▎ 5-Amino-1MQ Ubushakashatsi
Ni ubuhe bushakashatsi bwakozwe kuri 5-Amino-1MQ?
Mu rwego rwiterambere rwubuzima bwa metabolike nubushakashatsi burambye, kumenya ingamba zifatika zo gukemura ibibazo bya metabolike no gutinda gusaza bikomeje kwibandwaho na siyansi. Nikotinamide N-methyltransferase (NNMT) yerekana ibikorwa byinshi mumyanya ya adipose numwijima. Mugukoresha methylating nicotinamide, igabanya ihinduka ryayo kuri nikotinamide adenine dinucleotide (NAD⁺). NAD⁺ ningirakamaro muburyo bwimikorere ya selile, kubyara ingufu, gusana ADN, no kwerekana inzira. Kugumana urwego rwiza rwiza ningirakamaro kubuzima bwimikorere no kurwanya gusaza no kudakora neza. Muri 2017, abashakashatsi bo muri kaminuza ya Texas babanje gukora iperereza kuri 5-Amino-1MQ mu gihe bashakisha uburyo bwo kubuza NNMT. Bitewe n’ubufatanye bukomeye bwa NNMT n’umubyibuho ukabije na diyabete yo mu bwoko bwa 2, abashakashatsi bavuze ko guhagarika NNMT bishobora gufungura inzira nshya zo kuvura umubyibuho ukabije n’ingaruka ziterwa na metabolike. Ibi byagize uruhare runini mubushakashatsi bwa 5-Amino-1MQ.
Nubuhe buryo bwo gukora kuri 5-Amino-1MQ?
Kubuza ikwirakwizwa rya kanseri y'inkondo y'umura: 5MQ ni ingirabuzimafatizo ntoya ya nicotinamide N-methyltransferase (NNMT) igaragaza ingaruka zikomeye zo kurwanya antiproliferative kuri selile ya selile ya HeLa epithelial cervical carcinoma, hamwe n'ingaruka zishingiye ku gihe. NNMT ni enzyme ya metabolike ijyanye no gutera ibibyimba na metastasis. Muguhagarika NNMT, 5MQ irashobora guhagarika urukurikirane rwinzira zo mu nda zifitanye isano no gukura kwikibyimba. Kurugero, 5MQ irashobora kubangamira nicotinamide metabolism ijyanye nibimenyetso byerekana inzira. Ubusumbane muri nicotinamide metabolism bushobora kurushaho kugira ingaruka ku mbaraga za selile metabolisme, gusana ADN, nibindi bikorwa, bityo bikagabanya ikwirakwizwa rya kanseri. Mu bushakashatsi, uko 5MQ yibanze cyane kandi igihe cyo kuvura cyongerewe, ikwirakwizwa rya selile ya HeLa ryerekanaga buhoro buhoro kubuza. Na none kandi, impinduka zijyanye na morfologiya zirimo kugabanuka kwingirabuzimafatizo, gutakaza ingirabuzimafatizo, hamwe n’imibiri ya apoptotique byagaragaye, byerekana ko 5MQ itera apoptose, bityo igahagarika ikwirakwizwa ry’utugingo [1].
Kugena imiterere ya Gene na Protein bifitanye isano: Nyuma yo kuvura 5MQ ya selile ya HeLa, urwego rwa mRNA rwa ZEB1, SIRT1, na CD16 rwiyongereye, mugihe urwego rwa TWIST na SERPIN1 mRNA rwaragabanutse. Mugihe kimwe, imvugo ya poroteyine ya oncogenic fosifore-Akt na SIRT1 yagabanutse. Izi genes na proteyine bigira uruhare runini muri tumorigenez no gutera imbere. Kurugero, TWIST na SERPIN1 mubisanzwe bifitanye isano no gutera ibibyimba na metastasis. Mugabanye imvugo yabo, 5MQ irashobora guhagarika ubushobozi butera kandi metastatike ya selile ya HeLa. Nubwo urwego rwa mRNA rwa ZEB1 na SIRT1 rwiyongereye, imvugo ya proteine oncogenic SIRT1 yagabanutse. Ibi birashobora kubaho kubera ko 5MQ igira ingaruka kumabwiriza nyuma yinyandiko-mvugo, ikabuza imikorere ya poroteyine ya SIRT1 bityo bikagira ingaruka ku gukwirakwira no kubaho. Fosifora ya Akt igira uruhare runini mubuzima bwimikorere, gukwirakwizwa, no kugenzura metabolike. Kugabanuka kwa 5MQ mu mvugo irashobora kubuza ikwirakwizwa rya kanseri no kubaho mu guhagarika inzira zerekana ibimenyetso [1].
Ni ubuhe buryo bukoreshwa bwa 5-Amino-1MQ?
Mubushakashatsi bwubuzima bwa metabolike, imikorere yingenzi ni ukugarura ingirabuzimafatizo ya selile muguhagarika NNMT. NNMT ikoresha nicotinamide (ibanziriza NAD⁺) kandi ikagira ingaruka kuri metabolisme ya methyl, mugihe 5-Amino-1MQ ihagarika iki gikorwa: kuruhande rumwe, igabanya ikoreshwa rya methylation ya nicotinamide muri adipocytes, ikazamura urwego rwa NAD⁺ rudasanzwe kugira ngo ikore ingirabuzimafatizo za Lipogène, zifata inzira ya mitochide, itera imbaraga za mitochide; kugenga ingufu za metabolisme mumyanya ya adipose, kandi igabanya ibinure byinshi. Ku rundi ruhande, igabanya kandi kurwanya insuline ikunze kugaragara mu ihungabana ry’imihindagurikire y’imihindagurikire y’imihindagurikire y’imihindagurikire y’imihanda, mu gihe ishobora kuba igenga mu buryo butaziguye gluconeogenezi y’umwijima kugira ngo ifashe mu gukomeza umuvuduko w’amaraso glucose. Byongeye kandi, ingaruka zishobora kugira kuri microbiota yo mu nda zirimo gukorwaho iperereza, hakekwa ko ishobora gushyigikira mu buryo butaziguye homeostasis ya metabolike muri rusange igenga ibikorwa bya mikorobe (urugero, kugabanya umusaruro wa metabolite wangiza).
Mu bushakashatsi bwa kanseri, ikoreshwa ryayo ryibanda ku kurwanya 'metabolic weakability ' ya selile yibibyimba. Kugira ngo ikwirakwizwa ryihuse, selile yibibyimba akenshi yishingikiriza kumikorere idasanzwe ya metabolike (nkingaruka za Warburg), kandi NNMT igaragara cyane mumasemburo amwe n'amwe y'ibibyimba, ashyigikira metabolism. Muguhagarika NNMT, 5-Amino-1MQ ihagarika metabolisme yibibyimba muburyo bubiri: Icya mbere, igabanya urwego rwa NAD⁺ rudasanzwe, rwangiza umusaruro, biganisha ku mbaraga zidahagije hamwe nubutaka bwa biosynetique bukenewe kugirango ikwirakwizwa; Icya kabiri, bibangamira ikoreshwa ryabaterankunga ba methyl, bigahungabanya inzira igenga epigenetike nka methylation ya ADN mu ngirabuzimafatizo, bityo igahagarika imvugo ya gene ijyanye no gukwirakwizwa na metastasis. Byongeye kandi, irashobora kubuza mu buryo butaziguye imikurire yikibyimba no gukwirakwira muguhindura ibintu bya metabolike muri microen ibidukikije yibibyimba, bigatanga urufatiro rwo gushakisha ingamba zo kuvura ibibyimba.
Nibikoresho byibanze byubushakashatsi, ikora nkuburyo bwingenzi bwo gusobanura imikorere ya NNMT. Abashakashatsi barashobora guhagarika neza ibikorwa bya NNMT bakoresheje 5-Amino-1MQ muburyo bwa selile cyangwa inyamaswa kugirango barebe impinduka zikurikira mubipimo bya metabolike. Kurugero, mubushakashatsi bwakagari, kugenzura ubunini bwa NAD⁺, urwego rwabaterankunga ba methyl, nigikorwa cyimisemburo igira uruhare muri synthesis ya aside irike irashobora gusobanura uruhare rwa NNMT muri metabolism selile. Mubyitegererezo byinyamanswa, bifatanije nisesengura ryihariye rya tissue, bifasha gukora ubushakashatsi kumikorere yihariye ya NNMT-nkingaruka zayo kuri metabolisme ya hepatike mugihe cyo gusaza cyangwa kugenzura itangwa ryingufu muri neuron. Ikigeretse kuri ibyo, gukoresha ibisubizo bitandukanye mumirongo ya selile (urugero, selile zisanzwe zerekana sensibilité nkeya hamwe nibisubizo byavuzwe muri selile metabolique idasanzwe cyangwa ibibyimba) birashobora gufasha mugusobanura uburyo bwihariye bwimikorere ya selile, bikayobora ubushakashatsi bwakurikiyeho.
Mubice byubuzima bwimitsi no kumenya, ikoreshwa ryibanze kumubano 'imbaraga metabolism - imikorere ya selile '. Mu bushakashatsi ku buzima bw’imitsi, gusana imitsi bishingiye ku gukora no gukwirakwiza ingirabuzimafatizo, inzira isaba gutanga ingufu zihagije. —5-Amino-1MQ iteza imbere icyogajuru gikora mugukomeza urwego NAD⁺ rudasanzwe mu ngirangingo. Icyarimwe, itezimbere imikorere ya mitochondial kugirango yongere imbaraga zimitsi ya metabolism imikorere, igabanya imihangayiko yo gukira nyuma yimvune. Irashobora kandi kugabanya imihangayiko ya okiside mumitsi yimitsi, ikarinda selile kwangirika guterwa na metabolike ikabije. Mu bushakashatsi bwubwenge, ubwonko bwubwonko bugaragaza ingufu nyinshi cyane, kandi kugabanuka kwa NAD⁺ bifitanye isano no kugabanuka kwimikorere. 5-Amino-1MQ irinda ubwonko bwa NAD⁺ kubuza NNMT, bityo bikarinda imikorere ya mitochondial no kugabanya neuroinflammation. Irashobora kandi kugira ingaruka kuri metabolism ya neurotransmitter (ikoresheje imisemburo iterwa na NAD⁺ igira uruhare muri synthesis ya neurotransmitter) kugirango ishyigikire ibikorwa bijyanye nubwonko bujyanye nubwonko (urugero, imikorere ya selile mukwiga / uturere twibuka nka hippocampus), bitanga ibitekerezo bishya kubushakashatsi bwo kubungabunga imikorere yubwenge.
Umwanzuro
Nkumwanya wihariye wa nicotinamide N-methyltransferase (NNMT), 5-Amino-1MQ yerekana agaciro kingenzi muri domaine nyinshi muguhitamo inzira ya metabolike ya NNMT. Irashobora kunoza umubyibuho ukabije no kurwanya insuline ikomeza urwego rwa NAD⁺, igahindura imikorere ya mito-iyambere, ikanagarura uburinganire bwa metabolike. Irwanya kandi intege nke za metabolike mungirangingo yibibyimba, bikabangamira umusaruro wabyo no kugenzura epigenetike kugirango ibuze ikura. Byongeye kandi, ni igikoresho cyubushakashatsi mugusobanura imikorere ya NNMT mugihe kigaragaza uruhare rushoboka mugusana imitsi no kubungabunga ubwenge, bitanga icyerekezo cyingenzi cyubushakashatsi bwokwitabira indwara ziterwa na metabolike, kanseri, nibindi bihe bifitanye isano nayo.
Ibyerekeye Umwanditsi
Ibikoresho byavuzwe haruguru byose byakorewe ubushakashatsi, byahinduwe kandi byakozwe na Cocer Peptides.
Umwanditsi w'ikinyamakuru
Akar s numushakashatsi umurimo wibanda kumikorere ya molekuline no kuvura. Yagize uruhare mu bushakashatsi bukora ubushakashatsi ku ruhare rwa enzymes na molekile ntoya mu kugenzura ikwirakwizwa rya selile. Ubushakashatsi bwe bushimangira akamaro ko kwibasira inzira za metabolike, nka nicotinamide N-methyltransferase, kugira ngo hamenyekane ingamba nshya z’ibinyabuzima.Akar s yanditse ku murongo wa 2.
