Shuɗin methylene, tau, da amyloid: dalilin da hanyoyin kawar da furotin suka bambanta

Idan ka tambayi abin da shuɗin methylene yake yi wa furotin na cutar Alzheimer, za ka ji amsa guda mai cikakken tabbaci a inda ya kamata ka ji amsoshi uku masu iyakoki. A cikin bututun gwaji, yana hana tau manne wa juna. A wani samfurin gwaji na beraye, yana rage amyloid mai narkewa amma ba ya canza tau. A wani kuma, yana rage aikin enzayim ɗin da yake samar da amyloid tun farko. Kowanne daga cikin waɗannan sakamakon gaskiya ne. Babu wanda ya ƙunshi dukan bayanin, kuma ba dukansu suke faruwa a dabba ɗaya a lokaci ɗaya ba. Wannan maƙala ta ware waɗannan hanyoyi uku domin a daina ambaton sakamakon wani gwaji a matsayin hujjar wani dabam.

Masu karatu da suke son cikakken bayani game da yadda shuɗin methylene yake aiki a cikin ƙwayoyin halitta su fara daga can. Masu son sanin ko wani daga cikin waɗannan ya taimaka wa marasa lafiya su karanta bayanan gwaje-gwajen asibiti kan cutar Alzheimer, domin a can ne sakamakon gwaje-gwajen mutane yake. Babu abin da ke cikin wannan maƙala da yake maimaita waɗannan bayanan.

Sakamakon tau ya shafi gwaje-gwajen tattaruwar furotin

Mafi daɗewa daga cikin waɗannan bayanai uku ya fito ne daga binciken tau da aka yi ba tare da ƙwayoyin halitta ba. Tau shi ne furotin da yake samar da dunƙulallun zaren jijiya. A gwajin haɗuwar tau da tau, gutsattsarin tau suna haɗuwa su zama zaruruwa masu karkacewa da suke tafiya bibbiyu, kuma rini na phenothiazine, ciki har da shuɗin methylene, suna hana wannan haɗuwar a ƙananan matakan taro na micromolar. Binciken ilimin sinadarai na halittu da aka yi daga baya ya ba da bayanin sinadaran da ke jawo hakan: rinin yana oksidantar da ragowar cysteine da ke kan tau, wanda yake tabbatar da zaman tau a matsayin guda ɗaya kuma yana hana ƙananan zaruruwan da da za su girma. Matakan taron da aka ruwaito suna hana tattaruwar tau suna kusan daga micromolar mai lamba guda zuwa farkon gomomin micromolar, iyaka da take da muhimmanci ga duk abin da zai biyo baya.

Ka lura da irin da'awar da ake yi a nan. Ba ta faɗi komai game da samar da tau, ƙara rukunin phosphate ga tau a cikin kwakwalwa mai rai, ko kawar da tau ba. Tana cewa, a ƙarƙashin ƙayyadaddun yanayi a cikin bututun gwaji, rinin da aka oksidantar yana hana tau taruwa a kan juna. Wannan sakamako ne takamaimai, mai iyaka, kuma mai amfani. Matsala tana farawa idan aka faɗaɗa shi zuwa da'awar cewa shuɗin methylene yana kawar da sauye-sauyen cuta da tau yake jawowa, domin bayanan gwaje-gwajen dabbobi ba su goyi bayan wannan fassarar ba.

Sakamakon proteasome ya shafi berayen 3xTg-AD, kuma ya nuna bambanci tsakanin amyloid da tau

Gwajin da ya fi bayyana bambancin sakamakon abubuwan da aka auna shi ne binciken ciyarwa na makonni 16 a berayen da suke ɗauke da sauye-sauyen kwayoyin gado uku masu alaƙa da Alzheimer. Dabbobin sun ci abincin da yake ɗauke da shuɗin methylene tun daga lokacin da shekarunsu suka kai watanni shida, kuma masu binciken sun auna abubuwa uku lokaci guda: proteasome, matakan amyloid, da tau.

Aikin proteasome ya canza. Aiki mai kama da na chymotrypsin ya ƙaru da kusan kashi ɗaya bisa huɗu, kuma aiki mai kama da na trypsin ya ƙaru da kusan rabi, amma aiki na uku na hanzarta halayen sinadarai bai canza sosai ba. Amyloid-beta 40 da 42 masu narkewa kowannensu ya ragu da kusan kashi ɗaya bisa huɗu. Marubutan sun fassara wannan a matsayin ƙaruwa wajen kawar da amyloid maimakon raguwar samar da shi, domin furotin na farko da ake samar da amyloid daga gare shi da gutsattsarin da sarrafa shi yake haifarwa ba su canza ba, kuma koyo da ƙwaƙwalwa sun inganta a gwajin tantancewa na hanyar ruwa mai sarƙaƙiya.

Sai kuma abubuwan da ba su canza tare da waɗancan ba. Amyloid marar narkewa bai canza ba. Gwajin rini don gano tarin amyloid bai canza ba. Jimillar tau na ɗan Adam da phospho-tau a threonine 181 ba su canza ba, kuma kasancewar tau a wuraren da ba nasa ba bai canza ba. Ma'aunan mitochondria su ma ba su canza ba: babu wani gagarumin tasiri kan aikin cytochrome-c oxidase, kan furotin na oxidase, ko kan ATP. Don haka, a wannan samfurin gwaji da wannan tsarin bayarwa, shuɗin methylene ya ƙara biyu daga cikin ayyukan proteasome uku, ya rage amyloid mai narkewa, ya gyara sakamakon ma'aunin hali, kuma ya bar ma'aunan tau, amyloid marar narkewa, da ma'aunan mitochondria da aka gwada yadda suke.

Wani abin lura yana ƙara fayyace wannan batu maimakon raunana shi. Waɗannan berayen ba su riga sun samar da tarin tau ba a shekarun da aka gwada su, don haka gwajin ba zai iya nuna cewa shuɗin methylene ba ya aiki kan dunƙulallun tau ba. Yana nuna cewa amyloid mai narkewa zai iya raguwa alhali ma'aunan tau da aka auna ba su canza ba. Wannan shi ne irin sakamakon da wannan batu yake buƙata: furotin ɗaya ya canza, wani bai canza ba. Idan ka zo nan da tunanin cewa kunna proteasome da shuɗin methylene yake yi yana kawar da manyan furotin biyu da suke alamomin cutar tare, wannan binciken ya gyara wannan fahimta.

Sakamakon samar da amyloid ya shafi tsofaffin berayen PSAPP, kuma ya saɓa wa hanyar aiki ta baya

Wata ƙungiya dabam, wani samfurin gwaji dabam, da bayani mai kishiyar na baya game da matakin farko na hanyar aiki. A binciken watanni uku na bayar da abu ta bututu zuwa ciki a berayen PSAPP masu watanni 15, adadin 3 mg/kg da aka bayar ta baki kowace rana ya rage tarin amyloid a sassan kwakwalwa da kusan kashi ɗaya bisa uku zuwa rabi, kuma ya rage nau'o'in amyloid da dama, ciki har da oligomers da aka auna da gwajin da aka keɓe musu. Amma a nan, hanyar aiki da aka gabatar ita ce rage samarwa, ba hanzarta kawarwa ba: furotin BACE1 na kwakwalwa ya ragu, abin da yake samarwa, C99, ya ragu, amma RNA mai ɗaukar saƙo bai ragu ba. Wannan yana nuna tasiri a matakin furotin maimakon raguwar aikin bayyana kwayoyin gado.

Binciken ƙwayoyin halitta ya ƙarfafa wannan bayani. A gwajin da ba ya ƙunshe da ƙwayoyin halitta, wanda aka yi da enzayim da aka samar ta hanyar haɗa DNA, shuɗin methylene ya hana aikin BACE1 kai tsaye. A ƙwayoyin ƙwai na hamster da suke samar da furotin na ɗan Adam da ake samun amyloid daga gare shi, amyloid 40 da 42 da aka fitar sun ragu a matakan taro masu ƙaranci har zuwa 1.56 micromolar, yayin da furotin na farko da ake samar da su daga gare shi bai canza ba. Kwatanta wannan da binciken da ya gabata, inda gutsattsarin sarrafa furotin na farko ba su canza ba, kuma aka danganta sakamakon da kawar da amyloid. Dukansu ba za su iya bayyana hanya guda ta aiki da take faruwa a kowane yanayi ba, domin samfuran gwaji, shekaru, adadin da aka bayar, hanyoyin bayarwa, da tsawon lokacin gwaji sun bambanta. Wannan shi ne babban batu. Tasirin shuɗin methylene kan amyloid yana faruwa ta hanyar samarwa a wani tsarin gwaji, kuma ta hanyar kawarwa a wani. Ambaton ɗayansu ba tare da tsarin gwajin da ya fito daga gare shi ba yana ɓatar da fahimta.

Hanyar sinadarai ɗaya, abubuwan da ake shafa da dama: alaƙar oksidantar da cysteine

Wani layin bincike na uku yana bayyana yadda hanyar sinadarai guda ta redox za ta iya bayyana a binciken furotin da ba su da alaƙa da juna. A binciken ilimin sinadarai na halittu kan hana aikin caspase, shuɗin methylene ya kashe aikin caspase-6 ta hanyar oksidantar da cysteine ɗinsa mai gudanar da aikin enzayim zuwa sulfenic acid. An tabbatar da hakan ta hanyar auna sinadarai bisa nauyi, tare da matakin taron da yake haifar da rabin mafi girman tasiri kusa da 10.6 micromolar. An hana aikin caspase-3 a makamancin matakin taro. Marubutan sun danganta wannan kai tsaye da wallafe-wallafen tau: hanyar sinadarai ɗaya ta oksidantar da cysteine da aka gabatar a matsayin abin da yake riƙe tau a matsayin guda ɗaya tana iya kashe aikin protease mai dogaro da cysteine, kuma matakan taron da suke haifar da tasiri suna cikin iyakoki masu haɗuwa.

Wannan bayani yana da armashi, amma kuma gargaɗi ne. Kwayar sinadari mai aikin redox da take oksidantar da cysteine da yake a buɗe za ta shafi fiye da abu ɗaya a duk wani matakin taro da yake aiki. Bayanin warware tarin tau, bayanin caspase, da wataƙila wasu, suna da aikin sinadarai guda ɗaya amma abubuwan da aikin yake shafa sun bambanta. Raba wannan aikin ba ya sa a iya maye gurbin wani sakamako da wani. Yana nufin cewa adadin da aka bayar da yanayin gwaji su ne suke ƙayyade abin da tasirinsa ya fi muhimmanci. Haka kuma, bayarwa na dogon lokaci da aka nufa zuwa wani tsari mai dogaro da cysteine na iya shafar wasu, batun da marubutan binciken caspase suka ambata kai tsaye. Tambayoyi masu alaƙa game da yadda aikin redox na shuɗin methylene yake zaɓar abubuwan da yake shafa, abin da kunna proteasome yake nufi ga sauran furotin da suka tattaru, da ko bayarwa na dogon lokaci yana canza jerin abubuwan da ake shafa kowannensu ya cancanci bayanin kansa.

Hanyar aiki bisa abin da aka auna: wane sakamako ya shafi wane samfurin gwaji

Ka karanta teburin layi bayan layi, kuma darasin zai bayyana. Babu wani layi guda da ya canza a kowane ginshiƙi. Sakamakon da ya fi ƙarfi kan samar da amyloid ya fito ne daga binciken da bai taɓa gwada proteasome ba. Sakamakon da ya fi ƙarfi kan proteasome ya fito ne daga binciken da sarrafa furotin na farko bai canza ko kaɗan ba. Sakamakon tau yana kasancewa galibi a bututun gwaji da kuma a hanyar sinadarai da yake rabawa da enzayim da ba su ne aka nufa ba. Duk wanda ya haɗa waɗannan ginshiƙai ya mayar da su da'awa guda, cewa shuɗin methylene yana kawar da furotin masu alaƙa da cuta a matsayin rukuni, yana rubuta bitar gwajin da ba a taɓa yi ba.

Wannan tsantseni ya shafi marasa lafiya ma. Ko waɗannan hanyoyin aiki suna haɗuwa su haifar da amfani a asibiti wata tambaya ce dabam, mai nata gwaje-gwaje da nata hukunce-hukuncen sakamako. Ana amsa ta a ƙarƙashin hujjojin asibiti kan Alzheimer, ba a nan ba.