I-methylene blue ne-progeria: izifundo ezivela kumodeli yokuguga kwamaseli

Ukushintsha kohlamvu olulodwa kufuzo olulodwa kwenza izingane ziguge ngesivinini esethusayo. Ukuqothuka kwezinwele, ukuqina kwamalunga, ukuncipha kwemithambo ethwala igazi lisuka enhliziyweni, nokuphila okulindelekile okugcina eminyakeni yobusha. Leso sifo yi-Hutchinson-Gilford progeria syndrome, futhi iminyaka eminingi ucwaningo ngaso lwalugxile kunucleus, lapho iphrotheni eguqukile idala khona umonakalo. Ucwaningo lwango-2016 lwase-University of Maryland lwabuza umbuzo ohlukile: abukeka kanjani ama-mitochondria kula maseli? Impendulo yaxhumanisa izingxenye ezimbili zeseli, futhi udayi oluhlaza okwesibhakabhaka osuneminyaka eyikhulu wasithinta zombili.

Lolu cwaningo oluka-Xiong nozakwabo, lwashicilelwa ku-Aging Cell ngo-2016. Lwasebenza kuphela ngamaseli akhuliswe elabhorethri. Leli qiniso liyisisekelo sakho konke okulandelayo. Okutholakele kuyiqiniso futhi kuqondile. Ibanga eliphakathi kwakho nanoma yikuphi ukwelashwa nalo licacile.

Imodeli: ukuguquka okukodwa kofuzo, iphrotheni eyodwa enamathelayo

I-progeria iqala ngokushintshwa kuka-C abe ngu-T endaweni engu-1824 kufuzo lwe-LMNA. Lolu shintsho aluguquli i-amino acid. Lwenza kusebenze indawo efihlekile yokuhlanganisa izingxenye ze-RNA, okususa ama-amino acid angu-50 kuphrotheni ye-lamin A. Umkhiqizo ofushanisiwe, obizwa nge-progerin, ulahlekelwa indawo yokusikwa evame ukuvumela iseli ukuba lisuse ihange lawo le-farnesyl. Ngakho i-progerin ihlala ine-farnesyl unomphela futhi inamathele kulwelwesi lwangaphakathi lwenucleus, lapho i-lamin A evamile yayizonamathela khona iphinde ihlukane nalo ngezikhathi ezithile.

Imiphumela kunucleus ibhalwe kahle futhi ibonakala ngesibonakhulu. Ama-nucleus aba namaqhubu nemibimbi kunokuba agcine ukuma okusaqanda okubushelelezi. I-heterochromatin, okuyi-DNA eminyene engasebenzi evame ukwelamela unqenqema lwenucleus, iyancipha. Ukuvezwa kwezinkulungwane zezakhi zofuzo kuyashintsha. Cabanga nge-nuclear lamina njengohlaka olusekela udonga ngemuva kwephepha lokuluhlobisa: uma ingxenye eyodwa yohlaka ishiselwa endaweni engafanele, udonga luyakhukhumala futhi iphethini yephepha iyaphazamiseka kulo lonke igumbi.

Ucwaningo lwasebenzisa ama-fibroblast esikhumba eziguli ezine-progeria kanye namaseli okuqhathanisa ayedlule enanini elifanayo lemijikelezo yokudluliselwa ekukhulisweni kabusha, kanye neqoqo lesibili elaliguqulwe ukuze ama-fibroblast avamile akhiqize i-progerin ngokuqondile. Amaseli aguquliwe aba nokukhubazeka okufanayo, okukhomba i-progerin njengembangela, hhayi umlando weziguli noma isikhathi amaseli ayesekhuliswe ngaso elabhorethri. Ubunzima bokukhubazeka babuhambisana nenani: iqoqo elalikhiqiza i-progerin eningi labonisa ukukhubazeka okukhulu kuzo zonke izilinganiso.

Indlela ama-mitochondria ayebukeka ngayo

Ama-mitochondria kuma-fibroblast aphilile akha inethiwekhi enamagatsha ezungeze inucleus, enamashubhu amade ahamba emizileni yohlaka lweseli. Emaqoqweni amaseli e-progeria, leyo nethiwekhi yayingasekho. Ingxenye enkulu yama-mitochondria yayiphukile yaba yizingcezu, amaningi ayevuvukele, futhi ukuhlolwa ngesibonakhulu sama-electron kwabonisa ukuthi inani lama-organelle alimele kakhulu lalicishe liphindeke kabili. Izithombe ezithathwe ngezikhathi ezilandelanayo zawabonisa ehamba amabanga amafushane ngesivinini esiphansi kunalawo akumaseli okuqhathanisa.

Ukusebenza kwalandela ukuma kwawo. Amazinga e-superoxide kuma-mitochondria nawezinto ezibangela i-oxidation kulo lonke iseli akhuphuka. Amaseli amaningi abonisa ukuphazamiseka komehluko wamandla kagesi olwelwesini. Ukukhiqizwa kwe-ATP kwehla. Akukho kulokhu okumangazayo uma kubhekwa ngakunye, ngoba ama-mitochondria alimele avuza izinhlobo zomoya-mpilo ezisebenza ngokushesha kumakhemikhali futhi akhiqiza amandla amancane. Okwakusha kwakuyimbangela eyayiphakanyiswa. I-PGC-1alpha, iphrotheni esiza ukuqalisa ukubhalwa kolwazi lwezakhi zofuzo futhi ekhuthaza ukwakhiwa kwama-mitochondria ngezinto ezisebenza ngaphansi kwayo ezifana ne-NRF1, TFAM, kanye nabalawuli bokuhlangana nokuhlukana, i-MFN1, MFN2, OPA1, FIS1, ne-DRP1, yayicindezelwe cishe ngokuphindwe kasishiyagalombili ezingeni le-mRNA kumaseli e-progeria, kanye nokwehla okuhambisanayo kwephrotheni. I-progerin yayibonakala icindezela iswishi eyinhloko yokwakha nokugcina ama-mitochondria. Lokho kuxhumana phakathi komonakalo we-nuclear lamina nokucutshungulwa kwamandla kuyingxenye yencazelo ebanzi yokukhiqizwa kwamandla ngama-mitochondria, kanti uhlangothi lwezinto ezibangela i-oxidation kulokhu kulinganisela luchazwa ekucindezelekeni okubangelwa i-oxidation nasekulawulweni kwe-ROS.

Lokho okwashintshwa yi-methylene blue

Abacwaningi bafaka i-methylene blue emaselini ngesilinganiso esiphansi esingu-100 nanomolar, ngokuqhubekayo amasonto amaningi. Ngokwemibandela yokukhulisa amaseli elabhorethri, lokhu kuwukuchayeka isikhathi eside ngesilinganiso esiphansi, hhayi ukuchayeka emuthini isikhashana. I-methylene blue ishintshashintsha phakathi kwesimo esine-oxidation nesibuyiselwe emuva futhi ingathwala ama-electron ngaphakathi kwama-mitochondria, yingakho ichazwa njengenhlanganisela ye-redox eqondiswe kuma-mitochondria kunokuba ibe yi-antioxidant evamile ephela lapho iqeda into eyodwa ebangela i-oxidation.

Ama-mitochondria asabela kumaseli avamile nakumaseli e-progeria. I-ATP yakhuphuka, amazinga ezinto ezibangela i-oxidation ehla, futhi ingxenye yama-mitochondria ayekhubazeke kakhulu yancipha. Ukuvezwa kwe-PGC-1alpha kwabuyela ngokwengxenye, kanye nokunye okuqondiswe yiyo. Kuze kube lapha, lokhu kuwumphumela ojwayelekile wokusekela ama-mitochondria, hhayi oqondene ne-progeria kuphela.

Imiphumela kunucleus yiyona eyamangaza, futhi yayiqondene namaseli anesifo. Amaqhubu enucleus ancipha ngokokuhlaziywa kwezilinganiso zokuma kwayo. Amanani aphelele ama-lamin A no-C akhuphuka. Okuphawuleka kakhulu ukuthi i-progerin yashintsha indawo eyayikuyo: kumaseli e-progeria angazange achayekiswe, cishe amaphesenti angu-30 kuphela e-progerin ayesengxenyeni encibilikayo ye-nucleoplasm, kanti enye yayibambelele olwelwesini. Ngemva kokuchayekiswa, ingxenye encibilikayo yakhuphuka yaya cishe kumaphesenti angu-65, eduze nokuziphatha okuvamile kwe-lamin. Lapho isikhululekile olwelwesini, i-progerin idonsa okuncane kwamaphrotheni angomakhelwane bayo, futhi izingxenye ezincibilikayo zama-lamin A no-C nazo zabuyela esimweni sazo.

Ngenxa yalokho kukhululeka, izici ezimbili zenucleus zaba ngcono. I-heterochromatin ezungeze inucleus, eyahlolwa ngesibonakhulu sama-electron nangokufakwa kombala ukuze kubonakale iphrotheni ye-heterochromatin i-HP1-alpha, yabuyiselwa ngendlela ebonakalayo. Ukuhlaziywa kokulandelana kwe-RNA kwabonisa ukuthi iqoqo lonke lemibhalo ye-RNA lalibuyela esimweni esivamile: amaseli e-progeria angazange achayekiswe ayehlukile kwawokuqhathanisa ezakhini zofuzo ezingaphezu kuka-3,200, kuyilapho amaseli e-progeria achayekisiwe ayehlukile kwezicishe zibe ngu-1,670. Kumaseli avamile, ukuchayekiswa okufanayo kwashintsha izakhi zofuzo ezimbalwa kuphela ezibalelwa emashumini, okusekela ukuthi umphumela kunucleus uxhumene ne-progerin kunokuba ube ukuguquka okuvamile okukhulu kokubhalwa kolwazi lwezakhi zofuzo. Umgomo wokuthi izivivinyo zamaseli nezilwane ziphendula imibuzo emincane kunaleyo esikiselwa yizihloko zazo uchazwa kokuthi ungalufunda kanjani ucwaningo nge-methylene blue.

Kungani lokhu kungelona ukwelashwa

Imikhawulo emine igcina lolu cwaningo lapho lufanele khona: ngaphakathi elabhorethri.

Okokuqala, konke kwenzeka ezitsheni zokukhulisa amaseli. Ama-fibroblast akhuliswe elabhorethri awanakuhlinzekwa ngegazi, umongo wamasosha omzimba, ukwakheka kwezicubu, nokusebenza kwemithi emzimbeni wonke okunquma ukuthi inhlanganisela iyafika yini nhlobo lapho iqondiswe khona. Kuleli phepha, akukho silwane esanikezwa umthamo futhi akukho siguli esalashwa.

Okwesibili, ama-fibroblast e-progeria ayimodeli yohlobo olulodwa lweseli. Lesi sifo siholela ekufeni ikakhulukazi ngokuthinta imithambo ethwala igazi lisuka enhliziyweni, amathambo, namafutha, kanti ucwaningo lwahlola kuphela ama-fibroblast kanye nesampula elilodwa lomsipha obushelelezi. Ezinye izicubu zingase ziziphathe ngendlela ehlukile.

Okwesithathu, ukubuyiselwa kwenucleus kwavela ngemva kwamasonto okuchayeka okuqhubekayo ngesilinganiso se-nanomolar oketshezini lokukhulisa amaseli. Izilinganiso ezisezitsheni azizona izilinganiso zomthamo, futhi akukho kuleli phepha okuguqula u-100 nanomolar oketshezini kube uhlelo lokusetshenziswa kumuntu. I-methylene blue inendlela yayo yokusabela kuye ngomthamo nephrofayela yokuphepha kwezinye izindawo zezokwelapha, futhi lolu cwaningo alunikezi sisekelo sokuyisebenzisa ekhaya. Umongo ojwayelekile wokuphepha utholakala kokuthi ukuphepha kwe-methylene blue nemiphumela engemihle.

Okwesine, i-progeria ayikona ukuguga okuvamile. Iyisifo esingavamile esibangelwa ukuguquka okukodwa kofuzo, lapho uhlaka lwenucleus lulimala ngendlela ethile. Inhlanganisela enciphisa lowo monakalo othile kumaseli akhuliswe elabhorethri isitshela okuncane ngokuguga kwabantu abangenakho lokho kuguquka kofuzo. Izici zeseli ziyindlela yokubheka ukuxhumana phakathi kwenucleus nama-mitochondria, hhayi umphumela wokuphila isikhathi eside.

Ngakho isifinyezo esifanele sincike kule mibandela. Kuma-fibroblast e-progeria, i-progerin icindezela i-PGC-1alpha futhi ishiya ama-mitochondria ephukile aba yizingcezu, ehamba kancane, enezinto eziningi ezibangela i-oxidation, futhi enamandla amancane. I-methylene blue ngesilinganiso esiphansi yabuyisela izilinganiso zokusebenza kwama-mitochondria kuwo wonke amaseli futhi yakhulula ne-progerin olwelwesini lwenucleus kumaseli anesifo, kanye nokubuyela ngokwengxenye kokuma kwenucleus, kwe-heterochromatin, nokokuvezwa kwezakhi zofuzo. Leso senzo esikabili senza lolu cwaningo lufanele ukwaziwa. Asenzi i-methylene blue ibe ukwelashwa kwe-progeria noma kokuguga.