Los ntawm Cocer Peptides 
1 month ago
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.
Basic Information about KPV
KPV yog ib qho tripeptide nrog cov khoom tseem ceeb los tiv thaiv kab mob, uas ua rau nws ua lub luag haujlwm hauv ntau qhov chaw.
Daim duab 1 Cov Kev Kho Mob ntawm HA-KPV-NPs tawm tsam UC Qhov ncauj kev tswj hwm ntawm HA-KPV-NPs embedded hauv hydrogel (chitosan / alginate) confers kev sib xyaw ua ke los tiv thaiv UC los ntawm kev ua kom cov mucosa kho thiab txo qhov mob.
Anti-inflammatory Mechanism ntawm KPV
1. Kev cai ntawm Cell Signaling Pathways
NF-κB Kev Tshaj Tawm Txoj Kev: NF-κB yog qhov tseem ceeb ntawm kev sau ntawv ua lub luag haujlwm tseem ceeb hauv cov lus teb inflammatory. Thaum cov hlwb raug inflammatory stimuli, NF-κB translocates los ntawm cytoplasm mus rau lub nucleus, pib transcription ntawm pro-inflammatory cytokine noob. KPV tuaj yeem inhibit qhov ua kom NF-κB. Nyob rau hauv tib neeg lub plab hnyuv epithelial hlwb thiab tib neeg T hlwb, hlwb tau txhawb nrog pro-inflammatory cytokines, thiab KPV tau ntxiv ib txhij. Siv txoj hauv kev xws li NF-κB luciferase gene reporter assays, protein immunoblotting, real-time reverse transcription polymerase chain reaction, thiab enzyme-linked immunosorbent assay (ELISA), nws tau pom tias KPV ntawm nanomolar concentrations tuaj yeem inhibit NF-κB activation, yog li txo qhov tso tawm ntawm pro-inflammatory cytokines. Cov txheej txheem no yog qhov tseem ceeb hauv kev tswj hwm txoj hnyuv, vim tias kev ua kom ntau dhau ntawm NF-κB hauv plab hnyuv epithelial hlwb thiab lub cev tsis muaj zog yog qhov tseem ceeb ntawm cov kab mob plab hnyuv (IBD) thiab lwm yam kab mob hauv plab hnyuv.
MAP kinase signaling pathway: Txoj kev taw qhia mitogen-activated protein kinase (MAPK) yog lwm txoj hauv kev tseem ceeb hauv cov lus teb inflammatory, suav nrog cov xov tooj hluav taws xob ntxiv- tswj kinase (ERK), c-Jun N-terminal kinase (JNK), thiab p38 MAPK. Cov kinases no tau qhib thaum cov hlwb raug rau cov inflammatory stimuli, ua rau cov phosphorylation ntawm downstream transcription yam thiab txhawb kev qhia ntawm o ntawm cov noob caj noob ces. KPV tseem tuaj yeem cuam tshuam MAP kinase inflammatory signaling txoj kev. Thaum cov hlwb raug inflammatory stimuli, KPV tuaj yeem thaiv MAPK ua kom, txo nws cov phosphorylation ntawm downstream transcription yam, yog li txo cov zus tau tej cov pro-inflammatory cytokines. Nyob rau hauv lub xeev inflammatory, ua kom p38 MAPK ua rau muaj kev nthuav qhia ntawm pro-inflammatory cytokines xws li TNF-α thiab IL-6, thaum KPV muaj peev xwm inhibit p38 MAPK kev ua, txo qhov tso tawm ntawm cov cytokines thiab yog li alleviating inflammatory teb.
2. Cell transporter-mediated teebmeem
PepT1 transporter: PepT1 yog di / tripeptide transporter feem ntau qhia hauv cov hnyuv me tab sis raug ntxias hauv cov nyuv thaum IBD. Cov tshuaj tiv thaiv kab mob ntawm KPV yog ib nrab kho los ntawm PepT1. Hauv kev sim uptake, txias KPV tau siv los ua kev sib tw inhibitor rau hPepT1 raws li cov xov tooj cua sau npe substrate, lossis [⊃3;H]KPV tau siv los txiav txim siab cov yam ntxwv ntawm KPV uptake. KPV nkag mus rau hauv lub cev tiv thaiv kab mob thiab plab hnyuv epithelial hlwb ntawm hPepT1. Qhov no qhia tau hais tias PepT1, raws li kev thauj mus los, pab txhawb KPV nkag mus rau hauv cov hlwb kom siv nws cov teebmeem los tiv thaiv. Thaum PepT1 muaj nuj nqi yog inhibited, tus nqi ntawm KPV nkag mus rau hauv hlwb txo, thiab nws cov teebmeem los tiv thaiv tsis muaj zog. Hauv cov qauv ntawm tes nrog knockdown ntawm PepT1 kev qhia, txawm tias thaum tswj hwm tib lub siab, KPV nthuav tawm qhov txo qis inhibitory cuam tshuam ntawm NF-κB ua kom muaj zog thiab txo qis kev tso tawm ntawm cov cytokines piv rau cov hlwb nrog cov lus qhia PepT1, ntxiv kev lees paub lub luag haujlwm tseem ceeb ntawm PepT1 hauv kev tiv thaiv kev tiv thaiv ntawm KPV.
3. Kev tswj ntawm inflammatory cytokines
Inhibition ntawm pro-inflammatory cytokines: KPV tuaj yeem cuam tshuam kev tsim khoom thiab tso tawm ntau yam pro-inflammatory cytokines. TNF-α yog ib qho tseem ceeb cytokine nyob rau hauv cov lus teb inflammatory, muaj peev xwm ua kom lub cev tiv thaiv kab mob, inducing zus tau tej cov pro-inflammatory cytokines, thiab ua rau cov ntaub so ntswg puas. Hauv ntau cov qauv inflammatory, cov theem qhia ntawm TNF-α tau txo qis tom qab kho KPV. Piv txwv li, hauv cov qauv sodium sulfate-induced nas colitis, kev kho mob nrog KPV ua rau txo qis hauv mRNA qhia ntawm TNF-α hauv cov hnyuv, raws li tshawb pom los ntawm lub sijhawm tiag tiag RT-PCR, thiab qhov txo qis ntawm cov protein ntawm TNF-α hauv cov ntshav, raws li ELISA pom. IL-1β, IL-6, thiab lwm yam pro-inflammatory cytokines kuj inhibited los ntawm KPV. IL-1β tuaj yeem ua rau cov tshuaj tiv thaiv kab mob sib kis, txhawb kev tso tawm ntawm lwm cov tshuaj kho mob. KPV tuaj yeem txo nws txoj kev qhia thiab tso tawm hauv cov ntaub so ntswg, yog li txo qhov kev siv ntawm cov lus teb inflammatory.
Txhawb kev tiv thaiv kab mob cytokines: Ntxiv nrog rau inhibiting pro-inflammatory cytokines, KPV kuj tseem tuaj yeem txhawb kev qhia ntawm cov tshuaj tiv thaiv cytokines. Interleukin-10 (IL-10) yog ib qho tseem ceeb los tiv thaiv cytokine uas tuaj yeem cuam tshuam kev ua kom lub cev tiv thaiv kab mob thiab txo qis kev tsim cov cytokines pro-inflammatory.
4. Kev tswj ntawm lub cev tiv thaiv kab mob
Kev tswj ntawm T cell muaj nuj nqi: T hlwb ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob thiab kev tswj kev mob. Nyob rau hauv cov mob inflammatory, T hlwb tau qhib thiab tso tawm pro-inflammatory cytokines. Cov kev tshawb fawb tau pom tias KPV tuaj yeem tswj T cell muaj nuj nqi. Hauv kev sim nrog tib neeg T cell kab Jurkat, thaum Jurkat hlwb raug txhawb nrog pro-inflammatory cytokines, qhov sib ntxiv ntawm KPV inhibited T cell activation thiab txo qhov tso tawm ntawm pro-inflammatory cytokines xws li IFN-γ. Qhov no tuaj yeem ua tiav los ntawm inhibiting NF-κB thiab MAPK txoj hauv kev hauv T hlwb. Tsis tas li ntawd, hauv qee cov qauv tsiaj, xws li CD45RB (hi) colonic o qauv, KPV kev kho mob tuaj yeem tswj T cell infiltration thiab ua haujlwm hauv cov hnyuv, txo cov kab mob T cell subsets xws li Th1 thiab Th17 hlwb, thiab nce qhov kev faib ua feem ntawm kev tswj T hlwb, li no alleviating plab hnyuv o.
Modulation ntawm macrophage muaj nuj nqi: Macrophages yog cov tshuaj tiv thaiv kab mob tseem ceeb hauv cov lus teb inflammatory thiab tuaj yeem muab faib ua classical activated M1 macrophages thiab activated M2 macrophages raws li lawv lub xeev ua kom. M1 macrophages secrete ntau ntawm pro-inflammatory cytokines, thaum M2 macrophages muaj cov tshuaj tiv thaiv thiab kho cov ntaub so ntswg. KPV tuaj yeem tswj cov macrophage polarization. Cov kev sim hauv vitro tau pom tias thaum macrophages tau txhawb nqa nrog lipopolysaccharide (LPS) kom polarize mus rau hom M1, kev tswj hwm ntawm KPV inhibited macrophage polarization mus rau hom M1, txo qhov kev qhia ntawm M1 macrophage cov cim, thaum txhawb lawv cov polarization mus rau hom M2, nce kev qhia ntawm M2-macrophage. Arg-1). Nyob rau hauv vivo inflammatory qauv, xws li DSS-induced colitis nyob rau hauv nas, kev kho mob nrog KPV ua rau ntau macrophages nyob rau hauv cov hnyuv polarizing rau hom M2, li no alleviating inflammatory teb thiab txhawb cov ntaub so ntswg kho.
5. Kev tiv thaiv los ntawm cov kab mob hauv plab hnyuv epithelial
Txhim kho cov kab mob epithelial barrier muaj nuj nqi: Lub cev thaiv lub cev tsim los ntawm txoj hnyuv epithelial ua haujlwm ua thawj kab ntawm kev tiv thaiv kab mob thiab kev cuam tshuam cov tshuaj phem. Hauv cov xeev inflammatory, kev ua haujlwm tsis zoo ntawm plab hnyuv epithelial barrier ua rau cov kab mob translocation thiab endotoxin to, ntxiv exacerbating inflammatory teb. KPV tuaj yeem txhim kho kev ua haujlwm ntawm cov kab mob hauv plab hnyuv epithelial. Hauv vitro cell thwmsim, qhov uas cov kab mob plab hnyuv epithelial tau kho nrog pro-inflammatory cytokines los simulate ib puag ncig inflammatory, ua rau txo qis kev nthuav qhia ntawm cov proteins nruj (xws li ZO-1 thiab occludin) thiab kev ua haujlwm tsis zoo. Txawm li cas los xij, qhov sib ntxiv ntawm KPV tswj cov kev qhia ntawm cov nqaij sib txuas nruj nreem, txhim kho kev sib txuas ntawm cov cellular, thiab rov ua haujlwm ntawm cov kab mob hauv plab hnyuv epithelial. Nyob rau hauv DSS-induced colitis nas kho nrog KPV, immunohistochemistry thiab Western blot tsom xam qhia tau hais tias muaj zog hlws ris cov proteins nyob rau hauv cov hnyuv thiab txo txoj hnyuv permeability, qhia tias KPV tiv thaiv plab hnyuv epithelial barrier nyob rau hauv vivo, txo cov kev cuam tshuam ntawm cov teeb meem tshuaj, thiab alleviates.
Txhawb nqa epithelial cell proliferation thiab kho: o tuaj yeem ua rau kev puas tsuaj thiab kev tuag ntawm cov plab hnyuv epithelial, ua rau lub plab zom mov tsis zoo. KPV muaj peev xwm txhawb kev loj hlob thiab kho cov kab mob hauv plab hnyuv epithelial. Hauv vitro cell kab lis kev cai thwmsim pom tau hais tias kho cov kab mob plab hnyuv epithelial nrog KPV txhim kho cell proliferation, raws li kuaj pom los ntawm Cell Counting Kit (CCK-8). Tsis tas li ntawd, kev tshuaj ntsuam xyuas immunofluorescence tau nthuav tawm ntau ntxiv ntawm kev nthuav tawm ntawm cov xov tooj ntawm tes nuclear antigen (PCNA), qhia tias cov hlwb nyob hauv lub xeev muaj zog. Hauv TNBS-induced ulcerative colitis nas qauv, tom qab kev kho mob nrog KPV / SH-PGA hydrogel, histological kev soj ntsuam qhia tau hais tias kev puas tsuaj rau colonic epithelial hlwb raug kho, thiab crypt cov qauv maj mam rov qab mus rau qhov qub. Qhov no tej zaum yuav muaj feem xyuam rau KPV qhov kev txhawb nqa ntawm epithelial cell proliferation thiab kho, uas yuav pab txo qhov mob thiab txhawb txoj hnyuv rov qab.
Daim duab 2 KPV yog kho nyob rau hauv DSS colitis.
6. Cov teebmeem Antioxidant
Kev tswj ntawm oxidative stress-related markers: Inflammation feem ntau nrog oxidative kev nyuaj siab tshwm sim, nrog nce zus tau tej cov pa reactive oxygen hom (ROS) thiab reactive nitrogen hom (RNS), ua rau oxidative puas hlwb thiab cov ntaub so ntswg. KPV nthuav tawm cov teebmeem antioxidant thiab tuaj yeem tswj oxidative kev ntxhov siab txog cov cim. Hauv qee cov qauv inflammatory, xws li paj rwb pob-induced nas granuloma qauv thiab qe dawb-induced nas dorsal air sac synovitis qauv, nce qib ntawm malondialdehyde (MDA) thiab txo qis superoxide dismutase (SOD) kev ua haujlwm tau kuaj pom hauv cov ntaub so ntswg. Tom qab KPV kev kho mob, MDA qib txo qis, thiab SOD kev ua haujlwm tau nce. MDA yog cov khoom ntawm lipid peroxidation, thiab nws cov qib txo qis qhia tias txo qis lipid peroxidation puas rau cov hlwb; SOD yog ib qho tseem ceeb antioxidant enzyme, thiab nws cov kev ua ub no ntxiv qhia txog kev muaj peev xwm los tshem tawm cov dawb radicals. KPV tuaj yeem txo oxidative kev puas tsuaj hauv cov ntaub so ntswg los ntawm kev tswj cov qib oxidative kev nyuaj siab, yog li ua rau muaj kev cuam tshuam los tiv thaiv.
7. Lwm yam muaj peev xwm Mechanisms
Kev sib raug zoo nrog melanocortin receptor: KPV yog tripeptide muab los ntawm α-MSH. Txawm hais tias nws cov tshuaj tiv thaiv kab mob yog ib feem ntawm MC1R signaling, lawv tuaj yeem cuam tshuam nrog MC1R hauv qee cov ntsiab lus. Hauv cov tsiaj uas qhia txog MC1Re/e, KPV kev kho mob tom qab DSS-induced colitis tseem ua rau muaj kev tiv thaiv kab mob tseem ceeb, cawm txhua tus tsiaj hauv pab pawg kho mob los ntawm kev tuag thaum lub sij hawm DSS-induced colitis, qhia tias KPV cov tshuaj tiv thaiv kab mob tsawg kawg yog ib feem ntawm MC1R signaling. Hauv cov tsiaj uas muaj MC1R ib txwm qhia, KPV tuaj yeem txhim kho kev tiv thaiv kab mob los ntawm kev cuam tshuam nrog MC1R lossis tswj nws cov kev taw qhia hauv qab.
Anti-inflammatory teebmeem ntawm KPV
1. Lub luag hauj lwm hauv cov kab mob plab hnyuv
DSS-induced colitis qauv: Nyob rau hauv DSS-induced nas colitis qauv, KPV tau pom muaj kev cuam tshuam loj heev. Nyob rau hauv cov nqe lus ntawm qhov hnyav hloov, nas kho nrog KPV rov qab lawv qhov hnyav ua ntej thiab ntau dua piv rau cov nas tsis kho. Cov kev soj ntsuam histological tau qhia txog qhov txo qis hauv kev nkag mus rau hauv cov nqaij mos ntawm KPV-kho nas, ntxiv kev lees paub los ntawm kev txo qis hauv myeloperoxidase (MPO) kev ua haujlwm. MPO yog ib qho enzyme tam sim no nyob rau hauv neutrophils, thiab nws cov qib kev ua ub no cuam tshuam txog qhov cuam tshuam ntawm cell infiltration hauv cov ntaub so ntswg. Qhov txo qis hauv MPO kev ua haujlwm tom qab KPV kev kho mob qhia tau tias txo qis neutrophil infiltration hauv cov hnyuv thiab txo cov lus teb inflammatory. Los ntawm kev kuaj pom mRNA kev qhia ntawm pro-inflammatory cytokines nyob rau hauv cov ntaub so ntswg colonic, xws li TNF-α thiab IL-1β, nws tau pom tias KPV kev kho mob txo cov kev qhia theem ntawm cov pro-inflammatory cytokines. KPV alleviated DSS-induced colitis cov tsos mob los ntawm ntau yam, nrog rau txo cov kab mob ntawm tes infiltration, txo cov inflammatory factor qhia, thiab txhawb yuag rov qab.
CD45RB(hi) colonic inflammatory model: Hauv CD45RB(hi) colonic inflammatory model, KPV kuj pom zoo los tiv thaiv kab mob. Cov qauv no tau raug ntxias los ntawm kev hloov T hlwb heev qhia CD45RB rau hauv cov nas uas tsis muaj zog. Tom qab KPV kev kho mob, cov nas tau nthuav tawm cov tsos mob zoo dua qub, rov ua kom lub cev hnyav dua, thiab kev kuaj mob histological tau qhia txog kev hloov pauv hauv plab hnyuv. KPV-kho pab pawg tau pom tias txo qis ntawm cov cell infiltration thiab txo cov txheej txheem kev puas tsuaj hauv cov plab hnyuv, qhia tias KPV ua haujlwm zoo rau CD45RB(hi)-induced plab hnyuv o thiab restores cov kab mob hauv plab hnyuv thiab ua haujlwm.
TNBS-induced ulcerative colitis model: Nyob rau hauv TNBS-induced ulcerative colitis rat model, KPV kuj pom tau tias muaj txiaj ntsig zoo. Tom qab siv KPV / SH-PGA hydrogel rectally rau cov nas, cov tsos mob ntawm tus kab mob colitis zoo dua. Cov qib kev poob phaus hauv nas tau txo qis, thiab cov qhab nia ntawm tus kab mob (DAI) poob qis. Qhov qhab nia DAI suav nrog cov ntsuas ntsuas xws li kev hloov pauv hauv nas lub cev hnyav, tus yam ntxwv fecal, thiab hematochesia. Nws qhov txo qis qhia tau tias KPV / SH-PGA hydrogel tuaj yeem txo qhov hnyav ntawm TNBS-induced ulcerative colitis. KPV / SH-PGA hydrogel kev kho mob kuj tiv thaiv txoj hnyuv loj hauv cov nas, txo qis cov qib myeloperoxidase, thiab kho cov kab mob colonic morphological, nrog rau cov kab mob epithelial, crypts, thiab cov kab mob goblet tsis zoo. Kev nthuav qhia ntawm pro-inflammatory cytokines, TNF-α thiab IL-6, nyob rau hauv cov ntaub so ntswg colonic kuj tau txo qis, ntxiv ua kom pom cov nyhuv anti-inflammatory ntawm KPV hauv TNBS-induced ulcerative colitis qauv.
Xaus
KPV, raws li ib qho tripeptide nrog cov tshuaj tiv thaiv kab mob, qhia tau hais tias muaj txiaj ntsig zoo hauv kev tiv thaiv thiab kho mob plab hnyuv thiab ntau yam kab mob ntsig txog mob. Nws cov txheej txheem tiv thaiv kab mob koom nrog ntau yam, suav nrog kev tswj hwm ntawm cellular signaling pathways, antioxidant stress, thiab modulation of apoptosis thiab autophagy.
Qhov chaw
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[2] Sun J, Xue P, Liu J, et al. Self-Cross-Linked Hydrogel ntawm Cysteamine-Grafted γ-Polyglutamic Acid Stabilized Tripeptide KPV rau Alleviating TNBS-Induced Ulcerative Colitis hauv nas [J]. Acs Biomaterials Science & Engineering, 2021,7(10):4859-4869.DOI:10.1021/acsbiomaterials.1c00792.
[3] Xiao B, Xu Z, Viennois E, et al. Orally Targeted Delivery ntawm Tripeptide KPV ntawm Hyaluronic Acid-Functionalized Nanoparticles Efficiently Alleviates Ulcerative Colitis[J]. Molecular Therapy, 2017,25(7):1628-1640.DOI:10.1016/j.ymthe.2016.11.020.
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[5] Kannengiesser K, Maaser C, Heidemann J, et al. Melanocortin-derived tripeptide KPV muaj peev xwm tiv thaiv kab mob hauv murine qauv ntawm cov kab mob plab hnyuv [J]. Inflammatory Bowel Diseases, 2008,14(3):324-331.DOI:10.1002/ibd.20334.
Cov khoom muaj rau kev tshawb fawb siv nkaus xwb:
