Imethylene blue xa ithelekiswa neendlela ze-NAD+: iindlela zokusebenza, ubungqina, namabango okuzidibanisa

Imethylene blue nezongezelelo ezithengiswa njengezinyusi ze-NAD+ zombini zichazwa kusetyenziswa amagama athi iimitokondriya namandla eeseli. Akukho nanye kwezo nkcazelo ikuxelela ukuba imveliso yenza ntoni kanye kanye.

Ezi ndlela zimbini zisebenza kwizinto ezahlukeneyo eziguqukayo. Enye izama ukutshintsha ubungakanani be-NAD+ kwiiseli zakho. Enye itshintsha umlinganiselo phakathi kweemo zayo ezimbini. Ezi asizondlela zimbini zisiya kwindawo enye.

Amanani amabini ahlala ebhidaniswa

I-NAD+ yicoenzyme. Yamkela isibini seelektroni, ezikwimo yeayoni yehydride, ize ibe yi-NADH. Xa i-NADH idlulisela ezo elektroni phambili, iphinda ibe yi-NAD+. Iiseli zisebenzisa lo mjikelo rhoqo: yindlela amandla athathwe ekutyeni afikelela ngayo koomatshini beeproteni abavelisa i-ATP.

Ngenxa yokuba i-NAD+ ne-NADH ziimo ezimbini zemolekyuli enye, kukho imilinganiselo emibini eyahlukeneyo ekufanele ilandelwe kwiseli. Owokuqala bubungakanani obupheleleyo: ukuba ingakanani i-NAD+ ne-NADH xa zizonke. Owesibini ngumlinganiselo phakathi kwazo, ochaza ukuba abathwali bee-elektroni balayishwe kangakanani ngelo xesha.

Idama lamanzi lenza lo mahluko ucace. Umthamo wamanzi emva kodonga lwedama bubungakanani obupheleleyo. Ukwahlulwa kwamanzi phakathi kwalawo agcinwe ngasentla nalawo akhutshwa ngasezantsi ngumlinganiselo. Ungawunyusa loo mlinganiselo ngaphandle kokongeza ilitha, ngokuvula isango. Lo asingomzekeliso wento eyenziwa yimethylene blue. Usondele ngakumbi kwinkcazelo yoko kwenzeka ngokwenene.

Indlela yokwandisa ubonelelo

Izongezelelo zezandulela ze-NAD+, eziquka i-nicotinamide riboside, i-nicotinamide mononucleotide, ne-nicotinamide, zizinto zokwakha. Iiseli zakha i-NAD+ ngenkqubo yokuphinda kusetyenziswe izinto ebizwa ngokuba yindlela yokubuyisela nokuphinda kusetyenziswe, kwaye izandulela zingeniswa kuyo. Injongo kukwandisa ubungakanani obupheleleyo.

Kwizilwanyana, oku kusekwe kakuhle: i-NAD+ kwizicubu iyehla ngokukhula kweminyaka nangesifo semetabolism kwiimodeli ezininzi, kwaye ukondla izandulela kudla ngokuyinyusa. Ebantwini, ubungqina bunemida engaphezulu. Uvavanyo ebantwini lubonisa ukuba ezi khompawundi zinyusa amanqanaba e-NAD+ alinganiswa egazini. Into olungakhange luyivelise kukuphucuka okungaguquguqukiyo kwisiphumo seklinikhi, okuthetha izinto umntu anokuziqaphela okanye uvavanyo oluyilelwe ukuzilinganisa.

“Amanqanaba e-NAD+ anyukile” kulinganisa into engaphakathi emzimbeni. Ayisosiphumo esichaza indlela umntu azive ngayo, ahambe ngayo, okanye achache ngayo.

Into eyenziwa yimethylene blue endaweni yoko

Imethylene blue ayisosandulela. Yidayi yeredox, ekudala isetyenziswa kwezamayeza ngaphezu kwenkulungwane, kwaye ukusetyenziswa kwayo okugunyazisiweyo kumxinwa kunoko kuphandwayo.

Ngaphakathi kwiseli, ii-enzayim ezixhomekeke kwiflavin ziyinciphisa ibe yimo engenambala, i-leucomethylene blue, ethi emva koko iphinde ifakwe kwi-oxidation. Iielektroni ebeziza kudlula kwikhompleksi I, indawo yokuqala kwikhonkco lokuphefumla kweseli zinokukhutshwa kwi-NADH ngemethylene blue endaweni yoko. I-NADH iba yi-NAD+.

Umlinganiselo uyenyuka. Ubungakanani obupheleleyo abukhuli.

Uphononongo lweempuku kwintliziyo enesifo seswekile lwalinganisa oku ngokuthe ngqo kwiimitokondriya zentliziyo ezahluliweyo. Ukongeza imethylene blue kumanqanaba ukusuka ku-6 ukuya ku-18 micromolar ngexesha le-oxidation yeeasidi ezinamafutha kwabangela ukuhla kwe-NADH nomlinganiselo we-NADH ukuya kwi-NAD+, okwakuxhomekeke kumthamo. Ubungakanani obupheleleyo be-NAD+ basabela kancinane kakhulu kune-NADH, nto leyo obunokuyilindela kwikhompawundi eguqula enye imo ibe yenye endaweni yokuvelisa ezingaphezulu kuyo nayiphi na kwezi mo.

Indawo ezifika kuyo ezo elektroni ibalulekile. Kwiimitokondriya zobuchopho ezahluliweyo, imethylene blue kumanqanaba e-100 nanomolar ukuya ku-1 micromolar yaphucula ukuveliswa kwamandla xa ikhonkco lokuphefumla lalithintelwe, yaza kwangaxeshanye yandisa ukuveliswa kwehydrogen peroxide ngoxa inciphisa ukususwa kwayo, kuzo zonke iimeko ezavavanywayo. Ababhali bachaza ukuba ihydrogen peroxide ivela ekuncitshisweni kweoksijini ngokuthe ngqo yimethylene blue esele incitshisiwe. Iielektroni eziphuma kwi-NADH ngale ndlela azinyamalali. Zifika kwioksijini.

Uphononongo olwahlukileyo kwizicubu zomthambo we-Achilles luyicacisa kakuhle le ngongoma. Imethylene blue yabuyisela ulungelelwano lwe-NAD+/NADH yaza yanyusa ukuveliswa kwe-ATP kwiiseli zemithambo ezonzakeleyo nakwimodeli yeempuku yesifo semithambo, kwaye iphepha lophando libhala ukuba ubungakanani obupheleleyo be-NAD abuzange butshintshe ngokuphawulekayo.

Oko kusekwa luvavanyo lwezicubu nezilwanyana

Uvavanyo olune olwenziwa kumashumi amane eminyaka lulandela ingcamango enye kwaye lubonisa imida yayo ngokuphindaphindiweyo.

Ekondliweni kweempuku utywala ixesha elide, i-ethanol yehlisa imilinganiselo ye-NAD+/NADH kwisibindi, kwi-cytosol nakwiimitokondriya. Ukongeza imethylene blue ekutyeni kwaluthintela ubukhulu becala olo tshintsho. Akuzange kunciphise ukuqokelelana kwamafutha kwisibindi okwabangelwa yi-ethanol. Ukulungisa umlinganiselo akuzange kulungise isiphumo. Eso siphumo sika-1985 sifanele sikhunjulwe phambi kwalo naliphi na ibango lokuba utshintsho lweredox yindlela evelisa inzuzo.

Kwiiseli zesibindi nakwiimpuku ezazisitya ukutya okunamafutha amaninzi, imethylene blue yanyusa umlinganiselo we-NAD+/NADH, yandisa i-SIRT1, yanciphisa ukufakwa kwamaqela e-acetyl kwi-PGC-1alpha, yavuselela i-AMPK, yaza yanciphisa ukuqokelelana kwamafutha kwisibindi. Apha isiphumo satshintsha kunye nomlinganiselo. Eli phepha linye libonisa ukuba isiphumo asihambi kwicala elinye rhoqo: iimiligram ezintathu ngekilogram ngosuku zandisa ubungakanani be-DNA yeemitokondriya ngempumelelo engaphezulu kuneshumi, ngoxa ukusetyenziswa kweoksijini nokudluliswa kwemiqondiso ye-AMPK kwanyuka ngokunyuka komthamo.

Kwintliziyo enesifo seswekile, imethylene blue enikwe emanzini okusela kangangeeveki ezilishumi elinanye yehlisa umlinganiselo we-NADH ukuya kwi-NAD+ kwiimitokondriya zentliziyo yaza yanyusa ukusebenza kwe-sirtuin 3. Ukufakwa kwamaqela e-acetyl kwi-lysine kwehla kwiindawo ezingama-83 kwiiproteni ezingama-34, ingakumbi kwezo zithutha ii-asidi ezinamafutha nezenza i-oxidation yazo. Umlinganiselo wegazi elimpompelwa ngaphandle yintliziyo waphucuka. Kodwa ukuphefumla okuxhaswa yikhompleksi I akuzange kulungiswe. Kwaye uvavanyo lokucima ufuzo lwahlula iziphumo ezibini ekulula ukuzibhidanisa: utshintsho lomlinganiselo lwenzeka ubukhulu becala ngaphandle kwe-sirtuin 3, ngoxa ukususwa kwamaqela e-acetyl kwakuxhomekeke kuyo.

Kuphononongo lwemithambo, imethylene blue yasetyenziswa ngoxa ikhompleksi I yayivaliwe ngokwekhemikhali nge-rotenone. Yaphinda yabuyisela ulungelelwano lwe-NAD+, kodwa yaphinda yasilela ukuthintela uxinzelelo lwe-oxidation, ukuwohloka kwezinto ezixhasa iiseli, nokulahleka kokukwazi kweeseli ukuhlala ziphila. Ukubuyisela umlinganiselo kwakunganelanga ukuba izicubu zichache.

Iphepha elinokuprintwa elineembekiselo ezipheleleyo lisebenzisa imiqolo efanayo.

Kutheni iisirtuin zifakwa kule ngxoxo

Iisirtuin zisusa amaqela e-acetyl kwiiproteni, kwaye zisebenzisa i-NAD+ ukwenza oko. Ukusebenza kwazo kusabela ekufumanekeni kwe-NAD+, ngoko nayiphi na ikhompawundi etshintsha ukufumaneka kwayo itshintsha nokusebenza kweesirtuin okulandela oko.

Le yintsika uninzi lwentengiso ethi “imethylene blue ye-NAD+” luxhomekeke kuyo. Ikwalapho ukucinga kulahleka khona. Ukutshintsha umlinganiselo kunokunyusa ukusebenza kweesirtuin. Oko akuthethi ukuba imveliso ibonelela nge-NAD+, kwaye akuthethi ukuba isiphumo siyafana nokuthatha isandulela. Ukutolikwa kwale milinganiselo ngokweredox kunezako iingxaki ezinokukhokelela kwimpazamo ekufanele ufunde ngazo ngaphambi kokwamkela nayiphi na kwezi ndlela zokuyichaza.

Oko kuvavanywe ebantwini

Imethylene blue inamashumi eminyaka isetyenziswa eklinikhi kwiimeko ezingxamisekileyo ezibekwe esweni: i-methemoglobinemia, ubuthi obuchaphazela inkqubo yemithambo-luvo obunxulumene ne-ifosfamide, noxinzelelo lwegazi oluphantsi kakhulu ngexesha lotyando. Ezi ziindlela zokusetyenziswa ezinomda nezijongwayo, hayi ubungqina bokuyithatha ngomlomo mihla le njengoncedo lokuphucula indlela umntu asebenza ngayo.

Uphando olwenzelwe eli nqaku alufumananga phononongo ebantwini olulinganisa iimveliso zemetabolism ye-NAD+ emva kokunikwa imethylene blue kumavolontiya asempilweni. Iziphumo ezingasentla zivela kwiimitokondriya ezahluliweyo, kwiiseli ezikhuliswe elebhu, kwizicubu zeempuku, nakwizicubu zabantu ezikhutshiweyo. Umthambo okhutshiweyo ogcinwe uphila kwisitya selabhoratri linyathelo eliluncedo elingaphezulu kokusebenzisa nje udidi lweeseli ezikhuliswa elebhu. Sekunjalo, ayingomntu.

Uncwadi lophando ngezandulela ngokwenene lolwabantu, kwaye iziphumo zalo zithobekile. I-NAD+ egazini iyenyuka. Iziphumo zeklinikhi zixubekile kwaye ngokubanzi zincinci.

Ngoko ibango lokuzidibanisa liphakamisa umbuzo ofanelekileyo onempendulo enganelisiyo: akukho phononongo lupapashiweyo, uvavanyo, okanye uthotho lweengxelo zeemeko olufunyenwe ngeli nqaku oluvavanye imethylene blue kunye ne-nicotinamide riboside, i-nicotinamide mononucleotide, okanye ukufakwa kwe-NAD+ ngomthambo. Nabani na ochaza ukuba ukudibanisa ezi zinto kuxhaswa bubungqina, okanye ukuba zisebenzisana ukwandisa isiphumo, uthatha izigqibo ezidlula oko kuboniswe ngamaqela amabini ahlukeneyo obungqina.

Ukuthatha izigqibo ezinjalo kunokusilela kumacala omabini. Kunokuba nethemba eligqithisileyo, ukuba ubungakanani obupheleleyo bebungaseyiyo into ebeka umda emva kokubuyiselwa komlinganiselo. Kunokuba lula ngokugqithisileyo, kuba imethylene blue inolwalamano phakathi komthamo nesiphumo olutshintsha indlela oluhamba ngayo. Abaphandi bayo bayichaza njengekhompawundi ene-hormesis: amanqanaba asezantsi akhuthaza ukuncitshiswa, ngoxa amanqanaba aphezulu ethumela iielektroni kwenye indlela kude nekhonkco lokuphefumla kwaye enokukhuthaza i-oxidation. Ukongeza into engaphezulu ekusetyenzwa kuyo akulwenzi olo lwalamano lukhuseleke ngakumbi.

Kukwakho iinkxalabo ngokusebenzisana kwayo nezinye izinto ezingenanto yakwenza ne-NAD+. Imethylene blue ithintela i-monoamine oxidase A, nto leyo ebangela ukuba ibe nomngcipheko onxulumene ne-serotonin xa isetyenziswa kunye namayeza athile okudakumba; uphononongo lweengxelo zobuthi kwinkqubo yemithambo-luvo ephakathi lwafumanisa ukuba iimeko ezili-13 kwezili-14 zazihlangabezana nemiqathango ye-Hunter yobuthi be-serotonin. Isenokubangela i-methemoglobinemia xa umntu efumana amanqanaba aphezulu ayo. Ukuba uthatha amayeza abhalwe ngugqirha, umbuzo ngokudibanisa ekufanele uwubuze kugqirha wakho umalunga nezo ndlela zokusebenza, hayi ngolungelelwano lweredox. Ukucinga ngononophelo okufanayo kuyasebenza nakwindibaniselwano eziqhelekileyo: ezinye izongezelelo ezithathwa kunye nemethylene blue zinesiseko sazo sobungqina, ubukhulu becala esingekavavanywa.

Kutheni ubunyulu bugqiba ukuba loluphi uvavanyo olwenzayo ngokwenene

Imveliso yemethylene blue ngumxube de ilabhoratri ingqine okwahlukileyo. Ukungcola okubalulekileyo apha yi-Azure B, i-phenothiazine esuswe iqela le-methyl engengonto ingasebenziyo. Yidayi esebenzayo kwiredox enesiseko esifanayo sekhemistri yombane, ngoko imveliso equlethe ubungakanani obubalulekileyo be-Azure B ayilohlobo olucocekileyo okanye olungcole ngakumbi longenelelo olufanayo. Ngumxube owahlukileyo osebenza kwindlela enye, ngomlinganiselo ongekho mntu uwuchazileyo.

Umgangatho we-USP yindlela umthengi afumana ngayo into echazwe ngokucacileyo. Imveliso engekho kumgangatho we-USP kusenokwenzeka kakhulu ukuba yidayi yomgangatho wamalaphu, kwaye loo migangatho inezinto ezingcolisayo ezenza ingafaneleki ukusetyenziswa emzimbeni, kuquka izinyithi ezinzima nezinyibilikisi ezishiyekileyo.

Umsantsa awukho phakathi kwemigangatho kuphela. Abathengisi abaninzi abathi bayahambelana ne-USP bavavanya izinyithi ezinzima kuphela, baze babonise loo seti yovavanyo inye njengobungqina bokuthobela ngokupheleleyo. Inkcazelo epheleleyo yomgangatho ibandakanya ukuqinisekiswa kokuba yintoni into, ubunyulu, ukungcola okuvela kwiikhompawundi zekhabhoni, izinyibilikisi ezishiyekileyo, ukungcola kweziqalelo, intsalela emva kokutshiswa, imida yeentsholongwane, nee-endotoxin zebhaktheriya. Iseti yovavanyo engaphelelanga ayinakungqina nantoni ngezinto ezishiyiweyo, kwaye ezo zinto zishiyiweyo ziquka izinto ezinxulumeneyo neentsalela zezinyibilikisi.

Blupreme ithenga kumvelisi wemethylene blue wamayeza kwaye ipapasha isatifikethi sohlalutyo esibandakanya inkcazelo epheleleyo yomgangatho, ukuze into esebhotileni ibe yile ichazwa luphando. Ukuba ufuna ukujonga ingqiqo ngokwakho ngaphambi kokuthenga, indlela yokufunda uphando lwemethylene blue ichaza oko uhlobo ngalunye lophononongo lunokukubonisa nelingakwaziyo ukukubonisa.

Umahluko osahlala ucacile emva kokuhlolwa ngononophelo

Ukongeza isandulela se-NAD+ kutshintsha ukuba ingakanani i-NAD+ ekhoyo. Imethylene blue itshintsha into eyenziwa yi-NAD+ esele ikhona. Eyokuqala ngumbuzo wobonelelo, eyesibini ngumbuzo wokuqukuqela, kwaye uvavanyo oluxhasa enye luthetha kancinane ngenye.

Into exhasa imethylene blue yindlela yokusebenza ehambelanayo, eqinisekiswe kwiimitokondriya ezahluliweyo nakwizicubu zezilwanyana, kunye nomda ocacileyo nophindaphindiweyo: ukutshintsha umlinganiselo akufani nokulungisa izicubu. Into esilela kuyo luvavanyo ebantwini olulinganisa isiphumo sayo kwi-NAD+ ebantwini. Into engekho kulo naliphi na kula macandelo luvavanyo oluthe ngqo lwezi zimbini zithathwa kunye.

Omabini la macandelo afanele ukuphathwa ngendlela efanayo. Buza ukuba yeyiphi into eguqukayo imveliso ethi iyayitshintsha, uze ubuze ukuba yeyiphi imilinganiselo yaloo nto ekhoyo ebantwini. Xa impendulo iluphononongo lweeseli, impuku, okanye indlela yokusebenza ebonakala isengqiqweni, yiloo nto kanye eyiyo. Ayiyondibaniselwano yezongezelelo.