Methylene blue neALS: nei zvabuda zvichisiyana pakati pemienzaniso yekuedza

Ukatsvaga methylene blue neALS unowana zvirevo zviviri zvinoita sezvinopikisana. Chimwe chinoti dhayi yebhuruu yakadzivirira masero etsinga mumienzaniso yeALS. Chimwe chinoti haina chayakaita mugonzo reALS. Zvirevo zvose zviri zviviri zvinonongedzera kumapepa etsakurudzo chaiwo, uye mapepa acho ose anofanira kutorwa zvakakomba. Kupokana uku kunopera kana watsanangura pfungwa iri shure kwekuedza kumwe nokumwe: muenzaniso ndiwo unotara zvinogona kunzi zvakaratidzwa.

Zvakabuda mugonye zvinotaura nezvegonye. Zvakabuda muhove iri padanho rekutanga rekukura zvinotaura nezvehove iri padanho iroro. Hapana chimwe chazvo chinotaura nezvemurwere kusvikira kuenderera kwechirwere mumhuka inoyamwisa kwatsigira izvozvo. Chinyorwa ichi chinoenzanisa mapepa maviri anonyanya kunongedzerwa kwaari kuti uone nei mhinduro dzawo dzichisiyana.

Kuedza kuviri mutafura imwe

Ramba wakatarisa tafura iyi paunenge uchiverenga. Misiyano yose inokosha pakati petsakurudzo idzi iri mairi.

Mageni anosiyana, marudzi emhuka anosiyana, nzira yekupa mushonga inosiyana, nguva inosiyana, uye zvinoyerwa zvinosiyana. Mamiriro emageni anongova mumwe wemisiyano mishanu, saka kuenzanisa uku hakugoni kuratidza kuti methylene blue inoshanda chete pane imwe nzira yeALS. Kunoratidza chinhu chakamanikana asi chichiri kubatsira: kuvandudzwa kukuru kwakawanikwa nekutanga kuratidzwa zvakananga kumushonga mumienzaniso iri nyore hakuna kuenderera mberi mukufamba kwechirwere kwenguva refu mumhuka inoyamwisa yaipiwa mushonga nomuromo.

Mhedzisiro yekuvandudzwa: zvakataurwa netsakurudzo yemakonye nehove

Tsakurudzo yemakonye nehove ya2012 yakaita kuti masero etsinga anodzora kufamba mumakonye agadzire TDP-43 kana FUS yemunhu yakachinja, uye yakabaya mRNA yemunhu yakachinja mumaembryo ehove. Iyi mienzaniso yekukuvadzwa kunokonzerwa nemapuroteni. Inobudisa kukanganisa kunokonzerwa nepuroteni yakachinja pakufamba nechimiro chemasero etsinga kwemazuva, kwete kufamba kwose kweALS mumunhu mukuru kwemakore.

Kupihwa mushonga kwakatanga mangwanani zvikuru. Makonye akakurira paagar ine methylene blue kubva pakuchochonya. Maembryo ehove akagara mumvura ine mushonga usiku hwose, kutanga pa24 hours mushure mekusangana kwezai nembeu, uye maitiro awo akaedzwa anenge mazuva maviri gare gare. Chipingaidzo chiri pakati peropa nehuropi hachina kumira pakati pemushonga nesero retsinga sezvachinoita mumhuka inoyamwisa, uye huwandu hwemushonga muplasma kana muhuropi hahuna kuyerwa.

Pasi pemamiriro iwayo, kuvandudzwa kwacho kwakanga kukuru uye kwaienderana. Zvose 6 ne60 μM zvakaderedza kuoma mitezo kunowedzera nezera mumakonye eTDP-43 neFUS. Pazuva 12 rehupenyu hwemakonye akura, anenge 80 percent emakonye eTDP-43 asina kupiwa mushonga akanga aoma mitezo, zvichienzaniswa neanenge 10 percent emakonye akapiwa mushonga kubva pakuchochonya. Bvunzo yemabatanidzo etsinga yakaratidzawo zvakafanana: makonye eTDP-43 aipindura zvakanyanya ku aldicarb, mushonga unoshandiswa kuongorora kufambiswa kwezviratidzo pakati petsinga nemhasuru, uye methylene blue yakadzosa kupindura kwacho pedyo nemamiriro akajairika. Huwandu hwezvikamu zvinotambanuka zvemasero etsinga anodzora kufamba zvaiparara hwakaderera, uye izvi zvakanyanya kuoneka pa60 μM. Muhove, kushambira kunotangwa nekubatwa kwakavandudzika zvikuru, uye maaxon etsinga dzinodzora kufamba akanga apfupika akakurazve achiswedera pakureba kwakajairika pa30 kana 60 μM, kunyange zvazvo kuvandudzwa kwaiva kwechikamu chete, kwete kuzere.

Mashoko pamusoro pekushushikana kunokonzerwa neoxidation aienderana netsananguro yekushanda seantioxidant. Makonye nehove zvaive nemageni akachinja zvakaratidza zviyero zvakakwira zvemhando dzeoxygen dzinokurumidza kuita makemikari, izvo zvakaderera pakupiwa mushonga, uye makonye akajairika aiva pamethylene blue akararama kwenguva yakareba zvikuru paaedzwa nechinhu chinowedzera oxidation kupfuura makonye asina kupiwa mushonga. Asi pane miganhu miviri inokosha. Huwandu hwose hwemapuroteni eTDP-43 neFUS akachinja hahuna kuderera, uye tsakurudzo haina kuyera zvakananga kuungana kwemapuroteni, saka inoratidza kuvandudzwa kwekushanda isingaratidzi kuti mapuroteni akaungana akabviswa. Munhu anotevera matsanangurirwo anowanzoitwa pfungwa dzetsakurudzo dzeredox nemitochondria anofanira kuona nzira yekushanda iyi seinotsigirwa asi isati yasimbiswa zvizere.

Nguva yekutanga mushonga ndiyo yakapa chidzidzo chakanyanya kukosha. Vanyori pavakamirira kusvika pazuva 5 rehupenyu hwemakonye akura kuti vatange kupiwa mushonga, huwandu hweainge aoma mitezo pazuva 12 hwaiva hunenge 55 percent, panzvimbo peanenge 10 percent kana mushonga watangwa kubva pakuchochonya. Mushonga mumwe chete, gonye rerudzi rumwe chete, shanduko yemageni imwe chete, asi kuvandudzwa kuduku zvikuru. Kuratidzwa kumushonga kare kuti zviratidzo zvisatanga ndiko kwakapa chikamu chikuru chekubatsira kwaiita sekwakaonekwa.

Mhedzisiro isina kuratidza kuvandudzwa: zvakataurwa netsakurudzo yemakonzo eSOD1

Tsakurudzo yemakonzo ya2011 yakabvunza mubvunzo wakaoma zvikuru mumamiriro ane kuongorora kwakasimba. Makonzo eSOD1 G93A ane mamiriro emageni akafanana kunze kwechikamu chakachinjwa anotangira pakudedera kwemakumbo ekumashure, achizotadza kufamba zvakanaka nekurasikirwa nekuzvigadzirisa kuti amire zvakanaka kana atenderedzwa, kusvika pamuganhu wekupedzisira wakagara watsanangurwa. Kupihwa mushonga kwakatanga zviratidzo zvisati zvaoneka pazuva 45 uye kwakaenderera zuva nezuva, vaongorori vachipa zviyero zvezviratidzo zvetsinga pachikero che0 kusvika 6. Uku kuedza kunotevera kufamba kwose kwechirwere, izvo kunoita kuti kuve pedyo nezvingakosha kumurwere kupfuura girafu chero ripi rekutangira kwekuoma mitezo mugonye.

Mhinduro huru hadzina kuratidza kuvandudzwa kwakakosha. Kutanga kwezviratidzo zvose kwakaitika pa121 days muboka rekuenzanisa, zvichienzaniswa ne124 days neboka remethylene blue, musiyano wakanga usina kukosha maererano nehuwandu. Kurarama kusvika padanho rekupedzisira kwaiva 167 days zvichienzaniswa ne170 days, izvo zvakare zvakanga zvisina kukosha maererano nehuwandu. Zvimwe zvikamu zviduku zvezvakabuda zvakatsigira kupihwa mushonga: makonzo echikadzi akaratidza kunonoka kwekutanga kwezviratidzo kweanenge 7 day, uye mhuka dzakapiwa mushonga dzakapedza nguva yakati rebei mumatanho asina kunyanya kuoma uye shoma mumatanho akaoma. Sezvo mapoka akapatsanurwa nehurume kana hukadzi aiva maduku uye pakaitwa kuenzanisa kwakawanda kwematanho, zvikamu izvi zvinofanira kuonekwa sezvinobereka pfungwa dzekuzoongorora, kwete sehumbowo. Hapana kuverengwa kwemasero etsinga, hapana bvunzo yekuungana kweSOD1, uye hapana zviratidzo zveoxidation kana kuzvimba zvakayerwa, saka tsakurudzo haigoniwo kutaura kana mushonga wakasvika pazvinhu zvaifanira kunanga ukatadza kushanda, kana kuti hauna kumboshanda pazviri padosi iri. Dosi rimwe chete ndiro rakaedzwa.

Vanyori pachavo vakataura muganhu mukuru, unoshanda kumativi ose. Mienzaniso yeSOD1 G93A ine makopi akawanda inomiririra zvakanaka chirwere chinokonzerwa nekukuvadza kweSOD1, asi chirwere cheSOD1 chikamu chiduku cheALS inopfuudzwa mumhuri uye chine mashandiro emuviri akasiyana neALS yakawanda isingateverani mumhuri. Vakakurudzira kuedzazve zvinhu zvinogona kuzova mishonga mumienzaniso yemhuka dzinoyamwisa yakavakirwa paTDP-43. Pfungwa iyoyo yakazova yakaoma zvikuru, nokuti vanyori vetsakurudzo yemakonye nehove vanocherechedza kuti imwe tsakurudzo yakasiyana yemethylene blue mumakonzo eTDP-43 yakatadzawo kuvandudza kufamba. Saka chinhu chinogona kuratidza kushanda kwakasimba mune imwe nzira yekuedza yeTDP-43 asi chisaratidze kuvandudzwa mune imwe. Mamiriro ekuedza anokosha sezvinoita geni racho.

Nei kuvandudzwa mugonye kana muhove kusingagoni kusimbisa kubatsira kuvarwere

Funga nezvemuenzaniso mumwe nomumwe seuri kupindura mubvunzo wakasiyana.

Chokutanga, mashandiro emuviri anosiyana. TDP-43 neFUS mapuroteni anosungirira kunucleic acid uye ane kudyidzana kwemageni kwakafanana mumienzaniso iyi iri nyore, nepo kukuvadza kweSOD1 kuchipfuura nenzira dzepedyo dzakati siyanei. Mushonga unoderedza kumwe kushushikana kunokonzerwa nemapuroteni haufaniri hazvo kuderedza kumwe, uye kubudirira pakugadzirwa kwepuroteni yakawandisa mumaembryo hakufaniri hazvo kufanotaura kubudirira pakuderera zvishoma nezvishoma kwemasero etsinga mumunhu mukuru, kunosanganisira kuzvimba, kupindira kwemasero eglia, uye kuderera kwemuviri wose.

Chechipiri, kuratidzwa kumushonga kunosiyana. Kugara uri mumvura ine mushonga pahuwandu hwemicromolar hakusi kupiwa dosi nomuromo. Kupinzwa kwemushonga muropa kubva muura, kushandurwa kwawo kwekutanga mumuviri, kusungirira kumapuroteni eplasma, kupinda muhuropi, uye kubviswa mumuviri zvose zviri pakati pedosi rakamedzwa nesero retsinga rinodzora kufamba mumuzongoza. Hapana patsakurudzo mbiri idzi pakayerwa huwandu hwemushonga muhurongwa hwetsinga, saka hapana inogona kubatanidza huwandu hwayo nehweimwe.

Chechitatu, nguva inosiyana. Kubatsira kwakaonekwa mumakonye nehove kwainyanya kutsamira pakupiwa mushonga kukuvadzwa kwechirwere kusati kwaungana. Kupihwa mushonga kumakonzo kwakatangawo zviratidzo zvisati zvaoneka, chinova chinhu chakasimba patsakurudzo iyi, asi muvanhu kupihwa mushonga kunenge nguva dzose kuchitanga mushure mekutanga kwezviratidzo, kureva kuti kunototanga gare gare. Chiratidzo chekubatsira pakudzivirira chinobuda mubvunzo yeembryo yemazuva maviri chinongova pekutangira kutsvakurudza, kwete muenzaniso wekushandiswa mukurapa.

Chechina, zvinoyerwa zvinosiyana. Kuoma mitezo pa12 days, kupindura ku aldicarb, kureba kweaxon mumicrometers, uye nhambwe yekushambira zviratidzo zviri pedyo nemashandiro ari kuongororwa. Kutanga kwezviratidzo nekurarama mumhuka inoyamwisa zvinosanganisa nzira dzose dzemuviri dzinotsiva basa rakarasika kana kuwedzera kuoma kwemamiriro. Mishonga inowanzoshandura zviyero zviri pedyo izvi isingachinji kurarama, ndokusaka zviyero zvenguva kusvika pachiitiko mumhuka dzinoyamwisa zvichishandiswa.

Vaverengi vanoda runyorwa rwezvavanofanira kutarisa pamusoro wenhau unotevera vanogona kutora rumwe kubva pakuti ungaverenga sei tsakurudzo dzisati dzaitwa muvanhu: bvunza rudzi rwemhuka, geni rakaiswa, dosi nenzira yekuripa, kana huwandu hwemushonga hwakayerwa, nguva yakatangwa kupihwa mushonga zvichienzaniswa nekutanga kwekukuvadzwa kwechirwere, kana chakayerwa chaiva chiratidzo chenguva pfupi kana kufamba kwechirwere, uye kana zvakabuda zvakadzokororwa mune rimwe rabhoritari. Humbowo hwakakura huri muvanhu hwemethylene blue ndihwo hunofanira kuramba huchitariswa kuti uone kana zviratidzo izvi zvekutanga zvakazokura zvikava mashoko etsakurudzo yekurapa.

Zvinorehwa neizvi kuvarwere nemhuri

Mapepa aya haapi nzira yakasimbiswa yekushandisa methylene blue paALS. Tsakurudzo yakaratidza kuvandudzwa inotsigira kumwe kutsvakurudza nzira dzeoxidation nedzemabatanidzo etsinga mumashandiro eTDP-43 neFUS. Tsakurudzo isina kuratidza kuvandudzwa inoderedza chikonzero chekutarisira kuti chirwere chichashandurwa nekupiwa mushonga nomuromo kwenguva refu pahuwandu uhwu muchirwere cherudzi rweSOD1. Pamwe chete, dzinotsanangura kusawirirana pakati pemienzaniso, kwete kurudziro yekurapa.

Kuchengeteka kunofanira kutaurwa nekungwarira kwakafanana nekushanda kwemushonga. Tsakurudzo dzeALS mumakonzo hadzitauri chinhu pamusoro pemadosi akachengeteka kuvanhu, uye methylene blue ine njodzi chaidzo dzekuparara kwemasero matsvuku eropa kana G6PD iri kushomeka, uye dzekukuvadza kunokonzerwa neserotonin kana yasanganiswa nemishonga inoshanda paserotonin. Kufungidzirwa kwekushomeka kweG6PD, kushandiswa kwemishonga yekuora mwoyo panguva ino, uye chero shanduko yemishonga iri kurongwa zvinofanira kukurukurwa nachiremba, sezvinofanirawo kuongororwa mashoko akajairika ekuchengeteka kwemethylene blue munhu asati aita chimwe chinhu achitevera misoro yenhau dzemurabhoritari.

Mhedziso inogona kutaurwa mumutsara mumwe chete. Methylene blue yakaratidza kuvandudzwa kukuru pakuratidzwa kumushonga kare muzviratidzo zvemakonye nehove dzichiri padanho rekutanga rekukura dzeTDP-43 neFUS, asi haina kunyatsoratidza kubatsira pakunonotsa kutanga kwezviratidzo kana kuwedzera kurarama mutsakurudzo yemakonzo eSOD1 akapiwa mushonga nomuromo kwenguva refu, saka dudziro yakatendeseka ndeyokuti uhwu humbowo hunotsamira pamuenzaniso uye husingatsigiri kushandiswa muvarwere.