I-methylene blue ne-progeria: izifundo ezivela kwimodeli yokuguga kweeseli

Ukutshintsha konobumba omnye kwijini enye kubangela ukuba abantwana baguge ngesantya esoyikekayo. Ukulahleka kweenwele, ukuqina kwamalungu, ukucutheka kwemithambo ethwala igazi lisuka entliziyweni, neminyaka yobomi elindelekileyo efikelela kuphela kweyeshumi elivisayo. Eso sifo yi-Hutchinson-Gilford progeria syndrome, yaye kangangeminyaka uphando ngaso lwalugxile kwinucleus, apho iprotheyini eguqulweyo yenza khona umonakalo. Uphando luka-2016 lweYunivesithi yaseMaryland lwabuza umbuzo owahlukileyo: zinjani iimitokhondriya kwezi seli? Impendulo yadibanisa iindawo ezimbini zeseli, yaye idayi eluhlaza okwesibhakabhaka esele isetyenziswe kangangenkulungwane yachaphazela zombini.

Olu phando lolukaXiong noogxa bakhe, olwapapashwa kwi-Aging Cell ngo-2016. Lwenziwa ngokupheleleyo ngeeseli ezikhuliswe elebhu. Loo nto isisiseko sayo yonke into elandelayo. Iziphumo ziyinyani yaye zichanekile kwizinto ezithile. Ngokufanayo, umsantsa phakathi kwazo nalo naluphi na unyango ucacile.

Imodeli: utshintsho olunye lwemfuza, iprotheyini enye encamathelayo

I-progeria iqala ngokutshintshwa kuka-C abe ngu-T kwindawo engu-1824 kwijini ye-LMNA. Olu tshintsho aluyitshintshi i-amino acid. Luvusa indawo efihlakeleyo yokusikwa nokudityaniswa kwe-RNA, nto leyo esusa ii-amino acid ezingama-50 kwiprotheyini ye-lamin A. Le protheyini imfutshane, ebizwa ngokuba yi-progerin, ilahlekelwa yindawo yokusikwa ebidla ngokuvumela iseli ukuba isuse iankile yayo ye-farnesyl. Ngoko i-progerin ihlala iqhotyoshelwe ngokusisigxina kwi-farnesyl, incamathele kwinwebu yangaphakathi yenucleus, apho i-lamin A eqhelekileyo ibidla ngokuncamathela ize iphinde ihlukane nayo.

Iziphumo ezikwinucleus zibhalwe kakuhle yaye ziyabonakala ngemikroskopu. Iinucleus zenza amaqhuma nemibimbi endaweni yokugcina ukumila okumbhoxo nokugudileyo. I-heterochromatin, eyi-DNA epakishwe yaxinana nengasebenziyo edla ngokuba ngakwimiphetho yenucleus, iyancipha. Amawaka eejini atshintsha indlela avakaliswa ngayo. Cinga nge-nuclear lamina njengesakhiwo senkxaso esisemva kwephepha lokuhombisa udonga: xa inxenye enye yenkxaso idityaniswe ngokusisigxina kwindawo engafanelekanga, udonga luyadumba yaye ipateni yephepha iyagqwetheka kulo lonke igumbi.

Uphando lwasebenzisa iifibroblast zolusu ezivela kwizigulana ze-progeria kunye neeseli zokuthelekisa ezazidlule kwinani elifanayo lemijikelo yokukhuliswa nokudluliselwa, kwakunye neqela lesibini leeseli elaliguqulwe ukuze iifibroblast eziqhelekileyo zivelise i-progerin ngqo. Ezo seli ziguqulweyo zaba neziphene ezifanayo, nto leyo ekhomba kwi-progerin njengonobangela, kungekhona kwimbali yezigulana okanye kwixesha lokukhuliswa elebhu. Ubunzima beziphene babulandela ubungakanani be-progerin: iqela elalivelisa i-progerin eninzi labonisa iziphene ezimbi ngakumbi kuzo zonke iinkalo.

Indlela ezazibonakala ngayo iimitokhondriya

Iimitokhondriya zeefibroblast ezisempilweni zenza uthungelwano olunamasebe olujikeleze inucleus, olunemibhobho emide ehamba kwiindlela zesakhiwo senkxaso yeseli. Kumaqela eeseli ze-progeria, olo thungelwano lwalungekho. Inxalenye enkulu ngakumbi yeemitokhondriya yayiqhekeke yangamaqhekeza, ezininzi zazidumbile, yaye imikroskopu yee-electron yabonisa ukuba inani lamalungu amancinane eseli awonakele kakhulu lalimalunga nokuphinda kabini. Ukufotwa kwazo ngamaxesha alandelelanayo kwabonisa ukuba zihamba imigama emifutshane nangesantya esiphantsi kunaleyo yeeseli zokuthelekisa.

Ukusebenza kwazo kwalandela ukumila kwazo. Amanqanaba e-superoxide kwiimitokhondriya nawezinto ezibangela i-oxidation kwiseli iphela anyuka. Iiseli ezininzi ngakumbi zabonisa ukuphazamiseka komahluko wombane kwinwebu. Ukuveliswa kwe-ATP kwehla. Akukho nanye kwezi zinto eyothusayo xa ijongwa yodwa, kuba iimitokhondriya ezonakeleyo zivuza iintlobo zeoksijini ezisebenza ngamandla yaye zivelisa amandla amancinane. Into entsha yayingunobangela owacetywayo. I-PGC-1alpha, engumncedisi ovuselela ukukhutshelwa kolwazi lwemfuza nowenza kuveliswe iimitokhondriya ngezinto ezisebenza emva kwayo ezifana ne-NRF1, TFAM, nezilawuli zokudibana nokwahlukana ezithi MFN1, MFN2, OPA1, FIS1, ne-DRP1, yacinezelwa malunga nokuphinda kasibhozo kwinqanaba le-mRNA kwiiseli ze-progeria, kwaza kwabakho nokuncipha okuhambelanayo kweprotheyini. I-progerin yabonakala icinezela iswitshi ephambili yokwenziwa nokugcinwa kweemitokhondriya. Olo nxibelelwano phakathi komonakalo we-nuclear lamina nokusetyenziswa kwamandla luyinxalenye yenkcazelo ebanzi yokuveliswa kwamandla kwiimitokhondriya, yaye icala lezinto ezibangela i-oxidation kolu lungelelwano linye lichazwa kuxinzelelo lwe-oxidation nokulawulwa kwe-ROS.

Oko kwatshintshwa yi-methylene blue

Abaphandi babeka iiseli kwi-methylene blue ekuxinaneni kwe-100 nanomolar, okuphantsi, ngokuqhubekayo kangangeeveki. Xa kuthethwa ngokukhuliswa kweeseli elebhu, oku kukuvezwa ixesha elide kumlinganiselo ophantsi, kungekhona ukuvezwa okwethutyana elifutshane kwichiza. I-methylene blue ijikeleza phakathi kweemo zayo ezikwi-oxidation nezikwi-reduction yaye inokuthwala ii-electron ngaphakathi kweemitokhondriya. Yiyo loo nto ichazwa njengomxube we-redox ojolise kwiimitokhondriya, kunokuba ibe sisithinteli se-oxidation esiqhelekileyo esiphelayo xa sithomalalisa into enye ebangela i-oxidation.

Iimitokhondriya zasabela kwiiseli eziqhelekileyo nakwiiseli ze-progeria. I-ATP yanyuka, amanqanaba ezinto ezibangela i-oxidation ehla, yaye inxalenye yeemitokhondriya ezineziphene ezinzima yancipha. Ukuvakaliswa kwe-PGC-1alpha kwabuyela ngokuyinxenye, kunye nezinye zezinto ezijoliswa yiyo ezisebenza emva kwayo. Ukuza kuthi ga apha, esi sisiphumo esixhasa iimitokhondriya ngokubanzi, esingajolisanga kuphela kwi-progeria.

Iziphumo zenucleus zizo ezothusayo, yaye zazibonakala kuphela kwiiseli ezinesifo. Amaqhuma kwinucleus ancipha ngokohlalutyo lokumila olwalusebenzisa imilinganiselo yamanani. Izixa ezipheleleyo zee-lamin A no-C zanyuka. Eyona nto yaphawulekayo kukuba i-progerin yatshintsha indawo eyayisasazeke kuyo: kwiiseli ze-progeria ezingazange zifakwe i-methylene blue, malunga nama-30 ekhulwini kuphela e-progerin ayekwinxalenye enyibilikayo ye-nucleoplasm, ngoxa enye yayibotshelelwe kwinwebu. Emva kokufakwa kwayo, inxalenye enyibilikayo yanyuka yaya malunga nama-65 ekhulwini, isondela kwindlela ii-lamin eziqhelekileyo eziziphatha ngayo. Xa ikhululekile kwinwebu, i-progerin itsala izinto ezingabamelwane bayo kancinane, yaye iinxalenye ezinyibilikayo zee-lamin A no-C nazo zabuyela.

Emva kolo khululo, iimpawu ezimbini zenucleus zaphucuka. I-heterochromatin ejikeleze inucleus, eyahlolwa ngemikroskopu yee-electron nangokufakwa kombala ojolise kwiprotheyini ye-heterochromatin i-HP1-alpha, yabonakala ibuyile. Yaye ulandelelwano lwe-RNA lwabonisa ukuba i-transcriptome ibuyela kwimeko eqhelekileyo: iiseli ze-progeria ezingazange zifakwe i-methylene blue zahluka kwezo zokuthelekisa kwiijini ezingaphezu kwama-3,200, ngoxa ezo zazifakwe yona zahluka kwiijini ezimalunga ne-1,670. Kwiiseli eziqhelekileyo, ukufakwa kwayo ngendlela efanayo kwatshintsha kuphela iijini ezingamashumi ambalwa, nto leyo exhasa ukuba isiphumo esikwinucleus sinxulumene ne-progerin, kunokuba ibe kukuphazamiseka ngokubanzi kokukhutshelwa kolwazi lwemfuza. Umgaqo wokuba iimodeli zeeseli nezilwanyana ziphendula imibuzo emxinwa kunaleyo icetyiswa zizihloko zophando uchazwa kwinqaku elithi indlela yokufunda uphando nge-methylene blue.

Kutheni oku kungelulo unyango

Imida emine igcina olu phando kwindawo olufanele ukuba kuyo: ngaphakathi elebhu.

Okokuqala, yonke into yenzeka kwizitya zelebhu. Iifibroblast ezikhuliswe elebhu azinalo igazi elizifikelelayo, imeko yamajoni omzimba, ulwakhiwo lwezicwili, okanye indlela umzimba wonke oqhuba ngayo ichiza, egqiba ukuba umxube ufikelela na kwindawo ojolise kuyo. Akukho silwanyana sanikwa idosi yaye akukho sigulana sanyangwa kolu phando.

Okwesibini, iifibroblast ze-progeria ziyimodeli yohlobo olunye lweseli. Esi sifo sibangela ukufa ikakhulu ngokuchaphazela imithambo ethwala igazi lisuka entliziyweni, amathambo namafutha, yaye uphando lwahlola kuphela iifibroblast kunye neqela elinye lezicwili zesihlunu esigudileyo. Ezinye izicwili zisenokuziphatha ngokwahlukileyo.

Okwesithathu, ukuphucuka kwenucleus kwavela emva kweeveki zokuvezwa ngokuqhubekayo ekuxinaneni okukwinqanaba le-nanomolar kulwelo lokukhulisa iiseli. Ukuxinana kwizitya zelebhu akuzizo iidosi, yaye akukho nto kweli phepha eguqula i-100 nanomolar kulwelo ibe yindlela yokunika umntu ichiza. I-methylene blue inendlela yayo yokusabela kwiidosi neempawu zokhuseleko kwezinye iindawo zonyango, yaye olu phando aluniki siseko sokuyisebenzisa ekhaya. Ulwazi olubanzi ngokhuseleko lufumaneka kwinqaku elithi ukhuseleko lwe-methylene blue neziphumo ebezingalindelekanga.

Okwesine, i-progeria ayikokuguga okuqhelekileyo. Sisifo esinqabileyo esibangelwa lutshintsho olunye lwemfuza, apho isakhiwo senkxaso yenucleus sonakala ngendlela ethile. Umxube onciphisa loo monakalo uthile kwiiseli ezikhuliswe elebhu uthetha okuncinane ngokuguga kwabantu abangenalo olo tshintsho lwemfuza. Uphawu olubonakalayo lweeseli lusivulela indlela yokuqonda unxibelelwano phakathi kwenucleus neemitokhondriya, alisosiphumo esibonisa ubomi obude.

Ngoko isishwankathelo esithembekileyo sixhomekeke kule meko. Kwiifibroblast ze-progeria, i-progerin icinezela i-PGC-1alpha ize ishiye iimitokhondriya ziqhekekile, zihamba kancinane, zinezinto ezininzi ezibangela i-oxidation, yaye zinamandla amancinane. I-methylene blue ekuxinaneni okuphantsi yabuyisela imilinganiselo yokusebenza kweemitokhondriya kuzo zonke iiseli yaza, ukongezelela, yakhulula i-progerin kwinwebu yenucleus kwiiseli ezinesifo, kunye nokubuyela ngokuyinxenye kokumila kwenucleus, i-heterochromatin, nokuvakaliswa kweejini. Esi senzo sintlu-mbini senza ukuba olu phando lufanele ukwaziwa. Asiyenzi i-methylene blue ibe lunyango lwe-progeria okanye lokuguga.