatizo bakwiye gutangirira aho. Abashaka kumenya niba hari icyo ibi byafashije abarwayi bakwiye gusoma ibyagaragajwe n'igerageza ku barwayi ba Alzheimer, kuko ari ho havugwa ibyavuye mu magerageza yakozwe ku bantu. Nta na kimwe muri iyi nyandiko gisubiramo ibyo bimenyetso.

Ibyagaragaye kuri tau bireba ibizamini byo kwibumbira hamwe

Icyakera muri ibi bitatu gikomoka ku bushakashatsi bwakorewe kuri tau hatarimo ingirabuzimafatizo; tau ni poroteyine ikora amasobekerane y'utudodo mu ngirabuzimafatizo z'imyakura. Mu kizamini cyo kureba uko tau yifatanya n'indi tau, ibice bya tau biraterana bigakora ududodo tubiri twizingiye hamwe, maze amarangi yo mu bwoko bwa phenothiazine, harimo methylene blue, akabuza iryo terana ku bipimo byo hasi bya micromolar. Ubushakashatsi bwakurikiyeho mu binyabutabire byo mu binyabuzima bwatanze ibisobanuro by'uko ibyo bibaho: irangi ritera oksidasiyo y'ibice bya sisteyine biri kuri tau, bigatuma tau iguma mu buryo bwa molekile imwe imwe kandi bikabuza ududodo twari gukura. Ibipimo byatangajwe bibuza tau kwibumbira hamwe biri hafi yo hagati y'umubare w'igice kimwe n'imibare mito y'ibice bibiri bya micromolar; urwo rugero rufite akamaro ku bisobanuro byose bikurikira.

Zirikana ubwoko bw'umwanzuro uri hano. Nta cyo uvuga ku ikorwa rya tau, ku iyongerwaho ry'amatsinda ya fosifate kuri tau mu bwonko buzima, cyangwa ku ikurwaho rya tau. Uvuga ko, mu bihe byagenwe mu gahombo, irangi ryanyuze muri oksidasiyo ribuza tau guterana. Icyo ni icyagaragaye gisobanutse neza, gifite imipaka kandi gifite akamaro. Ikibazo gitangira iyo gikuwe muri iyo mipaka kikagirwa imvugo rusange y'uko methylene blue ikuraho impinduka ziterwa na tau mu ndwara, kuko amakuru yo ku nyamaswa adashyigikira iyo mvugo.

Ibyagaragaye kuri poroteyazome bireba imbeba za 3xTg-AD, kandi byatandukanyije amyloid na tau

Igerageza rigaragaza neza ko ibipimwa byahindutse mu buryo butandukanye ni ubushakashatsi bw'ibyumweru 16 bwo kugaburira imbeba zifite ihinduka ritatu mu ngirabuzima fatizo rifitanye isano na Alzheimer. Izo nyamaswa zatangiye kurya ibiryo birimo methylene blue zifite amezi atandatu, maze abashakashatsi bapima ibintu bitatu icyarimwe: poroteyazome, ingano ya amyloid na tau.

Imikorere ya poroteyazome yarahindutse. Imikorere isa n'iya chymotrypsin yiyongereye hafi kimwe cya kane, naho isa n'iya trypsin yiyongera hafi kimwe cya kabiri, mu gihe imikorere ya gatatu yo kwihutisha imyitwarire y'ibinyabutabire itahindutse ku buryo bufite ubusobanuro mu ibarurishamibare. Amyloid-beta 40 na 42 zishonga, buri imwe yagabanutse hafi kimwe cya kane. Abanditsi babisobanuye nk'ikurwaho ryiyongereye aho kuba ikorwa ryagabanutse, kuko poroteyine ibanziriza amyloid n'ibice biva mu gutunganywa kwayo bitahindutse, kandi kwiga no kwibuka byarushijeho kuba byiza mu kizamini cyo kugenzura ukwibuka mu nzira z'amayobera zo mu mazi.

Ariko hari n'ibitatandukanye mu buryo bumwe n'ibyo. Amyloid idashonga ntiyahindutse. Ibara ryifashishwa mu kugaragaza ibipande bya amyloid ntiryahindutse. Ingano yose ya tau y'umuntu na tau yongewemo fosifate kuri threonine 181 ntibyahindutse, kandi kuba tau yaragiye ahantu hatari ho na byo ntibyahindutse. Ibipimo bya mitokondiriya na byo ntibyahindutse: nta ngaruka zifite ubusobanuro mu ibarurishamibare ku mikorere ya cytochrome-c oxidase, ku ngano ya poroteyine ya oxidase, cyangwa kuri ATP. Bityo, muri iki cyitegererezo no muri iyi gahunda yo gutanga methylene blue, yongereye imikorere ibiri muri itatu ya poroteyazome, igabanya amyloid ishonga, ikosora igipimo kimwe cy'imyitwarire, ariko ibipimo bya tau, amyloid idashonga n'ibipimo bya mitokondiriya byasuzumwe biguma uko byari bimeze.

Hari icyitonderwa kimwe gituma iyi ngingo irushaho gusobanuka aho kuyigabanyiriza agaciro. Izi mbeba zari zitaragira tau yibumbiye hamwe ku myaka yazo igihe zasuzumwaga, bityo iri gerageza ntirishobora kugaragaza ko methylene blue idakora ku masobekerane ya tau. Rigaragaza ko amyloid ishonga ishobora kugabanuka mu gihe ibipimo bya tau byasuzumwe bidahinduka; ibyo ni byo byagaragaye byerekana ko poroteyine imwe yahindutse indi ntihinduke, kandi iyi ngingo ikeneye bene ibyo bimenyetso. Niba wageze hano wibwira ko kongera imikorere ya poroteyazome na methylene blue bikuraho icyarimwe poroteyine zombi ziranga iyi ndwara, ubu bushakashatsi burakosora iyo myumvire.

Ibyagaragaye ku ikorwa rya amyloid bireba imbeba za PSAPP zishaje, kandi bivuguruza uburyo bwavuzwe mbere

Itsinda ritandukanye, icyitegererezo gitandukanye, n'ibisobanuro binyuranye ku kibanza kuba. Mu bushakashatsi bw'amezi atatu bwo guha imbeba za PSAPP zifite amezi 15 ibintu binyuze mu muyoboro ugera mu gifu, igipimo cya buri munsi cya 3 mg/kg cyatangwaga mu kanwa cyagabanyije ubwinshi bw'ibipande bya amyloid mu bice bitandukanye by'ubwonko hafi kimwe cya gatatu kugeza kuri kimwe cya kabiri, kandi kigabanya ibyiciro byinshi bya amyloid, harimo oligomeri zapimwe n'ikizamini cyabigenewe. Ariko aha, uburyo bwatanzwe nk'ibisobanuro bwari ikorwa ryagabanutse, aho kuba ikurwaho ryihuse kurushaho: poroteyine ya BACE1 mu bwonko yaragabanutse, icyo ikora ari cyo C99 kiragabanuka, ariko RNA itwara ubutumwa ntiyagabanutse; ibyo byerekana ingaruka ku rwego rwa poroteyine aho kuba igabanuka ry'imikorere y'ingirabuzima fatizo.

Ubushakashatsi ku ngirabuzimafatizo bwashimangiye ibyo bimenyetso. Mu kizamini kitarimo ingirabuzimafatizo cyakoresheje anzime yakozwe hifashishijwe ikoranabuhanga ryo guhuza ADN, methylene blue yabujije BACE1 gukora mu buryo butaziguye. Mu ngirabuzimafatizo z'intanga ngore za hamster zakoraga poroteyine y'umuntu ibanziriza amyloid, amyloid 40 na 42 zasohorwaga zaragabanutse ku bipimo biri hasi bigera kuri 1.56 micromolar, mu gihe poroteyine ibanziriza amyloid ubwayo itahindutse. Gereranya ibi n'ubushakashatsi bwabanje, aho ibice biva mu gutunganywa kwa poroteyine ibanziriza amyloid bitahindutse, maze igabanuka risobanurwa n'ikurwaho. Ibyo byombi ntibishobora gusobanura uburyo bumwe bukora hose, kuko ibyitegererezo, imyaka, ibipimo, inzira zo gutanga methylene blue n'igihe ubushakashatsi bwamaze bitandukanye. Iyo ni yo ngingo. Ingaruka za methylene blue kuri amyloid zinyura mu ikorwa ryayo mu igerageza rimwe, no mu ikurwaho ryayo mu rindi; gutanga ibyavuye muri rimwe utavuze uko ryakozwe birayobya.

Imyitwarire imwe y'ibinyabutabire, ibintu byinshi byibasirwa: isano itangwa na oksidasiyo ya sisteyine

Urundi ruhererekane rw'ubushakashatsi rusobanura uko imyitwarire imwe yo kwakira no gutanga elegitoroni ishobora kugaragara mu bushakashatsi bwa poroteyine butajyanye. Mu bushakashatsi bw'ibinyabutabire byo mu binyabuzima ku kubuza caspase gukora, methylene blue yahagaritse imikorere ya caspase-6 itera oksidasiyo ya sisteyine yayo igira uruhare mu kwihutisha imyitwarire y'ibinyabutabire, iyihindura aside sulfenic. Ibyo byemejwe n'isesengura rishingiye ku misa ya molekile, kandi igipimo cyatanze kimwe cya kabiri cy'ingaruka ntarengwa cyari hafi ya 10.6 micromolar. Caspase-3 na yo yabujijwe gukora ku gipimo gisa n'icyo. Abanditsi bahuje ibi ku buryo bweruye n'ubushakashatsi bwanditswe kuri tau: imyitwarire imwe itera oksidasiyo ya sisteyine, yatanzwe nk'isobanura uko tau iguma ari molekile imwe imwe, ishobora guhagarika imikorere ya poroteyase ya sisteyine, kandi ibipimo bigira ingaruka birahurirana.

Ibi bisobanuro birahuye neza, ariko binatanga umuburo. Molekile igira uruhare mu kwakira no gutanga elegitoroni kandi itera oksidasiyo ya sisteyine zigerwaho izagira icyo ikora ku bintu birenze kimwe ku gipimo icyo ari cyo cyose igiraho ingaruka. Ibisobanuro by'ugutatana kwa tau yari yibumbiye hamwe, ibyerekeye caspase, ndetse wenda n'ibindi, bihuriye ku gikorwa kimwe cy'ibinyabutabire ariko kikabera ku bintu bitandukanye. Kuba bihuriye kuri icyo gikorwa ntibituma ibyagaragaye bisimburana. Bisobanura ko igipimo n'uko ibintu bimeze ari byo bigena icyibasirwa gifite akamaro, kandi ko gutanga methylene blue igihe kirekire hagamijwe igikorwa kimwe gishingiye kuri sisteyine bishobora kugira icyo bikora no ku bindi; icyo ni icyitonderwa abanditsi b'ubushakashatsi kuri caspase bavuze ku buryo bweruye. Ibibazo bifitanye isano na byo, birimo uko imyitwarire ya methylene blue yo kwakira no gutanga elegitoroni igena ibyo yibasira, icyo kongera imikorere ya poroteyazome bisobanura ku zindi poroteyine zibumbiye hamwe, ndetse no kumenya niba gutanga methylene blue igihe kirekire bihindura ibyo yibasira, buri kimwe gikeneye gusuzumwa ukwacyo.

Uburyo bukora hakurikijwe ibipimwa: icyagaragaye kijyanye n'ikihe cyitegererezo

Soma iyi mbonerahamwe umurongo ku wundi, maze isomo riragaragare. Nta murongo n'umwe ugaragaza ihinduka muri buri nkingi. Icyagaragaye gikomeye kurusha ibindi ku ikorwa rya amyloid gikomoka mu bushakashatsi butigeze busuzuma poroteyazome. Icyagaragaye gikomeye kurusha ibindi kuri poroteyazome gikomoka mu bushakashatsi aho itunganywa rya poroteyine ibanziriza amyloid ritigeze rihinduka. Ibyagaragaye kuri tau ahanini bishingiye ku byakorewe mu duhombo no ku myitwarire y'ibinyabutabire iboneka no kuri anzime zitari zigambiriwe. Umuntu wese uhuza izi nkingi mu mwanzuro umwe w'uko methylene blue ikuraho poroteyine zifitanye isano n'indwara nk'itsinda rimwe, aba yandika isesengura ry'igerageza ritigeze rikorwa.

Uku kwitondera ibisobanuro bireba n'abarwayi. Kumenya niba ubu buryo bukora butanga inyungu mu buvuzi ni ikindi kibazo gifite amagerageza yacyo n'imyanzuro yacyo; gisubizwa mu bimenyetso by'igerageza ku barwayi ba Alzheimer aho kuba hano.