Methylene Blue ndi Matenda a Shuga: Zimene Kafukufuku wa Maselo ndi Zinyama Akuonetsa

Funso limene lili kumbuyo kwa kutamandidwa kopitirira muyeso

Mfundoyo imaoneka yomveka, koma yachokera pa kumvetsa kolakwika. Imaona zinthu zitatu zosiyana ngati chinthu chimodzi: glucose kulowa m'selo limodzi m'chotengera cha labotale, kagayidwe ka zinthu mkati mwa mitochondrion ya mtima, ndi kuwongolera glucose m'thupi lonse la munthu. Chilichonse chili ndi miyeso yake ndi malire ake. Nkhaniyi ikusiyanitsa zinthuzi.

Yankho lachidule: methylene blue imayambitsadi mayendedwe a glucose mu gulu limodzi la maselo lofufuzidwa bwino, ndipo imasinthadi zochitika za mankhwala m'mitochondria ndi miyeso ina ya mtima mwa makoswe a matenda a shuga. Koma mu kafukufuku wa makoswe amene anatenga nthawi yaitali kwambiri, siinasinthe glucose yoyezedwa atakhala osadya kapena hemoglobin yomangiriridwa ndi glucose. Ndipo palibe umboni wofalitsidwa wa anthu wosonyeza kuti methylene blue yoperekedwa kuti igwire ntchito m'thupi lonse imapangitsa shuga m'magazi, HbA1c, kapena insulini kukhala bwino pa matenda a shuga.

Maselo: glucose kulowa mwachangu kudzera mwa zonyamulira zomwe zili kale pa nembanemba

Ofufuza anagwiritsa ntchito maselo a fibroblast a L929, gulu la maselo amene kulowetsa kwawo glucose kumadalira chonyamulira chimodzi chokha, GLUT1. Popeza pali chonyamulira chimodzi chokha, kusintha kulikonse kwa kulowetsa glucose kuyenera kuchokera pa chonyamuliracho.

Pamene gulu la ofufuza linaika methylene blue pa maselowa, kulowa kwa glucose yokhala ndi chizindikiro chotsatirira kunawonjezeka mkati mwa mphindi 10 ndipo kunadalira kuchuluka kwa methylene blue. Kunafika pafupifupi 800 percent ya mulingo woyambira pa 50 micromolar kwa mphindi 45. Tsatanetsatane wa liwiro lake ndi wofunika: liwiro lapamwamba kwambiri (Vmax) linakwera, pamene mphamvu yomangirira (Km) ndi kuchuluka kwa puloteni ya GLUT1 sizinasinthe. Zitseko zomwezo zinalola glucose wochuluka kudutsa pa mphindi iliyonse. Utotowo unayambitsa zonyamulira zomwe zinali kale pa nembanemba m'malo mowonjezera zatsopano.

Mayeso oyerekezera amathandiza kumvetsa bwino. Mtundu wa utotowo umene walandira maelekitironi (wopanda mtundu) sunachite chilichonse. Chinthu choyambitsa oxidation kunja kwa selo, chimene chinaletsa utotowo kulowa, chinaletsa zonse ziwiri: kusintha mtundu wa maselo ndi kuwonjezera kulowa kwa glucose. Zinthu zoletsa njira za AMP kinase ndi PI kinase sizinasinthe chilichonse, zomwe zimatsutsa kuti njira ziwiri zodziwika bwino zotumizira zizindikirozi ndi zimene zinachititsa kusinthako.

Lingaliro loyamba linali kusinthanasinthana kwa redox: utotowo umasamutsa maelekitironi, umaika selo pa kupanikizika pang'ono, ndipo maselo opanikizikawo amatsegula zipata za glucose. Kafukufuku wotsatira anayesa lingaliro limeneli. Ofufuza anagwiritsa ntchito methyl-beta-cyclodextrin, molekyulu yooneka ngati mphete imene imatsekera methylene blue mkati mwa gulu la mamolekyulu (mtengo wokhazikika wa kulumikizana pafupi ndi 310 M-1). Utoto wotsekerezedwawo sunasinthe mtundu wa maselo kapena kuwonjezera kulowa kwa glucose. Ndipo kuchotsa utotowo mwa kutsuka kunagwirizana kwambiri ndi kutha kwa kusinthako. Mfundo imene anapeza inatsutsana ndi lingaliro la redox: kuyambitsako n'kutheka kuti kumachokera pa utotowo kulumikizana mwachindunji ndi puloteni ina m'njira yoyambitsa GLUT1, osati pa kupanikizika kwa oxidation mwachisawawa.

Mfundo ya mmene izi zimagwirira ntchito ili ndi malire. Methylene blue ingayambitse mwachangu kulowetsa glucose kwa GLUT1 m'maselo a L929, ndipo kusinthako kungabwerere m'mbuyo, kudzera pa kulowa m'selo ndi kulumikizana ndi puloteni. Izi sizikunena chilichonse chokhudza insulini, kapamba, kapena shuga m'magazi mwa nyama yamoyo. Kuti mumvetse ntchito ya utotowo monga chonyamulira maelekitironi, onani mmene methylene blue imagwirira ntchito monga chonyamulira maelekitironi. Kuti mudziwe mfundo zowerengera kafukufuku wa maselo, onani mmene mungawerengere kafukufuku wa methylene blue.

Makoswe a matenda a shuga: mitima inasintha, shuga m'magazi sanasinthe

Kafukufuku wa zinyama ukusamukira ku chinthu china: mtima wa nyama ya matenda a shuga. Kafukufuku onse awiri wa makoswe anagwiritsa ntchito streptozotocin, poizoni amene amawononga maselo a beta opanga insulini ndipo amachititsa mkhalidwe wofanana ndi matenda a shuga a mtundu 1. Owerenga amene akufufuza za methylene blue ndi matenda a shuga a mtundu 2 ayenera kuzindikira kusiyana kumeneku kuyambira pachiyambi. Zinyamazi sizinali ndi matenda a shuga a mtundu 2.

Mu kafukufuku wa nthawi yaitali, makoswe aamuna a Lewis anapatsidwa 10 mg pa kg patsiku m'madzi akumwa kwa masabata 11, pamodzi ndi insulini wochepa kuti asawonde koopsa koma osabweretsa glucose pa mulingo wabwinobwino. M'mitochondria ya mtima, utotowo unathandiza oxidation ya NADH, unawonjezera NAD+, ndipo unawonjezera ntchito ya Sirtuin 3 yochotsa magulu a acetyl. Kafukufuku wa mapuloteni anapeza kuchepa kwa kulumikizidwa kwa magulu a acetyl pa malo 83 a mapuloteni 34 a mitochondria okhudzana ndi oxidation ya mafuta, kuzungulira kwa citric acid, ndi kusamutsa maelekitironi. Oxidation ya mafuta a maunyolo aatali ndi ntchito ya hydroxyacyl-CoA dehydrogenase zinachepa. Izi zinatanthauziridwa ngati kuchepetsa kudalira kwambiri mafuta kosasintha kwa mtima wa nyama ya matenda a shuga. Miyeso ya kuchuluka kwa magazi m'zipinda za mtima ndi gawo la magazi lotulutsidwa pa kugunda kulikonse zinasintha kukhala bwino, ndipo chizindikiro cha kukula mopitirira muyeso kwa mtima chinabwerera pa mulingo wabwinobwino, ngakhale kuthamanga kwa magazi mkati mwa mtima ndi liwiro la kukokana kwake zinakhalabe zochepa.

Izi ndi zotsatira zofunika kwambiri: mulingo wa shuga m'magazi sunasinthe. Glucose yoyezedwa atakhala osadya ndi atadya inakhalabe yokwera, ndipo HbA1c inakhalabe pafupi ndi 5.6 percent mwa makoswe a matenda a shuga omwe analandira methylene blue komanso omwe sanailandire. Panalibe kusintha kofunika pa ziwerengero chifukwa cha mankhwalawo. Utotowo sunakonzenso vuto la ntchito yopumira ya complex I ndi II m'mitochondria yopatukana. Ntchito ya mtima inasintha kukhala bwino pa miyeso ina, pamene kuwongolera glucose ndi vuto lalikulu la ntchito yopumira sizinasinthe. Zotsatira zosiyana zinakhalabe zosiyana.

Kafukufuku wachiwiri anayesa zinthu pa mulingo waung'ono kwambiri: mitochondria yopatukana kuchokera ku mitima ya makoswe athanzi ndi makoswe amene anali ndi matenda a shuga kwa miyezi iwiri, yopatsidwa kamodzi kuchuluka kochepa kwa 0.1 micromolar pamene miyeso inkachitika. Kugwiritsa ntchito okosijeni kunakwera ndi zinthu zomwe complex I ndi II zimagwiritsa ntchito mofanana. Koma kutulutsidwa kwa hydrogen peroxide kunasiyana malinga ndi gwero la mphamvu: kunakwera ndi glutamate pamodzi ndi malate, ndipo kunatsika ndi succinate. Kusunga calcium sikunasinthe. Uwu ndi kafukufuku wa mmene mankhwala amagwirira ntchito m'mitochondria, osati kuyesa ntchito ya mtima kapena glucose. Phunziro lake ndi lakuti utotowo si chinthu chochepetsa oxidation mofanana nthawi zonse. Kaya kutulutsidwa kwa zinthu zoyambitsa oxidation kumakwera kapena kutsika zimadalira chimene mitochondrion imagwiritsa ntchito popanga mphamvu. Kuti muwerenge nkhani yofanana, onani methylene blue mu kafukufuku wa mtima ndi mitsempha ya magazi.

Tebulo la zoyeserera ndi miyeso ya zotsatira: zimene zinayesedwa, zimene zinasintha, ndi zimene sizinasinthe

Choyeserera	Zimene methylene blue inachita	Muyeso wa zotsatira	Zotsatira
Maselo a fibroblast a L929, GLUT1 yokha, kulowa kwa glucose yokhala ndi chizindikiro chotsatirira	Kuyambitsa mwachangu zonyamulira zomwe zilipo kale, Vmax inakwera, Km sinasinthe, palibe puloteni yatsopano ya GLUT1	Liwiro la kulowa kwa glucose m'chotengera cha labotale	Linawonjezeka kufika mpaka kuwirikiza ~8 pa 50 micromolar, ndipo linabwerera m'mbuyo utotowo utachotsedwa mwa kutsuka
Maselo a fibroblast a L929 pamodzi ndi chotsekera cha cyclodextrin	Utoto unatsekerezedwa kunja kwa maselo, kusintha mtundu kunatha	Kuwonjezeka kwa kulowa kwa glucose	Kunaletsedwa limodzi ndi kusintha mtundu, zomwe zimagwirizana kwambiri ndi kulumikizana mwachindunji ndi puloteni osati kupanikizika kwa redox mwachisawawa
Makoswe a matenda a shuga oyambitsidwa ndi STZ, 10 mg/kg/day kudzera pakamwa, masabata 11	Oxidation ya NADH, NAD+ yokwera, ntchito ya Sirtuin 3 yokwera, magulu a acetyl anachotsedwa pa malo 83 a mitochondria, oxidation ya mafuta a maunyolo aatali inachepa	Kuchuluka kwa magazi m'zipinda za mtima, gawo lotulutsidwa pa kugunda kulikonse, chizindikiro cha kukula mopitirira muyeso kwa mtima	Zinasintha kukhala bwino pang'ono (kuchuluka kwa magazi m'zipinda ndi gawo lotulutsidwa zinasintha kukhala bwino, ANP inabwerera pa mulingo wabwinobwino; kuthamanga ndi dP/dt zinakhalabe zochepa)
Kafukufuku yemweyo wa makoswe wa nthawi yaitali	Kupereka mankhwala mofanana	Glucose atakhala osadya, glucose atadya, HbA1c	Panalibe kusintha kofunika pa ziwerengero; matenda a shuga anakhalabe
Kafukufuku yemweyo wa makoswe wa nthawi yaitali, mitochondria yopatukana	Kupereka mankhwala kudzera pakamwa kwa nthawi yaitali kenako kuyeza ntchito yopumira kunja kwa thupi	Oxidative phosphorylation yothandizidwa ndi complex I ndi II	Vuto silinakonzedwe
Mitochondria yopatukana ya mitima yathanzi ndi ya matenda a shuga, 0.1 micromolar kwa nthawi yochepa	Kusintha njira ya maelekitironi poyezera ntchito yopumira	Kugwiritsa ntchito okosijeni	Kunawonjezeka ndi zinthu zomwe complex I ndi II zimagwiritsa ntchito
Kafukufuku yemweyo wa mitochondria wa nthawi yochepa	Kupereka mankhwala mofanana	Kutulutsidwa kwa hydrogen peroxide	Kunadalira chinthu chogwiritsidwa ntchito: kunakwera ndi glutamate/malate, kunatsika ndi succinate
Anthu, kupereka mankhwala kuti agwire ntchito m'thupi lonse	Palibe kuyesa kofalitsidwa kokhala ndi mulingo wa shuga m'magazi monga chotsatira chachikulu ndiponso zotsatira zofalitsidwa	HbA1c, glucose atakhala osadya, insulini	Palibe kusintha kukhala bwino komwe kunapezeka mu zotsatira zofalitsidwa

Anthu: umboni wokhudza shuga m'magazi mwa anthu ukusowa pafupifupi wonse

Kuyesa kungafufuze zilonda mwa anthu a matenda a shuga popanda kufufuza kuwongolera glucose, ndipo chithandizo cha mano chinganene za HbA1c monga muyeso wowonjezera popanda kuyesa chithandizo cha matenda a shuga.

Kuyesa kumodzi kolembetsedwa, NCT05850611, kukukonzekera kupereka methylene blue kudzera pakamwa (70 mg m'mkaka, masabata anayi) pa chilonda cha phazi cha matenda a shuga. Glucose yoyezedwa atakhala osadya, insulini, ndi HbA1c zili pakati pa miyeso yake, koma sikunafalitse zotsatira. Kafukufuku woyambirira waung'ono wofalitsidwa anaphatikiza gel ya madzimadzi a m'magazi okhala ndi mapulateleti ambiri ndi utoto wochepa woperekedwa kudzera pakamwa pa chilonda cha phazi. Unafotokoza zotsatira za chilonda ndi kupezeka kwa okosijeni, osati za shuga m'magazi. Mayeso a chithandizo cha mano amene anaika utotowo pamalo okhawo monga mankhwala opha tizilombo oyambitsidwa ndi kuwala mwa odwala a periodontitis ndi matenda a shuga sanapeze phindu lofunika pa ziwerengero pa HbA1c. Kuika utoto m'thumba la nkhama ndi chinthu chosiyana ndi chithandizo cha kagayidwe ka zinthu m'thupi lonse, choncho kusapezeka kwa kusintha m'mayesowo sikukunenanso chilichonse chokhudza kupereka mankhwala kudzera pakamwa.

Chidule choona mtima: palibe umboni wofalitsidwa wa anthu wosonyeza kuti methylene blue yoperekedwa kuti igwire ntchito m'thupi lonse imapangitsa HbA1c, glucose yoyezedwa atakhala osadya, kapena insulini kukhala bwino pa matenda a shuga. Kusowa kwa umboni si umboni wakuti palibe kusintha, koma sikuvomereza kutsatsa komwe kumaonetsa kulowa kwa glucose m'maselo kapena zotsatira za mitima ya makoswe ngati umboni wa kuwongolera glucose. Kuti mudziwe malire a chitetezo musanayese nokha, kuphatikizapo chiopsezo cha serotonin syndrome ndi mankhwala odziwika bwino a matenda ovutika maganizo, onani chitetezo cha methylene blue ndi mmene imagwirizanirana ndi mankhwala ena.

Mmene mungagwiritsire ntchito umboniwu popanda kudzinamiza

Ganizirani makina atatu. Makina oyamba ndi chitseko cha glucose m'selo limodzi lokulitsidwa mu labotale. Makina achiwiri ndi mitochondrion mumtima wa khoswe. Makina achitatu ndi munthu wa matenda a shuga, wokhala ndi kapamba, chiwindi, minofu, impso, mankhwala, ndi zakudya. Zasonyezedwa kuti utotowo umakhudza makina oyamba ndi achiwiri. Sizinasonyezedwe kuti makina achitatu amayankha mwa kuwongolera glucose bwino.

Kusiyana kumeneko ndi chidule cha nkhaniyi m'ndime imodzi. Mawu onena za methylene blue posamalira matenda a shuga amene amalozera ku kuyambitsa zonyamulira kapena kulumikizidwa kwa magulu a acetyl m'mitochondria m'malo mwa zotsatira za shuga m'magazi asintha nkhani imene ikukambidwa. Zotsatira za Sirtuin 3 ndi oxidation ya mafuta zikadali zofunika kuzitsatira, koma kuyesa koyenera kuyang'aniridwa n'kodziwika bwino: kuyesa koyendetsedwa ndi gulu loyerekezera mwa anthu a matenda a shuga, kuyeza HbA1c, glucose atakhala osadya, kapena insulini monga chotsatira chachikulu.