Methylene blue ndi progeria: zomwe taphunzira kuchokera ku chitsanzo cha kukalamba kwa maselo

Kusintha kwa chilembo chimodzi mu jini imodzi kumachititsa ana kukalamba mofulumira mochititsa mantha. Tsitsi limathothoka, mfundo za mafupa zimauma, mitsempha ya magazi imachepa, ndipo moyo umayembekezeka kufika zaka za pakati pa 13 ndi 19 zokha. Matendawa ndi Hutchinson-Gilford progeria syndrome, ndipo kwa zaka zambiri kafukufuku wake ankayang'ana kwambiri phata la selo, kumene puloteni yosinthidwayo imawononga zinthu. Kafukufuku wa mu 2016 wochokera ku University of Maryland anafunsa funso lina: kodi mitochondria zimawoneka bwanji m'maselo amenewa? Yankho lake linalumikiza zigawo ziwiri za selo, ndipo utoto wabuluu womwe wakhalapo kwa zaka zana unakhudza zonsezi.

Kafukufukuyu ndi wa Xiong ndi anzake, wofalitsidwa mu Aging Cell mu 2016. Unagwiritsa ntchito maselo okulitsidwa mu labotale okha. Mfundo imeneyi ndiyo maziko a zonse zomwe zili pansipa. Zotsatirazo ndi zenizeni komanso zachindunji. Kusiyana kwake ndi umboni wa chithandizo kulinso kwachindunji.

Chitsanzocho: kusintha kumodzi kwa jini, puloteni imodzi yomamatira

Progeria imayamba pamene C ilowedwa m'malo ndi T pa malo a 1824 mu jini ya LMNA. Kusinthaku sikusintha amino acid. Kumayambitsa malo obisika odulira ndi kulumikiza RNA, zomwe zimachotsa ma amino acid 50 mu puloteni ya lamin A. Puloteni yofupikitsidwayo, yotchedwa progerin, imataya malo odulira omwe nthawi zambiri amalola selo kuchotsa chomangira chake cha farnesyl. Choncho progerin imakhalabe yolumikizidwa ndi farnesyl kwamuyaya komanso yomamatira ku nembanemba yamkati ya phata la selo, pamene lamin A yabwinobwino imalumikizana ndi nembanembayo kenako n'kuchokapo mobwerezabwereza.

Zotsatira zake pa phata la selo zalembedwa bwino ndipo zimaoneka pogwiritsa ntchito maikulosikopu. Maphata a maselo amatuluka matuza ndi kukwinya m'malo mokhala ndi mawonekedwe osalala ozungulira otambasuka. Heterochromatin, DNA yopanikizika kwambiri komanso yosagwiritsidwa ntchito popanga RNA yomwe nthawi zambiri imakhala m'mphepete mwa phata, imachepa. Kugwiritsidwa ntchito kwa majini masauzande ambiri kumasintha. Ganizirani za nuclear lamina ngati chimango chomwe chili kuseri kwa pepala lokongoletsa khoma: chidutswa chimodzi cha chimangochi chikawotcheredwa pamalo olakwika, khomalo limatupa ndipo kapangidwe ka pepalalo kamasokonekera m'chipinda chonse.

Kafukufukuyu anagwiritsa ntchito maselo a fibroblast a pakhungu ochokera kwa odwala progeria pamodzi ndi maselo oyerekezera omwe anali atadutsa maulendo ofanana osamutsidwa ndi kukulitsidwanso. Anagwiritsanso ntchito gulu lina la maselo osinthidwa kuti maselo a fibroblast abwinobwino azipanga progerin mwachindunji. Maselo osinthidwawo anakhala ndi zolakwika zomwezo, zomwe zimasonyeza kuti progerin ndiyo inachititsa, osati mbiri ya odwalawo kapena nthawi yomwe maselowo anakhala akukulitsidwa. Kuopsa kwa zolakwikazo kunagwirizana ndi kuchuluka kwa progerin: gulu lomwe linkapanga progerin yambiri linasonyeza zolakwika zoopsa kwambiri m'mbali zonse.

Mmene mitochondria zinkaonekera

Mitochondria za maselo a fibroblast athanzi zimapanga ukonde wokhala ndi nthambi kuzungulira phata la selo, wokhala ndi timachubu tatalitali tomwe timayenda m'njira za chimango chamkati cha selo. M'magulu a maselo a progeria, ukondewo unali utatha. Gawo lalikulu la mitochondria linali litasweka kukhala zidutswa, zambiri zinali zitatupa, ndipo maikulosikopu ya ma elekitironi inasonyeza kuti tigawo tamkati mwa selo towonongeka kwambiri tinali titawonjezeka pafupifupi kawiri. Kujambula zithunzi motsatizana pakapita nthawi kunasonyeza kuti mitochondriazo zinkayenda mtunda waufupi komanso pang'onopang'ono kuposa za maselo oyerekezera.

Kugwira ntchito kunagwirizana ndi mawonekedwe. Kuchuluka kwa superoxide m'mitochondria ndi zinthu zochititsa oxidation mu selo lonse kunakwera. Maselo ambiri anasonyeza kusokonekera kwa kusiyana kwa mphamvu ya magetsi pa nembanemba. Kupanga ATP kunachepa. Palibe mwa zimenezi chomwe chili chodabwitsa pachokha, chifukwa mitochondria zowonongeka zimatulutsa mitundu ya oxygen yogwira ntchito mwamphamvu ndipo zimapanga mphamvu zochepa. Chatsopano chinali chifukwa chomwe ochita kafukufuku anapereka. PGC-1alpha, puloteni yothandiza kuyambitsa kulembedwa kwa majini yomwe imayendetsa kupangidwa kwa mitochondria kudzera m'zinthu zotsatira monga NRF1, TFAM, ndi zolamulira kulumikizana ndi kugawikana kwa mitochondria, MFN1, MFN2, OPA1, FIS1, ndi DRP1, inali itachepetsedwa pafupifupi kasanu ndi katatu pa mulingo wa mRNA m'maselo a progeria, ndipo puloteni yakenso inachepa mofanana. Progerin inkaoneka kuti ikupondereza choyatsira chachikulu cha kupanga ndi kusamalira mitochondria. Kulumikizana kumeneku pakati pa kuwonongeka kwa nuclear lamina ndi kagwiritsidwe ntchito ka mphamvu ndi mbali ya kufotokoza kwakukulu kwa kupanga mphamvu m'mitochondria, ndipo mbali ya zinthu zochititsa oxidation pa mgwirizano womwewu ikufotokozedwa pa kupsinjika chifukwa cha oxidation ndi kuwongolera ROS.

Zomwe methylene blue inasintha

Ochita kafukufuku anaika maselowo mu methylene blue ya 100 nanomolar, kuchuluka kochepa, mosalekeza kwa milungu ingapo. Pankhani ya maselo okulitsidwa mu labotale, uku ndi kukhudzidwa kwa nthawi yaitali ndi kuchuluka kochepa, osati kupatsidwa mankhwala kwa nthawi yochepa. Methylene blue imasinthana pakati pa mawonekedwe amene ataya ma elekitironi ndi amene alandira ma elekitironi, ndipo imatha kunyamula ma elekitironi mkati mwa mitochondria. N'chifukwa chake imafotokozedwa ngati chinthu cha redox cholunjika ku mitochondria, osati antioxidant wamba yemwe amatha pamene achepetsa mphamvu ya chinthu chimodzi chochititsa oxidation.

Mitochondria zinasonyeza kusintha m'maselo abwinobwino komanso a progeria. ATP inakwera, kuchuluka kwa zinthu zochititsa oxidation kunachepa, ndipo gawo la mitochondria zowonongeka kwambiri linachepa. Kupangidwa kwa PGC-1alpha kunabwerera pang'ono, pamodzi ndi zina mwa zinthu zomwe imayendetsa. Mpaka pamenepa, izi zinali zotsatira zothandiza mitochondria mwachisawawa, osati za progeria yokha.

Zotsatira za phata la selo ndizo zinadabwitsa, ndipo zinaoneka m'maselo a matendawa okha. Kusanthula mawonekedwe pogwiritsa ntchito miyeso kunasonyeza kuchepa kwa matuza a phata la selo. Kuchuluka konse kwa ma lamin A ndi C kunakwera. Chochititsa chidwi kwambiri chinali kusintha kwa malo omwe progerin inkapezeka: m'maselo a progeria omwe sanalandire methylene blue, pafupifupi 30 percent yokha ya progerin inali m'gawo losungunuka la madzi amkati mwa phata la selo, ndipo yotsalayo inali yomangiriridwa ku nembanemba. Pambuyo poika methylene blue, gawo losungunukalo linakwera kufika pafupifupi 65 percent, kufanana ndi mmene lamin yabwinobwino imakhalira. Ikamasulidwa ku nembanemba, progerin imakokera zinthu zochepa zoyandikana nayo, ndipo magawo osungunuka a ma lamin A ndi C anabwereranso.

Chifukwa cha kumasulidwa kumeneko, makhalidwe awiri a phata la selo anasintha kukhala abwinopo. Heterochromatin ya m'mphepete mwa phata, yomwe inaonedwa pogwiritsa ntchito maikulosikopu ya ma elekitironi ndi kupaka utoto wodziwitsa puloteni ya heterochromatin ya HP1-alpha, inaoneka itabwezeretsedwa. Ndipo kuwerenga motsatana zigawo za RNA kunasonyeza kuti ma RNA onse opangidwa m'selo ankayamba kubwerera ku mkhalidwe wabwinobwino: maselo a progeria omwe sanalandire methylene blue anasiyana ndi maselo oyerekezera pa majini oposa 3,200, pamene maselo a progeria omwe analandira methylene blue anasiyana pa majini pafupifupi 1,670. M'maselo abwinobwino, kuchitidwa chimodzimodzicho kunasintha majini makumi ochepa chabe, zomwe zimasonyeza kuti zotsatira pa phata la selo zimagwirizana ndi progerin, osati kusintha kwakukulu kwa kulembedwa kwa majini mwachisawawa. Mfundo yakuti zitsanzo za maselo ndi nyama zimayankha mafunso ochepa kuposa mmene mitu ya nkhani imasonyezera ikufotokozedwa mu mmene mungawerengere kafukufuku wa methylene blue.

Chifukwa chake izi si chithandizo

Malire anayi amasunga kafukufukuyu pamalo ake oyenera: mkati mwa labotale.

Choyamba, zonse zinachitika m'mbale za labotale. Maselo a fibroblast okulitsidwa alibe magazi owafikira, malo ozungulira okhala ndi chitetezo cha m'thupi, kapangidwe ka minofu, kapena mmene thupi lonse limagwirira ntchito ndi mankhwala, zomwe zimatsimikiza ngati chinthu chikufika kumalo omwe chikuyenera kugwira ntchito. Palibe nyama yomwe inapatsidwa mlingo wa mankhwalawo, ndipo palibe wodwala amene analandira chithandizo mu kafukufukuyu.

Chachiwiri, maselo a fibroblast a progeria ndi chitsanzo cha mtundu umodzi wa selo. Matendawa amapha makamaka kudzera m'mitsempha ya magazi, mafupa, ndi mafuta a m'thupi, ndipo kafukufukuyu anayang'ana maselo a fibroblast okha kuphatikiza chitsanzo chimodzi cha minofu yosalala. Minofu ina ingachite mosiyana.

Chachitatu, kusintha kwabwino kwa phata la selo kunachokera ku kukhudzidwa mosalekeza kwa milungu ingapo ndi kuchuluka kwa nanomolar m'madzi okulitsira maselo. Kuchuluka kwa chinthu m'mbale ya labotale si mlingo wopatsa munthu, ndipo palibe m'nkhaniyi chomwe chimasandutsa 100 nanomolar m'madzi okulitsira maselo kukhala ndondomeko yopatsa munthu mankhwala. Methylene blue ili ndi mmene zotsatira zake zimasinthira malinga ndi mlingo komanso mbiri yake ya chitetezo m'malo ena a zamankhwala, ndipo kafukufukuyu sapereka maziko alionse ogwiritsira ntchito kunyumba. Mfundo zambiri zokhudza chitetezo zili mu chitetezo cha methylene blue ndi zotsatira zake zosafunika.

Chachinayi, progeria si kukalamba kwabwinobwino. Ndi matenda osowa amene amachokera ku kusintha kumodzi kwa jini, ndipo chimango cha phata la selo chimawonongeka m'njira inayake. Chinthu chomwe chimachepetsa kuwonongeka kwapaderako m'maselo okulitsidwa mu labotale sichimanena zambiri za kukalamba kwa anthu opanda kusintha kwa jiniko. Makhalidwe a maselowa amatipatsa mwayi woona kulumikizana pakati pa phata la selo ndi mitochondria, osati zotsatira zokhudza kutalikitsa moyo.

Choncho chidule choyenera chimadalira mikhalidwe imeneyi. M'maselo a fibroblast a progeria, progerin imachepetsa PGC-1alpha ndipo imasiya mitochondria zitasweka kukhala zidutswa, zikuyenda pang'onopang'ono, zili ndi zinthu zambiri zochititsa oxidation, komanso zili ndi mphamvu zochepa. Methylene blue ya kuchuluka kochepa inabwezeretsa miyeso ya ntchito ya mitochondria m'maselo onse, komanso inamasula progerin ku nembanemba ya phata m'maselo a matendawa, ndi kubwerera pang'ono kwa mawonekedwe a phata, heterochromatin, ndi kugwiritsidwa ntchito kwa majini. Zotsatira ziwirizi zimapangitsa kafukufukuyu kukhala woyenera kumudziwa. Sizipangitsa methylene blue kukhala chithandizo cha progeria kapena cha kukalamba.