N-Succinyl-S-Farnesyl-L-Cysteine ​​(SFC): Ib Novel Isoprenylcysteine ​​Analog Nrog Hauv Vitro Anti-Inflammatory Activity thiab Clinical Skin Protecting Properties

Thov hu rauoscar.xiao@wecistanche.comyog xav paub ntxiv

Abstract:Tshaj li 15 xyoo dhau los, cov molecule me me isoprenylcysteine ​​(IPC) analogs tau raug txheeb xyuas raws li cov chav kawm tshiab ntawm cov tshuaj tiv thaiv kab mob. Cov kev tshawb fawb soj ntsuam tau pom tias IPCs muaj kev nyab xeeb thiab siv tau zoo hauv kev txhawb nqa cov tawv nqaij noj qab haus huv thaum siv tshuaj pleev. Qhov haujlwm no yog ua kom pom tau tias N-Succinyl-S-farnesyl-L-cysteine ​​(SFC) ua ib qho IPC molecule tshiab uas muab cov txiaj ntsig dav dav rau daim tawv nqaij. Tib neeg promyelocytic cell kab HL-60, tib neeg dermal microvascular endothelial hlwb (HDMECs), tib neeg dermal fibroblasts (HDFs), thiab tib neeg epidermal keratinocytes (NHEKs) tau nthuav tawm hauv kab lis kev cai rau ntau yam inducers los ua kom muaj cov pa oxygen reactive, cytokines, los yog collagenase ntau lawm. A 49-kev kawm randomized ob qhov muag tsis pom kev, lub tsheb-tswj, sib cais-lub ntsej muag sim tau ua nrog 1 feem pua ​​​​SFC gel, lossis 5 feem pua ​​​​Niacinamide, thiab lub tsheb tau thov rau 12 lub lis piam los soj ntsuam kev tiv thaiv thiab tiv thaiv kev laus. cov ntsiab lus kawg. Peb tau pom tias SFC inhibited GPCR thiab TLR-induced pro-inflammatory cytokine tso tawm hauv NHEKs thiab HDMECs los ntawm ob peb inflammatory inducers xws li UVB, tshuaj, cathelicidin, thiab kab mob. SFC tau ua tiav txo GPCR-induced oxidation nyob rau hauv sib txawv neutrophils. Ntxiv mus, kev tshawb fawb yees duab pom tau tias SFC txo UVA-induced collagenase (pro-MMP-1) ntau lawm hauv HDFs. Kev soj ntsuam kev soj ntsuam ntawm 1 feem pua ​​​​SFC gel pom tau tias kev txhim kho saum lub tsheb kom txo qis, hydration, kev ntxhib los mos, thiab tag nrho cov tsos ntawm daim tawv nqaij. N-Succinyl-S-farnesyl-L-cysteine ​​(SFC) yog ib qho tshiab los tiv thaiv me me molecule thiab yog thawj farnesyl-cysteine ​​IPC pom los kho cov tsos mob thiab cov tsos mob ntawm kev laus, thaum tseem muaj peev xwm los kho cov kab mob ntawm daim tawv nqaij. .

Thov nias ntawm no kom paub ntxiv

Ntsiab lus:isoprenylcysteine; anti-aging; tshuaj pleev ib ce; G-protein ua ke receptor; tus xov tooj zoo li receptor

1. Taw qhia

Me me molecule isoprenylcysteine ​​(IPC) analogs tau raug txheeb xyuas raws li cov chav kawm tshiab ntawm cov tshuaj tiv thaiv kab mob. IPC analogs muaj 15- lossis 20-carbon sab saw txuas rau cov amino acid cysteine ​​​​, ua raws li C-terminus ntawm cov txheej txheem CAAX proteins, uas yog ib qho tseem ceeb rau daim nyias nyias lub hom phiaj ntawm heterotrimeric thiab me G-proteins uas kho. receptor signaling nyob rau hauv eukaryotic hlwb. IPC analogs inhibit qhov taw qhia ua kom muaj zog ntawm daim nyias nyias los ntawm kev sib tw nrog cov pab pawg isoprenoid rau prenyl-binding sites [1,2] thiab los ntawm kev cuam tshuam cov teeb liab hloov los ntawm kev tiv thaiv heterotrimeric G-protein tsim thiab / lossis xav tias yog los ntawm kev thaiv cov dej hauv qab G-protein-effector cuam tshuam[ 3-5].

Txij li thaum thawj qhov kev tshawb pom ntawm N-Acetyl-S-farnesyl-L-cysteine ​​(AFC) raws li thawj IPC analog los ua kom muaj txiaj ntsig zoo txo ​​qis cov tshuaj tiv thaiv kab mob hauv platelets, macrophages, thiab neutrophils [6-8], ntau qhov sib txawv IPC analogs tau ua. tshawb pom thiab tshaj tawm rau pro-vide ntau yam kev ua ub no hauv daim tawv nqaij, suav nrog inhibiting G-protein coupled receptor (GPCR)-induced pro-inflammatory cytokine tso, edema, thiab neutrophil infiltration thaum siv topically [9]. Piv txwv li, N-acetylglutaminoyl-S-farnesyl-L-cysteine ​​(SIG-1191) qhia txog kev tiv thaiv kab mob thiab dej hauv tib neeg keratinocytes thiab tib neeg daim tawv nqaij 3D [10]. Cov kev tshawb fawb tsis ntev los no qhia tau hais tias IPC analogs kuj tsis ncaj ncees; ulate non-G-protein mediated inflammatory in human epidermal keratinocytes, human dermal fibroblasts, human dermal endothelial cells, thiab peripheral blood mononuclear cells los ntawm abrogating tus xov tooj zoo li receptors 2,4, thiab 6 ( TLR2, TLR4, TLR6) thiab T-cell receptor (TCR) signaling [11,12]. Tsis tas li ntawd, phytyl-cysteine ​​IPC analogues kuj tau pom tias muaj txiaj ntsig zoo tiv thaiv pob txuv [13] thiab kev laus ntawm daim tawv nqaij [14], qhia txog kev ua tau zoo ntawm cov chav kawm ntawm cov tshuaj tiv thaiv kab mob hauv daim tawv nqaij, thiab txhim kho cov tawv nqaij sib txawv thaum siv tshuaj pleev.

Cistanche tuaj yeem tiv thaiv kev laus

Ntawm no, yog cov ntaub ntawv tshiabIPCanalogN-Succinyl-S-farnesyl-L-cysteine ​​(SFC) (Daim duab S1) muaj ntau yam kev tiv thaiv kab mob thiab cov tawv nqaij tiv thaiv cov khoom los pab qeeb o thiab kev laus los ntawm kev ua haujlwm tsis paub yav dhau los. Cov kev tshawb fawb siv dermal endothelial hlwb qhia tias SFC inhibits cathelicidin (L-37) GPCR-induced o. Ntxiv mus, nyob rau hauv vitro kev tshawb fawb nyob rau hauv epidermal keratinocytes qhia tau hais tias SFC ntse inhibits pro-inflammatory cytokine tso tawm los ntawm ntau yam kev ntxhov siab xws li UVB, tshuaj, thiab kab mob.cistanche tubulosa noj redditCov kev tshawb fawb yees duab qhia tau tias SFC tuaj yeem ua tiav txo UVA-induced collagenase (pro-MMP-1) ntau lawm hauv dermal fibroblasts. Muab qhov kev ua haujlwm ntau yam hauv daim tawv nqaij, peb mam li sim SFC kev kho mob hauv lub ntsej muag sib cais, ob qhov muag tsis pom kev, kev tswj xyuas tsheb, thiab pom tau tias 1 feem pua ​​​​SFC gel tau txais txiaj ntsig zoo thiab ua tau zoo tshaj lub tsheb uas qhia txog kev txhim kho tseem ceeb hauv txhua qhov chaw kho mob. , suav nrog kev txo qis, hydration, thiab tag nrho cov tsos ntawm daim tawv nqaij.

2. Cov ntaub ntawv thiab cov txheej txheem

2.1.Chemicals thiab Reagents

All reagents were purchased from Sigma Chemical Co. (St. Louis,MO, USA).Organic solvents were purchased from Fisher Scientific (Hampton, NH, USA). SFC was synthesized according to methods as described in US patent US10314802B2. All chemicals were ana-lyzed by LC/MS (Agilent 1100), H,and l3CNMR (500 MHz and 125 MHz, Bruker) for structural identity,and confirmed to be >95 feem pua ​​​​tshiab los ntawm kev tshuaj ntsuam HPLC (Agilent 1200). 2.2.Cell Treatments

HL-60 hlwb (CCL-240TM) tau txais los ntawm American Type Culture Collection (ATCC; Manassas, VA, USA), loj hlob hauv cov kab lis kev cai raug tshem tawm, thiab ntxias kom sib txawv rau hauv daim ntawv myeloid paub tab (dHL{ {2}}) los ntawm kev cog qoob loo ntawm 1.3 feem pua ​​(y/v) dimethyl sulfoxide (DMSO)[15]. Kev ntsuam xyuas tawg tau ua raws li tau piav qhia yav dhau los [16]. Luv luv dHL-60 (2 × 10 degree hlwb/mL) tau incubated nrog formyl-Met-Leu-Phe-OH((MLP) induce superoxide tso tawm los ntawm neutrophils. ferricytochrome c rau ferrocytochrome c los ntawm kev nyeem cov absorbance ntawm 550 nm. Cov tshuaj tiv thaiv kev sib xyaw ua ke tau npaj hauv Hanks 'Balanced Salt Solution (HBSS) nrog 160 uM cytochrome c, 100 U / mL superoxide dismutase (SOD), thiab 16 uM TPA ({ {18}}O-Tetradecanoylphorbol 13-acetate). Absorbance yog ntsuas nyob rau hauv lub phaj nyeem ntawv ntawm 550 nm raws li qhov kawg (tom qab 20 min raug).

Tib neeg lub hlwb tau txais los ntawm cov menyuam yug tshiab pub dawb tau yuav los ntawm Ther-moFisher (NHEKs, HDFs; Carlsbad, CA, USA) thiab ScienCell (HDMECs; Carlsbad, CA, CA, USA).Cells(1 × 10 degree cells / mL) tau loj hlob ntawm ib txwm muaj (5 feem pua ​​​​CO2; 37 degree), thiab tom qab ntawd pre-incubated rau 2 h nrog cov tebchaw (0.1 feem pua ​​​​v / v ethanol tsheb) hauv kev loj hlob ntawm cov xov xwm tshiab hauv triplicates. NHEKs raug ntxias los ntawm 5 ng / mL TPA, 25 m / / cm2 broadband 305 ± 12 nm UVB (Daavlin; Bryan, OH, USA) lossis 10 ug / mL peptidoglycan. HDMECs thiab HDFs raug ntxias nrog 10 ug/mL ntawm LL-37(Tocris Bioscience; Bristol, UK) thiab 12.5J/cm2 broadband 350 ± 12 nm UVA (Daavlin; Bryan, OH, USA), feem. Cells tau raug mus rau kev ntsuam xyuas muaj peev xwm los ntawm tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-( 4-sulfophenyl)-2H-tetrazolium, sab hauv ntsev; MTS] assay (Promega; Madison, WI, USA). Media supernatants raug sau tom qab 24 teev induction rau cytokines (TNF- , IL-6, IL-8) thiab collagenase (pro-MMP-1) ntsuas.

2.3.Enzyme-Linked Immunosorbent Assays (ELISA)

Cov theem ntawm tib neeg cytokines thiab collagenase tau ntsuas los ntawm cov ntaub so ntswg kab lis kev cai media supernatants los ntawm cov qhaub cij ELISA, siv cov qauv tsim nyog thiab ua raws li cov chaw tsim khoom cov txheej txheem. IL-6 thiab IL-8 cov khoom siv tau yuav los ntawm BD Biosciences (San Jose, CA, USA).Pro-MMP-1 thiab TNF- cov khoom siv tau yuav los ntawm R&D Systems Inc. (Minneapolis, MN, USA).

2.4.Clinical Study

Kev sim tshuaj xyuas hauv cov neeg ua haujlwm pab dawb noj qab haus huv tau ua nyob rau ntawm SGS Stephens (Study# C20-J156; Tokyo, JP), thiab sau ntawv ceeb toom kev pom zoo ua raws li International Council for Harmonization (ICH) E6(r2) Tshooj 4.8.10 tau txais los ntawm txhua qhov kev kawm. Qhov no yog ib qho chaw, sib cais lub ntsej muag, ob chav dig muag tsheb-tswj kev kawm nrog tag nrho ntawm 49 tus poj niam Nyij Pooj ua tiav 12- txoj kev kawm lub lim tiam. Cov ntsiab lus tau muab rau ib qho ntawm ob lub hlwb kho, raws li kev txiav txim siab randomization. Nyob rau hauv txhua lub cell, cov neeg kawm tau ntxiv randomized siv SFC lossis niacinamide ntawm ib sab ntawm lub ntsej muag, thiab kev tswj lub tsheb ntawm lub ntsej muag (cell 1: 31 cov neeg kawm tau txais 1 feem pua ​​​​SFC gel thiab tsheb, thiab cell 2: 18 cov ntsiab lus tau txais 5 feem pua ​​​​niacinamide gel thiab tsheb) (Saib Table S1 rau tag nrho cov khoom xyaw).npaum li cas cistanche cojTxoj kev tshawb no tau ua raws li "Cov Lus Qhia rau Kev Ntsuam Xyuas Cov Khoom Siv Tiv Thaiv Wrinkle" los ntawm Japanese Cosmetic Science Society. Cov neeg kawm tau siv cov khoom siv ntsuas rau sab ntawm lub ko taw ko taw thiab tag nrho ib nrab ntawm lub ntsej muag 2x txhua hnub. Cov neeg kawm tau ua thawj daim ntawv thov ntawm cov ntaub ntawv xeem hauv tsev kho mob tom qab ua tiav cov kev ntsuam xyuas hauv paus. Kev soj ntsuam kev soj ntsuam tau ua thaum mus ntsib ib qho (cov hauv paus ntsiab lus thiab 15 feeb tom qab thov), mus ntsib ob (lub lim tiam 8) thiab mus ntsib peb (lub lim tiam 12).cistanche แอมเวCrow's ko taw wrinkle tej yam kev mob raug xaiv nyob rau hauv me me mus rau nruab nrab ntau yam (cov qhab nia {{0}}} raws li Japanese Society of Cosmetic Chemists (JSCC) scale qhov twg 0= tsis muaj thiab 7= qhov tob tob wrinkles tau pom). Kev ntsuas qhov ntsuas ntawm qhov ua tau zoo tau raug soj ntsuam sib cais ntawm sab xis thiab sab laug ntawm lub ntsej muag thoob ntiaj teb siv qhov hloov kho Griffith 10-point scale, nrog rau ib nrab ntawm cov qhab nia raws li qhov tsim nyog (0—tsis muaj (qhov zoo tshaj plaws), 1 rau 3= mob me,4 mus rau 6= nruab nrab, 7 txog 9= mob hnyav (mob phem tshaj plaws)). Cov kev ua tau zoo tau muab qhab nia raws li cov teev teev teev tseg hauv Table 1.

2.5.Kev txheeb xyuas qhov tseeb

Kev txheeb xyuas qhov tseem ceeb tau txiav txim siab los ntawm ANOVA ua raws li Dunnett ntau qhov kev sib piv uas siv p-values ​​tsawg dua 0.05 raws li qhov sib txawv tseem ceeb. Rau tag nrho cov kev ntsuas tshuaj tua kab mob thiab qib cytokine, cov qauv raug soj ntsuam hauv triplicate. Cytokine koob tshuaj tiv thaiv kab mob tau tsim los ntawm cov ntaub ntawv haum nrog Hill, peb qhov sib npaug sib npaug siv Sigma Plot software (Systat Software Inc., Chicago, IL, USA), los ntawm IC50 thiab qhov siab tshaj plaws inhibition tau txiav txim siab.

3. Cov txiaj ntsig

3.1. SFCInhibits GPCR-Induced Oxidative Stress thiab Inflamation

Formyl peptide receptor-1(FPRL1) yog GPCR nyob rau ntawm qhov chaw ntawm neutrophils thiab endothelial hlwb uas ua lub luag haujlwm tseem ceeb hauv kev teb rau ntau qhov inflammatory stimuli[17]. Piv txwv li, N-Formyl Methionyl-leucyl-phenylalanine (fMLP) yog chemotactic peptide uas khi rau FPRL1 nrhiav cov neutrophils, thiab thaum lawv tuaj txog, ua rau muaj kev tso tawm sai ntawm cov pa oxygen reactive (ROS) thiab ntau yam tshuaj tua kab mob [18] . Txawm li cas los xij, yog tias kev nrhiav neeg ua haujlwm neutrophil tseem muaj, qhov tseem ceeb dysregulation ntawm inflammatory cascade tshwm sim, uas tau cuam tshuam neutrophil infiltration hauv pathogenesis ntawm rosacea thiab ntau lwm yam kab mob ntawm daim tawv nqaij [19]. Catelicidin (LL-37) yog lwm FPRL1 ligand nrog pleiotropic kev ua, suav nrog cov khoom siv tshuaj tua kab mob, kev nrhiav neeg ua haujlwm, thiab mob uas tau txuas rau atopic dermatitis, psoriasis, thiab rosacea [20].dab tsi yog cistancheYog li, peb nrhiav kev tshawb xyuas yog tias SFC tuaj yeem ua tiav FPRL1-kho oxidative tawg thiab mob. Siv cov neutrophils sib txawv (DHL-60)[21], fMLP tau ntxiv los pib ROS, thiab cov txiaj ntsig tau pom tias SFC ua haujlwm zoo los thaiv kev tsim cov superoxide nyob rau hauv ib koob tshuaj (IC50=25 μM) (Daim duab 1A) nrog cov teebmeem tsis muaj tshuaj lom (Daim duab S2). Tsis tas li ntawd, tib neeg dermal microvascular endothelial hlwb (HDMECs) kho nrog 10 ug/mL LL-37 induces the overproduction of pro-inflammatory cytokine IL-6. Kev kho mob nrog SFC inhibited qhov tso tawm ntawm IL-6 koob tshuaj-nyob ntawm 100 feem pua ​​(Daim duab 1B) nrog cov teebmeem tsis muaj tshuaj lom (Daim duab S2) thiab muaj zog zoo sib xws (IC50=2 uM) rau eczema tshuaj FK{{ 19}} (IC50=1 uM), thiab zoo dua li kev kho mob rosacea metronidazole (IC50=14 uM) thiab azelaic acid (IC50 =100 uM). Cov tshuaj pleev xim glucocorticoid clobetasol tau nthuav tawm qhov muaj zog tiv thaiv kev ua haujlwm raws li qhov xav tau (IC50=0.08 μM; cov ntaub ntawv tsis qhia).

3.2. SFC tiv thaiv UVA thiab UVB-Induced Photoaging

Ultraviolet (UV) lub teeb yog ib qho kev ntxhov siab ib puag ncig uas tawm tsam peb cov tawv nqaij txhua hnub. Ntev wavelength UVA (320-400 nm) nkag mus tob rau hauv lub dermis, thaum lub wavelength luv dua, lub zog siab dua, UVB (290-320} nm) feem ntau cuam tshuam rau peb cov epidermis.

Tshwj xeeb, UVA induces secretion ntawm matrix metalloproteinases (MMPs), uas ua lub luag haujlwm tseem ceeb hauv kev txiav cov duab txiav [22]. MMP-1, tseem hu ua interstitial collagenase, rhuav tshem collagen (Type I, II, thiab III), ua rau cov tsos ntawm cov kab zoo thiab wrinkles. Txhawm rau txiav txim siab SFC lub peev xwm los tiv thaiv wrinkle, peb tau tshuaj xyuas nws lub peev xwm los txo UVA-induced pro-MMP-1 tso tawm los ntawm tib neeg dermal fibroblasts (HDFs). SFC koob tshuaj-dependently inhibits pro-MMP-1 ntau lawm ua kom pom qhov tshwj xeeb muaj zog nrog ICso=10 pM (Table 2) nrog cov teebmeem tsis muaj tshuaj lom (Daim duab S2), thaum cov tshuaj pleev ib ce tiv thaiv kev laus xws li ascorbic acid thiab a-tocopherol tsis txo qis pro-MMP-1 tso tawm ntawm qhov ntsuas siab tshaj plaws (Table 2). Zoo ib yam li UVA, txuas ntxiv raug rau UVB ua rau muaj kev mob tshwm sim thiab tsim cov cytokines pro-inflammatory uas ua lub luag haujlwm tseem ceeb hauv kev laus ntawm cov tawv nqaij hnub ci[23]. Tshwj xeeb, tib neeg cov kab mob epidermal keratinocytes raug UVB ua rau kev tso tawm ntawm interleukin-6 (IL-6) thiab qog necrosis factor-a (TNF-a), uas kuj tau txuas rau daim tawv nqaij qhuav [24] . Peb cov txiaj ntsig tau pom tias SFC thaiv ob qho tib si IL-6 thiab TNF-x tso tawm raws li kev noj tshuaj nrog ICso=10 pM thiab 100 pM, feem, nrog cov teebmeem tsis muaj tshuaj lom (Daim duab S2).bioflavonoidsNtxiv mus, qhov muaj zog muaj zog no yog 4-5 kev txiav txim siab ntau dua li qhov tau pom rau ascorbic acid thiab -tocopherol uas kuj pom cov khoom tiv thaiv kab mob (Table 2).

3.3.SFC Tiv thaiv cov tshuaj lom neeg thiab kab mob ua rau mob

Ntxiv rau UV rays los ntawm tshav ntuj, ntau lwm yam exogenous ib puag ncig kev nyuaj siab ua rau o ntawm daim tawv nqaij, thiab tuaj yeem ua kom cov txheej txheem ntawm daim tawv nqaij laus yog tias tsis muaj kev tiv thaiv. Ob tug culprits no yog tshuaj thiab kab mob. 12-O-tetradecanoyl--phorbol-13-acetate (TPA) yog ib qho tshuaj lom neeg uas siv los kuaj tshuaj pleev rau hauv vivo tiv thaiv kev ua haujlwm [9]. Ntxiv mus, cov kev tshawb fawb yav dhau los qhia tau hais tias tib neeg cov kab mob epidermal keratinocytes (NHEKs) kho nrog TPA ua rau muaj zog ntau ntxiv ntawm ntau tus neeg kho mob pro-inflammatory [25,26]. Peb lub xov tooj ntawm tes-raws li NHEK assay qhia tau hais tias muaj qhov tseem ceeb TPA induction ntawm TNF-a, thiab tias SFC inhibits nws tso tawm nyob rau hauv ib koob tshuaj raws li ib tug IC 50=0.75 uM (siab tshaj inhibition ntawm 70 feem pua) (Daim duab 2A) nrog cov teebmeem tsis muaj tshuaj lom (Daim duab S2). Lub caij no, cov tshuaj tiv thaiv kab mob glucocorticoid clobetasol kuaj ntawm 3 uM qhia qhov siab tshaj plaws inhibition ntawm tsuas yog 58 feem pua, qhia tias SFC muaj zog dua hauv qhov kev ntsuam xyuas tshwj xeeb no.

TLRs ua lub luag haujlwm tseem ceeb hauv daim tawv nqaij tswj lub cev tiv thaiv kab mob hauv lub cev rau cov kab mob, thiab TLR2 cov teeb liab tshwj xeeb tau pom tias ua lub luag haujlwm tseem ceeb hauv kev tsim kab mob ntawm ntau yam kab mob dermatological [27]. Peptidoglycan (PGN) yog cov kab mob ntawm cov phab ntsa ntawm cov kab mob thiab cov xov tooj hu xov tooj zoo li receptor-2(TLR2) ligand. Peb cov txiaj ntsig tau pom tias SFC koob tshuaj-raws li txo PGN-induced interleukin-8 (IL-8) ​​tso tawm hauv NHEKs nrog ICso=0.8 uM, piv rau clobetasol nrog IC{{11 }} μM (Daim duab 2B).

3.4. SFC Txo Wrinkles thiab txhim kho ntau yam ntawm daim tawv nqaij tsis muaj nyob rau hauv tib neeg kev yees duab ntawm daim tawv nqaij ntawm lub ntsej muag yog ib qho ntawm ob peb yam uas ua rau pom cov tsos mob ntawm kev laus, thiab yog tus cwj pwm los ntawm muaj cov kab zoo, wrinkles, thiab kev hloov ntawm pigmentation. Cov ntaub ntawv qhia ntawm no qhia tau hais tias SFC's hauv vitro tiv thaiv kab mob, tiv thaiv kev laus, thiab oxidative tawg tiv thaiv kev ua ub no tuaj yeem ua tau zoo hauv kev ua kom qeeb ntawm kev laus thiab kev laus thaum ntxov thaum siv tshuaj pleev rau tib neeg. Yog li, peb tau nrhiav kev tshuaj xyuas SFC hauv tsev kho mob txhawm rau ntsuas nws cov haujlwm raws li kev thov tshuaj pleev ib ce. SFC tau tsim los ntawm 1 feem pua ​​​​hauv ib lub gel, thiab tau soj ntsuam hauv lub ntsej muag sib cais, ob lub qhov muag tsis pom kev, kev tswj xyuas tsheb, qhov twg nws tau siv ob zaug hauv ib hnub rau 12 lub lis piam. Ua ntej txoj kev tshawb no, SFC gel tau sim nyob rau hauv 100 yam tib neeg rov hais dua qhov kev thuam thiab pom tias muaj kev nyab xeeb rau daim tawv nqaij (cov ntaub ntawv tsis qhia).

Tag nrho ntawm 49 tus poj niam ua tiav txoj kev kawm nrog txhua yam kev siv tsheb ntawm ib sab ntawm lawv lub ntsej muag, thiab rau sab nraud, 31 ntawm cov kev kawm siv 1 feem pua ​​SFC gel; 18 cov ntsiab lus ntxiv tau siv 5 feem pua ​​​​niacinamide ua tus piv, raws li nws tau pom yav dhau los los txhim kho lub ntsej muag ntawm daim tawv nqaij [28]. Cov txiaj ntsig ntawm kev kho mob ntawm cov pob khaus ntawm thaj tsam ntawm ko taw qhia pom tias muaj kev txhim kho tseem ceeb ntawm lub hauv paus thiab lub tsheb ntawm lub lis piam 8 thiab 12 rau 1 feem pua ​​​​SFC gel, thaum 5 feem pua ​​​​niacinamide tsuas pom kev txhim kho tseem ceeb ntawm lub lim tiam 12 (Daim duab 3). Nyob rau lub lim tiam 8,1 feem pua ​​​​SFC gel qhia txog kev txhim kho ~ 32 feem pua, thaum 5 feem pua ​​​​niacinamide thiab lub tsheb tsuas yog qhia txog ~ 11 feem pua ​​​​thiab ~ 6 feem pua ​​​​kev txhim kho raws li (Daim duab 3). Ntxiv rau qhov txo qis, 1 feem pua ​​​​SFC gel ua tau zoo tshaj lub tsheb ntawm ob peb lwm qhov kawg, suav nrog kev ntxhib los mos (tactile) thiab hydration (visual) ntawm lub lis piam 8 thiab 12 radiance / luminosity / brightness, thiab kev ntxhib los mos (pom) ntawm lub lim tiam 12, thiab tag nrho. Cov tsos mob ntawm daim tawv nqaij (zoo) ntawm lub ntsej muag tom qab daim ntawv thov (Table 3). Ntxiv mus, nyob rau hauv ob peb kawg cov ntsiab lus 1 feem pua ​​SFC gel tsis tsuas yog outperforms tsheb, tab sis kuj niacinamide. Piv txwv li, kev tsom xam ntawm qhov radiance / luminosity / brightness parameter ntawm lub lim tiam 12 qhia tias cov kev kawm siv 1 feem pua ​​​​SFC gel qhia txog qhov tseem ceeb tshaj plaws ~ 52 feem pua ​​​​kev txhim kho piv rau tsuas yog ~ 22 feem pua ​​​​rau cov neeg thov 5 feem pua ​​​​niacinamide (Table 3). 1 feem pua ​​​​SFC gel kuj tseem ua tau zoo tshaj 5 feem pua ​​​​niacinamide ntawm lub lim tiam 8 rau hydration (~ 42 feem pua ​​​​piv rau ~ 3 feem pua ​​​​) (Table3).Thaum kawg rau daim tawv nqaij firmness (tactile) kawg, txawm tias tsis zoo heev outperforming tsheb, 1 feem pua ​​SFC gel qhia. statisticically kev txhim kho tseem ceeb ntawm 19 feem pua ​​​​ntawm cov hauv paus (p tus nqi {{40}}}031), thaum lub tsheb tsuas yog kho cov tawv nqaij zoo dua los ntawm ~ 10 feem pua ​​(p tus nqi 0.063), thiab cov 5 feem pua ​​​​niacinamide kho pab pawg pom tau tias 0 feem pua ​​kev txhim kho. Ua ke, cov txiaj ntsig no qhia tau tias SFC thaum siv tshuaj pleev ib ce txhim kho cov tsos mob ntawm kev laus thiab txhawb kev noj qab haus huv ntawm daim tawv nqaij.

4. Kev sib tham

Thawj IPC molecule, N-acetyl-S-farnesyl-L-cysteine ​​(AFC) tau tshawb pom ntau dua 30 xyoo dhau los [6,29], thiab tom qab ntawd tau pom tias muaj txiaj ntsig zoo txo ​​edema thiab neu-trophil infiltration thaum siv tshuaj pleev hauv vivo. tsiaj qauv ntawm o thiab hu rau hypersensitivity [9]. Ob peb lwm yam farlnesyl-cysteine ​​derivatives tau tshaj tawm kom ua tiav inhibit qhov mob thiab oxidative kev ntxhov siab tso tawm [21]. Ntxiv mus, lwm qhov deb-nesylated IPC molecule, SIG-1191, tau pom tias muaj kev tiv thaiv kab mob hauv NHEKs, thiab muaj peev xwm moisturizing kev ua si thaum pleev xim rau 3D tib neeg daim tawv nqaij [10]Zoo, cov txiaj ntsig no qhia txog lub peev xwm rau chav kawm ntawm cov tebchaw no siv los kho cov tawv nqaij mob thiab / lossis kho kab mob ntawm daim tawv nqaij. Txawm hais tias muaj kev cog lus hauv vitro thiab hauv vivo kev ua haujlwm profile, tsis muaj farnesylated IPC compound tau raug kuaj hauv kev ua haujlwm. Yog li, peb tau nrhiav kev txiav txim siab thawj zaug ntawm kev ua haujlwm ntawm farnesylated IPC N-Succinyl-S-farnesyl-L-cysteine ​​(SFC) hauv kev tshawb fawb soj ntsuam, thiab pib elucidate nws cov txheej txheem ntawm kev ua los piav qhia cov txiaj ntsig no.

IPC molecules tau raug tshaj tawm los hloov kho GPCRs, tus xov tooj hu-zoo li receptors (TLRs), thiab peroxisome proliferator-activated receptor gamma (PAR-y) signaling [30]; Txawm li cas los xij, cov txheej txheem ntawm cov tshuaj tiv thaiv kab mob no tsis nkag siab zoo. Siv dermal microvascular endothelial hlwb, AFC yav dhau los tau pom tias inhibit purinergic GPCR inflammatory signaling (ATP-P2Y receptor-induced cytokine tso) [31]. Ntxiv mus, SIG-1191 tau pom los tswj kev qhia ntawm daim tawv nqaij hydration marker aquaporin 3 (AQP3) ntawm mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) pathway [10]. Ntxiv mus, IPC compounds SIG-1273 thiab SIG{16}} tswj TLR thiab T-cell receptor (TCR) signaling, uas ua lub luag haujlwm tseem ceeb hauv cov kab mob ntawm pob txuv thiab atopic dermatitis [11,12]. Ntawm no, peb qhia tau hais tias SFC hloov kho GPCR-FPRL1 signaling los ntawm kev ua tiav thaiv cathelicidin (LL-37)-induced FPRL1 pro-inflammatory tso tawm hauv HDMECs. Los ntawm tshwj xeeb tsom rau cov neeg kho mob inflammatory tso tawm los ntawm HDMECs, SFC tej zaum yuav yog ib tug muaj zog inhibitor ntawm mob o, raws li IL-6 plays lub luag hauj lwm tseem ceeb nyob rau hauv ob peb cutaneous mechanisms thiab mob, nrog rau lub qhov txhab kho [32]. Tsis tas li ntawd, epithelial cell-derived inflammatory mediators tau hais kom ua lub luag haujlwm hauv rosacea thiab psoriasis los ntawm LL-37 [33,34], uas yog ib qho tseem ceeb cuam tshuam rau cov kab mob ntawm daim tawv nqaij, nrog rau atopic dermatitis[20 ]. Raws li tau tshaj tawm ntawm no, ob qho tshuaj tiv thaiv kab mob rosacea metronidazole (IC=o=14} uM) thiab azelaic acid (IC50 =100 uM), nrog rau kev kho mob atopic dermatitis FK{{37} } (IC50 =1 uM), txo LL-37-FPRL1-induced cytokine release with different potencies. SFC qhia txog qhov muaj zog zoo sib xws rau FK-506, ua haujlwm zoo dua ob qho tib si tshuaj rosacea, thiab inhibits FPRL-1-induced ROS tso tawm (Daim duab 1A) los ntawm neutrophils. Ua ke, cov ntaub ntawv no qhia tau hais tias muaj peev xwm ntawm IPC molecules los cuam tshuam rau ntau yam kev taw qhia sib txawv thiab hom cell uas tseem ceeb rau cov tawv nqaij o. Txog rau qhov kawg no, dhau los ~ 20 xyoo dhau los, TLR2 tau tshwm sim los ua ib qho tseem ceeb ntawm cov receptors ntawm daim tawv nqaij mob xws li pob txuv, rosacea, atopic dermatitis, thiab lwm yam [27,35-37]. Tshaj tawm hauv peb cov tawv nqaij, TLR2 yog ib feem ntawm peb thawj kab ntawm kev tiv thaiv kab mob tiv thaiv kab mob hauv kev teb rau cov kab mob nkag mus. TLR2 signaling ua haujlwm nyob rau ntawm GPCRs, TCR, thiab PPAR yav dhau los tau pom tias tau hloov kho los ntawm IPC analogs. Cov txiaj ntsig tau nthuav tawm ntawm no qhia tau tias SFC muaj zog tiv thaiv PGN-TLR2-induced IL-8 tso tawm los ntawm NHEKs (Daim duab 2B), thiab ua tiav txo TPA-induced TNF-ib tso tawm hauv keratinocytes (Daim duab 2A). TPA yog lub npe hu ua activator ntawm protein kinaseC (PKC), uas tseem ua lub luag haujlwm tseem ceeb hauv GPCR signaling. Yog li, SFCmay kuj inhibit qhov inflammatory signaling teb downstream ntawm PKC-induced cytokine tso tawm hauv NHEKs.

Kev mob ntev yog ib qho tseem ceeb hauv kev tsav cov kab mob ntawm daim tawv nqaij thiab kev laus. Raws li tau tshaj tawm ntawm no, ntxiv rau inhibiting GPCR thiab TLR-induced inflammatory signaling, SFC kuj thaiv UVB thiab UVA-induced o, nrog rau MMP-1 ntau lawm hauv fibroblasts, uas degrades collagen thiab accelerates tawv nqaij laus [22]. MP-1 ntau lawm yog tswj los ntawm kev nce MAP kinase/AP-1 kev ua [38]. Muab lub peev xwm ntawm SFC los muab kev tiv thaiv kev ua haujlwm hauv keratinocytes alnd endothelial hlwb, thiab qeeb oxidative kev nyuaj siab thiab cov duab-laus nyob rau hauv neutrophils thiab dermal fibroblasts, peb xav tias SFC qhov dav spectrum ntawm kev ua si yuav muaj txiaj ntsig zoo rau tib neeg cov tawv nqaij thaum siv tshuaj pleev. Cov ntaub ntawv kho mob tau nthuav tawm ntawm no qhia tau tias 1 feem pua ​​​​SFC gel txo qis wrinkles, txhim kho hydration, daim tawv nqaij zoo nkauj, tawv nqaij ci, thiab tag nrho cov tawv nqaij noj qab haus huv zoo dua li lub tsheb. Cov txiaj ntsig no yog qhov txaus siab tshwj xeeb, vim tias feem ntau cov kev tshawb fawb tshuaj pleev ib ce tau ua yam tsis muaj kev tswj xyuas tsheb. Tsis tas li ntawd, SFC cov kev noj qab haus huv ntawm daim tawv nqaij txhawb nqa prop-erties hauv qee qhov xwm txheej qhia tau tias muaj kev txhim kho tseem ceeb tshaj li 5 feem pua ​​​​niacinamide, tshuaj pleev ib ce los tiv thaiv kev laus thiab kev tiv thaiv kab mob (Table 3). Txawm hais tias cov kev tshawb fawb ntxiv tseem yuav tsum tau ua kom paub ntxiv txog cov txheej txheem ntawm kev ua ntawm SFC raws li nws cuam tshuam rau ntawm daim tawv nqaij o thiab kev laus, peb tawm tswv yim ntawm no ib qho kev xav ua haujlwm ntawm seb SFC muab nws cov tawv nqaij noj qab haus huv kev ua ub no tswj hwm ntau lub hom phiaj, suav nrog TLR thiab GPCR signaling ( Daim duab 4). Ua ke, cov txiaj ntsig no qhia tau tias SFC kho mob txhim kho cov tsos mob ntawm kev laus, thiab tej zaum yuav muaj txiaj ntsig zoo hauv kev txhim kho daim tawv nqaij noj qab haus huv thiab tiv thaiv ntau yam kab mob dermal.

Kab lus no yog muab rho tawm los ntawm Cosmetics 2021, 8, 110. https://doi.org/10.3390/cosmetics8040110 https://www.mdpi.com/journal/cosmetics