I-methylene blue, i-tau ne-amyloid: kutheni iindlela zokususa iiproteni zahlukile

Buza ukuba i-methylene blue yenza ntoni kwiiproteni zesifo sika-Alzheimer, uze uve impendulo enye eqinisekileyo apho bekufanele ukuba uve ezintathu ezinemida ecacisiweyo. Kwityhubhu yovavanyo, iphazamisa ukunamathelana kwe-tau. Kwenye imodeli yeempuku, yehlisa i-amyloid enyibilikayo kodwa ishiya i-tau ingatshintshanga. Kwenye, inciphisa ukusebenza kwe-enzyme evelisa i-amyloid kwasekuqaleni. Ngasinye kwezi ziphumo siyinyani. Akukho nasinye esilibali elipheleleyo, kwaye aziveli zonke kwisilwanyana esinye ngexesha elinye. Eli nqaku lahlula ezi zintathu ukuze isiphumo sovavanyo olunye siyeke ukucatshulwa njengobungqina bolunye.

Abafundi abafuna umfanekiso obanzi wendlela i-methylene blue esebenza ngayo ngaphakathi kweeseli mab aqale apho. Abafundi abafuna ukwazi ukuba ngaba nayiphi na kwezi zinto yazinceda izigulana mabafunde ingxelo yezifundo zekliniki kwisifo sika-Alzheimer, apho iziphumo zovavanyo ebantwini zifanele ukubekwa khona. Akukho nto kweli nqaku iphinda loo ngxelo.

Isiphumo se-tau sivela kwiimvavanyo zokuqokelelana

Elona lidala kula mabali mathathu livela kumsebenzi owenziwe ngaphandle kweeseli kwi-tau, iproteni eyenza amaqhina emicu ngaphakathi kweeseli zemithambo-luvo. Kuvavanyo lokubophana kwe-tau ne-tau, iziqwenga ze-tau zidibana zenze imicu ephotheneyo ngazibini, yaye iidayi zephenothiazine, eziquka i-methylene blue, zithintela oko kudibana kumaqondo oxinaniso aphantsi e-micromolar. Umsebenzi wamva wenzululwazi ngemichiza yezinto eziphilayo wanika oku ingcaciso yemichiza: idayi yenza i-oxidation kwiintsalela zecysteine ezikwi-tau, nto leyo ezinzisa uhlobo lwe-tau oluyimolekyuli enye ize icinezele imicu emincinane ebinokukhula ngaphandle koko. Amaqondo oxinaniso axeliweyo athintela ukuqokelelana kwe-tau asusela malunga neeyunithi ezinomvo omnye ukuya kumashumi asezantsi e-micromolar, uluhlu olubalulekileyo kuyo yonke into elandelayo.

Qaphela ukuba olu luhlobo luni lwebango. Alithethi nto ngokuveliswa kwe-tau, ukufakwa kwamaqela ephosphate kwi-tau kwingqondo ephilayo, okanye ukususwa kwe-tau. Lithi phantsi kweemeko ezichaziweyo kwityhubhu, idayi eyenziwe i-oxidation ithintela i-tau ekufumbekeni. Eso sisiphumo esichanileyo, esinomda ocacileyo nesiluncedo. Ingxaki iqala xa sandiswa sibe libango ngokubanzi lokuba i-methylene blue isusa utshintsho lwe-tau olunxulumene nesifo, kuba idatha yezilwanyana ayiyixhasi loo ngcaciso.

Isiphumo seproteasome sivela kwiimpuku ze-3xTg-AD, kwaye sahlula i-amyloid kwi-tau

Olona vavanyo lubonisa ngokucacileyo ukwahlukana kwezalathisi ezilinganiswayo luphononongo lokutya lweeveki ezili-16 kwiimpuku ezithwele iinguqu ezintathu zemfuza ezinxulumene nesifo sika-Alzheimer. Ezi zilwanyana zatya ukutya okuqulethe i-methylene blue ukususela xa zazineenyanga ezintandathu ubudala, yaye abaphandi balinganisa izinto ezintathu ngaxeshanye: iproteasome, amanqanaba e-amyloid ne-tau.

Iproteasome yatshintsha. Ukusebenza okufana nokwechymotrypsin kwanda malunga nekota, nokufana nokwetrypsin kwanda malunga nesiqingatha, ngoxa umsebenzi wesithathu wokukhawulezisa iintshukumo zemichiza ungazange utshintshe ngokuphawulekayo. I-amyloid-beta 40 ne-42 enyibilikayo nganye yehla malunga nekota. Ababhali bakutolika oku njengokwanda kokususwa kunokuncipha kokuveliswa, kuba iproteni eyandulelayo neziqwenga ezivela ekusetyenzweni kwayo azizange zitshintshe, kwaye ukufunda nokukhumbula kwaphucuka kuvavanyo lokuhlola kwilabyrinth yamanzi.

Kwavela ke ukwahlukana kweziphumo. I-amyloid enganyibilikiyo ayizange itshintshe. Ukudaywa kokubonisa iidipozithi akuzange kutshintshe. Isixa esipheleleyo se-tau yabantu kunye ne-tau eneqela lephosphate kwithreyonine 181 azizange zitshintshe, nokubekwa kwe-tau kwiindawo ezingafanelekanga akuzange kutshintshe. Imilinganiselo yeemitochondria nayo ayizange itshintshe: kwakungekho futhe libonakalayo ekusebenzeni kwecytochrome-c oxidase, kwiproteni ye-oxidase okanye kwi-ATP. Ngoko kule modeli, ngale nkqubo yokuyinika, i-methylene blue yandisa imisebenzi emibini kwemithathu yeproteasome, yehlisa i-amyloid enyibilikayo, yaphucula isalathisi sokuziphatha, yaza yashiya izalathisi ze-tau, i-amyloid enganyibilikiyo nezalathisi zeemitochondria ezavavanywayo zingatshintshanga.

Isilumkiso esinye siyayicacisa le ngongoma kunokuba siyibuthathakise. Ezi mpuku zazingekaphuhlisi amaqela e-tau aqokeleleneyo kubudala ezavavanywa kubo, ngoko olu vavanyo alunakubonisa ukuba i-methylene blue ayisebenzi kumaqhina e-tau. Lubonisa ukuba i-amyloid enyibilikayo inokwehla ngoxa izalathisi ze-tau ezilinganisiweyo zingatshintshi, nto leyo kanye eluhlobo lwesiphumo esifunekayo kulo mba: iproteni enye itshintshile, enye ayitshintshanga. Ukuba uze apha ukholelwa ukuba ukuvuselelwa kweproteasome yi-methylene blue kususa zombini iiproteni eziphawula esi sifo kunye, olu phononongo lulungisa loo mbono.

Isiphumo sokuveliswa kwe-amyloid sivela kwiimpuku ze-PSAPP ezindala, kwaye siyaphikisana nendlela yangaphambili

Iqela elahlukileyo, imodeli eyahlukileyo, nengcaciso echaseneyo yenkqubo eyenzeka kuqala. Kuphononongo lweenyanga ezintathu lokufaka into esiswini ngombhobho kwiimpuku ze-PSAPP ezineenyanga ezili-15 ubudala, idosi yemihla ngemihla ethathwa ngomlomo eyi-3 mg/kg yanciphisa ubungakanani beedipozithi kwiindawo ezahlukeneyo zengqondo malunga nesinye kwisithathu ukuya kwisiqingatha, yaza yehlisa iinxalenye ezininzi ze-amyloid, kuquka ii-oligomer ezalinganiswa ngovavanyo olulungiselelwe zona ngokukodwa. Kodwa apha indlela ecetywayo yayikukuncipha kokuveliswa, hayi ukususwa ngokukhawuleza: iproteni ye-BACE1 engqondweni yehla, imveliso yayo eyi-C99 yehla, kodwa i-RNA yesithunywa ayizange yehle, nto leyo ekhomba kwifuthe kwinqanaba leproteni kunokuncipha kokubonakaliswa kwemfuza.

Umsebenzi weeseli womeleza obo bungqina. Kuvavanyo olungenazo iiseli olusebenzisa i-enzyme eyenziwe ngobuchule bokudibanisa imfuza, i-methylene blue yayithintela ngokuthe ngqo i-BACE1; kwiiseli zamaqanda ehamster ezivelisa iproteni yabantu eyandulela i-amyloid, i-amyloid 40 ne-42 ekhutshelwa ngaphandle kweeseli yehla kumaqondo oxinaniso asezantsi njenge-1.56 micromolar, ngoxa iproteni eyandulelayo yona yahlala ingatshintshanga. Thelekisa oku nophononongo lwangaphambili, apho iziqwenga ezivela ekusetyenzweni kweproteni eyandulelayo zazingatshintshanga, kwaza ukususwa kwathathwa njengonobangela. Zombini azinakuchaza indlela enye esebenza kuzo zonke iimeko, kuba iimodeli, ubudala, iidosi, iindlela zokunika namaxesha zahlukile. Yiyo kanye le ngongoma. Iziphumo ze-methylene blue kwi-amyloid zidlula ekuvelisweni kwenye inkqubo yovavanyo, nasekususweni kwenye, kwaye ukucaphula nasiphi na ngaphandle kwemeko yaso kuyalahlekisa.

Umsebenzi omnye wemichiza, izinto ekujoliswa kuzo ezininzi: ikhonkco le-oxidation yecysteine

Omnye umgca wesithathu wophando uchaza indlela umsebenzi omnye wemichiza we-redox onokuvela ngayo kumabali eeproteni anganxulumananga. Kuphononongo lwemichiza yezinto eziphilayo malunga nokuthintelwa kwecaspase, i-methylene blue yayeka ukusebenza kwecaspase-6 ngokwenza i-oxidation kwicysteine yayo ethatha inxaxheba ekukhawuleziseni intshukumo yemichiza, iyiguqulele kwi-asidi yesulfenic. Oku kwaqinisekiswa ngespektrometri yobunzima, kwiqondo loxinaniso elivelisa isiqingatha sefuthe eliphezulu elimalunga ne-10.6 micromolar. Icaspase-3 yathintelwa kwiqondo loxinaniso elifanayo. Ababhali bakunxulumanisa ngokucacileyo oku noncwadi lwe-tau: umsebenzi ofanayo wemichiza owenza i-oxidation kwicysteine, ocetywa ukuba ugcine i-tau ikwimo yemolekyuli enye, unokuyekisa ukusebenza kweprotease esebenzisa icysteine, yaye amaqondo oxinaniso asebenzayo ayadibana.

Oku kuyathandeka, kodwa kukwasisilumkiso. Imolekyuli esebenzayo kwi-redox eyenza i-oxidation kwiicysteine eziveziweyo iya kuba nezinto ezingaphezu kwenye ejolise kuzo nakweliphi na iqondo loxinaniso esebenza kulo. Ibali lokuqhawulwa kwamaqela e-tau aqokeleleneyo, ibali lecaspase, mhlawumbi namanye, abelana ngesenzi somsebenzi wemichiza kodwa asebenzisa izibizo ezahlukeneyo. Eso senzi sifanayo asenzi ukuba iziphumo zitshintshiselane. Sithetha ukuba idosi nemeko zigqiba ukuba yeyiphi into ekujoliswe kuyo ebalulekileyo, nokuba ukunika iidosi ixesha elide ngenjongo yokuchaphazela inkqubo enye exhomekeke kwicysteine kunokuchaphazela nezinye, ingongoma ababhali becaspase abayiphakamisa ngokuthe ngqo. Imibuzo enxulumene nendlela umsebenzi wemichiza we-redox we-methylene blue okhetha ngayo izinto ekujoliswa kuzo, ukuba ukuvuselelwa kweproteasome kuthetha ntoni kwezinye iiproteni eziqokeleleneyo, kunye nokuba ukunika iidosi ixesha elide kuyazitshintsha na izinto ekujoliswa kuzo ngamnye ufuna ingcaciso yawo.

Indlela ngokwesalathisi esilinganisiweyo: sesiphi isiphumo esivela kweyiphi imodeli

Funda itheyibhile umqolo ngomqolo, yaye isifundo sicacile. Akukho mqolo mnye utshintsha kuzo zonke iikholam. Esona siphumo sinamandla sokuveliswa kwe-amyloid sivela kuphononongo olungazange luvavanye iproteasome. Esona siphumo sinamandla seproteasome sivela kuphononongo apho ukusetyenzwa kweproteni eyandulelayo kungazange kutshintshe. Isiphumo se-tau sivela ikakhulu kwiityhubhu nakumsebenzi wemichiza ekwabelwana ngawo nee-enzyme ezingezizo ebezijoliswe kuzo. Nabani na odibanisa ezi kholam zibe libango elinye, lokuba i-methylene blue isusa iiproteni ezinxulumene nesifo njengeqela, ubhala uphononongo lovavanyo olungazange lwenziwe.

Olu qeqesho lokwahlula iziphumo lukwabhekisela kwizigulana. Ukuba ezi ndlela zidibana zivelise inzuzo yekliniki ngumbuzo owahlukileyo, oneemvavanyo zawo nezigqibo zawo, yaye uphendulwa phantsi kobungqina beekliniki besifo sika-Alzheimer kunokuba uphendulwe apha.