Inqaku
I-Methylene Blue neSifo seSwekile: Ingcaciso ngoThutho lweGlucose noPhando lweZilwanyana
Umbuzo osisiseko sengxolo yokuyincoma
Eso sigqibo sivakala sisengqiqweni, kodwa sisekelwe kwindlela engachanekanga yokuyiqonda le nto. Sithatha izinto ezintathu ezahlukileyo ngokungathi yinto enye: iglucose engena kwiseli enye ekwisitya selabhoratri, inkqubo yemetabolism ngaphakathi kwemitochondrion yentliziyo, nolawulo lweglucose emntwini opheleleyo. Nganye inemilinganiselo nemida yayo. Eli nqaku liyazahlula.
Impendulo emfutshane: i-methylene blue iyaluvuselela uthutho lweglucose kudidi olunye lweeseli olufundwe ngokubanzi, kwaye iyayitshintsha ikhemistri yeemitochondria neminye imilinganiselo yentliziyo kwiimpuku ezinesifo seswekile. Kodwa kuphando lweempuku oluthathe elona xesha lide, ayizange iyitshintshe iglucose xa kungatywanga okanye ihemoglobin edityaniswe neglucose, kwaye abukho ubungqina obupapashiweyo kubantu obubonisa ukuba i-methylene blue efikelela kuwo wonke umzimba iyayiphucula iswekile yegazi, i-HbA1c, okanye i-insulin kwisifo seswekile.
Iiseli: iglucose ingena ngokukhawuleza ngabathuthi abasele bekwinwebu
Abaphandi basebenzisa iifibroblast ze-L929, udidi lweeseli ukufunxa kwazo iglucose okuxhomekeke kumthuthi omnye, i-GLUT1. Xa kukho umthuthi omnye kuphela, naluphi na utshintsho ekufunxweni kufuneka luvele kuloo mthuthi.
Xa iqela lafaka ezi seli kwi-methylene blue, ukufunxwa kwesiphawuli sokulandela umkhondo kwanda kwimizuzu eyi-10, kwaye ukwanda kwakuxhomekeke kwidosi, kwafikelela malunga ne-800 percent yomlinganiselo wokuqala kwi-50 micromolar kangangemizuzu eyi-45. Iinkcukacha zesantya zibalulekile: esona santya siphezulu (Vmax) sanda, ngoxa amandla okubophelela (Km) nobungakanani beprotheyini ye-GLUT1 zahlala zingatshintshanga. Inani elifanayo leengcango lavumela iglucose eninzi ukuba ingene ngomzuzu. Idayi yavuselela abathuthi abasele bekwinwebu kunokuba yongeze abatsha.
Uvavanyo lokuthelekisa lwenza umfanekiso ucace ngakumbi. Uhlobo olufumene ii-electron, olungenambala, aluzange lwenze nto. Into eyi-oxidant engaphandle kweseli, eyathintela idayi ukuba ingangeni, yathintela kokubini ukungena kombala nokuvuselela. Izithinteli zeendlela ze-AMP kinase ne-PI kinase azizange zitshintshe nto, nto leyo engaxhasi ingcamango yokuba ezi ndlela zimbini zaziwayo zokudlulisa imiqondiso zibandakanyekile.
Uqikelelo lokuqala yayikukujikeleza kwe-redox: idayi ihambisa ii-electron, ibeke iseli phantsi koxinzelelo oluncinane, zize iiseli eziphantsi koxinzelelo zivule iingcango zeglucose. Uphando olulandelayo lwavavanya loo ngcamango. Abaphandi basebenzisa i-methyl-beta-cyclodextrin, imolekyuli emile okweringi ebamba i-methylene blue ngaphakathi kwesakhiwo esidibeneyo (i-association constant ekufutshane ne-310 M-1). Idayi ebanjiweyo ayizange ifake umbala kwiiseli okanye ivuselele ukufunxwa, kwaye ukuhlanjwa kwedayI ukuze isuswe kwahambelana ngokusondeleyo nokuphela kwesiphumo. Isigqibo sabo sachasa ingcaciso ye-redox: kusenokwenzeka ukuba ukuvuselela kuvela kunxibelelwano oluthe ngqo phakathi kwedayI neprotheyini ethile kwindlela yokuvuselela i-GLUT1, kungekhona kuxinzelelo ngokubanzi olubangelwa zii-oxidant.
Umgaqo wokusebenza unomda omncinane. I-methylene blue inokuluvuselela ngokukhawuleza, nangendlela ebuyisekayo, ukufunxwa nge-GLUT1 kwiiseli ze-L929, ngokungena kwiseli ize inxibelelane neprotheyini. Oku akuthethi nto nge-insulin, udakada, okanye iswekile yegazi kwisilwanyana esiphilayo. Ukuze uqonde idayi njengomthwali wee-electron, funda indlela i-methylene blue esebenza ngayo njengomthwali wee-electron. Ukuze ufumane imigaqo yokufunda uphando lweeseli, funda indlela yokufunda uphando lwe-methylene blue.
Iimpuku ezinesifo seswekile: iintliziyo ezitshintshileyo, iswekile yegazi engatshintshanga
Uphando lwezilwanyana ludlulela kwinto eyahlukileyo: intliziyo enesifo seswekile. Zombini izifundo zeempuku zasebenzisa i-streptozotocin, ityhefu etshabalalisa iiseli ze-beta ezivelisa i-insulin ize idale imeko efana nesifo seswekile sohlobo 1. Abafundi abafuna ulwazi nge-methylene blue nesifo seswekile sohlobo 2 kufuneka bawuqaphele lo mahluko kwasekuqaleni. Ezi ayizozilwanyana ezinesifo seswekile sohlobo 2.
Kuphononongo lwexesha elide, iimpuku ezingamaduna zohlobo lwe-Lewis zafumana i-10 mg nge-kg ngosuku emanzini okusela kangangeeveki eziyi-11, kunye needosi ezincinane ze-insulin ukuthintela ukubhitya okugqithisileyo ngaphandle kokubuyisela iglucose kwinqanaba eliqhelekileyo. Kwiimitochondria zentliziyo, idayi yanceda ukwenza i-oxidation ye-NADH, yandisa i-NAD+, yaza yandisa umsebenzi we-deacetylase ye-Sirtuin 3. Uhlalutyo lweeprotheyini lwafumanisa ukuncipha kokufakwa kwamaqela e-acetyl kwiindawo eziyi-83 kwiiprotheyini zeemitochondria eziyi-34 ezibandakanyeka kwi-oxidation yamafutha, kumjikelo we-citric acid, nakuthutho lwee-electron. I-oxidation yamafutha aneekhonkco ezinde nomsebenzi we-hydroxyacyl-CoA dehydrogenase zehla, nto leyo eyatolikwa njengokuncipha kokuxhomekeka kakhulu nangokungaguqukiyo kumafutha kwentliziyo enesifo seswekile. Imithamo yentliziyo neqhezu legazi elikhutshwayo zaphucuka, kwaye isalathisi sokukhula ngokugqithisileyo kwesihlunu sentliziyo sabuyela kwinqanaba eliqhelekileyo, nangona uxinzelelo nesantya sokufinyela zahlala ziphantsi.
Nasi esona siphumo sibalulekileyo: amanqanaba eglucose egazini akazange atshintshe. Iglucose xa kungatywanga naxa kutyiwe yahlala iphezulu, kwaye i-HbA1c yahlala ikufutshane ne-5.6 percent kuzo zombini iimpuku ezinesifo seswekile ezanyangwayo nezinganyangwanga, kungekho siphumo sonyango sibalulekileyo ngokwezibalo. Idayi nayo ayizange ilungise isiphene sokuphefumla kwe-complex I ne-II kwiimitochondria ezahluliweyo. Umsebenzi wentliziyo waphucuka kweminye imilinganiselo, ngoxa ulawulo lweglucose nesiphene esisisiseko sokuphefumla zingazange ziphucuke. Iziphumo ezahlukileyo zahlala zahlukile.
Uphando lwesibini lwasebenza kwinqanaba elincinane ngakumbi: iimitochondria ezahlulwe kwiintliziyo eziphilileyo nakwiintliziyo ezazinesifo seswekile kangangeenyanga ezimbini, zanikwa idosi enye ephantsi ye-0.1 micromolar ngexesha lokulinganisa. Ukusetyenziswa kweoksijini kwanda ngezinto ezisetyenziswa yi-complex I kwakunye ne-complex II. Kodwa ukukhutshwa kwe-hydrogen peroxide kwahluka ngokohlobo lwesibaso: kwanda nge-glutamate kunye ne-malate, kwehla nge-succinate. Ukugcinwa kwecalcium akuzange kutshintshe. Olu luphando lwendlela iyeza elisebenza ngayo kwiimitochondria, alulovavanyo lomsebenzi wentliziyo okanye lweglucose. Isifundo salo sesokuba idayi ayisebenzi njenge-antioxidant ngendlela efanayo kuzo zonke iimeko. Ukuba ukukhutshwa kwee-oxidant kuyanda okanye kuyehla kuxhomekeke kwinto etshiswa yimitochondrion njengesibaso. Ngolwazi olunxulumene noku, funda nge-methylene blue kuphando lwentliziyo nemithambo yegazi.
Itheyibhile yeemodeli neziphumo ezilinganisiweyo: okwavavanywayo, okwatshintshayo, nokungazange kutshintshe
| Imodeli | Okwenziwa yi-methylene blue | Isiphumo esalinganiswa | Isiphumo |
|---|---|---|---|
| Iifibroblast ze-L929, i-GLUT1 kuphela, ukufunxwa kwesiphawuli sokulandela umkhondo | Ukuvuselelwa ngokukhawuleza kwabathuthi abasele bekho, i-Vmax yanda, i-Km ayitshintshanga, akukho protheyini intsha ye-GLUT1 | Isantya sokufunxwa kweglucose kwisitya selabhoratri | Sanda safikelela ekuphindaphindweni ~8 kwi-50 micromolar, sabuyela umva xa idayi yahlanjwa yasuswa |
| Iifibroblast ze-L929 kunye nesibambi se-cyclodextrin | Idayi yabanjwa ngaphandle kweeseli, ukungena kombala kwaphela | Ukuvuselelwa kokufunxwa | Kwathintelwa kunye nokungena kombala, nto leyo exhasa unxibelelwano oluthe ngqo neprotheyini kunoxinzelelo lwe-redox ngokubanzi |
| Iimpuku ezinesifo seswekile esibangelwe yi-STZ, 10 mg/kg/day ngomlomo, iiveki eziyi-11 | I-oxidation ye-NADH, i-NAD+ ephezulu, umsebenzi ophezulu we-Sirtuin 3, ukususwa kwamaqela e-acetyl kwiindawo eziyi-83 zeemitochondria, ukuncipha kwe-oxidation yamafutha aneekhonkco ezinde | Imithamo yentliziyo, iqhezu legazi elikhutshwayo, isalathisi sokukhula ngokugqithisileyo kwesihlunu sentliziyo | Zaphucuka ngokuyinxenye (imithamo, iqhezu legazi elikhutshwayo, ne-ANP zabuyela kwinqanaba eliqhelekileyo; uxinzelelo ne-dP/dt zahlala ziphantsi) |
| Kwaolo phando lwexesha elide lweempuku | Kwaezo dosi | Iglucose xa kungatywanga, iglucose xa kutyiwe, i-HbA1c | Akukho tshintsho lubalulekileyo ngokwezibalo; imeko yesifo seswekile yahlala injalo |
| Kwaolo phando lwexesha elide lweempuku, iimitochondria ezahluliweyo | Ukunikwa idosi ngomlomo ixesha elide, kulandele ukulinganiswa kokuphefumla ngaphandle komzimba | I-oxidative phosphorylation exhaswa yi-complex I ne-II | Isiphene asizange silungiswe |
| Iimitochondria ezahlulwe kwiintliziyo eziphilileyo nezinesifo seswekile, 0.1 micromolar ngexesha elifutshane | Ukutshintshwa kwendlela yee-electron ngexesha lokulinganisa ukuphefumla | Ukusetyenziswa kweoksijini | Kwanda ngezinto ezisetyenziswa yi-complex I ne-II |
| Kwaolo phando lwexesha elifutshane lweemitochondria | Kwaezo dosi | Ukukhutshwa kwe-hydrogen peroxide | Kuxhomekeke kwinto esetyenziswa njengesibaso: kwanda nge-glutamate/malate, kwehla nge-succinate |
| Abantu, idosi efikelela kuwo wonke umzimba | Akukho vavanyo lupapashiweyo olunesiphumo esiphambili seglucose kunye neziphumo ezibhengeziweyo | I-HbA1c, iglucose xa kungatywanga, i-insulin | Akukho phuculo lupapashiweyo lufunyenweyo |
Abantu: ingxelo yobungqina beglucose ebantwini phantse ayinanto
Uvavanyo lunokufunda amanxeba kubantu abanesifo seswekile ngaphandle kokufunda ulawulo lweglucose, kwaye inkqubo yamazinyo inokunika ingxelo ye-HbA1c njengomlinganiselo osecaleni ngaphandle kokuvavanya unyango lwesifo seswekile.
Uvavanyo olunye olubhalisiweyo, i-NCT05850611, luceba ukusebenzisa i-methylene blue ngomlomo (70 mg ebisini, iiveki ezine) kwisilonda sonyawo esinxulumene nesifo seswekile, kunye neglucose xa kungatywanga, i-insulin, ne-HbA1c phakathi kwemilinganiselo, kodwa alukabhengezi ziphumo. Uphononongo oluncinane lokuqala olupapashiweyo lwadibanisa ijeli yeplasma eneplatelet ezininzi nedayi yedosi ephantsi ethathwa ngomlomo kwisilonda sonyawo, lwaza lwanika ingxelo ngeziphumo zenxeba nokufumaneka kweoksijini, kungekhona ngeglucose. Uvavanyo lwamazinyo olusebenzisa idayi kwindawo ethile njengento ebulala iintsholongwane xa ivuselelwe kukukhanya kwizigulana ezinesifo seentsini nesifo seswekile alufumananga nzuzo ibalulekileyo ngokwezibalo kwi-HbA1c. Idayi efakwe epokothweni yentsini yinto eyahlukileyo kunyango lwemetabolism olufikelela kuwo wonke umzimba, ngoko ezo ziphumo zokungafumani nzuzo azithethi nto nangedosi ethathwa ngomlomo.
Isishwankathelo esinyanisekileyo: abukho ubungqina obupapashiweyo kubantu obubonisa ukuba i-methylene blue efikelela kuwo wonke umzimba iyayiphucula i-HbA1c, iglucose xa kungatywanga, okanye i-insulin kwisifo seswekile. Ukungabikho kobungqina akubobungqina bokuba akukho siphumo, kodwa kuyakuchasa ukuthengisa okubonisa ukufunxwa ziiseli okanye okufunyenwe kwiintliziyo zeempuku njengobungqina bolawulo lweglucose. Ukuze uqonde imida yokhuseleko ngaphambi kokuba nabani na azilinge, kuquka umngcipheko we-serotonin syndrome xa isetyenziswa kunye namayeza aqhelekileyo okunyanga ukudakumba, funda ukhuseleko lwe-methylene blue nokusebenzisana kwayo namayeza.
Indlela yokusebenzisa obu bungqina ngaphandle kokuzikhohlisa
Cinga ngoomatshini abathathu. Umatshini wokuqala lucango lweglucose kwiseli enye ekhuliswe elabhoratri. Umatshini wesibini yimitochondrion kwintliziyo yempuku. Umatshini wesithathu ngumntu onesifo seswekile, onodakada, isibindi, izihlunu, izintso, amayeza, nokutya. Kubonisiwe ukuba idayi iyabachaphazela oomatshini bokuqala nowesibini. Akukaboniswa ukuba umatshini wesithathu usabela ngolawulo olungcono lweglucose.
Lo mahluko ushwankathela inqaku lonke kumhlathi omnye. Ibango lokusebenzisa i-methylene blue kukhathalelo lwesifo seswekile elibhekisa ekuvuseleleni abathuthi okanye ekufakweni kwamaqela e-acetyl kwiimitochondria endaweni yesiphumo seglucose esilinganisiweyo litshintshe umxholo. Okufunyenweyo nge-Sirtuin 3 ne-oxidation yamafutha kusafanele ukulandelwa, kodwa uvavanyo ekufuneka kujongwe lona lucacile: uvavanyo olunolawulo kubantu abanesifo seswekile, olulinganisa i-HbA1c, iglucose xa kungatywanga, okanye i-insulin njengesiphumo esiphambili.