Los ntawm Cocer Peptides 
25 hnub dhau los
Tag nrho cov kab lus thiab cov ntaub ntawv ntawm cov khoom lag luam muab rau ntawm lub vev xaib no tsuas yog rau cov ntaub ntawv tshaj tawm kev tshaj tawm thiab cov hom phiaj kev kawm.
Cov khoom muab rau hauv lub vev xaib no yog npaj tshwj xeeb rau kev tshawb fawb hauv vitro. Kev tshawb fawb hauv vitro (Latin: * hauv iav *, lub ntsiab lus hauv iav) yog ua los ntawm tib neeg lub cev. Cov khoom no tsis yog tshuaj, tsis tau txais kev pom zoo los ntawm US Food and Drug Administration (FDA), thiab yuav tsum tsis txhob siv los tiv thaiv, kho, lossis kho txhua yam mob, kab mob, lossis mob. Nws raug txwv nruj raws li txoj cai los qhia cov khoom no rau hauv tib neeg lossis tsiaj lub cev hauv txhua daim ntawv.
Kev txhais ntawm AOD9604
AOD9604 yog peptide muab los ntawm C-terminal fragment ntawm human growth hormone (hGH). Nws muaj cov amino acids 177-191 ntawm hGH, nrog ib qho ntxiv tyrosine residue (Tyr) ntxiv ntawm N-terminal kawg ntawm peptide, piv txwv li, Tyr-hGH 177-191. Cov amino acid ib ntus ntawm AOD9604 txiav txim siab nws qhov kev sib haum xeeb, uas ua rau nws cuam tshuam nrog ntau yam receptors thiab molecules hauv lub cev. Cov tyrosine residue ntxiv ntawm N-terminus tuaj yeem cuam tshuam rau kev ruaj ntseg ntawm peptide hauv lub cev, cell uptake efficiency, thiab khi affinity nrog cov receptors tshwj xeeb. AOD9604 belongs rau chav kawm ntawm peptide tebchaw, uas koom nrog ntau yam txheej txheem physiological hauv lub cev, xws li cov teeb liab hloov pauv thiab kev tswj hwm metabolic. Vim nws cov keeb kwm tshwj xeeb thiab cov qauv, AOD9604 muaj cov haujlwm tshwj xeeb ntawm lub cev, tshwj xeeb tshaj yog nthuav tawm cov txiaj ntsig tseem ceeb hauv kev tswj hwm lipid metabolism.
Mechanism ntawm AOD9604 hauv Regulating Lipid Metabolism
(1) Koom nrog txoj hauv kev β-adrenergic
Kev tswj hwm ntawm β-adrenergic receptor qhia: AOD9604 tuaj yeem cuam tshuam lipid metabolism los ntawm kev cuam tshuam nrog β-adrenergic txoj hauv kev, tshwj xeeb yog los ntawm kev tswj hwm ntawm β(3)-adrenergic receptor (β(3)-AR). Hauv cov qauv nas rog rog, tom qab 14 hnub sib law liag ntawm kev txhaj tshuaj intraperitoneal ntawm AOD9604, qib qhia ntawm β(3)-AR RNA hauv adipocytes tau nce. Lub β(3)-AR yog thawj lipolytic receptor hauv adipocytes, thiab nws cov lus qhia ntxiv txhawb lipolysis. AOD9604 tuaj yeem txhim kho qhov kev qhia ntawm β(3)-AR noob los ntawm kev ua kom muaj feem cuam tshuam txog kev taw qhia, yog li ua kom nws qhov chaw nthuav tawm hauv hlwb. Nws tuaj yeem cuam tshuam kev khi ntawm qee yam kev hloov pauv mus rau thaj tsam txhawb nqa ntawm β(3)-AR noob, yog li txhim kho qhov ua tau zoo ntawm kev pib hloov pauv noob.
Cov kev cuam tshuam cascading ntawm β-adrenergic txoj kev ua kom: Thaum β(3)-AR nthuav qhia nce, nws khi rau ligands kom qhib cov kev taw qhia hauv qab. Activated β(3)-AR khub niam txiv nrog G proteins, ua rau kom ua kom cov adenylate cyclase, uas nyob rau hauv lem nce lub intracellular theem ntawm lub thib ob messenger cyclic adenosine monophosphate (cAMP). cAMP activates protein kinase A (PKA), uas phosphorylates thiab activates hormone-sensitive lipase (HSL), ib tug tseem ceeb enzyme nyob rau hauv lipolysis uas catalyzes hydrolysis ntawm triglycerides rau hauv fatty acids thiab glycerol, yog li txhawb lipolysis thiab tswj lipid metabolism.
(2) Cov teebmeem ncaj qha ntawm β(3)-AR
Kev tshawb pom mob hnyav: Hauv kev sim mob hnyav nrog β(3)-AR gene-knockout nas, AOD9604 tseem nce kev siv hluav taws xob thiab roj oxidation. Qhov no qhia tau hais tias AOD9604 txoj kev tswj xyuas cov nyhuv ntawm lipid metabolism tsis yog nyob ntawm β(3)-AR. Txawm hais tias cov txheej txheem tshwj xeeb tseem tsis tau nkag siab tag nrho, lwm txoj hauv kev lossis cov phiaj xwm ncaj qha tuaj yeem tshwm sim. AOD9604 tuaj yeem ua ncaj qha rau mitochondria, cuam tshuam mitochondrial muaj nuj nqi thiab txhim kho β-oxidation ntawm fatty acids. Mitochondria yog lub hauv paus hubs ntawm cellular zog metabolism, thiab fatty acid β-oxidation tshwm sim nyob rau hauv mitochondria. AOD9604 tuaj yeem txhawb fatty acid nkag mus rau hauv mitochondria thiab pab txhawb oxidative degradation los ntawm kev tswj cov kev ua ntawm thauj cov proteins los yog muaj feem xyuam rau cov enzymes ntawm lub mitochondrial membrane, yog li nce zog siv nyiaj thiab fatty acid oxidation.
Muaj peev xwm ntxiv kev taw qhia txoj hauv kev: AOD9604 tseem koom nrog hauv kev tswj hwm lwm txoj hauv kev. Nws tuaj yeem cuam tshuam cov haujlwm ntawm peroxisome proliferator-activated receptor (PPAR) tsev neeg. PPARs yog ib chav kawm ntawm nuclear receptors uas ua lub luag haujlwm tseem ceeb hauv kev tswj cov lipid metabolism, lub zog sib npaug, thiab cov lus teb inflammatory. AOD9604 tuaj yeem cuam tshuam nrog PPARs los tswj cov kev qhia ntawm lawv lub hom phiaj cov noob, yog li cuam tshuam rau kev hloov pauv thiab kev txhais cov lipid metabolism ntsig txog cov noob, yog li tswj cov lipid metabolism. Nws kuj tseem tuaj yeem koom nrog hauv kev tswj hwm ntawm txoj kev taw qhia cov tshuaj insulin. Txawm hais tias AOD9604 tsis muaj cov kab mob ntshav qab zib ua rau muaj kev phiv cuam tshuam nrog hGH, nws tuaj yeem cuam tshuam ncaj qha rau cov txheej txheem lipid metabolism los ntawm kev kho cov tshuaj insulin kom zoo.
Cov teebmeem ntawm AOD9604
(1) Kev cuam tshuam rau lub cev hnyav thiab rog
Tsiaj cov pov thawj: Hauv cov qauv nas rog rog, kev txhaj tshuaj ntev ntev ntawm AOD9604 (14 hnub ntawm kev tswj hwm ntev) ua rau lub cev hnyav thiab lub cev muaj roj ntau. Qhov kev txo qis hauv lub cev hnyav thiab rog tau cuam tshuam nrog nce β(3)-AR RNA qhia theem, qhia tias AOD9604 txhawb nqa lipolysis los ntawm kev tswj hwm β(3)-AR qhia, yog li ua tiav qhov txo qis hauv lub cev hnyav thiab lub cev rog. Tshwj xeeb, muaj kev txo qis hauv subcutaneous thiab visceral rog rog, nrog rau tag nrho qhov hnyav. Thaum lub sij hawm sim, kev ntsuas tus nas qhov hnyav thiab qhov tseeb tom qab ntsuas qhov hnyav ntawm cov nqaij rog tau qhia tias AOD9604-kho nas tau nthuav tawm qhov hnyav ntawm lub cev thiab rog hnyav piv rau pawg tswj hwm, nrog qhov txo qis no qhia txog kev noj tshuaj ntau ntxiv.
Daim duab 2 Tam sim no thiab yav tom ntej Cov Hom Phiaj Tshuaj hauv Kev Tswj Kev Nyuaj Siab
Rau kev kho mob ntawm tib neeg kev rog rog, cov teebmeem ntawm AOD9604 tuav cov peev txheej ntawm daim ntawv thov. Kev rog rog yog qhov tseem ceeb ntawm kev pheej hmoo rau ntau yam kab mob ntev xws li kab mob plawv thiab ntshav qab zib, thiab txo lub cev hnyav thiab rog yog qhov tseem ceeb rau kev txhim kho kev noj qab haus huv ntawm cov neeg mob rog.
(2) Kev cuam tshuam rau lub zog Metabolism
Kev siv hluav taws xob ntau ntxiv: AOD9604 nce kev siv hluav taws xob hauv ob qho tib si nas thiab β(3)-AR gene knockout nas. Hauv cov nas ib txwm muaj, siv cov calorimetry tsis ncaj los ntsuas cov pa oxygen thiab cov pa roj carbon dioxide ntau lawm, qhia tias AOD9604 ua rau muaj zog metabolism ntau ntxiv. Cov nyhuv no yog ntaus nqi rau AOD9604 txhawb lipolysis, nrog rau cov roj fatty acids tso tawm los ua lub zog substrates rau oxidation thiab siv, yog li ua kom muaj zog siv nyiaj. Hauv β(3)-AR knockout nas, txawm hais tias nws cov txheej txheem ntawm kev ua haujlwm tsis yog nyob ntawm β(3)-AR, kev nce hauv kev siv hluav taws xob tseem tau pom, ntxiv ua pov thawj tias AOD9604 muaj lub zog metabolism hauv txoj kev ywj pheej ntawm β(3)-AR.
Kev tswj cov roj oxidation: AOD9604 txhim kho cov txheej txheem roj oxidation. Hauv kev sim ntawm tes, siv cov xov tooj cua uas sau cov roj fatty acids los taug qab lawv cov oxidative metabolism, nws tau pom tias tus nqi ntawm fatty acid oxidation tau nrawm hauv hlwb kho nrog AOD9604. Qhov no tsis tsuas yog pab txo cov roj cia tab sis kuj muab lub cev muaj zog ntxiv. AOD9604 tuaj yeem txhim kho fatty acid oxidation efficiency los ntawm kev tswj mitochondrial muaj nuj nqi, nce mitochondrial biogenesis thiab kev ua haujlwm. Nws txhawb kev qhia thiab kev ua haujlwm ntawm enzymes ntsig txog fatty acid oxidation hauv mitochondria, suav nrog carnitine palmitoyltransferase I (CPT-I), uas yog qhov tseem ceeb ntawm cov enzymes rau fatty acids nkag mus rau mitochondria rau oxidation. AOD9604 tuaj yeem txhawb cov kua qaub nkag mus rau hauv mitochondria rau oxidative decomposition los ntawm upregulating CPT-I qhia.
(3) Kev cuam tshuam rau lub siab lipid metabolism
Hepatic lipid metabolism hauv tsiaj txoj kev tshawb fawb: Hauv tus qauv nas fatty siab, qhov cuam tshuam ntawm AOD9604 ntawm cov kab mob siab lipid metabolism tau tshawb xyuas. Cov nas tau muab faib ua pawg tswj hwm, pawg ua haujlwm, ib qho kev tawm dag zog + AOD9604 pawg, thiab pab pawg kho mob AOD9604 ib leeg. Cov txiaj ntsig tau pom tias cov qib alanine aminotransferase (ALT) hauv AOD9604 ib leeg pab pawg thiab kev tawm dag zog + AOD9604 pawg tau qis dua cov hauv pawg tswj hwm, qhia tias AOD9604 muaj qee yam kev tiv thaiv ntawm daim siab puas. Qhov no tuaj yeem raug ntaus nqi rau AOD9604 tswj cov lipid metabolism hauv daim siab, txo cov rog hauv daim siab, yog li txo qis hepatic steatosis thiab inflammatory teb.
Kev cuam tshuam rau daim siab enzymes thiab cytokeratin-18 (CK18): Cytokeratin-18 yog biomarker xav txog hepatocyte apoptosis. Hauv kev sim, txawm hais tias pawg AOD9604 monotherapy tsis txo qis CK18 qib, nws kuj tsis tsim qhov tsis zoo. Qhov no qhia tias AOD9604 tuaj yeem cuam tshuam ncaj qha rau cov txheej txheem apoptosis ntawm daim siab hlwb los ntawm kev tswj cov kab mob siab lipid metabolism, yog li tiv thaiv lub siab hlwb los ntawm kev puas tsuaj rau qee qhov. AOD9604 tuaj yeem tswj hwm qhov sib npaug ntawm cov kab mob siab lipid metabolism los ntawm kev tswj cov kev qhia ntawm cov noob muaj feem xyuam rau lipid synthesis, thauj, thiab degradation hauv daim siab, yog li txo qis cov rog tsis zoo hauv daim siab.
Kev siv ntawm AOD9604
(1) Muaj peev xwm siv tau hauv kev kho mob rog rog
Qhov Zoo thiab Kev Pom Zoo: Muab piv rau cov tshuaj poob phaus, AOD9604 muaj ntau yam zoo. Nws tsis muaj qhov mob ntshav qab zib muaj feem cuam tshuam nrog hGH. hGH tuaj yeem ua rau muaj kev phiv xws li insulin tsis kam thiab nce ntshav qabzib thaum siv los kho kev rog. AOD9604 zam cov kev mob tshwm sim los ntawm nws cov qauv tsim tshwj xeeb. AOD9604 tuaj yeem tshwj xeeb tswj cov lipid metabolism, txhawb kev rog rog, thiab nce kev siv zog, muab kev cia siab rau kev kho mob rau cov neeg mob rog yooj yim. Nws cov txheej txheem ntawm kev nqis tes ua cuam tshuam nrog ntau theem, tsis yog los ntawm kev tswj hwm ntawm β-adrenergic txoj hauv kev tab sis kuj los ntawm kev ywj pheej ntawm β(3)-AR, muab kev cuam tshuam ntau dua rau kev kho mob rog.
(2) Muaj peev xwm siv tau hauv kev kho mob siab
Muaj peev xwm kho cov kab mob uas tsis yog-alcoholic fatty siab (NAFLD): NAFLD yog ib hom kab mob siab uas tshwm sim los ntawm cov rog ntau hauv daim siab. Hauv cov qauv nas ntawm cov kab mob rog rog, AOD9604 tuaj yeem tswj cov kab mob siab lipid metabolism, txo cov rog hauv siab, thiab txhim kho daim siab ua haujlwm. AOD9604 muaj qee tus nqi thov rau kev kho mob NAFLD. Nws tuaj yeem txo cov rog nyob hauv daim siab los ntawm kev txhawb nqa kev tawg thiab thauj cov rog hauv daim siab, yog li txo qis hepatic steatosis thiab inflammatory teb. AOD9604 tseem tuaj yeem tswj oxidative kev nyuaj siab thiab inflammatory signaling txoj kev nyob rau hauv lub siab, ntxiv tiv thaiv daim siab hlwb los ntawm kev puas tsuaj.
Xaus
Raws li peptide muab los ntawm C-terminal cheeb tsam ntawm tib neeg txoj kev loj hlob hormone, AOD9604 cov txheej txheem ntawm kev ua haujlwm hauv kev tswj cov lipid metabolism cuam tshuam nrog kev cuam tshuam nrog β-adrenergic txoj hauv kev thiab cov teebmeem ncaj qha ntawm β(3)-AR. Los ntawm cov txheej txheem no, AOD9604 zoo txo lub cev hnyav thiab lub cev rog, nce kev siv hluav taws xob, tswj cov roj oxidation, thiab txhim kho hepatic lipid metabolism. Hais txog kev siv, AOD9604 tuav cov lus cog tseg tseem ceeb hauv kev kho mob rog rog, tshuaj kis las, thiab kab mob siab.
Qhov chaw
[1] Dehbashi M, Fathi M, Attarzadeh Hosseini SR, et al. Cov nyhuv ntawm yim lub lis piam Endurance Training, Somatropin Txhaj, thiab Nws Lipolytic Fragment (AOD9604) ntawm Cytokeratin-18 thiab lub siab Enzymes ntawm nas ua rau lub siab puas tsuaj vim yog noj zaub mov muaj roj ntau [J]. Peb lub hlis twg ntawm 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. Kev kuaj pom thiab hauv vitro metabolism ntawm AOD9604 [J]. Kev Ntsuas Tshuaj thiab Tshuaj Ntsuam Xyuas, 2015,7(1):31-38.DOI:10.1002/dta.1715.
[3] Stier H, Vos E, Kenley D. Phau ntawv Journal of Endocrinology thiab Metabolism, 2013, 3:7-15.
https://api.semanticscholar.org/CorpusID:56559133
[4] Witkamp R F. Tam sim no thiab yav tom ntej Cov Hom Phiaj Tshuaj hauv Kev Tswj Pwm [J]. Pharmaceutical Research, 2011,28(8):1792-1818.DOI:10.1007/s11095-010-0341-1.
Cov khoom muaj rau kev tshawb fawb siv nkaus xwb:
