Methylene blue, tau, uye amyloid: nei nzira dzekubvisa mapuroteni dzichisiyana

Bvunza kuti methylene blue inoitei kumapuroteni echirwere cheAlzheimer uye uchanzwa mhinduro imwe ine chivimbo, apo paunofanira kunzwa nhatu dzine miganhu yakatsanangurwa. Muchubhu yekuyedza inokanganisa kunamatirana kwetau. Mune imwe modheru yembeva inoderedza amyloid inonyungudika asi isingachinji tau. Mune imwe inoderedza enzayimu inotanga kugadzira amyloid. Zvose izvi zvakawanikwa chaizvo. Hapana chimwe chazvo chinotsanangura zvose, uye hazviitiki zvose mumhuka imwe panguva imwe chete. Chinyorwa ichi chinoparadzanisa zvinhu zvitatu izvi kuitira kuti zvakabuda muongororo imwe zvisaramba zvichitorwa seuchapupu hweimwe.

Vaverengi vanoda kunzwisisa zvakazara mashandiro anoita methylene blue mukati memasero vanofanira kutangira ipapo. Vaverengi vanoda kuziva kana chimwe chezvinhu izvi chakabatsira varwere vanofanira kuverenga zvakanyorwa kubva muongororo dzevarwere vane chirwere cheAlzheimer, uko kunofanira kukurukurwa zvakabuda muongororo dzevanhu. Hapana chiri muchinyorwa chino chinodzokorora zvakanyorwa izvozvo.

Zvakawanikwa pamusoro petau ndezveongororo dzekuungana kwemapuroteni

Nyaya yekutanga pane nhatu idzi inobva pabasa risina kushandisa masero pamusoro petau, puroteni inoumba tsinga dzakapetana dzinonzi neurofibrillary tangles. Muongororo yekunamatirana kwetau netau, zvidimbu zvetau zvinoungana kuita tambo mbiri dzakapetana pamwe chete, uye madhayi ephenothiazine, kusanganisira methylene blue, anovhara kuungana ikoko pakuwanda kwakaderera kunoyerwa nemicromolar. Basa rakazotevera rebiochemistry rakatsanangura izvi nemakemikari: dhayi rinooksidha zvikamu zvecysteine zviri mutau, zvichiita kuti chimiro chepuroteni imwe yoga chigadzikane uye zvichidzivisa kukura kwetambo diki dzaizokura pasina izvi. Kuwanda kwakataurwa kunodzivisa kuungana kwetau kunowanzova kubva panhamba dzine digit rimwe kusvika pamakumi mashoma emicromolar, chiyero chinokosha pane zvose zvinotevera.

Cherechedza rudzi rwemashoko ari kutaurwa pano. Haatauri chinhu pamusoro pekugadzirwa kwetau, kuiswa kwemapoka ephosphate pat tau muuropi hunorarama, kana kubviswa kwetau. Anoti mumamiriro akanyatsotsanangurwa muchubhu, dhayi rakaoksidhwa rinodzivisa kurongedzana kwetau. Izvi zvakawanikwa zvakajeka, zvine muganhu, uye zvinobatsira. Dambudziko rinotanga pazvinotambanudzwa kuita chirevo chakafara chekuti methylene blue inobvisa shanduko dzakaipa dzetau, nokuti zvakawanikwa mumhuka hazvitsigiri tsananguro iyoyo.

Zvakawanikwa pamusoro peproteasome ndezvembeva dze3xTg-AD, uye zvakaparadzanisa amyloid netau

Ongororo inonyatsoratidza kusiyana kwezvakayerwa ndeye ongororo yemavhiki 16 yezvekudya mumbeva dzine shanduko nhatu dzemajini dzine chekuita neAlzheimer. Mhuka dzacho dzakadya chikafu chine methylene blue kubva pazera remwedzi mitanhatu, uye vaongorori vakayera zvinhu zvitatu panguva imwe chete: proteasome, huwandu hweamyloid, uye tau.

Kushanda kweproteasome kwakachinja. Kushanda kwakafanana nechymotrypsin kwakakwira neinenge kota uye kwakafanana netrypsin nehafu, asi kushanda kwechitatu kunokurudzira maitiro emakemikari hakuna kuchinja zvakakosha. Amyloid-beta 40 ne42 zvinonyungudika chimwe nechimwe zvakaderera neinenge kota. Vanyori vakadudzira izvi sekuwedzera kwekubviswa, kwete kuderera kwekugadzirwa, nokuti puroteni inotangira amyloid nezvidimbu zvinobva pakugadziriswa kwayo hazvina kuchinja, uye kudzidza nekurangarira zvakavandudzika pabvunzo yekuongorora mundima dzemvura.

Zvino pakava nekusiyana kwezvakabuda. Amyloid isinganyungudiki haina kuchinja. Kuonekwa kwemaplaque mushure mekuiswa dhayi hakuna kuchinja. Huwandu hwose hwetau yevanhu uye tau ine phosphate pathreonine 181 hazvina kuchinja, uye kuwanikwa kwetau munzvimbo dzisiri dzayo hakuna kuchinja. Zviyero zvemitochondria hazvina kuchinjawo: hapana kukanganisa kwakakosha pakushanda kwecytochrome-c oxidase, papuroteni yeoxidase, kana paATP. Saka mumodheru iyi, pachirongwa ichi, methylene blue yakawedzera mabasa maviri pamatatu eproteasome, yakaderedza amyloid inonyungudika, yakavandudza chimwe chiyero chemaitiro emhuka, uye yakasiya zviyero zvetau, amyloid isinganyungudiki, nezviyero zvemitochondria zvakaongororwa zvisina kuchinja.

Chimwe chinofanira kungwarirwa chinosimbisa pfungwa iyi pane kuideredza. Mbeva idzi dzakanga dzisati dzava nekuungana kwetau pazera radzakaongororwa, saka ongororo iyi haigoni kuratidza kuti methylene blue haitadzi kubatsira pakupetana kwetau. Inoratidza kuti amyloid inonyungudika inogona kuderera asi zviyero zvetau zvakaongororwa zvisingachinji, zvinova ndizvo chaizvo zvinodiwa panyaya iyi: imwe puroteni yashanduka, imwe isina. Kana wauya pano uchitenda kuti kukurudzirwa kweproteasome nemethylene blue kunobvisa mapuroteni ose ari maviri anoratidza chirwere pamwe chete, ongororo iyi inogadzirisa pfungwa iyoyo.

Zvakawanikwa pamusoro pekugadzirwa kweamyloid ndezvembeva dzePSAPP dzakwegura, uye zvinopesana nenzira yakatsanangurwa yapfuura

Rimwe boka, imwe modheru, uye tsananguro inopesana pamusoro pezvinoitika pakutanga kwemaitiro acho. Mu ongororo yemwedzi mitatu yekupinza mushonga mudumbu nechubhu mumbeva dzePSAPP dzaiva nemwedzi 15, chipimo chezuva nezuva che3 mg/kg chaipiwa nemuromo chakaderedza huwandu hwemaplaque munzvimbo dzakasiyana dzeuropi nechinenge chikamu chimwe muzvitatu kusvika pahafu, uye chakaderedza zvikamu zvakawanda zveamyloid, kusanganisira maoligomer akayerwa neongororo yakagadzirirwa iwo. Asi pano nzira yaitsanangurwa yaiva yekuderedza kugadzirwa, kwete kukurumidza kubviswa: puroteni yeBACE1 muuropi yakaderera, chigadzirwa chayo C99 chakaderera, asi messenger RNA haina, zvinonongedzera pakukanganiswa kwepuroteni pachayo pane kuderera kwekushandiswa kweruzivo rwemajini.

Basa remumasero rakasimbisa tsananguro iyi. Muongororo isina masero yakashandisa enzayimu yakagadzirwa nerecombinant technology, methylene blue yakadzivisa BACE1 zvakananga, uye mumasero emuzai rehamster aigadzira puroteni yevanhu inotangira amyloid, amyloid 40 ne42 yaiburitswa yakaderera pakuwanda kwakaderera kusvika pa1.56 micromolar, asi puroteni inoitangira yacho isina kuchinja. Enzanisa izvi neongororo yapfuura, umo zvidimbu zvinobva pakugadziriswa kwepuroteni inotangira amyloid zvisina kuchinja uye kubviswa kwakatorwa sechikonzero. Tsananguro dzose dziri mbiri hadzigoni kuva nzira imwe inoshanda pose pose, nokuti mamodheru, mazera, zvipimo, nzira dzekupa mushonga, nenguva dzakasiyana. Ndiyo pfungwa yacho. Methylene blue inokanganisa amyloid kuburikidza nekugadzirwa kwayo mune imwe ongororo uye kuburikidza nekubviswa kwayo mune imwe, uye kutora imwe yedziri mbiri pasina mamiriro ayo kunotsausa.

Kemisitiri imwe, zvinonangwa zvakawanda: kubatana kuburikidza nekuoksidhwa kwecysteine

Imwe nzira yechitatu yekuongorora inotsanangura kuti kemisitiri imwe chete yeredox inogona kuoneka sei munyaya dzemapuroteni asina hukama. Mu ongororo yebiochemistry yekudziviswa kwecaspase, methylene blue yakaita kuti caspase-6 isashanda nekuoksidha cysteine yayo inoita basa rekukurumidzisa maitiro emakemikari kuita sulfenic acid, zvakatsigirwa nemass spectrometry, pakuwanda kunopa hafu yekukanganisa kukuru kunosvika pa10.6 micromolar. Caspase-3 yakadziviswa pakuwanda kwakafanana. Vanyori vakabatanidza izvi zvakajeka nezvakanyorwa pamusoro petau: kemisitiri imwe chete yekuoksidha cysteine inofungidzirwa kuchengetedza tau iri puroteni imwe yoga inogona kuita kuti cysteine protease isashanda, uye zviyero zvinokonzera izvi zvinopindirana.

Izvi zvinotsanangura zvinhu zvinoyevedza asi zvakare zvinopa yambiro. Morekuru rinoshanda muredox uye rinooksidha cysteine dziri pachena richava nezvinonangwa zvinopfuura chimwe pakuwanda kupi nokupi kwarinoshanda. Nyaya yekuparadzaniswa kwetau yakaungana, nyaya yecaspase, uye zvimwewo zvinogona kuva nechiito chimwe chemakemikari asi zvichiitika kuzvinhu zvakasiyana. Chiito ichocho chakafanana hachiiti kuti zvakawanikwa zvitsivane. Zvinoreva kuti chipimo nemamiriro ezvinhu ndizvo zvinosarudza chinonangwa chinokosha, uye kuti kupa mushonga kwenguva refu kwakanangana nemaitiro mamwe anoenderana necysteine kunogona kukanganisa mamwe, nyaya yakataurwa zvakananga nevanyori veongororo yecaspase. Mibvunzo ine hukama pamusoro pekuti kemisitiri yeredox yemethylene blue inosarudza sei zvinonangwa zvayo, kuti kukurudzirwa kweproteasome kunorevei kune mamwe mapuroteni akaungana, uye kana kupa mushonga kwenguva refu kuchichinja zvinonangwa zvawo mumwe nomumwe unoda kukurukurwa uri woga.

Nzira maererano nezvinoyerwa: zvakawanikwa zvipi ndezvemodheru ipi

Verenga tafura mutsara nomutsara uye chidzidzo chacho chinobuda pachena. Hapana mutsara mumwe unoshanduka muchikamu chose. Zvakawanikwa zvakasimba zvikuru pamusoro pekugadzirwa kweamyloid zvinobva muongororo isina kumboyedza proteasome. Zvakawanikwa zvakasimba zvikuru pamusoro peproteasome zvinobva muongororo umo kugadziriswa kwepuroteni inotangira amyloid kusina kumboshanduka. Zvakawanikwa pamusoro petau zvinonyanya kubva mumachubhu uye mukemisitiri yakafanana neinoshanda pamaenzayimu asiri iwo akanangwa. Ani naani anobatanidza zvikamu izvi kuita chirevo chimwe chekuti methylene blue inobvisa mapuroteni ane chekuita nechirwere seboka, anenge achinyora pfupiso yeongororo isina kumbobvira yaitwa.

Kunyatsochengeta misiyano iyi kunosvikawo kuvarwere. Kana nzira idzi dzichizopedzisira dzabatsira varwere mubvunzo wakasiyana une ongororo dzawo nemhedziso dzawo, uye unopindurwa pasi pe uchapupu hweongororo dzevarwere vane Alzheimer kwete pano.