Chinyorwa
Bhuruu yemethylene mubhayoroji yemaseru: zvinonangwa, mamodheru, nemigumisiro yakayerwa
Bhuruu yemethylene ine mashandiro akawanda pamwero wemamorekuru anotsigirwa nezviedzo, asi kungonyora mazita enzira dzemaseru kunovanza izvo chiedzo chimwe nechimwe chakanyatsoratidza. Kudzivisa kushanda kweenzayimu yakacheneswa, kushandura kushandiswa kweokisijeni mumasеру akakuriswa murabhoritari, uye kuderedza chiratidzo chepuroteni muuropi hwembeva zvinhu zvakasiyana zvinoonekwa. Zvinoda zviyero zvekudzora zvakasiyana uye zvinotsigira mhedziso dzakasiyana.
Indekisi iyi yetsvakurudzo inoronga zvinoonekwa izvi maererano nemaitiro, modheru, nechinoyerwa. Mufananidzo webutiro unoperekedza inyaya yekufananidzira masisitimu ezviedzo, kwete kutsanangurwa kwechimiro chemamorekuru kana mufananidzo wakatorwa nemakorosikopu. Pamusoro pekemisitiri iri pahwaro hweizvi, tangai nekemisitiri yeredox nemashandiro ezvipenyu.
Tangai maverenga mazita emhando dzeuchapupu
Uchapupu hwebhayokemisitiri hunoedza puroteni kana kuita kwemakemikari kwakatsanangurwa kunze kweseru rakakwana. Hunogona kuratidza kudziviswa kwekushanda kana kutamiswa kwemaerekitironi pasi pemamiriro akatsanangurwa. Uchapupu hwemaseru hunowedzera kupinda kwemushonga museru, kugadziriswa kwawo nemaseru, kupatsanurwa muzvikamu zveseru, uye nzira dzinoshanda pamwe chete. Uchapupu hwekutsamira panzira hunobvunza kana kubvisa chikamu chenzira inofungidzirwa kuchibvisa mhinduro yacho. Uchapupu hwechipenyu chose hunoyera migumisiro mumhuka ine kutenderera kweropa, kugadziriswa kwezvinhu mumuviri, uye nyama dzemuviri dzakawanda.
Mazita aya anotsanangura mubvunzo wapindurwa, kwete kungoronga uchapupu kubva pahwakasimba kusvika pahusina kusimba. Chiedzo chekubvisa geni chinogona kuziva chikamu chinodiwa pakutumira masaini pasina kuratidza kuti bhuruu yemethylene inosunga chikamu ichocho zvakananga. Mugumisiro wehunhu hwemhuka unogona kuratidza hunhu hunooneka pasina kuziva chikonzero chahwo pamwero wemamorekuru.
Mepu ine zvinongedzo yezvinonangwa pamwero wemamorekuru
Verengai mutsara mumwe nemumwe kubva kuruboshwe kuenda kurudyi. Chikamu chekutanga chine chinongedzo kuhurukuro yenzira yacho; chinongedzo chetsvakurudzo chinoratidza hwaro hwechiedzo. Iyi imepu yakasarudzwa yezviedzo zvinotsigira mashandiro acho, kwete rondedzero yakakwana yemigumisiro yose yemasеру yakambotaurwa.
| Maitiro kana chinonangwa | Sisitimu yechiedzo nerudzi rweuchapupu | Chinoyerwa nedudziro yacho |
|---|---|---|
| MAO nekugadziriswa kwezvinotumira masaini mutsinga | MAO-A neMAO-B zvevanhu zvakagadzirwa nenzira yerecombinant uye zvakacheneswa; kuyerwa kwemamhanyiro ekuita kwebhayokemisitiri | Ramsay nevamwe vake vakayera kudziviswa kwekushanda kwemaenzayimu. MAO-A yakanyanya kukanganiswa; hapana kuyerwa kwemanzwiro kana kweserotonin muuropi kwakaitwa. |
| NOS nekutumira masaini kwecGMP | NO synthase yakacheneswa, maseru eendothelium, tsinga dzeropa dzakaparadzaniswa; zviedzo zvebhayokemisitiri nezvekushanda | Mayer nevamwe vake vakapatsanura kuumbwa kwecitrulline, kugadzirwa kwecGMP, nekuzorora kwetsinga. Kudziviswa kweNOS hakugoni kunzi kudziviswa kwakasarudzika kwesoluble guanylyl cyclase. |
| Kutakurwa kwemaerekitironi mumitochondria | Maseru akashandurwa eHT-22 ehippocampus yembeva uye kuita kwebhayokemisitiri; uchapupu hwemaseru nehwebhayokemisitiri | Wen nevamwe vake vakayera kushandiswa kweokisijeni, kuwedzera kweasidhi, ATP, nekutamiswa kwemaerekitironi kunotsamira paredox. Zvinoyerwa izvi zvakaedzwa zvakaparadzana. |
| Kupfuura complex III neimwe nzira | Mitochondria dzakaparadzaniswa kubva muuropi hwembeva pamwe nezvinodzivisa kufema; chiedzo chenhengo diki dzeseru | Imwe tsvakurudzo yecomplex III neantimycin yakawana kuti kufema nemusiyano wemagetsi pamembrane hazvina kudzorerwa mushure mekuvharwa ikoko, kunyange zvazvo zvakadzorerwa zvishoma mushure mekudziviswa kwecomplex I. |
| Nrf2 nekuumbwa kwemitochondria mitsva | Mafibroblast embeva achiri mumaembryo, ane majini akajairika uye akabviswa geni reNrf2; kutsamira pamajini | Stack nevamwe vake vakayera zvinyorwa zveRNA zvemhinduro yeantioxidant. Kusavapo kwekuwedzerwa kwezvinyorwa izvi mumaseru akabviswa geni kunotsigira kutsamira paNrf2, kwete kusunga Nrf2 zvakananga. |
| Autophagy nekutumira masaini kwemTOR | Maseru eovary yeChinese hamster anogadzira tau yevanhu; zviedzo zvezviratidzi nezvekuderedza kushanda kwegeni | Congdon nevamwe vake vakaongorora zviratidzi zveLC3, kuiswa kwemapoka ephosphate pamakinase, uye tau. Kuderedzwa kwekushanda kweBECN1 kwakabvisa mhinduro yakaonekwa yekuderedzwa kwetau. |
| Kugadziriswa kwetau nekubviswa kwemapuroteni | Chiedzo cheHsp70 yakacheneswa nemaseru eHeLa anogadzira tau yevanhu; uchapupu hwebhayokemisitiri nehwemaseru | Jinwal nevamwe vake vakabatanidza kudziviswa kweATPase nekuderedzwa kwetau kunotsamira paproteasome. Izvi zvakasiyana nekudzivisa kuungana kwetau yakacheneswa kuita tambo diki. |
| Kuumbwa kwezviunganidzwa zvetau | Madonhwe etau yerecombinant akagadzirwazve; chiedzo chakasiyana chekukuvadza maseru eSH-SY5Y | Imwe tsvakurudzo yekuparadzana kwezvikamu yakaitwa muna 2023 yakayera kuumbwa kwemadonhwe nekushanduka kuita jeri kunze kwemasеру, yozoyera kuramba kwemasеру ari mapenyu ichishandisa MTT mushure mekunge aisirwa marudzi etau akanga achengetwa pasi pemamiriro echiedzo. Chiedzo chemaseru hachina kuyera kuumbwa kwezviunganidzwa mukati memasеру. |
Mepu yezvinonangwa pamwero wemamorekuru inogona kudhaunirodhwa inochengeta zvinongedzo kutsvakurudzo dzekutanga, mazita emhando dzeuchapupu, nemamiriro akakosha ezviedzo mugwaro remashoko rinogona kushandiswazve.
Zvinopatsanurwa nezviedzo zvekutanga
Kudziviswa kweenzayimu kunotsamira pamamiriro echiedzo
Tsvakurudzo yeenzayimu yevanhu yakacheneswa yakataura chiyero chekudziviswa kweMAO-A, Ki = 27 ± 3 nM, ichishandisa ongororo yekusunga kwakasimba. IC50 yayo yeMAO-A yaiva 164 ± 8 nM pasi pemamiriro echiedzo akataurwa. Ki neIC50 hazvitsivi mumwe nemumwe: IC50 inotsamira pamamiriro eenzayimu nesubstrate akashandiswa kuyera kudziviswa kwehafu yekushanda. Hapana pane nhamba idzi iri muyero wekupa munhu kana huwandu hunofungidzirwa kuti huchava munyama dzemuviri.
Kuenzaniswa kweNOS kunopawo ruzivo rwakafanana. NO synthase yakacheneswa yakarasikirwa nekushanda kwayo kwose kwakayerwa kwekuumba citrulline pa30 μM yebhuruu yemethylene. Muchinyorwa chimwe chetecho, guanylyl cyclase yakakurudzirwa neS-nitrosoglutathione yaida anenge 60 μM kuti hafu yekushanda kwayo idziviswe. Saka kuderera kwecGMP museru hakuratidzi kwega kuti mugumisiro wacho uri paguanylyl cyclase. Kunogona kuratidza kuderedzwa kwekugadzirwa kweNO inoita kuti ishande.
Kufema hakurevi chinhu chimwe chete nekugadzirwa kweATP
Mutsvakurudzo yeHT-22, vaongorori vakashandisa oligomycin, FCCP, nerotenone kuongorora maitiro ekufema. Vakayerawo ATP yakazvimirira. FCCP yavakashandisa pakuenzanisa yakawedzera kushandiswa kweokisijeni ichideredza ATP yemasеру, zvichiratidza zvakananga kuti nei chati yekushandiswa kweokisijeni isingagoni kupindura yega mubvunzo weATP. Gwaro rakanangana nekushandiswa kweokisijeni zvichienzaniswa neATP rinotevera musiyano iwoyo.
Basa rakazoitwa mumitochondria dzakaparadzaniswa kubva muuropi hwembeva rakashandisa masubstrate aisanganisira pyruvate nemalate. Pa1 μM, bhuruu yemethylene yakadzorera zvishoma kufema kwakanga kwadziviswa nerotenone asi yakaita zvishoma mushure meantimycin. Mugumisiro iwoyo unoisa muganhu pakutaura kuti dhayi iyi inogara ichipfuura complexes I neIII neimwe nzira. Rudzi rwechipenyu, magadzirirwo emitochondria, masubstrate, zvinodzivisa kushanda, nemamiriro echiedzo zvinofanira kuiswa pamwe chete nedhiyagiramu ipi neipi inotsanangura kutamiswa kwemaerekitironi.
Mhinduro yegeni haisi uchapupu hwekubatana kwakananga nechinonangwa
Muchiedzo cheNrf2, 0.1, 1, uye 10 μM yebhuruu yemethylene zvakawedzera chinyorwa cheRNA cheHO1 mumafibroblast embeva achiri mumaembryo ane majini akajairika, asi mhinduro yacho yakanga isipo mumaseru akabviswa geni reNrf2. Kuenzanisa uku kwemajini kunopa ruzivo rwakawanda pamusoro pekutsamira panzira kupfuura kungoyera kugadzirwa kwezvinyorwa zvemajini mumaseru akarapwa chete.
Kunyange zvakadaro, chiitiko chemamorekuru chinotanga izvi chinoramba chisina kutsanangurwa. Kunyorwa kweRNA kunotsamira paNrf2, kuumbwa kwemitochondria mitsva, kushandurwa kwemwero weNAD+/NADH, nekutumira masaini kweAMPK zvinofanira kuramba zviri zvikamu zvakasiyana kusvikira chiedzo chazvibatanidza. Kuwedzera kwekugadzirwa kwezvinyorwa zvegeni rimwe remitochondria hakuratidzi kuti maseru akagadzira mitochondria dzakawanda dzinoshanda.
Kubviswa kwemapuroteni kune nzira dzakawanda
Tsvakurudzo yeautophagy yakaisa maseru eCHO anogadzira tau mu0.01 μM yebhuruu yemethylene kwemaawa matanhatu ikaenzanisa nemasеру akaiswa mumvura yekutakurisa isina bhuruu yemethylene. Chiratidzi cheLC3 chine ruvara rutsvuku negirinhi zvakabatana chakabatsira kusiyanisa tumasaga twekutanga nemaautolysosome akanga awedzerwa asidhi; bafilomycin yakapa mamiriro ekuenzanisa ayo aikanganisa kufambira mberi kwemaitiro acho. Kuderedzwa kwekushanda kweBECN1 kwakaedza kana hurongwa hweautophagy hwaibatsira mukuderedzwa kwetau. Zviedzo izvi zvinopfuura kungoverenga makwapa ane LC3, ayo anogona kuwanda kana kuumbwa kuchiwedzera kana kubviswa kuchinonoka.
Asi tsvakurudzo yeHsp70 yakaongorora kushanda kweATPase nekubviswa kwetau kunotsamira paproteasome mune imwe sisitimu yemasеру. Zviedzo zvezviunganidzwa zvakaitwa muna 2023 zvakabvunza mumwe mubvunzo: kuti mamorekuru etau anoumba sei madonhwe nekushandura hunhu hwezvinhu zvawo. Tau yose, tau yakaiswa mapoka ephosphate, tambo diki dzisinganyunguduki, nezviunganidzwa zvakaita sejeri zvinhu zvakasiyana zvinoyerwa. Kuzvibatanidza mukutaura kumwe chete kwe“kurwisa tau” kunodzima mashandiro ari kuedzwa.
Sarudzai chiedzo chinotevera maererano nemusiyano usati watsanangurwa
Pachinyorwa chitsva, tangai matora ruzivo rwechokwadi rwechimiro chekhemikari, huwandu hwayo pamwero, nguva yekuiswa kwayo, chinonyungudutsa, mamiriro echiedza, modheru, chinhu chekuenzanisa, nechinoyerwa musati madudzira dhiyagiramu yenzira yacho. Fananidzai chiedzo nezviri kutaurwa: kufema nekufamba kwemaitiro ekufema, ATP nekuwanikwa kwesimba, mamhanyiro ekushanda kweenzayimu nekudziviswa kwayo, uye kushandurwa kwemajini nekutsamira panzira.
Gwaro remhinduro zvichienderana nemuyero rinotaura nezvemhinduro dzinoshandura divi radzinoenda kana huwandu hwachinja. Gwaro reantioxidant nepro-oxidant rinopatsanura kutenderera kweredox kubva pakungoti chinhu iantioxidant mumamiriro ose. Kupinda museru nekugovaniswa pamembrane kunotsanangura kuti nei huwandu hunotaurwa mumvura inokurisirwa maseru husingangoenzani nehuri mukati memasеру; tsvakurudzo yeAzure B inotsanangura kuti nei marudzi edhayi ane ukama asingafaniri kutorwa seanotsiviwa rimwe nerimwe.
Zvinyorwa zvakawanda zvetsvakurudzo zvinobatawo kushanda kwecaspase, ferroptosis, kutumira masaini kwekuzvimba, uye kukwegura kwemasеру. Idzi inzira dzinobatsira kana chinoyerwa chiri kufa kwemasеру, kutumira masaini kwemacytokine, kana kumira kwekukura kunoramba kuripo. Hadzisi humwe uchapupu hwokuti mashandiro ose emamorekuru anoitika museru rimwe chete pahuwandu humwe chete. Mepu iyi inoratidza nzira dzekutevera uchapupu hwezviedzo; haishanduri zviedzo izvozvo kuva zvakanakira varwere mukurapwa.