Methylene blue neprogeria: zvidzidzo zvinobva pamuenzaniso wekukwegura kwemasero

Kuchinja kwebhii rimwe mujini rimwe kunoita kuti vana vakwegure nokukurumidza kunotyisa. Kupera kwebvudzi, kuoma kwemajoini, kutetepa kwetsinga dzinotakura ropa kubva pamwoyo, uye upenyu hunotarisirwa kugumira mumakore ekuyaruka. Chirwere ichi chinonzi Hutchinson-Gilford progeria syndrome, uye kwemakore tsvakurudzo yacho yainangana nenyukireasi, uko puroteni yakachinjwa nejini inokuvadza. Imwe tsvakurudzo ya2016 yekuUniversity of Maryland yakabvunza mubvunzo wakasiyana: mitochondria dzakaita sei mumasero aya? Mhinduro yacho yakabatanidza zvikamu zviviri zvesero, uye dhayi yebhuruu yave nezana remakore ichizivikanwa yakashanda pazvose zviri zviviri.

Tsvakurudzo iyi yakaitwa naXiong nevamwe vake, ikabudiswa muAging Cell muna 2016. Yakashandisa masero akarimwa murabhoritari chete. Chokwadi ichi ndicho chinotungamirira zvose zvinotevera. Zvakawanikwa ndezvechokwadi uye zvine muganhu wakajeka. Kusiyana kwazvo nechinogona kunzi kurapa kune muganhu wakajekawo.

Muenzaniso: kuchinja kumwe kwejini, puroteni imwe inonamira

Progeria inotanga nokutsiviwa kweC neT panzvimbo 1824 yejini reLMNA. Kuchinja uku hakuchinji amino acid. Kunomutsa nzvimbo yakavanzika inoshandiswa pakubatanidza zvikamu zveRNA, zvichibvisa 50 amino acids mupuroteni ye lamin A. Puroteni yapfupiswa iyi, inonzi progerin, inorasikirwa nenzvimbo yokuchekwa iyo yaiwanzobvumira sero kubvisa chinonamisa chayo chefarnesyl. Saka progerin inoramba iine farnesyl uye yakanamira paganda remukati renyukireasi, apo lamin A yakajairika yaizoramba ichinamatira yobva yasununguka.

Zvinoitika kunyukireasi zvakanyatsonyorwa uye zvinoonekwa nemaikorosikopu. Nyukireasi dzinotutuma dzichiunyana pane kuramba dziine chimiro chezai chakatsetseka. Heterochromatin, DNA yakatsindirana isiri kushanda iyo inowanzogara pedyo nemucheto wenyukireasi, inoderera. Zviuru zvemajini zvinochinja mabudisiro azvinoita zvazvinoraira. Funga nezvenuclear lamina sechimiro chinotsigira rusvingo chiri seri kwepepa rinonamirwa pamadziro: kana chikamu chimwe chechimiro icho chikasungirirwa panzvimbo isiri iyo, rusvingo runotutuma uye mapatani epepa anokanganisika mukamuri rose.

Tsvakurudzo yakashandisa masero efibroblast eganda aibva kuvarwere veprogeria pamwe nemasero ekuenzanisa akanga atamiswa kubva mune imwe ndiro kuenda mune imwe nhamba dzakaenzana dzenguva, ichiwedzera rimwe boka rakagadziridzwa kuti mafibroblast akajairika agadzire progerin zvakananga. Masero akagadziridzwa aya akava nokukanganisika kwakafanana, zvichiratidza kuti progerin ndiyo yaikonzera izvi, kwete nhoroondo yevarwere kana nguva yakapedzwa masero achirimwa. Kukura kwekukanganisika kwaienderana nehuwandu hweprogerin: boka raigadzira progerin yakawanda rakaratidza kukanganisika kwakanyanya pazvinhu zvose.

Zvakanga zvakaita mitochondria

Mitochondria dzemafibroblast ane utano dzinoumba dandemutande rine mapazi rakatenderedza nyukireasi, dziri machubhu marefu anofamba pamakwara echimiro chinotsigira sero. Mumapoka emasero eprogeria, dandemutande iri rakanga risisipo. Chikamu chikuru chemitochondria chakanga chapatsanuka kuita zvidimbu, dzakawanda dzakanga dzazvimba, uye maikorosikopu anoshandisa maerekitironi akaratidza kuti nhamba yezvikamu izvi zvesero zvakanga zvakuvadzwa zvakanyanya yainge yawedzera kanenge kaviri. Mifananidzo yakatorwa ichitevedzana nenguva yakaratidza kuti dzaifamba madaro mapfupi uye zvishoma nezvishoma kupfuura dzemumasero ekuenzanisa.

Kushanda kwadzo kwakaenderana nechimiro chadzo. Mwero wesuperoxide mumitochondria newezvinhu zvinokonzera oxidation musero rose wakakwira. Masero akawanda akaratidza kukanganisika kwemusiyano wemagetsi pakati pemativi eganda remitokondrioni. Kugadzirwa kweATP kwakaderera. Hapana chinoshamisa pazvinhu izvi kana zvikatariswa zvoga, nokuti mitochondria dzakuvadzwa dzinobudisa marudzi eokisijeni anokurumidza kuita makemikari uye dzinogadzira simba shoma. Chitsva chaiva tsananguro yakataurwa yechikonzero. PGC-1alpha, chinhu chinobatsira kumutswa kwekunyorwa kwemajini kuti mitochondria dzigadzirwe kuburikidza nezvimwe zvinhu zvakaita seNRF1, TFAM, uye zvinodzora kubatana nokupatsanuka kwemitochondria zvinonzi MFN1, MFN2, OPA1, FIS1, neDRP1, yakanga yadzvinyirirwa kanenge kasere pamwero wemRNA mumasero eprogeria, puroteni yayo ichidererawo saizvozvo. Progerin yairatidza kunge yaidzvinyirira mudziyo mukuru unotonga kugadzirwa nokuchengetwa kwemitochondria. Kubatana uku pakati pekukuvadzwa kwenuclear lamina nemaitiro ekugadzira nokushandisa simba chikamu chetsananguro yakafara yekugadzirwa kwesimba nemitochondria, uye rutivi rwezvinhu zvinokonzera oxidation mukuyanana kumwe chete uku runotsanangurwa panyaya yekushushikana kunokonzerwa neoxidation nokudzorwa kweROS.

Zvakachinjwa nemethylene blue

Vatsvakurudzi vakaisa methylene blue pamasero pamwero wakaderera we100 nanomolar, nguva dzose kwemavhiki. Kana tichitaura nezvekurima masero, izvi zvinoreva kusangana nayo kwenguva refu pamwero wakaderera, kwete kupiwa mushonga kamwe kwenguva pfupi. Methylene blue inoshanduka ichidzokera pakati pechimiro chakaitwa oxidation nechimiro chakaitwa reduction uye inogona kutakura maerekitironi mukati memitochondria. Ndokusaka ichitsanangurwa sechinhu cheredox chinonangana nemitochondria, kwete sechinhu chinongodzivirira oxidation chinopedzwa pachinopedza simba rechinhu chimwe chinokonzera oxidation.

Mitochondria dzakachinja mumasero akajairika nemumasero eprogeria. ATP yakakwira, mwero wezvinhu zvinokonzera oxidation wakadzika, uye chikamu chemitochondria dzakanga dzakanganisika zvakanyanya chakaderera. Kubudiswa kwePGC-1alpha kwakadzorerwa zvishoma, pamwe nezvimwe zvinhu zvainotonga. Kusvika pano, uku kutsigirwa kwekushanda kwemitochondria kunoitika zvakafara, kwete kungonangana neprogeria.

Zvakawanikwa panyukireasi ndizvo zvakashamisa, uye zvakanga zvakangonangana nemasero ane chirwere. Kututuma kwenyukireasi kwakaderera maererano nekuongororwa kwechimiro kuchishandiswa zviyero zvenhamba. Huwandu hwose hwemalamins A neC hwakakwira. Chainyanya kushamisa ndechekuti progerin yakachinja nzvimbo dzayaigara: mumasero eprogeria asina kuiswa methylene blue, inenge 30 percent chete yeprogerin yaiva muchikamu chinonyungudika chomukati menyukireasi, imwe yose yakanamira paganda rayo. Pashure pekuiswa methylene blue, chikamu chinonyungudika chakakwira kusvika panenge 65 percent, pedyo nemaitiro elamin yakajairika. Yasunungurwa kubva paganda, progerin inodhonza zvinhu zviri pedyo nayo zvishoma, uye zvikamu zvinonyungudika zvemalamins A neC zvakadzorerwawo.

Somugumisiro wokusunungurwa uku, zvinhu zviviri zvinoonekwa panyukireasi zvakavandudzika. Heterochromatin yakapoteredza nyukireasi, yakaongororwa nemaikorosikopu anoshandisa maerekitironi uye nokuisa ruvara runoratidza puroteni yeheterochromatin inonzi HP1-alpha, yakadzorerwa zvinooneka. Uye kuongororwa kwekutevedzana kweRNA kwakaratidza kuti muunganidzwa weRNA dzinogadzirwa nemasero wakanga uchidzokera pedyo newakajairika: masero eprogeria asina kuiswa methylene blue aisiyana nemasero ekuenzanisa pamajini anopfuura 3,200, asi akaiswa methylene blue aisiyana nawo pamajini anenge 1,670. Mumasero akajairika, kuiswa kwechinhu chimwe chete ichi kwakachinja majini gumi-gumi mashoma chete, zvichitsigira pfungwa yokuti kuchinja kwenyukireasi kwakabatana neprogerin pane kuva kumutswa kwokunyorwa kwemajini kunoitika zvakafara. Pfungwa yokuti masero nemhuka zvinoshandiswa mutsvakurudzo zvinopindura mibvunzo ine miganhu yakatetepa kupfuura inoratidzwa nemisoro yenhau dzazvo inotsanangurwa munzira yekuverenga tsvakurudzo yemethylene blue.

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Chekutanga, zvose zvakaitika mundiro dzekurimira masero. Mafibroblast anorimwa haana ropa rinosvika paari, mamiriro anoenderana nemasoja emuviri, marongerwo enyama dzemuviri, kana maitiro anoita mushonga mumuviri wose ayo anosarudza kana chinhu chacho chichisvika panzvimbo yachakanangana nayo. Hapana mhuka yakapiwa mushonga uye hapana murwere akarapwa mutsvakurudzo iyi.

Chechipiri, mafibroblast eprogeria muenzaniso werudzi rumwe chete rwesero. Chirwere ichi chinonyanya kukonzera rufu kuburikidza nekukuvadza tsinga dzinotakura ropa kubva pamwoyo, mapfupa, nemafuta omuviri, uye tsvakurudzo yakaongorora mafibroblast chete pamwe neboka rimwe remasero etsandanyama dzakatsetseka. Dzimwe nyama dzemuviri dzingaita zvakasiyana.

Chechitatu, kuvandudzika kwenyukireasi kwakabva pakusangana nemethylene blue nguva dzose kwemavhiki pamwero wenanomolar mumvura inokurimirwa masero. Mwero wechinhu mundiro hausi mwero wemushonga wokupiwa munhu, uye hapana chiri muchinyorwa chino chinoshandura 100 nanomolar mumvura inokurimirwa masero kuva chirongwa chokushandiswa pamunhu. Methylene blue ine maitiro ayo anoenderana nehuwandu hunopiwa uye njodzi dzayo mukumwe kushandiswa mune zvekurapa, uye tsvakurudzo iyi haipe hwaro hwekuishandisa kumba. Mashoko akafara ezvekuchengeteka anowanikwa mukuchengeteka kwemethylene blue nemigumisiro yayo isingadiwi.

Chechina, progeria haisi kukwegura kwakajairika. Chirwere chisingawanzoitiki chinokonzerwa nokuchinja kumwe kwejini, chinoita kuti chimiro chinotsigira nyukireasi chikanganisike neimwe nzira yakatarwa. Chinhu chinoderedza kukanganisika ikoko mumasero akarimwa chinotaura zvishoma nezvekukwegura kwevanhu vasina kuchinja uku kwejini. Zvinoonekwa mumasero zvinopa mukana wokunzwisisa kutaurirana kwenyukireasi nemitochondria, kwete mugumisiro unoratidza kurebeswa kweupenyu.

Saka pfupiso yakarurama inofanira kutaura mamiriro ayo zvakawanikwa izvi zvinoshanda. Mumafibroblast eprogeria, progerin inodzvinyirira PGC-1alpha ichisiya mitochondria dzakapatsanuka kuita zvidimbu, dzichifamba zvishoma, dziine zvinhu zvakawanda zvinokonzera oxidation, uye dziine simba shoma. Methylene blue pamwero wakaderera yakadzorera zviyero zvekushanda kwemitochondria mumasero ose uye, pamusoro pazvo, yakasunungura progerin kubva paganda renyukireasi mumasero ane chirwere, pamwe nekudzorerwa zvishoma kwechimiro chenyukireasi, heterochromatin, nokubudiswa kwezvinhu zvinorairwa nemajini. Kushanda uku pazvikamu zviviri kunoita kuti tsvakurudzo iyi ikodzere kuzivikanwa. Hakuiti kuti methylene blue ive mushonga weprogeria kana wekukwegura.