Na Cocer Peptides 
hashize iminsi 25
INGINGO ZOSE N'AMAKURU Y’IBICURUZWA BITANZWE KURI URU RUBUGA BISANZWE KUBONA AMAKURU N'INTEGO Z'UBUREZI.
Ibicuruzwa byatanzwe kururu rubuga bigenewe gusa mubushakashatsi bwa vitro. Mu bushakashatsi bwa vitro (Ikilatini: * mu kirahure *, bisobanura mu bikoresho by'ibirahure) bikorwa hanze y'umubiri w'umuntu. Ibicuruzwa ntabwo ari imiti, ntabwo byemejwe n’ikigo cy’Amerika gishinzwe ibiryo n’ibiyobyabwenge (FDA), kandi ntigomba gukoreshwa mu gukumira, kuvura, cyangwa gukiza indwara iyo ari yo yose y’ubuvuzi, indwara, cyangwa indwara. Birabujijwe rwose n'amategeko kwinjiza ibyo bicuruzwa mumubiri wabantu cyangwa inyamaswa muburyo ubwo aribwo bwose.
Ibisobanuro bya AOD9604
AOD9604 ni peptide ikomoka kuri C-terminal igice cya hormone yo gukura kwabantu (hGH). Igizwe na aside amine 177–191 ya hGH, hamwe n’ibisigisigi bya tirozine (Tyr) byongewe kuri N-terminal ya peptide, ni ukuvuga Tyr-hGH 177–191. Urukurikirane rwa aminide ya AOD9604 igena ihinduka ryarwo, ari nako bigira ingaruka ku mikoranire yabyo na reseptor zitandukanye na molekile zitandukanye mu mubiri. Ibisigarira bya tirozine byongewe kuri N-terminus bishobora kugira ingaruka kuri peptide mu mubiri, gufata neza selile, no guhuza isano hamwe na reseptor yihariye. AOD9604 ni mubyiciro bya peptide, bigira uruhare mubikorwa bitandukanye bya physiologique mumubiri, nko guhererekanya ibimenyetso no kugenzura metabolike. Bitewe n'inkomoko yihariye n'imiterere, AOD9604 ifite imirimo idasanzwe ya physiologiya, cyane cyane igaragaza ingaruka zikomeye mugutunganya metabolisme ya lipide.
Uburyo bwa AOD9604 mugutunganya Lipid Metabolism
(1) Ihuriro hamwe na β-adrenergic inzira
Kugena imvugo β-adrenergic reseptor imvugo: AOD9604 irashobora guhindura metabolisme ya lipide ikorana ninzira ya β-adrenergique, cyane cyane binyuze mumabwiriza ya β (3) -yakira reseptor (β (3) -AR). Muburyo bwimbeba ifite umubyibuho ukabije, nyuma yiminsi 14 ikurikiranye yo guterwa intraperitoneal ya AOD9604, urwego rwo kwerekana β (3) -AR RNA muri adipocytes rwiyongereye. ((3) -AR niyambere ya reseptor ya lipolytic muri adipocytes, kandi imvugo yayo yiyongera itera lipolysis. AOD9604 irashobora kongera imvugo ya β (3) -AR gene mugukoresha inzira zerekana ibimenyetso, bityo bikongerera ubuso bwayo muri selile. Irashobora kugira uruhare mu guhuza ibintu bimwe na bimwe byandikirwa mukarere ka porotokoro ya β (3) -AR, bityo bikazamura imikorere yo gutangiza gene.
Imyitwarire ishimishije ya β-adrenergic yinzira yogukora: Iyo β (3) -AR imvugo yiyongereye, ihuza ligande kugirango ikore inzira yerekana ibimenyetso byinzira. Gukora β (3) -AR abashakanye hamwe na poroteyine G, biganisha kumikorere ya adenylate cyclase, nayo ikongerera urwego rwimitsi ya messenger cyclic adenosine monophosphate (cAMP). cAMP ikora protein kinase A (PKA), ikora fosifori kandi ikora lipase yangiza imisemburo (HSL), enzyme yingenzi muri lipolysis itera hydrolysis ya triglyceride muri acide yibinure na glycerol, bityo igatera lipolysis no kugenzura metabolisme ya lipide.
(2) Ingaruka zitaziguye zidashingiye kuri β (3) -AR
Ubushakashatsi bukabije bwubushakashatsi: Mubushakashatsi bukabije hamwe na β (3) -AR imbeba ya gene-knockout, AOD9604 iracyongera ingufu zikoreshwa ningufu za okiside. Ibi birerekana ko ingaruka za AOD9604 kuri metabolisme ya lipide idashingiye rwose kuri β (3) -AR. Nubwo uburyo bwihariye butarasobanuka neza, inzira zindi cyangwa intego yibikorwa birashobora kubaho. AOD9604 irashobora gukora kuri mitochondriya, bigira ingaruka kumikorere ya mitochondial no kongera β-okiside ya aside irike. Mitochondriya ni ihuriro ry’ingufu za selile metabolisme, kandi aside irike β-okiside iba muri mitochondria. AOD9604 irashobora guteza imbere aside irike yinjira muri mitochondriya kandi ikorohereza iyangirika rya okiside igenga ibikorwa bya poroteyine zitwara abantu cyangwa imisemburo ifitanye isano na mitochondrial membrane, bityo bikongerera ingufu ingufu hamwe na okiside ya aside irike.
Inzira zinyongera zerekana inzira: AOD9604 nayo igira uruhare mugutunganya izindi nzira zerekana ibimenyetso. Irashobora guhindura ibikorwa byumuryango wa peroxisome prolifator-ikora reseptor (PPAR). PPARs ni urwego rwakirwa na kirimbuzi rufite uruhare runini mugutegeka metabolisme ya lipide, kuringaniza ingufu, no gusubiza umuriro. AOD9604 irashobora gukorana na PPAR kugirango igenzure imvugo ya gen igamije, bityo igire ingaruka ku kwandukura no guhindura genes zijyanye na lipide metabolism, bityo bigenga metabolisme ya lipide. Irashobora kandi kwitabira kugenzura inzira ya insuline yerekana inzira. Nubwo AOD9604 idafite ingaruka ziterwa na diyabete ifitanye isano na hGH, irashobora kugira uruhare rutaziguye inzira ya metabolisme ya lipide muguhuza neza inzira yerekana insuline.
Ingaruka za AOD9604
(1) Ingaruka ku buremere bw'umubiri n'ibinure
Ibimenyetso byubushakashatsi bwibikoko: Muburyo bwimbeba ifite umubyibuho ukabije, inshinge ndende ya intraperitoneal ya AOD9604 (iminsi 14 yubuyobozi budakira) yagabanije cyane uburemere bwumubiri hamwe nibinure byumubiri. Uku kugabanuka kwibiro byamavuta hamwe nibinure byajyanye no kwiyongera β (3) -AR RNA imvugo yerekana, byerekana ko AOD9604 itera lipolysis muguhuza imvugo β (3) -AR, bityo bikagabanuka muburemere bwumubiri hamwe namavuta yumubiri. By'umwihariko, habayeho kugabanuka kw'ibinure byo munsi y'ubutaka na visceral, hamwe no kugabanuka muri rusange. Mu bushakashatsi bwakozwe, gupima buri gihe uburemere bwimbeba no gupima neza nyuma yipimwa ryibiro byamavuta yerekana ko imbeba zavuwe na AOD9604 zagaragaje cyane kugabanya ibiro byumubiri hamwe nuburemere bwibinure ugereranije nitsinda rishinzwe kugenzura, hamwe no kugabanuka kwerekana icyerekezo gishingiye ku kigero.
Igishushanyo cya 2 Intego nigihe kizaza Intego zo gucunga ibiro
Kuvura umubyibuho ukabije wabantu, ingaruka za AOD9604 zifite agaciro gashoboka. Umubyibuho ukabije ni ikintu gikomeye gishobora gutera indwara nyinshi zidakira nk'indwara z'umutima n'imitsi na diyabete, kandi kugabanya ibiro n'umubiri ni ngombwa mu kuzamura ubuzima bw'abarwayi bafite umubyibuho ukabije.
(2) Ingaruka kuri Metabolism Ingufu
Kongera ingufu zikoreshwa: AOD9604 byongera ingufu zikoreshwa mumbeba zisanzwe na β (3) -AR imbeba ya gene knockout. Imbeba zisanzwe, calorimetrie itaziguye yakoreshejwe mu gupima ikoreshwa rya ogisijeni n’umusemburo wa dioxyde de carbone, byerekana ko AOD9604 yongereye cyane igipimo cy’ingufu za metabolism. Izi ngaruka ziterwa na AOD9604 ziteza imbere lipolysis, hamwe na aside irike irekuwe ikora nk'ingufu zo gukwirakwiza no gukoresha, bityo ingufu zikoreshwa. Muri β (3) -AR imbeba za knockout, nubwo uburyo bwibikorwa byayo bidashingiye kuri β (3) -AR, ubwiyongere bwikoreshwa ryingufu bwakomeje kugaragara, bikomeza kwerekana ko AOD9604 ifite inzira yo kugenzura ingufu za metabolisme idashingiye kuri β (3) -AR.
Kugenga ibinure byamavuta: AOD9604 byongera uburyo bwa okiside yibinure. Mu bushakashatsi bwakorewe mu ngirabuzimafatizo, hifashishijwe radiyo yanditswemo amavuta acide kugira ngo ikurikirane metabolisme ya okiside, byagaragaye ko umuvuduko wa aside irike yihuta mu ngirabuzimafatizo zavuwe na AOD9604. Ibi ntibifasha kugabanya ububiko bwamavuta gusa ahubwo binatanga umubiri imbaraga nyinshi. AOD9604 irashobora kongera aside irike ya aside irike muguhindura imikorere ya mito-iyambere, kongera biogenezi ya mito-iyambere. Itera imbere imvugo nigikorwa cyimisemburo ijyanye na okiside ya aside irike muri mitochondriya, harimo na karnitine palmitoyltransferase I (CPT-I), iyi ikaba ari nisemburo nyamukuru igabanya umuvuduko wa aside irike yinjira mitochondriya kugirango okiside. AOD9604 irashobora guteza aside irike kwinjira muri mitochondriya kugirango ibore okiside igabanya imvugo ya CPT-I.
(3) Ingaruka kuri metabolism ya hepatike
Hepatic lipid metabolism inyigo yubushakashatsi bwinyamaswa: Mu bushakashatsi bwakozwe ku mbeba y’umwijima y’umwijima, hakozwe ubushakashatsi ku ngaruka za AOD9604 kuri hepatike ya lipide metabolism. Imbeba zagabanyijwemo itsinda rishinzwe kugenzura, itsinda ryimyitozo ngororangingo, imyitozo + AOD9604, hamwe na AOD9604 yonyine yo kuvura. Ibisubizo byerekanye ko urwego rwa alanine aminotransferase (ALT) mu itsinda rya AOD9604 rwonyine kandi imyitozo + AOD9604 yari hasi cyane ugereranije n’abari mu itsinda rishinzwe kugenzura, byerekana ko AOD9604 igira ingaruka runaka zo kwangiza umwijima. Ibi birashobora guterwa na AOD9604 igenga metabolisme ya lipide mu mwijima, bikagabanya ibinure mu mwijima, bityo bikagabanya indwara ya hepatike hamwe n’ibisubizo bitera.
Ingaruka kuri enzymes yumwijima na cytokeratin-18 (CK18): Cytokeratin-18 ni biomarker yerekana hepatocyte apoptose. Mu bushakashatsi, nubwo itsinda rya AOD9604 monotherapy ritagabanije cyane urwego rwa CK18, ntirwatanze ingaruka mbi. Ibi byerekana ko AOD9604 ishobora kugira uruhare rutaziguye inzira ya apoptose yingirangingo zumwijima muguhindura metabolism ya hepatike, bityo ikarinda selile umwijima kwangirika kurwego runaka. AOD9604 irashobora kugumana uburinganire bwa metabolisme ya hepatike mu kugenzura imiterere ya genes zijyanye no guhuza lipide, gutwara, no kwangirika mu mwijima, bityo bikagabanya ibinure bidasanzwe mu mwijima.
Porogaramu ya AOD9604
(1) Ibishoboka mubishobora kuvura umubyibuho ukabije
Ibyiza n'ibiteganijwe: Ugereranije n'imiti gakondo igabanya ibiro, AOD9604 ifite ibyiza byinshi bishoboka. Ntabwo ifite ingaruka ziterwa na diyabete zijyanye na hGH. HGH irashobora gutera ingaruka mbi nko kurwanya insuline no kuzamura glucose yamaraso mugihe ikoreshwa mukuvura umubyibuho ukabije. AOD9604 yirinda izo ngaruka zinyuze muburyo bwihariye bwimiterere. AOD9604 irashobora kugenga cyane metabolisme ya lipide, guteza imbere kugabanuka kw'amavuta, no kongera ingufu zikoreshwa, bitanga amahirwe yo kuvura abarwayi bafite umubyibuho ukabije. Uburyo bwibikorwa bukubiyemo urwego rwinshi, bitanyuze gusa muguhuza β-adrenergique gusa ahubwo no muburyo butagengwa na β (3) -AR, butanga uburyo bunoze bwo gutabara kuvura umubyibuho ukabije.
(2) Ibishobora gukoreshwa mukuvura indwara zumwijima
Ibishobora kuvura indwara zumwijima zidafite inzoga (NAFLD): NAFLD nindwara yumwijima isanzwe irangwa no kwirundanya kwinshi mwumwijima. Muburyo bwimbeba yindwara zumwijima, AOD9604 irashobora kugenga metabolisme ya hepatike, kugabanya ibinure byumwijima, no kunoza imikorere yumwijima. AOD9604 ifite agaciro gakoreshwa muburyo bwo kuvura NAFLD. Irashobora kugabanya ibinure mu mwijima iteza imbere gusenyuka no gutwara ibinure mu mwijima, bityo bikagabanya indwara ya hepatike hamwe n’ibisubizo byatewe. AOD9604 irashobora kandi kugabanya imbaraga za okiside hamwe ninzira yerekana ibimenyetso byumwijima, bikarinda selile umwijima kwangirika.
Umwanzuro
Nka peptide ikomoka mu karere ka C-ya hormone yo gukura kwabantu, uburyo bwa AOD9604 bwibikorwa muguhindura metabolisme ya lipide bikubiyemo imikoranire ninzira ya ad-adrenergique ningaruka zitaziguye zidashingiye kuri β (3) -AR. Binyuze muri ubwo buryo, AOD9604 igabanya neza uburemere bwumubiri n’ibinure byumubiri, byongera ingufu zikoreshwa, bigenga okiside yibinure, kandi bigahindura metabolism ya hepatike. Kubijyanye no gusaba, AOD9604 ifite amasezerano akomeye mukuvura umubyibuho ukabije, ubuvuzi bwa siporo, n'indwara y'umwijima.
Inkomoko
[1] Dehbashi M, Fathi M, Attarzadeh Hosseini SR, n'abandi. Ingaruka z'ibyumweru umunani Amahugurwa yo Kwihangana, Gutera Somatropine, hamwe na Lipolytike Yayo (AOD9604) kuri Cytokeratin-18 hamwe na Enzymes yumwijima yimbeba zangiza umwijima kubera indyo yuzuye amavuta [J]. Igihembwe cya Horizon yubumenyi bwubuvuzi, 2021,27: 502-517.DOI: 10.32598 / hms.27.4.3513.1.
[2] Cox HD, Smeal SJ, Hughes CM, n'abandi. Kumenya no muri vitro metabolism ya AOD9604 [J]. Kwipimisha no gusesengura ibiyobyabwenge, 2015,7 (1): 31-38.DOI: 10.1002 / dta.1715.
[3] Stier H, Vos E, Kenley D L. Umutekano no kwihanganira Hexadecapeptide AOD9604 mubantu [J]. Ikinyamakuru cya Endocrinology na Metabolism, 2013,3: 7-15.
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[4] Witkamp R F. Intego ziki gihe nigihe kizaza mugucunga ibiro [J]. Ubushakashatsi bwa farumasi, 2011,28 (8): 1792-1818.DOI: 10.1007 / s11095-010-0341-1.
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