I-methylene blue, i-tau, ne-amyloid: kungani izindlela zokususa amaprotheni zihlukile

Buza ukuthi i-methylene blue yenzani kumaprotheni esifo i-Alzheimer, uzwe impendulo eyodwa eqinisekile lapho bekufanele uzwe khona ezintathu ezinemibandela. Eshubhini lokuhlola iphazamisa ukunamathelana kwe-tau. Kwenye imodeli yamagundane inciphisa i-amyloid encibilikayo kodwa ingayishintshi i-tau. Kwenye inciphisa ukusebenza kwe-enzayimu ekhiqiza i-amyloid kwasekuqaleni. Ngamunye wale miphumela ungokoqobo. Awukho kuwo oyindaba yonke, futhi akwenzeki konke esilwaneni esisodwa ngesikhathi esisodwa. Lesi sihloko sihlukanisa lezi zinto ezintathu ukuze umphumela wokuhlolwa okukodwa uyeke ukucashunwa njengobufakazi bokunye.

Abafundi abafuna ukuqonda kabanzi indlela i-methylene blue esebenza ngayo ngaphakathi kwamangqamuzana kufanele baqale lapho. Abafundi abafuna ukwazi ukuthi kukhona yini kulokhu okwasiza iziguli kufanele bafunde irekhodi locwaningo lwezokwelapha ngesifo i-Alzheimer, lapho kufanele kuxoxwe khona ngemiphumela yokuhlolwa kubantu. Akukho kulesi sihloko okuphinda lelo rekhodi.

Umphumela ophathelene ne-tau ungowokuhlolwa kokuhlangana kwayo

Indaba endala kunazo zonke kulezi ezintathu ivela ocwaningweni olungenamangqamuzana nge-tau, iphrotheni eyakha izigaxa zemicu yezinzwa. Ekuhlolweni kokubophana kwe-tau ne-tau, izingcezu ze-tau zihlangana zibe yimicu emibili esontekene, futhi odayi be-phenothiazine, kuhlanganise ne-methylene blue, bavimba lokho kuhlangana emazingeni aphansi e-micromolar. Ucwaningo lwakamuva lwe-biochemistry lwakuchaza lokhu ngokwamakhemikhali: udayi wenza izinsalela ze-cysteine eziku-tau zibe ne-oxidation, okuqinisa isimo se-tau esiyiyunithi eyodwa futhi kucindezele ukukhula kwemicu emincane ebingakhula ngaphandle kwalokho. Amazinga okubikwa ukuthi avimbela ukuhlangana kwe-tau acishe abe phakathi kwamanani e-micromolar anedijithi eyodwa namashumi aphansi, okuyibanga elibalulekile kukho konke okulandelayo.

Qaphela ukuthi lokhu kuyisitatimende saluphi uhlobo. Akusho lutho ngokukhiqizwa kwe-tau, ngokwengezwa kwe-phosphate ku-tau ebuchosheni obuphilayo, noma ngokususwa kwe-tau. Kusho ukuthi ngaphansi kwezimo ezichaziwe eshubhini, udayi osube ne-oxidation uvimbela i-tau ukuba inqwabelane. Lowo ngumphumela oqondile, olinganiselwe, futhi owusizo. Inkinga iqala lapho welulwa ube isitatimende esivamile sokuthi i-methylene blue isusa izinguquko ze-tau ezihlobene nesifo, ngoba imininingwane yezilwane ayihambisani naleyo ncazelo.

Umphumela ophathelene ne-proteasome ungowamagundane e-3xTg-AD, futhi wahlukanisa i-amyloid ne-tau

Ukuhlolwa okubonisa ngokucace kakhulu ukwehlukana kwemiphumela wucwaningo lokudla lwamasonto angu-16 kumagundane anezinguquko ezintathu zofuzo ezihlobene ne-Alzheimer. Izilwane zadla ukudla okunemethylene blue kusukela zinezinyanga eziyisithupha ubudala, futhi abacwaningi balinganisa izinto ezintathu ngesikhathi esisodwa: i-proteasome, amazinga e-amyloid, ne-tau.

Ukusebenza kwe-proteasome kwashintsha. Ukusebenza okufana nokwe-chymotrypsin kwenyuka cishe ngekota, nokufana nokwe-trypsin kwenyuka cishe ngesigamu, kanti ukusebenza kwesithathu okubangela ukusabela kwamakhemikhali akushintshanga ngokuphawulekayo. I-amyloid-beta 40 ne-42 encibilikayo ngayinye yehla cishe ngekota. Ababhali bakuhumusha lokhu njengokwanda kokususwa kwayo kunokuncipha kokukhiqizwa kwayo, ngoba iphrotheni eyandulelayo nezingcezu ezivela ekucutshungulweni kwayo akuzange kushintshe, futhi ukufunda nenkumbulo kwathuthuka ekuhlolweni kokukhumbula indlela emzileni oyindida osemanzini.

Kwabe sekuvela izinto ezingashintshanga. I-amyloid engancibiliki ayishintshanga. Ukudaywa ukuze kubonakale ama-plaque akushintshanga. Inani eliphelele le-tau yabantu ne-phospho-tau ku-threonine 181 akushintshanga, futhi ukuba kwe-tau ezindaweni ezingafanele akushintshanga. Izilinganiso ze-mitochondria nazo azishintshanga: kwakungekho mphumela ophawulekayo ekusebenzeni kwe-cytochrome-c oxidase, kuphrotheni ye-oxidase, noma ku-ATP. Ngakho kule modeli, nangalolu hlelo lokunikezwa, i-methylene blue yandisa izinhlobo ezimbili kwezintathu zokusebenza kwe-proteasome, yanciphisa i-amyloid encibilikayo, yabuyisela esimweni esingcono isilinganiso sokuziphatha, kodwa yashiya izilinganiso ze-tau, i-amyloid engancibiliki, nezilinganiso ze-mitochondria ezahlolwa zingashintshile.

Isexwayiso esisodwa senza leli phuzu licace kakhudlwana kunokuba silenze buthaka. La magundane ayengakakhi amaqoqo e-tau eminyakeni yawo yokuphila ngesikhathi ehlolwa, ngakho ukuhlolwa akukwazi ukubonisa ukuthi i-methylene blue ayisebenzi ezigaxeni zemicu ye-tau. Kubonisa ukuthi i-amyloid encibilikayo ingehla kuyilapho izilinganiso ze-tau ezihloliwe zingashintshi, okuwuhlobo lomphumela othi iphrotheni eyodwa ishintshile kodwa enye ayishintshanga oludingwa yilesi sihloko. Uma ufike lapha ukholelwa ukuthi ukwenza i-proteasome isebenze kakhulu nge-methylene blue kususa womabili amaprotheni ayizimpawu eziyinhloko ndawonye, lolu cwaningo lulungisa lowo mbono.

Umphumela ophathelene nokukhiqizwa kwe-amyloid ungowamagundane e-PSAPP asekhulile, futhi uphikisana nendlela yokusebenza yangaphambilini

Iqembu elihlukile, imodeli ehlukile, nencazelo ephambene ngalokho okwenzeka ekuqaleni kwenqubo. Ocwaningweni lwezinyanga ezintathu lokunikeza umuthi ngeshubhu eliya esiswini kumagundane e-PSAPP anezinyanga ezingu-15 ubudala, umthamo wansuku zonke womlomo ongu-3 mg/kg wanciphisa ubuningi bama-plaque ezindaweni zobuchopho cishe ngengxenye eyodwa kwezintathu kuya esigamwini, futhi wanciphisa izingxenye eziningana ze-amyloid, kuhlanganise nama-oligomer alinganiswa ngokuhlolwa okukhethekile. Kodwa lapha indlela yokusebenza ehlongozwayo kwakuwukuncipha kokukhiqizwa, hhayi ukususwa ngokushesha: iphrotheni ye-BACE1 ebuchosheni yehla, umkhiqizo wayo i-C99 wehla, kodwa i-RNA eyisithunywa ayizange yehle, okukhomba umphumela osezingeni lephrotheni kunokuncipha kokusebenza kofuzo.

Ucwaningo lwamangqamuzana lwaqinisa lobu bufakazi. Ekuhlolweni okungenamangqamuzana nge-enzayimu eyenziwe ngobuchwepheshe bokuhlanganisa ufuzo, i-methylene blue yavimbela i-BACE1 ngokuqondile, futhi emangqamuzaneni esibeletho samaqanda e-hamster akhiqiza iphrotheni yabantu eyandulela i-amyloid, i-amyloid 40 ne-42 ekhishwa amangqamuzana yehla emazingeni aphansi afinyelela ku-1.56 micromolar, kuyilapho iphrotheni eyandulelayo ngokwayo ingashintshi. Qhathanisa lokhu nocwaningo lwangaphambilini, lapho izingcezu zokucutshungulwa kwephrotheni eyandulelayo zingashintshanga futhi ukususwa kwe-amyloid kwanikezwa njengencazelo. Zombili lezi zincazelo azikwazi ukuchaza indlela eyodwa esebenza kuyo yonke indawo, ngoba amamodeli, ubudala, imithamo, izindlela zokunikezwa, nobude besikhathi kuyahluka. Yilelo iphuzu. Imiphumela ye-methylene blue ku-amyloid idlula ekukhiqizweni kwayo kwesinye isimo sokuhlolwa, nasekususweni kwayo kwesinye, futhi ukucaphuna noma yimuphi ngaphandle kwezimo zokuhlolwa zawo kuyadukisa.

Ukusabela okukodwa kwamakhemikhali, izinto eziningi eziqondiwe: ukuxhumana nge-oxidation ye-cysteine

Umugqa wesithathu wocwaningo uchaza ukuthi ukusabela okukodwa kwe-redox kungavela kanjani ezindabeni zamaprotheni ezingahlobene. Ocwaningweni lwe-biochemistry lokuvinjelwa kwe-caspase, i-methylene blue yenza i-caspase-6 ingasebenzi ngokuguqula i-cysteine yayo ebangela ukusabela ibe yi-sulfenic acid nge-oxidation, okuqinisekiswe nge-mass spectrometry, ngezinga elicishe libe ngu-10.6 micromolar elenza ingxenye yomphumela omkhulu kakhulu. I-caspase-3 yavinjwa ezingeni elifanayo. Ababhali bakuxhumanisa ngokusobala lokhu nocwaningo lwe-tau: ukusabela okufanayo kwamakhemikhali okwenza i-cysteine ibe ne-oxidation, okuhlongozwa ukuthi kugcina i-tau iyiyunithi eyodwa, kungayekisa ukusebenza kwe-protease encike ku-cysteine, futhi amazinga asebenzayo ayagqagqana.

Lokhu kuyincazelo enhle, kodwa futhi kuyisixwayiso. I-molecule esebenzayo ekusabeleni kwe-redox futhi eyenza ama-cysteine asobala abe ne-oxidation izoba nezinto ezingaphezu kweyodwa eziqondiwe kunoma yiliphi izinga esebenza kulo. Indaba yokuhlakazwa kwamaqoqo e-tau, indaba ye-caspase, mhlawumbe nezinye, zabelana ngesenzo samakhemikhali kodwa zithinta izinto ezihlukile. Leso senzo esifanayo asenzi imiphumela ishintshekane. Kusho ukuthi umthamo nezimo kunquma ukuthi iyiphi into eqondiwe ebalulekile, nokuthi ukunikezwa isikhathi eside okuqondiswe enqubweni eyodwa encike ku-cysteine kungase kuthinte nezinye, okuyinto ababhali bocwaningo lwe-caspase abayiveza ngokuqondile. Imibuzo ehlobene ngokuthi ukusabela kwe-redox kwe-methylene blue kuzikhetha kanjani izinto eziqondiwe, ukuthi ukwandiswa kokusebenza kwe-proteasome kusho ukuthini kwamanye amaprotheni ahlangene aba amaqoqo, nokuthi ukunikezwa isikhathi eside kuyashintsha yini ukuthi yiziphi izinto ezithintekayo ngamunye udinga ukuchazwa ngokwehlukana.

Indlela yokusebenza ngokwesilinganiso somphumela: yimuphi umphumela ongowayiphi imodeli

Funda ithebula umugqa ngomugqa, futhi isifundo sicacile. Awukho umugqa owodwa oshintshayo kuwo wonke amakholomu. Umphumela oqine kakhulu wokukhiqizwa kwe-amyloid uvela ocwaningweni olungazange luhlole i-proteasome. Umphumela oqine kakhulu we-proteasome uvela ocwaningweni lapho ukucutshungulwa kwephrotheni eyandulelayo kungazange kushintshe. Umphumela we-tau ubonakala kakhulu emashubhini nasekusabeleni kwamakhemikhali okufanayo nokwama-enzayimu angezona izinto ezihlosiwe. Noma ubani ohlanganisa la makholomu abe isitatimende esisodwa sokuthi i-methylene blue isusa wonke amaprotheni ahlobene nesifo njengeqembu, ubhala ukubuyekezwa kokuhlolwa okungakaze kwenziwe.

Lokho kucophelela kuyasebenza nasezigulini. Ukuthi lezi zindlela zokusebenza zihlangana yini zibe yinzuzo ezigulini kuwumbuzo ohlukile onokuhlolwa kwawo neziphetho zawo, futhi uphendulwa ngaphansi kobufakazi bezokwelapha nge-Alzheimer kunalapha.