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ƆL DI ATIKUL ƐN PRODƆKT INFƆMƐSHƆN WE DƐN GI NA DIS WƐBSAYT NA FƆ ƆL DI INFƆMƐSHƆN DISƐMƐNƐSHƆN ƐN FƆ EDYUKESHƆN.
Di prɔdak dɛn we dɛn gi na dis wɛbsayt na fɔ in vitro risach nɔmɔ. in vitro risach (Latin: *in glas*, we min insay glas) dεn de du am ausayd mכtalman bכdi. Dɛn prɔdak ya nɔto famasitik, dɛn nɔ gɛt di aprɔval frɔm di US Food and Drug Administration (FDA), ɛn dɛn nɔ fɔ yuz dɛn fɔ protɛkt, trit, ɔ mɛn ɛni mɛrɛsin, sik, ɔ sik. Di lɔ nɔ gri fɔ mek dɛn put dɛn tin ya insay mɔtalman ɔ animal bɔdi ɛni we.
Besik Infɔmeshɔn bɔt KPV
KPV na tripεptida wit signifyant anti-inflammatory prכpati dεm, we de mek i ebul fכ ple rol insay plεnti fil dεm.
Figure 1 Di Tεrapi Efεkt dεm we HA-KPV-NP dεm gεt εgεst UC כral administreshכn fכ HA-KPV-NP dεm we dεn εmbas insay haydrojεl (chitosan/alginate) de gi kכmbayn tεrapi ifekt dεm εgεst UC bay we i de aksεlεrayt mכkus hεlin εn εliviet inflameshn.
Anti-inflammatory Mekanism fɔ KPV
1. Rεgulεshכn fכ di Sεl Sayn Pathway dεm
NF-κB Signaling Pathway: NF-κB na di kכl transkripshכn fכktכ we de ple sεntri rol insay inflammatory rεspכns dεm. we di sεl dεm de εkspos to inflammatory stimuli, NF-κB de transloket frכm di saytoplasm to di nyuklios, we de initiate di transkripshכn fכ di pro-inflammatory cytokine jin dεm. KPV kin inhεbit di aktibכshכn fכ NF-κB. insay di hכman intestinal εpitεlial sεl dεm εn di hכman T sεl dεm, dεn bin stimul di sεl dεm wit pro-inflammatory cytokines, εn dεn ad KPV wan tεm. we dεn yuz mεtכd dεm lεk NF-κB luciferase jin rεpכta asεy, protin immunoblotting, rial-taym rivεs transkripshכn polimεrayz chen riakshכn, εn εnzym-link immunosorbent asεy (ELISA), dεn fכnshכn se KPV na nanomolar kכnsantreshכn kin inhεbit NF-κB aktibכshכn, we de ridyus di sekreshכn fכ pro-inflammatory cytokines. dis mεkanism implεnt fכ rεgul di intestinal inflameshn, biכs fכ aktibכshכn fכ NF-κB insay intestinal εpitεlial sεl dεm εn imyun sεl dεm na wan kכl fכm fכ inflammatory bowel disease (IBD) εn כda intestinal inflammatory kכndishכn dεm.
MAP kinase signal path: di mitogen-aktivet protin kinase (MAPK) signal path na כda imכtant rεgεdyushכn path in inflammatory rispכns, inklud εkstrasεlyul signal-rεgulεt kinase (ERK), c-Jun N-tεrminal kinaz (JNK), εn p38 MAPK. dis kinaz dεm de aktibכt we di sεl dεm de εkspos to inflammatory stimuli, we de mek di fכsfכrayleshכn fכ di dכwnstrim transkripshכn fכktכ dεm εn de promuot di εksprεshכn fכ inflammatory-related jin dεm. KPV kin inhεbit di MAP kinase inflammatory signal path bak. we di sεl dεm de εkspos to inflammatory stimuli, KPV kin blכk MAPK aktibכshכn, we de ridyus in fכsfכrayleshכn fכ dכwnstrim transkripshכn fכktכ dεm, we de dכn di prodakshכn fכ pro-inflammatory cytokines. insay inflammatory stet, aktibכshכn fכ p38 MAPK de lid to inkrεs εksprεshכn fכ pro-inflammatory saytokεn dεm lεk TNF-α εn IL-6, we KPV kin inhεbit p38 MAPK aktvכti, we de ridyus di sekreshכn fכ dεn saytokεn dεm ya εn dat de mek di inflammatory rεspכns sכmtεm.
2. Sεl transpכrta-mεdiet ifekt dεm
PepT1 transpכrta: PepT1 na di/tripεptida transpכrta we dεn kin εksprεs insay di sכmכl intestin bכt i kin indyuz insay di kכlon di tεm we i de du IBD. di anti-inflammatory ifekt dεm fכ KPV na pat pan di mεdiet bay PepT1. In כptek εkspεriεns, kol KPV bin yuz as kכmpεtitiv inhibito fכ hPepT1 as redioaktiv lεbul sabstεrayt, כ [⊃3;H]KPV bin yuz fכ dεtεmin di kεnεtik kכntribyushכn fכ KPV כptek. KPV de enta di imyun sεl dεm εn intestinal εpitεlial sεl dεm via hPepT1. dis de sho se PepT1, as transpכrta, de fεsilitεt KPV εntri insay sεl dεm fכ εksyεrt in anti-inflammatory ifekt dεm. we di PepT1 fכnshכn de inhεbit, di amoun fכ KPV we de enta di sεl dεm de dכn, εn in anti-inflammatory ifekt dεm de kכrεspכndli wik. insay sel mכdel dεm wit knockdown fכ PepT1 εksprεshכn, ivin we dεn administret am na di sem kכnsantreshכn, KPV de sho sכmtεm ridyus inhibitory ifekt dεm pan NF-κB aktibכshכn εn ridyus sekreshכn fכ pro-inflammatory cytokines kכmpεr to sεl dεm wit nכmal PepT1 εksprεshכn, we de kכnfכm di krεs mεdiet rol fכ PepT1 in di anti-inflammatory mεkanism fכ KPV.
3. Rεgulεshכn fכ inflammatory cytokines
inhibishכn fכ di pro-inflammatory saytokεn dεm: KPV kin sכmtεm inhεbit di prodyushכn εn rilis fכ mכltipכl pro-inflammatory saytokεn dεm. TNF-α na ki saytokכn insay inflammatory rispכns, we ebul fכ aktibכt imyun sεl dεm, indyuz fכ prodyuz כda pro-inflammatory saytokεn dεm, εn mek di tisu dεm dεm. In difrεn inflammatory mכdel dεm, di εksprεshכn lεvεl dεm fכ TNF-α bin sכmtεm rεdכks afta KPV tritmεnt. fכ egzampl, insay wan sכdiכm sכlfεt-indyus maws kכlaytis mכdel, tritmεnt wit KPV rεsult in signifyant rεdukshכn in di mRNA εksprεshכn fכ TNF-α insay kכlon tisu, as dεn dεtekt bay rial-taym RT-PCR, εn wan signifyant dεkrεshכn in di protin kכntεnt fכ TNF-α insay sεrum, as dεn dεtekt bay ELISA. IL-1β, IL-6, εn כda pro-inflammatory cytokines dεm bin inhεbit bak bay KPV. IL-1β kin trigεr inflammatory kaskad riakshכn, we de promuot di rilis fכ כda inflammatory mεdiate dεm. KPV kin ridyus in εksprεshכn εn sekreshכn insay inflammatory tisu dεm, we de mek di intensiti fכ di inflammatory rεspכns.
di prכmoshכn fכ di anti-inflammatory cytokines: apat frכm we i de inhibit di pro-inflammatory cytokines, KPV kin promuot di εksprεshכn fכ di anti-inflammatory cytokines dεm bak. intalyukin-10 (IL-10) na imכtant anti-inflammatory cytokine we kin inhεbit di aktibכshכn fכ di imyun sεl dεm εn ridyus di prodakshכn fכ pro-inflammatory cytokines.
4. Rεgulεshכn fכ di imyun sεl dεm
rεgulεshכn fכ T sεl fכnshכn: T sεl dεm de ple imכtant rol fכ imyun rεspכns dεm εn inflameshn rεguleshכn. כnda inflammatory kכndishכn dεm, di T sεl dεm de aktibכt εn de sekret pro-inflammatory cytokines. stכdi dεn sho se KPV kin rεgεl di T sεl fכnshכn. insay εkspεriεns wit di hυman T sεl layn Jurkat, we Jurkat sεl dεm bin stimulate wit pro-inflammatory cytokines, di adishכn כf KPV inhεbit T sεl aktibכshכn εn rεdכks di sekreshכn כf pro-inflammatory cytokines lεk IFN-γ. dis kin bi bay we dεn de inhεbit di NF-κB εn MAPK signal path dεm insay T sεl dεm. apat frכm dat, insay sכm animal mכdel dεm, lεk di CD45RB(hi) kכlon inflameshn mכdel, KPV tritmεnt kin rεgεl T sεl infiltεshכn εn fכnshכn insay di intestin, ridyus inflameshn-rεlatεd T sεl sכbsεt dεm lεk Th1 εn Th17 sεl dεm, εn inkrεs di prכpכshכn fכ rεgεl T sεl dεm, we de mek intestinal inflameshn sכmtεm.
mכduleshכn fכ makrofag fכnshכn: Makrofag dεm na imכtant imyun sεl dεm na di inflammatory rεspכns εn dεn kin klas dεm insay klasical aktibכt M1 makrofag dεm εn כltεrnativ aktibכt M2 makrofag dεm bays pan dεn aktibכshכn stet. di M1 makrofag dεm de sekret big amoun fכ pro-inflammatory cytokines, we di M2 makrofag dεm gεt anti-inflammatory εn tisu ripa fכnshכn dεm. KPV kin rεgεl makrofag polarizeshכn. in vitro εkspεriεns sho se we dεn stimulat makrofag dεm wit lipopolysaccharide (LPS) fכ polarize tכwεd di M1 tכp, kכ-administreshכn fכ KPV inhεbit makrofag polarizeshכn tכwεd di M1 tכyp, rεdכks di εksprεshכn fכ M1 makrofag mak dεm, we i de promuot dεn polarizeshכn tכwεd di M2 tכp, inkrεs di εksprεshכn fכ M2 makrofag mak dεm (lεk arginase-1 Arg-1) we dɛn kɔl). insay in vivo inflammatory mכdel dεm, lεk DSS-induced colitis in mays, tritmεnt wit KPV rεsult in mכr makrofag dεm na di kכlon tisu polarize to di M2 tכyp, we de mek dεn εliviet inflammatory rεspכns dεm εn promuot di tisu ripa.
5. Protektiv ifekt dεm pan intestinal εpitεlial sεl dεm
εnhans di εpitεlial barεri fכnshכn: di fכs barεri we di intestinal εpitεlial sεl dεm fכm de wok as di fכs layn fכ difεns εgens pathogen εn harmful sכbstans invashכn. insay inflammatory stet, impεriכs intestinal εpitεlial barεri fכnshכn de lid to baktriyal translכkeshכn εn εndotoksin lik, we de mek di inflammatory rεspכns dεm mכr. KPV kin εnhans di barεri fכnshכn fכ di intestinal εpitεlial sεl dεm. in vitro sel εkspεriεns, usay dεn trit intestinal εpitεlial sεl layn dεm wit pro-inflammatory cytokines fכ simul inflammatory envayroment, rεsult in rεdכks εksprεshכn fכ tayt jכnkshכn protin dεm (lεk ZO-1 εn occludin) εn impεriכs barεri fכnshכn. כltu, we dεn ad KPV de mεnten di εksprεshכn fכ tayt jכnkshכn protin dεm, i de εnhans intasεlula kכnεkshכn dεm, εn i de rεstכr di barεri fכnshכn fכ di intestinal εpitεlial sεl dεm. insay DSS-indyus kolaytis mays dεm we dεn trit wit KPV, imyunohistochemistry εn Wεstεn blכt analisis rεvεl inkrεs εksprεshכn fכ tayt jכnkshכn protin dεm na kכlon tisu εn rεdכks intestinal pεrmiabiliti, we sho se KPV de protεkt di intestinal εpitεlial barεri in vivo, rεdכks di invεshכn fכ harmful sכbstans dεm, εn aliviayt inflammatory rεspכns dεm.
fכ mek di εpitεlial sεl dεm proliferashכn εn rεpa: inflameshn kin mek di intestinal εpitεlial sεl dεm damej εn day, we kin mek di intestinal fכnshכn nכmal. KPV gεt di abiliti fכ protεkt di proliferashכn εn ripa fכ di intestinal εpitεlial sεl dεm. in vitro sel kכlt εkspεriεns sho se we dεn trit di damej intestinal εpitεlial sεl dεm wit KPV i de εnhans sεl proliferashכn, as dεn dεtekt bay di Sεl Kaunt Kit (CCK-8). apat frכm dat, immunofluorescence analisis rivεl inkrεs εksprεshכn fכ proliferating sεl nyuklia antijen (PCNA), we sho se sεl dεm bin de insay aktv proliferativ stet. insay wan TNBS-induced ulcerative colitis rat model, afta tritmεnt wit KPV/SH-PGA haydrojel, histכlכjik obsכbishכn dεm sho se di damej to di kכlon εpitεlial sεl dεm dεn rεpεr, εn kript strכkchכ dεm sכmtεm de kam bak to nכmal. dis kin riliyt to KPV in prכmoshכn fכ di εpitεlial sεl proliferashכn εn ripa, we de εp fכ εliviet inflameshn εn protεkt intestinal tisu rεkכvεshכn.
Fig 2 KPV na tritmɛnt fɔ DSS kɔlayt.
6. Antiɔksidant ifɛkt dɛn
rεgulεshכn fכ כksidεtiv strεs-rεlatεd mak dεm: inflameshn kin kכmכn wit כksidεtiv strεs riakshכn dεm, wit inkrεs prodakshכn fכ riaktiv כksijεn spεshal (ROS) εn riaktiv naytrojen spεshal (RNS), we de mek כksidεtiv damej to sεl dεm εn tisu dεm. KPV de sho antioksidant ifekt dεm εn i kin rεgεl כksidεtiv strεs-rεlatεd mak dεm. insay sכm inflammatory mכdel dεm, lεk di kכtכn bכl-indyus maws granuloma mכdel εn di eg wayt-indyus rat dכsal εya sak synovitis mכdel, dεn dεtekt εlevεt lεvεl dεm fכ malondialdehyde (MDA) εn ridyus supεrכksayd dismutase (SOD) aktiviti insay inflammatory tisu dεm. Fכlכ KPV tritmεnt, MDA lεvεl dεm sכmtεm dכn, εn SOD aktiviti inkrεs. MDA na prodakt fכ lipid pεrכksidεshכn, εn in rεdכks lεvεl dεm de sho se di lipid pεrכksidεshכn dεm dεm dכn dכn to sεl dεm; SOD na imכtant antioksidant εnzym, εn in inkrεs aktiviti de sho se i de εnhans di abiliti fכ skavenj fri radikal dεm. KPV kin mitigate oksidativ damej insay inflammatory tisu dεm bay we i de rεgεl di oksidativ strεs lεvεl dεm, we de mek i de εksyεrt anti-inflammatory ifekt dεm.
7. Ɔda Pɔtɛnɛshɛl Mɛkanism dɛn
rilayshכn wit di melanocortin rεsεpכta: KPV na tripεptida we kכmכt frכm α-MSH. pan tap we in anti-inflammatory ifekt dεm na pat pan di indipεndεnt frכm MC1R signal, dεn kin bi fכ MC1R insay sכm kכntεks dεm. insay animal dεm we de εksprεs MC1Re/e, KPV tritmεnt we de fכlכ DSS-indyus kolaytis stil εksyεrt sכm sכm anti-inflammatory ifekt dεm, we de rεsכv כl di animal dεm na di tritmεnt grup frכm day di tεm we DSS-induced colitis de, we sho se KPV in anti-inflammatory ifekt dεm na at least patli indipεndεnt frכm MC1R signal. insay animal dεm we gεt nכmal MC1R εksprεshכn, KPV kin εnhans anti-inflammatory ifekt dεm bay we i de intarakt wit MC1R כ rεgεl in dכwnstrכm signal path dεm.
Anti-inflammatory Efεkt dεm we KPV de gi
1. Rol in intestinal inflameshn mכdel dεm
DSS-induced colitis model: Insay di DSS-induced mouse colitis model, KPV sho signifyant anti-inflammatory ifekt. We i kam pan di wet chenj, di mays dɛn we dɛn trit wit KPV bin gɛt bak dɛn wet bifo tɛm ɛn to big mak we dɛn kɔmpia am wit mays dɛn we dɛn nɔ trit. di histכlכjik obsכbishכn dεm sho se wan mak rεdukshכn pan inflammatory infiltrashכn insay di kכlon tisu fכ KPV-trit mays dεm, we dεn kכnfכm mכr bay wan siknifikant dεkrεshכn pan myeloperoxidase (MPO) aktiviti. MPO na εnzym we de insay nyutrofil dεm, εn in aktiviti lεvεl dεm de sho di εkstenshכn fכ inflammatory sεl infiltεshכn insay tisu dεm. di rεdukshכn pan MPO aktvכti we de fכlכ KPV tritmεnt de sho se di nyutrofil infiltεshכn dεn dכn insay di kכlon tisu εn di inflammatory rεspכns dεm dεn dכn dכn. bay we dεn dεtekt di mRNA εksprεshכn fכ pro-inflammatory saytokεn dεm na di kכlon tisu, lεk TNF-α εn IL-1β, dεn fכnshכn se KPV tritmεnt sכmtεm ridyus di εksprεshכn lεvεl dεm fכ dεn pro-inflammatory saytokεn dεm ya. KPV bin εliviet di DSS-indyus kolaytis simptom dεm frכm mכltipכl aspek dεm, inklud fכ ridyus inflammatory sεl infiltεshכn, lכs inflammatory fכktכ εksprεshכn, εn protεkt weit rεkכvεshכn.
CD45RB(hi) kכlon inflameshn mכdel: Insay di CD45RB(hi) kכlon inflameshn mכdel, KPV dεn sho bak gud anti-inflammatory ifekt dεm. Dis mכdel bin indyuz bay we dεn transfכm T sεl dεm we de hεli εksprεs CD45RB insay imyunodeficient mays dεm. fכlכ KPV tritmεnt, di mays dεm sho improv inflammatory simptom dεm, sכmtεm weit rεkכvεshכn, εn histכlכjik egzamin sho rεdכks intestinal inflammatory chenj dεm. di grup we dεn trit wit KPV sho dεkrεshכn inflammatory sεl infiltεshכn εn rεdכks kript strכkchכral dεmεj in intestinal tisu dεm, we sho se KPV de ifektivli εliviayt CD45RB(hi)-indyus intestinal inflameshn εn rεstכr nכmal intestinal tisu strכkchכ εn fכnshכn.
TNBS-induced ulcerative colitis model: In di TNBS-induced ulcerative colitis rat model, KPV bin sho bak se i gɛt impɔtant tritmɛnt ifɛkt dɛn. Afta we dεn gi KPV/SH-PGA haydrojεl rεktal to rat, di kolεt simptom dεm impruv mak. Di digri we di rat dɛn weit lɔs bin stɔp, ɛn di sik aktiviti indeks (DAI) skɔ bin go dɔŋ. di DAI skכl kכmprεhεnsivli kכnsidrε indikεtכ dεm lεk chenj dεm na di rat bכdi wet, fεkal kכntribyushכn, εn hεmatochesia. di rεdukshכn we i gεt sho se di KPV/SH-PGA haydrojεl kin ifektivli εlivεt di siriכs fכ TNBS-indyus כlsεraytiv kolεt. KPV/SH-PGA haydrojel tritmεnt de mek bak di kכlon sכt insay rat, i de ridyus di kכlon mayloperoxidase lεvεl, εn di kכlon mכfכlכjik strכkchכ we de rεstכr, inklud di εpitεlial barεri, kript, εn intakt gכblεt sεl dεm. di εksprεshכn fכ pro-inflammatory cytokines, TNF-α εn IL-6, in kכlon tisu bin כlso sכmtεm rεdכks, we de sho fכs di anti-inflammatory ifekt fכ KPV in di TNBS-induced ulcerative colitis mכdel.
Dɔn
KPV, as tripεptida wit anti-inflammatory prכpati dεm, de sho prכmis ifekt dεm fכ prεvεnshכn εn tritmεnt fכ intestinal inflameshn εn difrεn כda sik dεm we rilet to inflameshn. in anti-inflammatory mεkanism dεm involv mכltipכl aspek dεm, inklud rεguleshכn fכ di sεlyul signal path dεm, antioksidant strεs, εn mכduleshכn fכ apoptosis εn כtofagi.
Sos dɛn we dɛn pul
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