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ụbọchị 25 gara aga
Edemede na ozi ngwaahịa niile enyere na webụsaịtị a bụ naanị maka mgbasa ozi na ebumnuche mmụta.
Ngwaahịa ndị enyere na webụsaịtị a bụ naanị maka nyocha in vitro. A na-eme nyocha in vitro (Latin: * na iko *, nke pụtara na ihe eji enyo) na mpụga ahụ mmadụ. Ngwaahịa ndị a abụghị ọgwụ, ndị US Food and Drug Administration (FDA) akwadoghị ya, ha agaghịkwa eji ya gbochie, gwọọ, ma ọ bụ gwọọ ọnọdụ ahụike ọ bụla, ọrịa, ma ọ bụ ọrịa. Iwu amachibidoro nke ọma iwebata ngwaahịa ndị a n'ime ahụ mmadụ ma ọ bụ anụmanụ n'ụdị ọ bụla.
Nkọwa nke AOD9604
AOD9604 bụ peptide sitere na mpempe C-terminal nke hormone uto mmadụ (hGH). Ọ mejupụtara amino acid 177-191 nke hGH, yana mgbakwunye tyrosine residue (Tyr) agbakwunyere na njedebe N-terminal nke peptide, ntụgharị, Tyr-hGH 177-191. Usoro amino acid nke AOD9604 na-ekpebi nhazi oghere ya, nke n'aka nke ya na-emetụta mmekọrịta ya na ndị na-anabata ya na ụmụ irighiri ihe dị n'ime ahụ. Ihe fọdụrụ na tyrosine agbakwunyere na N-terminus nwere ike imetụta nkwụsi ike nke peptide n'ime ahụ, nrụpụta cell na-arụ ọrụ, na njikọ njikọ na ndị na-anabata ya. AOD9604 bụ nke klaasị nke ogige peptide, nke na-ekere òkè na usoro physiological dị iche iche na ahụ, dị ka ntụgharị mgbaàmà na usoro metabolic. N'ihi mmalite ya na nhazi ya, AOD9604 nwere ọrụ physiological pụrụ iche, na-egosipụta mmetụta dị ukwuu na nhazi metabolism lipid.
Usoro nke AOD9604 n'ịchịkwa metabolism lipid
(1) Njikọ na ụzọ β-adrenergic
Iwu nke okwu nnabata β-adrenergic: AOD9604 nwere ike imetụta metabolism lipid site na iji ụzọ β-adrenergic na-emekọrịta ihe, ọkachasị site na nhazi nke β (3) -adrenergic receptor (β (3) -AR). N'ime ụdị òké buru ibu, mgbe ụbọchị iri na anọ na-esochi gbachitere intraperitoneal nke AOD9604, ọkwa ngosipụta nke β(3) -AR RNA na adipocytes mụbara. β (3) -AR bụ onye na-anabata lipolytic bụ isi na adipocytes, na okwu ya na-abawanye na-akwalite lipolysis. AOD9604 nwere ike ịkwalite nkwupụta nke β (3) -AR gene site n'ịgbalite ụzọ mgbaàmà metụtara ya, si otú ahụ na-amụba ọdịdị elu ya na sel. Ọ nwere ike imetụta njikọ nke ụfọdụ ihe odide ederede na mpaghara nkwalite nke β(3) -AR gene, si otú ahụ na-eme ka arụmọrụ mmalite nke mkpụrụ ndụ ihe nketa dị mma.
Mmeghachi omume cascading nke β-adrenergic ụzọ ịgbalite: Mgbe β(3) -AR okwu na-abawanye, ọ na-ejikọta na ligands iji mee ka ụzọ mgbama ala. Arụ ọrụ β (3) - AR di na nwunye nwere protein G, na-eduga na ntinye nke adenylate cyclase, nke na-eme ka ọkwa intracellular nke adenosine monophosphate cyclic nke abụọ (cAMP) dịkwuo elu. cAMP na-arụ ọrụ protein kinase A (PKA), nke na-emepụta phosphorylates ma na-arụ ọrụ lipase hormone-sensitive lipase (HSL), bụ isi enzyme na lipolysis nke na-eme ka hydrolysis nke triglycerides banye n'ime acid fatty na glycerol, si otú ahụ na-akwalite lipolysis na ịhazi metabolism lipid.
(2) Mmetụta ozugbo na-adabereghị na β (3) -AR
Nchọpụta nnwale siri ike: N'ime nnukwu nnwale na ụmụ oke β(3) AR gene-knockout, AOD9604 ka na-abawanye mmefu ike yana oxidation abụba. Nke a na-egosi na mmetụta nchịkwa nke AOD9604 na metabolism lipid adabereghị kpamkpam na β (3) -AR. Agbanyeghị na aghọtabeghị usoro a kapịrị ọnụ, ụzọ ndị ọzọ ma ọ bụ ebumnuche ime ihe nwere ike ịdị. AOD9604 nwere ike ime ihe ozugbo na mitochondria, na-emetụta ọrụ mitochondrial na ịkwalite β-oxidation nke fatty acids. Mitochondria bụ etiti etiti nke cellular ume metabolism, na fatty acid β-oxidation na-apụta n'ime mitochondria. AOD9604 nwere ike ịkwalite ntinye abụba abụba n'ime mitochondria ma kwado mmebi oxidative site na ịhazi ọrụ nke protein na-ebugharị ma ọ bụ enzymes metụtara na akpụkpọ ahụ mitochondrial, si otú ahụ na-abawanye ume ike na fatty acid oxidation.
Ụzọ nrịbama nwere ike agbakwunyere: AOD9604 sokwa na ịhazi ụzọ mgbama ndị ọzọ. Ọ nwere ike imetụta ọrụ nke ezinụlọ peroxisome proliferator-activated receptor (PPAR). PPAR bụ otu klas nke ndị na-anabata nuklia nke na-arụ ọrụ nchịkwa dị mkpa na metabolism lipid, nguzozi ike, na nzaghachi mkpali. AOD9604 nwere ike na-emekọrịta ihe na PPAR iji mezie ngosipụta nke mkpụrụ ndụ ihe nketa ha, si otú ahụ na-emetụta ntụgharị na ntụgharị mkpụrụ ndụ ihe nketa metụtara metabolism lipid, si otú ahụ na-achịkwa metabolism lipid. Ọ nwekwara ike sonye na nhazi nke ụzọ mgbaàmà insulin. Ọ bụ ezie na AOD9604 enweghị mmetụta ndị na-akpata ọrịa shuga jikọtara ya na hGH, ọ nwere ike imetụta usoro metabolism lipid na-apụtaghị ìhè site na imeziwanye ụzọ mgbaàmà insulin.
Mmetụta nke AOD9604
(1) Mmetụta dị na arọ ahụ na abụba
Ihe akaebe nnwale anụmanụ: N'ụdị òké oke ibu, ịgba ọgwụ intraperitoneal ogologo oge nke AOD9604 (ụbọchị iri na anọ nke nchịkwa na-adịghị ala ala) belatara ibu ahụ na abụba anụ ahụ. Mbelata a na ibu ahụ na abụba jikọtara ya na ọkwa okwu β (3) -AR RNA mụbara, na-egosi na AOD9604 na-akwalite lipolysis site na ịhazi okwu β (3) -AR, si otú a na-enweta mbelata na ibu ahụ na abụba anụ ahụ. Kpọmkwem, e nwere mbelata nke subcutaneous na visceral arọ abụba, yana mkpokọta ibu ibu. N'oge nnwale ahụ, nha nha òké mgbe niile yana nha nha anụ ahụ ziri ezi na-egosi na ụmụ oke a na-emeso AOD9604 belatara ịdị arọ ahụ na abụba buru ibu ma e jiri ya tụnyere ndị njikwa, yana mbelata a na-egosi usoro dabere dose.
Ọgụgụ 2 Ugbu a na Ezubere Ezubere Ọgwụ Ọgwụ Ọdịnihu na njikwa ibu
Maka ọgwụgwọ oke oke mmadụ, mmetụta nke AOD9604 na-ejide uru ngwa ngwa. Oke ibu bụ ihe dị mkpa maka ọtụtụ ọrịa na-adịghị ala ala dịka ọrịa obi na ọrịa shuga, na ibelata ibu na abụba dị oke mkpa maka ịkwalite ọnọdụ ahụike nke ndị ọrịa buru ibu.
(2) Mmetụta na Metabolism Energy
Mmụba Mmefu Ike: AOD9604 na-abawanye mmefu ike na ụmụ oke nkịtị yana β(3) -AR gene knockout ụmụ oke. N'ime ụmụ oke nkịtị, a na-eji calorimetry na-apụtaghị ìhè iji tụọ oriri oxygen na mmepụta carbon dioxide, na-ekpughe na AOD9604 mụbara ọnụ ọgụgụ metabolism ike. A na-ekwu na mmetụta a sitere na AOD9604 na-akwalite lipolysis, yana fatty acids a tọhapụrụ na-eje ozi dị ka ihe ike maka oxidation na itinye n'ọrụ, si otú ahụ na-abawanye mmefu ike. Na β (3) - AR knockout ụmụ oke, ọ bụ ezie na usoro ya anaghị adabere na β (3) -AR, a ka na-ahụ mmụba nke mmefu ike, na-egosipụtakwa na AOD9604 nwere usoro nhazi usoro nhazi ume nke na-adabere na β (3) -AR.
Iwu nke oxidation abụba: AOD9604 na-eme ka usoro oxidation abụba dịkwuo mma. N'ime nnwale cellular, na-eji acid fatty akpọrọ radieshon iji soro metabolism ha oxidative, achọpụtara na ọnụego nke fatty acid oxidation agbagoro na sel ndị ejiri AOD9604 mesoo ya. Nke a abụghị naanị na-enyere aka belata nchekwa abụba kamakwa na-enye ahụ ahụ ike karịa. AOD9604 nwere ike ịkwalite arụmọrụ oxidation fatty acid site na ịhazi ọrụ mitochondrial, ịba ụba biogenesis na ọrụ mitochondrial. Ọ na-akwalite nkwupụta na ọrụ nke enzymes metụtara fatty acid oxidation na mitochondria, gụnyere carnitine palmitoyltransferase I (CPT-I), nke bụ isi ihe na-egbochi ọnụọgụ enzyme maka fatty acids na-abanye na mitochondria maka oxidation. AOD9604 nwere ike ịkwalite ntinye fatty acid n'ime mitochondria maka ire ere oxidative site na ịkwalite okwu CPT-I.
(3) Mmetụta na metabolism lipid imeju
Ọmụmụ nnwale anụmanụ imeju lipid metabolism: N'ime ụdị imeju abụba abụba, a nyochara nsonaazụ AOD9604 na metabolism lipid imeju. E kewara oke oke n'ime otu njikwa, otu mmega ahụ, mmega ahụ + AOD9604 otu, yana otu AOD9604 naanị otu ọgwụgwọ. Nsonaazụ gosipụtara na ọkwa alanine aminotransferase (ALT) na otu AOD9604 naanị yana mmega ahụ + AOD9604 dị ala karịa ndị nọ na njikwa ahụ, na-egosi na AOD9604 nwere mmetụta nchebe ụfọdụ na mmebi imeju. Enwere ike ịsị nke a na AOD9604 na-achịkwa metabolism lipid na imeju, na-ebelata mkpokọta abụba na imeju, si otú a na-ebelata steatosis imeju na nzaghachi mkpali.
Mmetụta na enzymes imeju na cytokeratin-18 (CK18): Cytokeratin-18 bụ biomarker na-egosipụta hepatocyte apoptosis. Na nnwale ahụ, ọ bụ ezie na otu monotherapy AOD9604 ebelataghị ọkwa CK18 nke ọma, ọ meghịkwa mmetụta ọjọọ. Nke a na-egosi na AOD9604 nwere ike imetụta usoro apoptosis nke mkpụrụ ndụ imeju n'ụzọ na-edoghị anya site na ịhazi metabolism lipid hepatic, si otú a na-echebe mkpụrụ ndụ imeju site na mmebi ruo n'ókè ụfọdụ. AOD9604 nwere ike ịnọgide na-enwe nguzozi nke metabolism lipid imeju site n'ịchịkwa okwu nke mkpụrụ ndụ ihe nketa metụtara njikọ lipid, mbugharị na mmebi imeju, si otú a na-ebelata mkpokọta abụba na-adịghị mma na imeju.
Ngwa nke AOD9604
(1) Ngwa nwere ike na ọgwụgwọ oke ibu
Uru na Atụmanya: Tụnyere ọgwụ ọdịnala na-efunahụ ibu, AOD9604 nwere ọtụtụ uru nwere ike. Ọ nweghị mmetụta ndị metụtara ọrịa shuga metụtara hGH. hGH nwere ike ibute mmeghachi omume ọjọọ dị ka nguzogide insulin na ọkwa glucose ọbara dị elu mgbe ejiri ya na-agwọ oke ibu. AOD9604 na-ezere mmetụta ndị a site na nhazi nhazi ya pụrụ iche. AOD9604 nwere ike ịhazi metabolism lipid, kwalite ndakpọ abụba, yana ịbawanye mmefu ike, na-enye atụmanya ọgwụgwọ na-ekwe nkwa maka ndị ọrịa nwere oke ibu dị mfe. Usoro ya na-agụnye ọtụtụ ọkwa, ọ bụghị naanị site na nhazi nke ụzọ β-adrenergic kamakwa site na usoro na-adabere na β (3) -AR, na-enye usoro ntinye aka zuru oke maka ọgwụgwọ oke ibu.
(2) Ngwa nwere ike ime na ọgwụgwọ ọrịa imeju
Enwere ike ịgwọ ọrịa imeju na-adịghị egbu egbu (NAFLD): NAFLD bụ ọrịa imeju na-emekarị site na nchịkọta abụba dị ukwuu na imeju. N'ụdị òké nke ọrịa imeju abụba abụba, AOD9604 nwere ike ịhazi metabolism lipid imeju, belata abụba imeju, ma melite akara ọrụ imeju. AOD9604 nwere ụfọdụ uru ngwa maka ọgwụgwọ NAFLD. Ọ nwere ike belata mkpokọta abụba n'ime imeju site n'ịkwalite ndakpọ na ibufe abụba n'ime imeju, si otú ahụ belata steatosis imeju na nzaghachi mkpali. AOD9604 nwekwara ike ịhazi nrụgide oxidative na ụzọ mgbaàmà mkpali n'ime imeju, na-echebekwa mkpụrụ ndụ imeju site na mmebi.
Mmechi
Dị ka peptide sitere na mpaghara C-terminal nke hormone uto mmadụ, usoro AOD9604 na-arụ ọrụ na-achịkwa metabolism lipid gụnyere mmekọrịta ya na ụzọ β-adrenergic na mmetụta kpọmkwem na-adabere na β(3) -AR. Site na usoro ndị a, AOD9604 na-ebelata ibu ahụ na abụba anụ ahụ nke ọma, na-abawanye mmefu ume, na-achịkwa oxidation abụba, ma na-emezi metabolism lipid imeju. N'ihe gbasara ngwa, AOD9604 nwere nkwa dị ịrịba ama na ọgwụgwọ oke ibu, ọgwụ egwuregwu, na ọrịa imeju.
Isi mmalite
[1] Dehbashi M, Fathi M, Attarzadeh Hosseini SR, et al. Mmetụta nke Ọzụzụ ntachi obi nke izu asatọ, Injection Somatropin, na Mpekere Lipolytic ya (AOD9604) na Cytokeratin-18 na Enzymes imeju nke ụmụ oke kpatara mmebi imeju n'ihi nri dị elu nke abụba [J]. Otu ụzọ n'ụzọ anọ nke Horizon of Medical Sciences, 2021,27:502-517.DOI:10.32598/hms.27.4.3513.1.
[2] Cox HD, Smeal SJ, Hughes CM, et al. Nchọpụta na in vitro metabolism nke AOD9604[J]. Nyocha na nyocha ọgwụ, 2015,7 (1): 31-38.DOI: 10.1002 / dta.1715.
[3] Stier H, Vos E, Kenley DL Safety and Tolerability of the Hexadecapeptide AOD9604 in Humans[J]. Akwụkwọ akụkọ nke Endocrinology na Metabolism, 2013,3:7-15.
https://api.semanticscholar.org/CorpusID:56559133
[4] Witkamp R F. Ebumnuche ọgwụ ugbu a na ọdịnihu na njikwa ibu[J]. Nnyocha ọgwụ, 2011,28 (8): 1792-1818.DOI: 10.1007 / s11095-010-0341-1.
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