Isihloko
I-Methylene Blue Nesifo Sikashukela: Kuchazwa Ukuthuthwa Kweglucose Nocwaningo Lwezilwane
Umbuzo obangelwa ukudunyiswa ngokweqile
Leso siphetho sizwakala sinengqondo, kodwa sisekelwe endleleni engalungile yokucabanga. Siphatha imiqondo emithathu ehlukene njengokungathi iyinto eyodwa: ukungena kweglucose kuseli elilodwa esitsheni socwaningo, ukuguqulwa kwezakhamzimba zibe amandla ngaphakathi kwe-mitochondrion yenhliziyo, kanye nokulawulwa kweglucose emzimbeni womuntu wonke. Ngamunye unezilinganiso nemikhawulo yawo. Lesi sihloko siyayihlukanisa.
Impendulo emfushane: i-methylene blue iyakuvuselela ukuthuthwa kweglucose ohlotsheni olulodwa lwamaseli olucwaningwe kahle, futhi iyayiguqula imisebenzi yamakhemikhali kuma-mitochondria nezinye izilinganiso zenhliziyo emagundaneni anesifo sikashukela. Kodwa ocwaningweni lwamagundane olwathatha isikhathi eside kunazo zonke ayizange iguqule iglucose ngesikhathi sokuzila ukudla noma i-hemoglobin eboshwe neglucose, futhi abukho ubufakazi obushicilelwe kubantu obubonisa ukuthi i-methylene blue esebenza emzimbeni wonke ithuthukisa ushukela wegazi, i-HbA1c, noma i-insulin kubantu abanesifo sikashukela.
Amaseli: ukungena kweglucose okusheshayo ngamaprotheni athuthayo asevele ekulwelwesini
Abacwaningi basebenzisa ama-fibroblast e-L929, uhlobo lwamaseli lapho ukungena kweglucose kuncike eprotheni elilodwa eliyithuthayo, i-GLUT1. Uma kukhona iphrotheni elilodwa kuphela elithuthayo, noma yiluphi ushintsho ekungeneni kweglucose kufanele luvele kulelo phrotheni.
Lapho iqembu lifaka i-methylene blue kulawa maseli, ukungena kweglucose enophawu lokulandela umkhondo kwakhula phakathi nemizuzu engu-10 futhi kwakhula ngokwenani elisetshenzisiwe, kwafinyelela cishe kumaphesenti angu-800 esilinganiso sokuqala ku-50 micromolar imizuzu engu-45. Imininingwane yesivinini sokuthutha ibalulekile: isivinini esiphezulu (Vmax) sakhula kuyilapho amandla okubopha iglucose (Km) nenani leprotheni i-GLUT1 kungashintshanga. Inani elifanayo leminyango lavumela iglucose eningi ukuba idlule ngomzuzu ngamunye. Udayi wavuselela amaprotheni athuthayo ayesevele ekulwelwesini kunokuba wengeze amasha.
Izivivinyo zokuqhathanisa zicacisa isithombe. Uhlobo olwamukele ama-electron (olungenambala) alwenzanga lutho. Into ebangela i-oxidation ngaphandle kweseli eyavimba udayi ukuba ungangeni yavimba kokubili ukufakwa kombala nokuvuselelwa. Izivimbeli zezindlela ze-AMP kinase ne-PI kinase aziguqulanga lutho, okuyinto ephikisana nokuthi lezi zindlela ezimbili ezaziwayo zokudlulisa izimpawu ziyabandakanyeka.
Ukuqagela kokuqala kwakuwukujikeleza kwe-redox: udayi udlulisa ama-electron, ubeke iseli ngaphansi kwengcindezi encane, bese amaseli acindezelekile evula amasango eglucose. Ucwaningo olwalandela lwahlola lowo mqondo. Abacwaningi basebenzisa i-methyl-beta-cyclodextrin, i-molecule emise okwendandatho ebamba i-methylene blue ngaphakathi kwesakhiwo esiyinhlanganisela (isilinganiso esingaguquki sokuhlangana sasiseduze no-310 M-1). Udayi obanjiwe awuzange ufake amaseli umbala noma uvuselele ukungena kweglucose, futhi ukususwa kukadayi ngokugeza kwahambisana eduze nokuphela komphumela. Isiphetho sabo saphikisana nencazelo ye-redox: ukuvuselelwa cishe kuvela ekusebenzisaneni okuqondile kukadayi nephrotheni elithile endleleni yokuvuselela i-GLUT1, hhayi ekucindezelekeni okuvamile okubangelwa i-oxidation.
Umgomo wokusebenza unomkhawulo omncane. I-methylene blue ingavuselela ngokushesha ukungena kweglucose nge-GLUT1 kumaseli e-L929, futhi lowo mphumela ungabuyiselwa esimweni sokuqala, ngokungena kwayo kuseli nokusebenzisana nephrotheni. Lokhu akusho lutho nge-insulin, amanyikwe, noma ushukela wegazi esilwaneni esiphilayo. Ukuze uqonde indima kadayi njengomthwali wama-electron, bheka indlela i-methylene blue esebenza ngayo njengomthwali wama-electron. Ukuze uthole imithetho yokufunda ucwaningo lwamaseli, bheka indlela yokufunda ucwaningo lwe-methylene blue.
Amagundane anesifo sikashukela: izinhliziyo zaguquka, ushukela wegazi awuguqukanga
Ucwaningo lwezilwane ludlulela komunye umqondo: inhliziyo enesifo sikashukela. Zombili izifundo zamagundane zasebenzisa i-streptozotocin, ubuthi obubhubhisa amaseli e-beta akhiqiza i-insulin bese budala isimo esifana nesifo sikashukela sohlobo 1. Abafundi abafuna ulwazi nge-methylene blue nesifo sikashukela sohlobo 2 kufanele bakuqaphele lokhu kungahambisani zisuka nje. Lezi akuzona izilwane ezinesifo sohlobo 2.
Ocwaningweni lwesikhathi eside, amagundane esilisa ohlobo lwe-Lewis athola 10 mg nge-kg ngosuku emanzini okuphuza amasonto angu-11, kanye namanani amancane e-insulin ukuze kuvinjelwe ukuwohloka komzimba ngaphandle kokubuyisela iglucose ezingeni elijwayelekile. Kuma-mitochondria enhliziyo, udayi wasiza ekwenzeni i-oxidation ye-NADH, wakhuphula i-NAD+, futhi wakhulisa ukusebenza kwe-Sirtuin 3 deacetylase. Ukuhlaziywa kwamaprotheni kwathola ukuncipha kokufakwa kwamaqembu e-acetyl ezindaweni ezingu-83 kumaprotheni angu-34 e-mitochondria abandakanyeka ku-oxidation yamafutha, umjikelezo we-citric acid, nokuthuthwa kwama-electron. I-oxidation yamafutha anamaketanga amade nokusebenza kwe-hydroxyacyl-CoA dehydrogenase kwehla, okwathathwa njengokuncipha kokuthembela ngokweqile nangokungaguquguquki emafutheni kwenhliziyo enesifo sikashukela. Izilinganiso zomthamo wegazi enhliziyweni nengxenye yegazi ekhishwa yinhliziyo zathuthuka, futhi inkomba yokukhula ngokweqile kwemisipha yenhliziyo yabuyela ezingeni elijwayelekile, nakuba umfutho nesivinini sokufinyela kwahlala kuphansi.
Nawu umphumela obaluleke kakhulu: izinga likashukela egazini aliguqukanga. Iglucose ngesikhathi sokuzila ukudla nangesikhathi sokungazili yahlala iphezulu, i-HbA1c yahlala iseduze namaphesenti angu-5.6 kokubili emagundaneni anesifo sikashukela ayelashwa nangayelashwa, kungekho mphumela wokwelashwa ophawulekayo ngokwezibalo. Udayi wehluleka futhi ukulungisa ukungasebenzi kahle kokuphefumula kwe-complex I ne-II kuma-mitochondria ahlukanisiwe. Ukusebenza kwenhliziyo kwathuthuka kwezinye izilinganiso kuyilapho ukulawulwa kweglucose nenkinga eyisisekelo yokuphefumula kungathuthukanga. Imiphumela ehlukene yahlala ihlukene.
Ucwaningo lwesibili lwalugxile ezingeni elincane: ama-mitochondria ahlukaniswe ezinhliziyweni ezinempilo nasezinhliziyweni ezazinesifo sikashukela izinyanga ezimbili, anikezwa inani elincane elilodwa elingu-0.1 micromolar ngesikhathi sokulinganisa. Ukusetshenziswa komoyampilo kwakhula ngezinto ezisetshenziswa yi-complex I ne-II ngokufanayo. Kodwa ukukhishwa kwe-hydrogen peroxide kwahluka ngokohlobo lwento esetshenziselwa ukukhiqiza amandla: kwakhula nge-glutamate kanye ne-malate, kwehla nge-succinate. Ukugcinwa kwe-calcium akuguqukanga. Lolu ucwaningo lokusebenza kwento kuma-mitochondria, hhayi ukuhlolwa kokusebenza kwenhliziyo noma kweglucose. Isifundo salo ukuthi udayi awusebenzi ngendlela efanayo njenge-antioxidant kuzo zonke izimo. Ukuthi ukukhishwa kwezinto ezibangela i-oxidation kuyakhula noma kuyehla kuncike ekutheni i-mitochondrion isebenzisa yiphi into ukukhiqiza amandla. Ukuze uthole ulwazi oluhlobene nalokhu, bheka i-methylene blue ocwaningweni lwenhliziyo nemithambo yegazi.
Ithebula lamamodeli nezilinganiso zomphumela: okwahlolwa, okwaguquka, nokungaguqukanga
| Imodeli | Okwenziwa yi-methylene blue | Isilinganiso somphumela esalinganiswa | Umphumela |
|---|---|---|---|
| Ama-fibroblast e-L929, i-GLUT1 kuphela, ukungena kweglucose enophawu lokulandela umkhondo | Ukuvuselelwa ngokushesha kwamaprotheni athuthayo asevele ekhona, i-Vmax yakhula, i-Km ayiguqukanga, akukho protheni elisha le-GLUT1 | Isivinini sokungena kweglucose esitsheni socwaningo | Sakhula saze safinyelela ku-~8 izikhathi ku-50 micromolar, sabuyela esimweni sokuqala lapho udayi ususwa ngokugeza |
| Ama-fibroblast e-L929 kanye nesibambi se-cyclodextrin | Udayi wabambeka ngaphandle kwamaseli, ukufakwa kombala kwaphela | Ukuvuselelwa kokungena kweglucose | Kwavinjwa kanye nokufakwa kombala, okusekela ukusebenzisana okuqondile nephrotheni kunokucindezeleka okuvamile kwe-redox |
| Amagundane anesifo sikashukela esidalwe yi-STZ, 10 mg/kg/day ngomlomo, amasonto angu-11 | I-oxidation ye-NADH, i-NAD+ ephakeme, ukusebenza okukhulile kwe-Sirtuin 3, ukususwa kwamaqembu e-acetyl ezindaweni ezingu-83 zama-mitochondria, ukuncipha kwe-oxidation yamafutha anamaketanga amade | Izilinganiso zomthamo wegazi enhliziyweni, ingxenye yegazi ekhishwayo, inkomba yokukhula ngokweqile kwemisipha yenhliziyo | Kwathuthuka ngokwengxenye (izilinganiso zomthamo wegazi, ingxenye yegazi ekhishwayo, i-ANP kwabuyela ezingeni elijwayelekile; umfutho ne-dP/dt kwahlala kuphansi) |
| Ucwaningo olufanayo lwamagundane lwesikhathi eside | Amanani afanayo | Iglucose ngesikhathi sokuzila ukudla, iglucose ngesikhathi sokungazili, i-HbA1c | Alukho ushintsho oluphawulekayo ngokwezibalo; isifo sikashukela sahlala sikhona |
| Ucwaningo olufanayo lwamagundane lwesikhathi eside, ama-mitochondria ahlukanisiwe | Ukunikezwa ngomlomo isikhathi eside, bese kulinganiswa ukuphefumula ngaphandle komzimba | I-oxidative phosphorylation esekelwa yi-complex I ne-II | Inkinga ayilungiswanga |
| Ama-mitochondria ahlukanisiwe ezinhliziyweni ezinempilo nezinesifo sikashukela, 0.1 micromolar ngesikhathi esifushane | Ukuqondiswa kabusha kwama-electron ngesikhathi sokulinganisa ukuphefumula | Ukusetshenziswa komoyampilo | Kwakhula ngezinto ezisetshenziswa yi-complex I ne-II |
| Ucwaningo olufanayo lwama-mitochondria lwesikhathi esifushane | Amanani afanayo | Ukukhishwa kwe-hydrogen peroxide | Kwakuncike entweni esetshenziswayo: kwakhula nge-glutamate/malate, kwehla nge-succinate |
| Abantu, ukunikezwa okusebenza emzimbeni wonke | Akukho ukuhlolwa okushicilelwe okunomphumela oyinhloko wokulawulwa koshukela kanye nemiphumela efakiwe | I-HbA1c, iglucose ngesikhathi sokuzila ukudla, i-insulin | Akukho ukuthuthuka okushicilelwe okutholakele |
Abantu: ubufakazi bokulawulwa koshukela kubantu cishe abukho
Ukuhlolwa kungacwaninga amanxeba kubantu abanesifo sikashukela ngaphandle kokucwaninga ukulawulwa kweglucose, futhi inqubo yokwelashwa kwamazinyo ingabika i-HbA1c njengesilinganiso esengeziwe ngaphandle kokuhlola ukwelashwa kwesifo sikashukela.
Ukuhlolwa okukodwa okubhalisiwe, i-NCT05850611, kuhlele ukunikeza i-methylene blue ngomlomo (70 mg obisini, amasonto amane) ngesilonda sonyawo esihlobene nesifo sikashukela, kuhlanganise iglucose ngesikhathi sokuzila ukudla, i-insulin, ne-HbA1c phakathi kwezilinganiso, kodwa akunayo imiphumela efakiwe. Ucwaningo oluncane lokuqala olushicilelwe lwahlanganisa ijeli ye-plasma enama-platelet amaningi nenani elincane likadayi onikezwa ngomlomo ngesilonda sonyawo futhi lwabika imiphumela yenxeba neyokutholakala komoyampilo, hhayi eyokulawulwa koshukela. Ukuhlolwa kokwelashwa kwamazinyo okwafaka udayi endaweni ethile njengento elwa namagciwane evuselelwa ukukhanya ezigulini ezine-periodontitis nesifo sikashukela akutholanga nzuzo ephawulekayo ngokwezibalo ku-HbA1c. Udayi osephaketheni lezinsini ungumqondo ohlukile ekwelapheni ukuguqulwa kwezakhamzimba zibe amandla emzimbeni wonke, ngakho leyo miphumela engenanzuzo ayisho lutho nangokunikezwa ngomlomo.
Isifinyezo esithembekile: abukho ubufakazi obushicilelwe kubantu obubonisa ukuthi i-methylene blue esebenza emzimbeni wonke ithuthukisa i-HbA1c, iglucose ngesikhathi sokuzila ukudla, noma i-insulin kubantu abanesifo sikashukela. Ukungabikho kobufakazi akubona ubufakazi bokuthi akukho mphumela, kodwa kuyaphikisana nokukhangisa okuveza ukungena kweglucose kumaseli noma okutholakele ezinhliziyweni zamagundane njengobufakazi bokulawulwa kweglucose. Ukuze uthole imikhawulo yokuphepha ngaphambi kokuba noma ubani azihlolele lokhu, kuhlanganise nengozi ye-serotonin syndrome uma kusetshenziswa nemithi evamile yokulwa nokucindezeleka, bheka ukuphepha kwe-methylene blue nokusebenzisana kwayo nemithi.
Indlela yokusebenzisa lobu bufakazi ngaphandle kokuzikhohlisa
Cabanga ngemishini emithathu. Umshini wokuqala uyisango leglucose kuseli elilodwa elikhuliswe elabhorethri. Umshini wesibili uyi-mitochondrion enhliziyweni yegundane. Umshini wesithathu ungumuntu onesifo sikashukela, onamanyikwe, isibindi, imisipha, izinso, imithi, nokudla. Kuyaboniswa ukuthi udayi uthinta umshini wokuqala nowesibili. Akukaboniswa ukuthi umshini wesithathu uphendula ngokulawulwa okungcono kweglucose.
Lowo mehluko ufingqa lesi sihloko esigabeni esisodwa. Isimangalo ngokunakekelwa kwesifo sikashukela nge-methylene blue esikhomba ukuvuselelwa kwamaprotheni athuthayo noma ukufakwa kwamaqembu e-acetyl kuma-mitochondria esikhundleni sesilinganiso somphumela wokulawulwa koshukela sisuke sesishintshe isihloko. Okutholakele nge-Sirtuin 3 ne-oxidation yamafutha kusafanele kubhekwe, kodwa ucwaningo okufanele lulindelwe lucacile: ukuhlolwa okulawulwayo kubantu abanesifo sikashukela okulinganisa i-HbA1c, iglucose ngesikhathi sokuzila ukudla, noma i-insulin njengomphumela oyinhloko.