Tuhinga
Te kikorangi metilīni me te koroheketanga pūtau: he aha e inehia ana e ngā whakamātau fibroblast
Koinei tētahi whakamāramatanga hē e kitea nuitia ana. Ka pūrongo tētahi tuhinga rangahau nā te kikorangi metilīni i tāpiri neke atu i te 20 whakaruanga taupori ki ngā fibroblast i whakatipuria, kātahi ka whakatau te kaipānui ka tango taua matū i ngā pūtau kua koroheketia, ka whakaroa rānei i te roanga ora o te tangata mā tētahi rahinga ōrite. He māmā te whai i taua whakatau. Heoi, e rua ngā wāhanga motuhake e hē ana.
He raruraru ariā te take matua, ehara i te raruraru tau. He pātai rerekē tā ngā whakaruanga taupori, ngā tohu koroheketanga pūtau, me ngā inenga telomere e whakautu ana. Ko te whakamāramatanga pai rawa mō ngā rangahau kikorangi metilīni ki ngā fibroblast, he rangahau mō te whakaroa i te urunga ki te koroheketanga pūtau i tētahi momo pūtau i roto i te rīhi, e tautokona ana e ngā inenga mitokōria. He rerekē tēnei i te tango tīpako i ngā pūtau kua koroheketia kē, ā, he rerekē anō i te koroheketanga o te rauropi katoa. Ko te horopaki whānui ake mō taua rerekētanga kei roto i te āhua e whakatau ai te kawe irahiko mitokōria i te pūngao pūtau me te whakamāramatanga o ngā kerēme rangahau mō te kikorangi metilīni.
Ka tatau ngā whakaruanga taupori i te hītori, kaua i te taiohitanga
Ko te nuinga o ngā kitenga matua ka ahu mai i ngā pūtau IMR90, he kāwai fibroblast noa nō te pūkahukahu kukune tangata, he whāiti tōna āheinga whakarea. I te rangahau tōmua mō te kikorangi metilīni me te roanga ora whakarea o ngā fibroblast IMR90, i whakawhitia ngā ahurea pūtau ki ngā rīhi hou i runga i tētahi hōtaka, ā, i tuhia te tapeke whakaruanga taupori kia mutu rā anō te wehewehenga o te ahurea. Nā te hoatu i ngā kukūtanga nanomolar, ko te 100 nM te kukūtanga matua, i taea ai e ngā ahurea te whakaemi neke atu i te 20 whakaruanga tāpiri i mua i te tūnga.
He waeine tatauranga te whakaruanga taupori. Ka tuhi i te maha o ngā wā kua tata rearua te taupori. Kāore e whakaatu tika ana mēnā kua koroheketia, e moe ana, kua whakarerekētia hei momo motuhake, kua mate rānei tētahi pūtau takitahi. Ka whai whakaruanga anō tētahi ahurea nā te mea ka āhei tonu ngā pūtau ki te wehe mō te wā roa ake, nā te mea he iti ake ngā pūtau ka tū wawe i raro i te taumahatanga, nā te mea rānei ka kōwhiria e ngā āhuatanga tētahi wāhanga taupori e kaha ana ki te whakarea. Kāore te tatauranga anake e taea te wehe i aua ara.
Koia te take ka whakamahia ngātahitia ngā tatauranga whakaruanga me ngā tohu. Ka whakaatu te tatauranga i te roa o te whakarea. Ka whakaatu ngā tohu i te āhua i uru atu ai ngā pūtau kua tū, ngā pūtau rānei i ora tonu.
He aratohu ki ngā inenga whakamutunga: he aha tā ia tohu e whakaatu ai
Ko te koroheketanga pūtau i roto i te ahurea he huinga āhuatanga ka tautuhia mā ētahi inenga motuhake. Kāore tētahi whakapoke, tētahi pūmua rānei, e whakamana ana i taua āhua ko ia anake.
Te tūnga tipu me te ngaronga o te hanga DNA. Ka tirohia te tūnga pūmau mā te hekenga o te whakaurunga BrdU, EdU rānei, te āhua papatahi, me te kore e tipu anō i muri i te whakatō anō ki te rīhi. Mā tēnei e wehe ai te tūnga nā te koroheketanga pūtau i te moe rangitahi.
Te beta galactosidase e pā ana ki te koroheketanga pūtau. Ka whakapoke te SA-beta-gal i te hohe o ngā lysosome e tata ana ki te pH 6.0. He maha ngā fibroblast kua koroheketia ka whai hua whakapoke tōrunga i te pikinga o te papatipu lysosome. Ehara tēnei i te tohu motuhake mō te koroheketanga pūtau, nō reira ka whakamāramatia me ngā tohu whakarea me ngā tohu rāpoi.
Ngā ara p16 me p21. Ka mahi te p16 mā te CDK4 me te CDK6 me te ara RB. He maha ngā wā ka whakaohohia te p21 mā te p53. Ka tautoko ngā taumata e piki ana i te tūnga, engari ehara ēnei pūmua e rua i te mea mō te koroheketanga pūtau anake.
Te āhua tuku matū. Ko te huinga āhuatanga tuku matū e pā ana ki te koroheketanga pūtau, arā te SASP, e kōrero ana mō te whakarerekētanga o te tukunga cytokine, chemokine, tauwehe tipu, me ngā protease. Ka whakaahua ngā whakamātautau RNA, pūmua rānei mō ngā tauwehe SASP i te āhua e tuku tohu ai ngā pūtau ki ō rātou hoa tata. Kāore ēnei e ine tika ana i te āheinga whakarea.
Ngā matū whakahāora me ngā inenga mitokōria. Ka tāpiri ngā tuhinga rangahau kikorangi metilīni i tētahi paparanga mitokōria: te nui me te hohe o te matatini IV, te whakapau hāora, te hanga heme, te papatipu kiriuhi, te ngaohiko puta noa i te kiriuhi, te ATP, me ngā tohu matū whakahāora. Ka whakaahua ēnei i te āhua pākia e haere tahi ana me te whakaroa i te tūnga. Kāore ēnei anake e tautuhi ana i te koroheketanga pūtau, engari ka whakamātau i te tikanga mahi e whakaarotia ana. Ko te tauira huringa hāora-tango, ka tango hāora ai te NAD(P)H i te kikorangi metilīni, ā, ka whakahāora anō ai te cytochrome c i taua matū, kua whakamāramatia i taua rangahau IMR90 e hono ana i te huringa hāora-tango ki te hekenga o te hanga matū whakahāora. Kei ngā kōrero mō te mātai rongoā o te kikorangi metilīni me te pānga ki ngā kiko ngā whakamāramatanga e pā ana ki te nui ka hoatu me te tohatoha.
Te tere horo telomere. Ko te waeine tika ko ngā takirua pūtake ka ngaro i ia whakaruanga i roto i ngā wiki, kaua ko te roa i tētahi wā kotahi. Ki te pōturi ake te horo, ka iti ake te whakapotonga i ia whakareatanga. Ehara tēnei i te whakaroanga, ā, ka taea e te taumahatanga te whakamutu i ngā pūtau IMR90 ahakoa he iti noa te panonitanga telomere.
He whakataurite i ngā hoahoa whakamātau fibroblast e toru
Ko te rauemi taketake mō tēnei whārangi ko te whakataurite i raro nei. Ka whakakotahi i te momo pūtau, te pānga matū, te inenga, me te herenga ki tētahi tirohanga kotahi.
| Rangahau | Ngā pūtau me te pānga matū | Ngā mea i inehia | Ngā mea kāore e taea te whakaatu |
|---|---|---|---|
| Atamna mā, FASEB J 2008 | Ngā fibroblast IMR90 noa, te kikorangi metilīni nanomolar mō te wā roa, ko te 100 nM te āhuatanga paerewa | Te tapeke whakaruanga, te nui o te matatini IV, te whakapau hāora i piki mā te 37 ki te 70 ōrau, te hanga heme, te whakaoranga mai i te koroheketanga pūtau wawe nā te hauwai peroxide, te cadmium rānei, ngā whākōkī wāhanga 2 i ngā pūtau HepG2 | Kāore he whakamātau mō te tango i ngā pūtau kua koroheketia. Kāore he inenga whakamutunga mō te roanga ora o te kararehe, o te tangata rānei. Ko te roanga ora whakarea i konei ko ngā whakaruanga i roto i te rīhi. |
| Atamna mā, Redox Biology 2015, kua whakaahuatia i te rangahau whai muri mō ngā tikanga mahi o te AMPK me te hanganga matatini IV | Ngā fibroblast IMR90, ko te nuinga i whiwhi 100 nM kikorangi metilīni, me te AICAR hei matū whakataurite e whakahohe ana i te AMPK mō te wā roa | Te panonitanga o te ōwehenga NAD ki te NADH i te wā, te ūnga phosphate rangitahi ki te AMPK, te whakaoho i te PGC-1alpha me te SURF1, te pikinga neke atu i te 100 ōrau o te hohe matatini IV, ngā matū whakahāora i heke mā te 28 ōrau, te horo telomere pōturi ake, tata ki te 18 whakaruanga tāpiri ki te whakataurite ki te tata ki te 2 mā te AICAR, kāore he pānga ki te huringa pūtau | He rerekē te nui o te AICAR ka hoatu mā te tata ki te 1000 whakareatanga, ā, he rerekē hoki te hāngaitanga o tana mahi, nō reira ka whakamātau i te tauira whakahohe, kaua i te kaha mahi kua whakaōritetia. E hāngai ana te kitenga telomere ki ngā ahurea e wehewehe ana i roto i ngā wiki. |
| Xiong mā, Aging Cell 2016, kua pūrongotia i te rangahau fibroblast progeria mō te whakaoranga mitokōria me te karihi | Ngā fibroblast kiri tuatahi nō te progeria Hutchinson-Gilford me ngā pūtau whakataurite noa kua whakaōritetia, ko te nuinga i whiwhi 100 nM mō te 5 ki te 12 wiki | Te āhua mitokōria mā te karu whakarahi kōrekoreko me te karu whakarahi irahiko, te neke mā te atahanga ora, te superoxide, te ngaohiko puta noa i te kiriuhi, te ATP, te PGC-1alpha, ngā tohu whakarea me te koroheketanga pūtau, me ngā pupuhi o te karihi, te wāhi noho o te progerin, te heterokromatini, me te whakaputanga ira | He tauira koroheketanga wawe e hāngai ana ki tētahi mate motuhake, ehara i te koroheketanga noa. Ehara te whakaoranga o te āhua me ngā tohu i te whakawātea i ngā pūtau kua koroheketia. Kāore he inenga whakamutunga mō te whaihua ki ngā kararehe, mō te haumanu rānei. |
| Xue mā, arotake Cells 2021, kua whakarāpopototia i te arotake i te kikorangi metilīni hei matū pea hei ārai i te koroheketanga | He whakakotahitanga o ngā tuhinga mō te koroheketanga roro, te paheketanga io, te kiri, te whakaora patunga, me te progeria | Ka whakaahua i te kikorangi metilīni hei kaiwhakatere huringa hāora-tango e taea ai te hipa i ētahi wāhanga o te rere mā ngā matatini I me III, me te whakataurite ki ngā ariā tuwhena herekore mō te koroheketanga | He whakakotahitanga ā-kōrero anake. Ka whakaraupapa i ngā whakapae, ka tohu hoki i ngā wāhi kāore anō ngā taunakitanga haumanu kia whakatau mārika. |
He nui ake te hiranga o te tauira puta noa i ngā rārangi i tētahi rārangi takitahi. He rite tonu te kitea o te hononga o te kikorangi metilīni iti te nui ki te wā whakarea roa ake, te hohe matatini IV teitei ake, ngā tohu matū whakahāora iti ake, me te āhua pai ake. He hoahoa whai haere i te wā tonu: ka tīmata ki ngā pūtau e wehewehe ana, ka hoatu i te matū i te wā e tipu ana te taupori, ā, ka tuhi i te roa e haere tonu ai te wehewehenga. Ka taea e taua hanganga te tautoko i tētahi kerēme whakaroa. Kāore e taea te tautoko i tētahi kerēme tangohanga ki te kore he hoahoa kē.
Ehara te whakaroa i te tīmatanga o te koroheketanga pūtau i te tango i ngā pūtau kua koroheketia
Ko te whakaroa, ka haere tonu te wehewehenga o ngā pūtau mō te wā roa ake i mua i tō rātou tūnga. Ko te tangohanga, e kīia nuitia ana he pānga senolytic, ka patua, ka whakaitihia rānei ngā pūtau kua koroheketia kē mā te tīpako, i te wā e ora tonu ana ngā pūtau tata e whakarea ana.
Ka whakamātau ngā tuhinga fibroblast mō te kikorangi metilīni i te hanganga tuatahi. Ka tīmata ngā ahurea i te āhua whakarea, ka whiwhi i te matū i ngā whakawhitinga rīhi raupapa, ā, ka tae tōmuri ake ki te tūnga. Nō reira, ka puta tōmuri ake ngā tohu pērā i te SA-beta-gal, te p16, te p21, me ngā tauwehe SASP, ka iti ake rānei ō rātou taumata i tētahi whakawhitinga rīhi kua whakaritea. Koinei te tauira e tūmanakohia ana ina neke te wā tīmatanga. Kāore e whakaū ana kua whakawāteatia tētahi pūtau kua koroheketia kē.
Me whai whakaritenga kē tētahi kerēme senolytic: i te tuatahi, me kawe tētahi ahurea ki te koroheketanga pūtau kua manatoko; kātahi ka hoatu i te matū; kātahi ka whakaatu i te ngaronga tīpako o aua pūtau kua koroheketia ki te whakataurite ki ngā pūtau whakataurite e whakarea ana, me ngā inenga tika o te ora me te mate. Kāore e ranea te hekenga o tētahi tohu anake, nā te mea ka taea te whakaputanga te whakarerekē me te kore ngaronga pūtau, ā, ka taea e ngā pūtau whakarea e toe ana te tipu kia kapi katoa te rīhi. Kāore tētahi o ngā puna e whā kua whakahuatia e whakamahi ana i taua hoahoa whakaiti tīpako mō te kikorangi metilīni. Nō reira, ko te ingoa tika tonu he mahi whakaroa i te tīmatanga o te koroheketanga pūtau, he mahi ārai koroheketanga pūtau rānei i roto i te ipu whakamātau, kaua ko te senolytic. Ka whakamāramatia anō te taha taumahatanga whakahāora o tēnei rerekētanga i te āhua e whakahaere ai ngā pūtau i ngā momo hāora tauhohe.
Ka whakakoi te kitenga tuku tohu rangitahi i tēnei kōrero. I te rangahau IMR90 o 2015, nā te kikorangi metilīni i whakapiki poto te ōwehenga NAD ki te NADH me te ūnga phosphate ki te AMPK, whai muri ko te whakaoho i te PGC-1alpha me te SURF1, e hono ana rāua tahi ki te hanganga matatini IV. He tino ngoikore ake te whakahohe AMPK mō te wā roa mā te AICAR mō te whakapiki i ngā whakaruanga tāpiri.
Ehara te roanga ora whakarea i te roanga ora o te tangata
Ka tatau te roanga ora whakarea pūtau i ngā whakaruanga i mua i te tūnga, i roto i tētahi rīhi whakahaere he pūmau te hāora, te reo whakatipu, me te auau whakawhiti rīhi. Ka whakakotahi te roanga ora o te tangata i ngā tekau tau o te whanaketanga, te ārai mate, te pūnaha ia toto, ngā wāhi noho pūtau kakau, te whanonga, me te mate. Ka taea e tētahi matū te whakaroa i te mea tuatahi me te kore e whakarerekē i te mea tuarua, ā, koinei te āhua o te nuinga.
Kei ngā fibroblast progeria tētahi irakētanga LMNA kua tautuhia e whakaputa ana i te progerin, me ngā mitokōria kua wāwāhia, he iti ake te neke, he iti te ATP, he hē te hanga o ngā karihi, me te ngaronga heterokromatini. Nā te kikorangi metilīni nanomolar i whakapai ngā inenga mitokōria, ā, i tino whakaora ngā inenga karihi, tae atu ki te tukunga o te progerin mai i te kiriuhi. He whakaoranga whakamīharo tēnei i te taumata pūtau. Heoi, he kitenga fibroblast tonu, ā, i whakatakotoria e ngā kaituhi te whakamātau kararehe hei mahi mō muri. Ka matapakihia anō taua tauira mate i te kikorangi metilīni i roto i ngā tauira progeria me te koroheketanga wawe.
Ka puta mai he rārangi arowhai whaihua mō te pānui i ēnei kōrero.
- Pātai mēnā i tīmata te hoatu i te matū i mua i te tūnga, i muri rānei i te whakapūmautanga o te tūnga. Ko te tīmatanga i mua ka tautoko i te whakaroa. Mō te tangohanga, me tīmata i muri, me whai raraunga mate tīpako hoki.
- Pātai he aha te āhua o te ānau whakaruanga o ngā pūtau whakataurite. Ki te kore te tapeke whakaruanga, kāore he horopaki mō ngā panonitanga tohu.
- Tonoa kia rua neke atu ngā momo tohu, pērā i tētahi tapanga whakarea me te p16, te p21 rānei, me te SA-beta-gal, kaua ko tētahi whakapoke kotahi anake.
- Pātai i pēhea te pūrongo i ngā telomere. He whai tikanga te tere i ia whakaruanga puta noa i te wā. Kāore tētahi inenga roa i te wā kotahi e pēnei.
- Pātai he aha ngā mea i puritia kia pūmau. Ka whakarerekē katoa te kiato pūtau i te whakawhitinga rīhi, te hāora, ngā panonitanga reo whakatipu, me ngā wairewa pūtake kikorangi metilīni hou, tawhito rānei, i te tūnga o ngā fibroblast.
Ki te pēnei te pānui, ka hoatu e ngā tuhinga fibroblast tētahi tūranga whai take, engari he whāiti, ki te kikorangi metilīni: he matū iti te nui, he hohe hāora-tango, e whakaroa ana i te tīmatanga o te koroheketanga whakarea o ngā fibroblast tangata kua whakatipuria, me te whakapai anō i ngā inenga mitokōria. Ko ngā taipitopito kaha rawa mō te tikanga mahi kei te tuku tohu pūngao rangitahi me te hanganga matatini IV, ā, kāore ēnei tuhinga e whakaatu ana i te whakawāteatanga o ngā pūtau kua koroheketia, i te whakaroanga rānei o te roanga ora o te tangata.