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FGIN-1-27 Inhibits Melanogenesis Los ntawm Regulating Protein Kinase A/cAMP-Responsive Element-Binding, Protein Kinase C- , Thiab Mitogen-Activated Protein Kinase Pathways Part 2

Apr 06, 2023

Cov teebmeem ntawm FGIN-1-27 ntawm Pigmentation hauv Zebrafish

Raws li kev tshawb fawb cuam tshuam,cistancheyog ib hom tshuaj ntsuab uas hu ua "cov tshuaj ntsuab miracle uas ua rau lub neej ntev". Nws lub ntsiab tivthaiv yog cistanoside, uas muaj ntau yam teebmeem xws li antioxidant, tiv thaiv kev mob, thiab kev tiv thaiv kev ua haujlwm. Lub mechanism ntawm cistanche thiabtawv nqaij dawblus dag hauvantioxidantCov txiaj ntsig ntawm cistanche glycosides.MelaninNyob rau hauv tib neeg daim tawv nqaij yog tsim los ntawm oxidation ntawm tyrosine catalyzed los ntawmtyrosinase, thiab cov tshuaj tiv thaiv oxidation yuav tsum muaj kev koom tes ntawm cov pa, yog li cov pa oxygen dawb radicals hauv lub cev dhau los ua ib qho tseem ceeb cuam tshuam rau kev tsim melanin. Cistanche muajcistanoside, uas yog ib qho antioxidant thiab tuaj yeem txo qhov tsim ntawm cov dawb radicals hauv lub cev, yog liinhibiting melanin ntau lawm.

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Zebrafish muaj cov xim melanin rau ntawm qhov chaw, uas tso cai rau kev soj ntsuam yooj yim ntawm pigmentation yam tsis muaj cov txheej txheem kev sim nyuaj (Choi et al., 2007). PTU, lub zog inhibitor ntawm melanogenesis, yog siv dav hauv kev tshawb fawb zebrafish (Elsalini thiab Rohr, 2003). Hauv kev tshawb fawb tam sim no, PTU tau siv los ua kev tswj hwm zoo. Raws li pom hauv daim duab 6, FGIN-1-27 cuam tshuam lub cev pigmentation ntawm zebrafish, zoo ib yam li PTU.

FGIN-1-27 Txo UVB-Induced Hyperpigmentation hauv Guinea npua daim tawv nqaij

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UVB-induced hyperpigmentation qauv hauv cov xim av guinea npua tau siv los tshuaj xyuas cov nyhuv whitening ntawm FGIN-1-27 hauv vivo. Raws li pom nyob rau hauv daim duab 7A, cov duab sawv cev ntawm guinea npua daim tawv nqaij qhia tau hais tias FGIN -1-27 (1 feem pua ​​) cuam tshuam cov xim pigmentation thaum piv nrog kev kho tsheb. Txhawm rau ntsuas qhov degree ntawm pigmentation ntxiv, peb tau txheeb xyuas qhov L tus nqi (qhov ci ntsa iab) siv Spectrophotometer. Tus nqi ΔL ntawm FGIN-1-27 pawg tau zoo siab dua li ntawm pawg tsheb tom qab 3 lub lis piam ntawm kev kho mob, qhia tias FGIN-1-27 txo UVB-induced hyperpigmentation hauv guinea npua daim tawv nqaij (Daim duab 7B). Masson-Fontana ammoniacal silver staining ntawm daim tawv nqaij pom tau tias FGIN{10}} cuam tshuam UVB-induced pigmentation nyob rau hauv epidermal basal txheej (Daim duab 7C). Immunohistochemical staining ntawm melanocyte marker protein, S-100, qhia tias melanocyte suav tsis cuam tshuam los ntawm FGIN-1-27 (Figures 7D, E). Cov txiaj ntsig no qhia tau hais tias FGIN-1-27 muaj cov nyhuv whitening ntawm UV-induced hyperpigmentation hauv vivo.

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Raws li Kev Tshawb Fawb Kev Lag Luam Thoob Ntiaj Teb, kev lag luam dawb thoob ntiaj teb yuav ncav cuag $ 31.2 nphom los ntawm 2024 (Kim li al., 2019). Ntau pab pawg tshawb fawb tau tsom mus rau lawv cov kev siv zog los qhia cov lus tshiab thiab cov tshuaj ntxuav hniav dawb zoo. Txawm hais tias muaj ntau tus neeg sawv cev tau tsim, tsuas yog ob peb tau pom tias muaj txiaj ntsig zoo vim yog cytotoxicity thiab tsis muaj zog (Kim li al., 2008; Singh li al., 2016). Yog li, nws yog ib qho tsim nyog yuav tsum tau tshawb nrhiav cov tshuaj tiv thaiv kab mob kom zoo thiab nyab xeeb dua.

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Hauv txoj kev tshawb fawb tam sim no, FGIN-1-27 inhibited basal melanogenesis thiab thim rov qab -MSH, OAG, lossis ET-1-induced melanin nce, tsis cuam tshuam rau cell viability (Daim duab 1 thiab 5). Tyrosinase, TRP-1, thiab TRP-2 yog cov enzymes tseem ceeb hauv melanogenesis, thaum -MSH thiab ET-1 txhawb nqa pigmentation los ntawm kev nce kev qhia ntawm peb qhov tseem ceeb melanogenic enzymes (Rzepka li al. , 2016; Corre et al., 2004; Regazzetti et al., 2015). Peb cov txiaj ntsig tau qhia tias FGIN-1-27 txwv tsis pub -MSH lossis ET-1-induced tyrosinase, TRP-1, thiab TRP-2 kev nthuav qhia nce (Figures 2A, B). Tyrosinase kev ua haujlwm tseem ceeb rau melanogenesis (Rzepka li al., 2016). 1-Oleoyl-2-acetyl-sn-glycerol (OAG) yog ib qho hluavtaws, membrane-permeable diacylglycerol (DAG) analog ua kom pom kev ua kom muaj zog ntawm tyrosinase (Thébault li al., 2005). Interestingly, FGIN{25}} ua rau muaj kev cuam tshuam OAG-induced tyrosinase kev ua haujlwm nce, thiab kev qhia ntawm tyrosinase tsis hloov pauv ntau tom qab 12 teev ntawm kev kho mob (Daim duab 2C, D). Mushroom tyrosinase kev ua ub no qhia tau tias FGIN -1-27 tsis ncaj qha inhibit tyrosinase kev ua, uas qhia tias FGIN -1-27 tsis yog ib qho ncaj qha inhibitor ntawm tyrosinase (Daim duab 2E). Microphthalmia-associated transcription factor (MITF) yog ib qho kev hloov pauv zoo rau melanogenesis thiab txhawb kev qhia ntawm tyrosinase, TRP-1, thiab TRP-2 (Levy and Fisher, 2011; Kawasaki et al., 2008) . Cov kev tshawb fawb tam sim no tau pom tias FGIN-1-27 suppressed basal, -MSH, thiab ET-1-induced MITF qhia nce (Daim duab 3). Raws li tau hais los saum no, FGIN-1-27 inhibits melanogenesis los ntawm kev txo qis kev qhia ntawm MITF, tyrosinase, TRP-1, thiab TRP-2 thiab inhibiting tyrosinase kev ua, uas yog qhov tsis sib xws nrog cov kev tshawb fawb yav dhau los uas tau qhia MDR. Kev ua kom muaj peev xwm nce melanogenesis (Lv li al., 2019). Muaj ob txoj kev piav qhia txog qhov tshwm sim no. Muab qhov kev ua haujlwm tsis zoo ntawm FGIN-1-27 vs. diazepam, peb xav tias FGIN-1-27 yog MDR inverse agonist es tsis yog feem ntau suav tias yog agonist hauv melanocytes. Tsis tas li ntawd, ntau lub tswv yim tseem koom nrog cov txiaj ntsig ntawm FGIN-1-27 nyob rau lub sijhawm, tej zaum, ua rau tsis pom lub luag haujlwm ntawm kev ua kom MDR. Cov kev tshawb fawb ntxiv yog xav tau los nthuav tawm cov haujlwm thiab cov txheej txheem hauv qab ntawm FGIN-1-27 thiab MDR hauv melanocytes.

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Tshaj UV irradiation yog suav tias yog ib qho tseem ceeb ua rau ntawm daim tawv nqaij darkening (Abdel-Naser li al., 2003). Tom qab raug UV hluav taws xob, keratinocytes, thiab melanocytes tau qhib thiab tsim -melanocyte-stimulating hormone (-MSH), diacylglycerol (DAG), thiab endothelin-1 (ET-1) (D'Mello li al. ., 2016; Bae-Harboe and Park, 2012). -MSH, ET-1, thiab DAG cuam tshuam rau melanin synthesis los ntawm txoj kev taw qhia hauv lub cev. Thaum -melanocyte-stimulating hormone (-MSH) khi rau melanocortin -1 receptor (MC1R), qib intracellular ntawm cAMP yog nce siab thiab PKA/CREB txoj kev qhib, thaum kawg txhawb melanogenesis (Corre li al., 2004; Rzepka et al., 2016). OAG tuaj yeem qhib PKC-, uas phosphorylates serine residues ntawm cytoplasmic domain ntawm tyrosinase thiab ua kom nws (Kim li al., 2006; Kawaguchi et al., 2012; Yuan thiab Jin, 2018). MAPK qhia txoj hauv kev nrog rau cov cellular p38, ERK, thiab JNK, tuaj yeem tswj hwm melanin synthesis (Zhou li al., 2014). Kev ua kom lub p38 taw qhia txoj hauv kev txo qis kev qhia ntawm MITF thiab txhawb nqa melanogenesis (Hirata li al., 2007). Lub luag haujlwm ntawm ERK thiab JNK txoj hauv kev hauv melanogenesis tseem muaj teeb meem (Lee li al., 2013; Peng li al., 2014). Endothelin-1 (ET-1) tau tshaj tawm tias yuav ua rau melanogenesis los ntawm kev ua kom ERK thiab p38 (Park et al., 2015; Regazzetti et al., 2015). Tsis tas li ntawd, kev sib tham sib tham ntawm PKA thiab PKC- tuaj yeem nthuav tawm cov nyhuv melanogenic thiab MAPK muab cov ntsiab lus sib tham rau kev sib tham ntawm cov kev taw qhia (Lee thiab Noh, 2013). Kev saib xyuas zoo tsis tu ncua tau tsom mus rau kev txhim kho ntawm cov tawv nqaij tshiab-dawb huv, uas inhibited melanogenesis los ntawm kev tswj cov xim pigmentation-txog kev taw qhia. Kim et al. kev tshawb fawb qhia tias piperlonguminine inhibited PKA/CREB-mediated melanogenesis tab sis tsis cuam tshuam rau PKC-mediated melanogenesis (Kim li al., 2006). Tsis tas li ntawd, muaj qhov txo qis melanogenesis los ntawm kev cuam tshuam ERK txoj hauv kev, tab sis tsis muaj kev cuam tshuam rau PKA / CREB txoj hauv kev (Fujimoto li al., 1988). Hauv kev tshawb fawb tam sim no, FGIN-1-27 txo qis kev qhia ntawm PKC-, p-PKA miv, p-CREB, p-p38, thiab p-ERK (Figures 4 thiab 5). Cov txiaj ntsig no tau qhia tias tag nrho peb ntawm cov lus qhia saum toj no hais txog kev cuam tshuam nrog melanogenesis raug cuam tshuam tom qab FGIN-1-27 raug kho. Qhov no tuaj yeem piav qhia vim li cas FGIN-1-27 inhibited -MSH, ET-1, lossis OAG-induced melanogenesis.

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Tsis tas li ntawd, peb tau tshawb xyuas qhov cuam tshuam ntawm FGIN-1-27 ntawm melanogenesis ntawm zebrafish. Zebrafish yog ib hom kab mob vertebrate uas muaj txiaj ntsig zoo vim tias nws cov kab mob hauv nruab nrog cev thiab cov noob caj ces zoo ib yam li tib neeg (Choi et al., 2007). Tsis tas li ntawd, zebrafish muaj cov xim melanin rau ntawm qhov chaw, uas tso cai rau kev soj ntsuam yooj yim ntawm pigmentation yam tsis muaj cov txheej txheem sim nyuaj (Kim li al., 2008). Hauv txoj kev tshawb fawb tam sim no, FGIN-1-27 txo qis lub cev pigmentation hauv zebrafish (Daim duab 6), uas yog qhov tsis sib xws nrog cov kev tshawb fawb yav dhau los uas tau qhia tias MDR ua kom melanocytes nce melanocytes hauv larval zebrafish (Allen li al., 2020) . Qhov laj thawj yog vim muaj qhov sib txawv ntawm cov tshuaj tiv thaiv melanogenic ntawm FGIN-1-27. Kev tshawb fawb ntxiv yog xav tau los txhawb lub luag haujlwm ntawm FGIN-1-27 hauv melanogenesis thiab melanocyte ntau lawm hauv zebrafish. Peb kuj tau tshawb xyuas qhov cuam tshuam ntawm FGIN-1-27 ntawm melanogenesis hauv daim tawv nqaij ntawm guinea npua. Raws li pom nyob rau hauv daim duab 7, peb pom tias cov tshuaj pleev ib ce ntawm FGIN-1-27 rau ntawm daim tawv nqaij dorsal ntawm ib tug guinea npua nyob rau hauv uas hyperpigmentation tau induced los ntawm raug rau UVB, ua rau cov nyhuv whitening. Cov txiaj ntsig no tau qhia tias FGIN -1-27 inhibited melanin ntau lawm hauv melanocytes nquag, tab sis tsis txo qis ntawm cov melanocytes.

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Hauv kev xaus, peb cov txiaj ntsig tau pom tias FGIN-1-27 tau tawm tsam cov teebmeem melanogenic, nrog rau cov txheej txheem ua haujlwm rau cov teebmeem no. FGIN-1-27 induced anti-melanogenic teebmeem hauv melanocytes los ntawm suppressing PKA/CREB, PKC-, thiab MAPK txoj kev, uas thaum kawg ua rau inhibition ntawm tyrosinase qhia thiab kev ua.(Daim duab 8). Thaum nyob hauv vivo kev sim, FGIN-1-27 inhibited lub cev pigmentation ntawm zebrafish thiab txo UVB-induced hyperpigmentation nyob rau hauv guinea npua daim tawv nqaij. Ua ke nrog qhov tseeb tias FGIN-1-27 tsis muaj kev ua haujlwm cytotoxic hauv peb qhov kev tshawb fawb, nws tau pom tias FGIN-1-27 tuaj yeem siv tau zoo li kev nyab xeeb ntawm daim tawv nqaij dawb.

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DAIM NTAWV THOV KEV PAB CUAM

Thawj qhov kev koom tes uas tau nthuav tawm hauv txoj kev tshawb fawb no suav nrog hauv tsab xov xwm / Cov Khoom Siv Ntxiv, cov lus nug ntxiv tuaj yeem xa mus rau tus kws sau ntawv.

AUTHOR CONTRIBUTIONS

JL, YC, thiab GS tau xeeb thiab tsim txoj kev kawm, muab cov lus tseem ceeb, thiab kho cov ntawv sau. SJ thiab YY tau ua qhov kev sim loj. XZ thiab RG tau soj ntsuam thiab txhais cov ntaub ntawv ntawm kev tshuaj ntsuam immunoblot. JL ua haujlwm ntawm kev sau cov ntaub ntawv. Txhua tus kws sau ntawv tau nyeem thiab pom zoo cov ntawv sau kawg.

NYIAJ

Txoj kev tshawb no tau txhawb nqa los ntawm Fund of Changzhou Sci&Tech Program (Grant No. CJ20180007) rau JL.

SUPPLEMENTARY KHOOM

Cov Khoom Siv Ntxiv rau tsab xov xwm no tuaj yeem pom hauv online

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