3. Kev sib tham

Txawm hais tias ZER nthuav tawm ntau yam kev ua haujlwm lom neeg, suav nrog kev tiv thaiv kab mob, tshuaj tiv thaiv kab mob, thiab tshuaj tiv thaiv kab mob, nws cov khoom tiv thaiv melanogenic tsis tau tshaj tawm [12]. Hauv txoj kev tshawb fawb tam sim no, peb tau pom thawj zaug tias Zingiber officinal (ZO) extract thiab nws cov khoom xyaw nquag, ZER, muaj cov nyhuv inhibitory muaj zog ntawm -melanocytes stimulating hormone (-MSH)-induced melanogenesis.

Raws li cov kev tshawb fawb cuam tshuam, cistanche yog ib hom tshuaj ntsuab uas hu ua "cov tshuaj ntsuab muaj txuj ci uas ua rau lub neej ntev". Nws lub ntsiab tivthaiv yogcistanoside, uas muaj ntau yam teebmeem xws liantioxidant, anti-inflammatory, thiabkev tiv thaiv kev ua haujlwm txhawb nqa. Cov txheej txheem ntawm cistanche thiab tawv nqaij dawb yog nyob rau hauv cov nyhuv antioxidant ntawm cistanche glycosides. Melanin nyob rau hauv tib neeg daim tawv nqaij yog tsim los ntawm oxidation ntawm tyrosine catalyzed los ntawmtyrosinase, thiab cov tshuaj tiv thaiv oxidation xav tau kev koom tes ntawm cov pa, yog li cov pa oxygen dawb radicals hauv lub cev dhau los ua qhov tseem ceeb cuam tshuam.melanin ntau lawm.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.

Nyem rau ntawm Rou Cong Rong Cov txiaj ntsig rau Kev Kho Kom Zoo Nkauj

Yog xav paub ntxiv:

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Qhov txawv txav melanogenesis tshwm sim los ntawm ultraviolet (UV) irradiation, inflammatory cytokines, thiab hormonal signaling, yog ze rau cov pigmentation mob, xws li chloasma thiab freckles [4]. Thaum raug UV, keratinocytes secrete -MSH, uas txhawb nqa melanin biogenesis hauv epidermal melanocytes [1]. Nyob rau hauv txoj kev tshawb no, peb tau pom tias methanolic cag extract ntawm Zingiber officinal (ZO) thiab ZER muaj zog suppresses -MSH-induced melanin tsub zuj zuj. Kev sib piv ntawm inhibitory teebmeem ntawm arbutin, uas yog ib tug paub zoo anti-melanogenic tshuaj, thiab ZER ntawm melanin tsub zuj zuj pom tau hais tias ZER ntawm 10 µM concentration exhibits kwv yees li 40 feem pua ​​muaj zog anti-melanogenic nyhuv tshaj arbutin nyob rau hauv -MSH-kho B16F10 nas melanogenic hlwb. .

Ntau qhov kev tshawb fawb biochemical tau pom tias cov roj tseem ceeb ntawm Zingiber zerumbet rhizomes muaj ntau cov ZER, suav txog kwv yees li 13-70 feem pua ​​​​ntawm cov nroj tsuag ZER cov ntsiab lus. Txawm li cas los xij, qee qhov me me ntawm ZER muaj nyob hauv Zingiber official thiab [20]. Qhov zoo siab, cov ntaub ntawv dhau los tau qhia tias Zingiber zerumbet cog hauv South Is Nrias teb muaj 76.3 txog 84.8 feem pua ​​​​ntawm ZER. Txawm li cas los xij, kev ua liaj ua teb silviculture hauv Is Nrias teb tau pom tias 1.81 feem pua ​​​​ZER cov ntsiab lus tau pom nyob rau hauv rhizome, 0.16 feem pua ​​​​hauv paus, thiab 0.09 feem pua ​​​​hauv nplooj ntawm Zingiber zerumbet [12]. Yog li ntawd, cov keeb kwm no qhia tias qhov sib txawv ntawm ZER cov ntsiab lus ntawm Zingiber zerumbet yuav tsis cuam tshuam nrog thaj chaw lossis kev hloov pauv hauv ecological, tab sis yog vim qhov sib txawv ntawm ZER chemotype [12]. Yog tias muaj, vim li cas ZO muaj kev tiv thaiv melanogenic? Qhov muaj peev xwm tuaj yeem pom tau tias lwm cov khoom siv nquag ntawm ZO, uas txawv ntawm ZER, tuaj yeem cuam tshuam melanogenesis. Tseeb, ib daim ntawv tshaj tawm yav dhau los tau qhia tias cov roj tseem ceeb ntawm Zingiber officinal rhizome muaj ntau cov khoom siv bioactive, xws li -pinene, valencene, thiab zingiberene [21]. Ntxiv mus, los tiv thaiv melanogenic los ntawm -pinene thiab valencene kuj tau pom nyob rau hauv B16F10 nas melanoma hlwb [22,23]. Tsis tas li ntawd, cov nyhuv melanogenesis-inhibitory ntawm [6]-tsev kawm ntawv, lub tsev kawm ntawv loj hauv Zingiber officinal rhizomes, tau raug pom los ntawm kev ua kom nrawm ntawm ERK1/2-kev kho MITF degradation [24]. Cov ntawv tshaj tawm yav dhau los no txhawb nqa peb qhov txiaj ntsig tias ntau hom kev ua haujlwm ntawm ZO thiab ZER muaj kev tiv thaiv melanogenic.

Microphthalmia-associated transcription factor (MITF) yog ib qho tseem ceeb rau melanogenesis los ntawm kev pab txhawb kev hloov pauv ntawm cov noob, xws li tyrosinase, tyrosinase-related protein 1 (TYRP1), thiab tyrosinase-related protein 2 (TYRP2), uas yuav tsum muaj rau melanin biosynthesis. thiab tsheb thauj mus los [2,25]. Raws li UV irradiation, -MSH muab tau los ntawm keratinocytes activates MITF thiab up-regulates cov kev qhia ntawm nws lub hom phiaj genes ntawm protein kinase A (PKA)-cAMP teb lub caij binding protein (CREB) signaling axis [25]. Tsis tas li ntawd, ntau yam kev hloov pauv, xws li SOX10 thiab LEF1, qhib cov kev ua haujlwm ntawm MITF [26]. SOX10 (kev txiav txim siab kev sib deev hauv cheeb tsam Y-box 10) tuaj yeem khi rau MITF txhawb nqa ntawm −264 thiab −266 thiab nce MITF transcription [27]. LEF1 (lymphoid enhancer-binding factor 1) kuj transcriptionally koom tes nrog MITF raws li ib tug non-DNA-binding activator los txhawb MITF noob qhia raws li Wnt (wingless-type) signaling [28]. Tom qab kev hloov pauv ntawm MITF, xws li phosphorylation thiab acetylation, tuaj yeem tswj hwm nws cov protein ruaj khov thiab kev ua haujlwm [26]. Tshwj xeeb tshaj yog, phosphorylation ntawm MITF ntawm Ser73, qhov twg degradation-txhim kho PEST ib ntus tam sim no, ua rau proteasome-dependent MITF degradation teb rau UV irradiation [17]. Proteasome-dependent MITF degradation kuj tshwm sim los ntawm phosphorylation ntawm MITF ntawm Ser409 [18]. Phosphorylation ntawm ob qho tib si Ser73 thiab Ser409 uas txhawb nqa MITF degradation yog nyob ntawm kev ua kom ERK1/2 txoj hauv kev [17,18]. Hauv txoj kev tshawb fawb tam sim no, peb pom tias ZER cuam tshuam qhov kev qhia ntawm MITF thiab nws lub hom phiaj cov noob, xws li tyrosinase, TYRP1, thiab TYRP2 raws li -MSH stimulation, ywj siab ntawm PKA-CREB signaling pathway (Daim duab 6). Qhov tseeb, peb cov txiaj ntsig tau pom tias ZER, tab sis tsis yog arbutin thiab kojic acid, txaus los txo qis -MSH-induced tyrosinase mRNA thiab protein qhia qib (Daim duab 2). Cov txiaj ntsig no qhia tau tias ZER suppresses melanogenesis los ntawm kev tswj hwm ntawm MITF-mediated transcription ntawm melanogenic noob thiab lawv cov protein qhia. Ubiquitin-mediated degradation ntawm MITF yog ib feem ntawm kev tswj hwm los ntawm kev txhawb nqa cov teeb liab-txheej txheem kinases (ERK1/2) ua kom [6,7]. Peb cov txiaj ntsig tau pom tias Zingiber officinal extract (ZO) thiab ZER nce ERK1/2 phosphorylation, thiab txo melanin tsub zuj zuj hauv B16F10 hlwb. Ntxiv mus, cov kev xaiv inhibitor ntawm mitogen-activated protein kinase (MAPK), U0126, zoo rov qab cov ntsiab lus melanin, txo qis los ntawm ZER, qhia tias ERK1/2 signaling yog txuam nrog cov nyhuv anti-melanogenic ntawm Zingiber officinal (ZO) extract thiab zerumbone.

Txo phosphorylation ntawm ERK1/2 los ntawm ZER hauv hepatocellular carcinoma thiab U937 macrophage hlwb tau pom yav dhau los [29]. Tsis tas li ntawd, ethanol extract ntawm Zingiber zerumbet rhizomes tau pom tias inhibit ERK1/2 phosphorylation hauv ntshav qab zib retinas [30]. Hauv qhov sib piv, hauv txoj kev tshawb no, peb pom tias ZER nce phosphorylation ntawm ERK1/2, tab sis tsis yog MEK, raws li kev siv tshuaj (Daim duab 3A). Raws li peb cov txiaj ntsig, ib tsab ntawv tshaj tawm dhau los tau qhia tias 6-gingerol thiab 6- tsev kawm ntawv, uas yog cov khoom tseem ceeb ntawm cov qhiav, attenuate nerve growth factor (NGF)-induced ERK1/2 phosphorylation in mouse hippocampus [31]. Ntxiv mus, lwm cov pov thawj kev sim tau pom tias ZER thiab 6-shogaol nrawm ERK1/2 phosphorylation hauv THP-1 monocytes thiab nas B16F10 melanoma hlwb, feem [24,32]. Tsis tas li ntawd, nyob rau hauv nas B16BL6 melanoma hlwb uas tau kho nrog isosakuranetin, ib tug 40 -O-methylated flavonoid, ib tug txo phosphorylation ntawm MITF thiab nce MITF stability tau pom los ntawm kev tawm tsam ntawm ERK1/2 uas tom qab nkoos melanogenesis [33 ]. Yog li, peb xav hais tias ZER thiab ZO extract-induced ERK1/2 activation tej zaum yuav yog vim li cas rau qhov nce phosphorylation ntawm MITF thiab nws destabilization, uas ua rau muaj kev cuam tshuam ntawm melanogenesis. Txawm li cas los xij, kev tshawb nrhiav dav dav yog tsim nyog los daws cov kev tsis sib haum xeeb txog Zingiber extracts thiab lawv cov khoom phosphorylate ERK1/2 sib txawv hauv ntau hom hlwb lossis cov ntaub so ntswg. Vim hais tias MEK yog ib qho tseem ceeb ntawm cov kinase [34] uas phosphorylates ERK1/2 raws li oncogenic loj hlob signaling, ZER tau txiav txim siab los hloov cov kev ua ntawm ERK1/2 upstream kinase ib yam nkaus. Txawm li cas los xij, peb cov txiaj ntsig tau pom tias ZER tsis cuam tshuam rau MEK phosphorylation. Yog li, muaj ob lub tswv yim los piav qhia txog cov txheej txheem molecular ntawm ZER kev ua. (1) ZER ncaj qha cuam tshuam thiab cuam tshuam cov kev ua kinase ntawm MEK los ntawm kev sib tw lossis allosteric inhibitory mechanism, thiab (2) Tsis muaj cov cim qhia tsis paub uas cuam tshuam ncaj qha lossis tsis ncaj qha cuam tshuam los ntawm ZER thiab ua tus activators ntawm ERK1/2. Interestingly, yav dhau los cov ntaub ntawv qhia tau hais tias ZER ua rau oxidative kev nyuaj siab los ntawm depletion ntawm intracellular glutathione (GSH) thiab induction ntawm intracellular reactive oxygen hom (ROS) nyob rau hauv cov hnyuv thiab pancreatic cancer hlwb, feem [35,36]. Ntxiv mus, nws kuj tau raug tshaj tawm tias muaj zog intracellular ROS modulates ERK1/2 phosphorylation los ntawm kev tawm tsam ntawm dual-specific phosphatase 3 (DUSP3) los ntawm oxidation ntawm Cys-124 [37]. Ib qho kev xav tau tuaj yeem yog tias muaj kev ntxhov siab oxidative thiab suppressed DUSP3 los ntawm ZER tej zaum yuav koom nrog ERK1/2 phosphorylation. Tsis tas li ntawd, Chen et al. tau tawm tswv yim tias ZER txo qis hauv cov cellular nitric oxide (NO) tsub zuj zuj los ntawm suppressing NF-κB thiab iNOS teeb liab txoj kev, uas tiv thaiv nas cornea los ntawm UVB-induced photokeratitis [38]. Nitric oxide (NO) yog ib qho melanogenesis-stimulating yam uas tawm ntawm melanocytes thiab keratinocytes raws li UV irradiation thiab proinflammatory cytokines [39,40]. Cov ntaub ntawv no qhia txog qhov ua tau tias ZER txo qis -MSH-induced melanogenesis los ntawm kev tswj hwm intracellular NO. Yog li ntawd, kev tshawb fawb txuas ntxiv los ua kom pom cov txheej txheem molecular los ntawm ZER ua rau ERK1/2 teeb liab txoj hauv kev tuaj yeem muab kev tshawb fawb keeb kwm yav dhau los rau kev txhim kho cov tawv nqaij-dawb tshuaj pleev ib ce.

ZER muaj ntau yam kev ua haujlwm lom neeg, xws li tshuaj tiv thaiv kab mob [41], tshuaj tiv thaiv kab mob microbial [42], antioxidant [43], thiab tiv thaiv kev ua xua [44]. Ntev raug rau ultraviolet A (UVA) irradiation ua rau photoaging-txog dermatological kab mob, xws li wrinkles thiab daim tawv nqaij mob cancer los ntawm ntau tsub zuj zuj ntawm reactive oxygen hom (ROS) [2]. Ib tsab ntawv tshaj tawm dhau los tau qhia tias ZER tawm cytoprotection tawm tsam UVA-irradiation-vim cellular puas tsuaj rau ntawm daim tawv nqaij keratinocytes los ntawm kev ua kom muaj zog nuclear (erythroid-derived 2)-zoo li 2 (Nrf2)-mediated antioxidants noob qhia [1]. Peb cov ntaub ntawv qhia tias ZER, ua ib qho tseem ceeb ntawm ZO extract, tuaj yeem siv los kho cov kab mob dermatological, xws li mob qog noj ntshav, wrinkles, thiab hyperpigmentation, uas yog tshwm sim los ntawm UV irradiation. Txawm hais tias ntawm no peb tau pom cov nyhuv anti-melanogenic ntawm ZER thiab ZO extract nyob rau hauv B16F10 nas thiab G361 tib neeg melanoma hlwb, lawv cov kev ua ub no los tiv thaiv melanogenesis yuav tsum tau soj ntsuam ntxiv nyob rau hauv tib neeg thawj melanocytes ua ntej txiav txim siab nyob rau hauv daim tawv nqaij-dawb tshuaj pleev ib ce.

4. Cov ntaub ntawv thiab cov txheej txheem

4.1. Reagents thiab Antibodies

Antibodies tiv thaiv MITF (#1259{39}}), p-AKTS473 (#4060), p-CREB (#9398), p-ERK1/2 (#4370), ERK1/2 (#9102), p-MEK (#9154), MEK (#9122), thiab ERK1/2 inhibitor U0126 tau yuav los ntawm Cell Signaling Technology (Danvers, MA, USA). Anti-Tyrosinase (sc-7833) thiab -tubulin (sc-9104) tau txais los ntawm Santa Cruz Biotechnology (Dallas, TX, USA). Anti-TYRP2 (DCT, ab74073) tau yuav los ntawm Abcam (Cambridge, UK). Zerumbone (Z3902), arbutin (A4256), kojic acid (K3125), -MSH (M4135), thiab L-DOPA (333786) tau yuav los ntawm Sigma-Aldrich (St. Louis, MO, USA). Ib qho kev daws teeb meem ntawm -Melanocyte stimulating hormone tau npaj rau hauv phosphate-buffered saline (PBS) ua ntej kho. Recombinant human SCF tau txais los ntawm R&D systems (Minneapolis, MN, USA) thiab nws cov kev daws teeb meem (10 µM) tau npaj hauv PBS. Cov kev daws teeb meem ntawm zerumbone (20 mM), arbutin (1 M), thiab kojic acid (0.2 M) tau npaj hauv dimethyl sulfoxide (DMSO). Lyophilized Zingiber officinal extract (035-061), cais los ntawm 99 feem pua ​​​​methanol, tau txais los ntawm Kauslim cog Extract Bank (KPEB) (Daejeon, Kauslim) thiab Kauslim Kev Tshawb Fawb Lub Tsev Haujlwm ntawm Bioscience thiab Biotechnology (KRIBB) (Daejeon, Kauslim). Ib qho kev daws teeb meem ntawm Zingiber officinal extract tau npaj hauv DMSO ua ntej kev kho mob.

4.2. Cell Culture thiab Cell Viability Assay

4.3. Immunoblotting thiab Immunoprecipitation

Immunoprecipitation tau ua los xyuas seb puas yog endogenous MITF yog phosphorylated ntawm Ser73. 1 mg ntawm cell lysates tau incubated nrog 1 µg ntawm anti-phospho-MITF antibody (pSer73; Sigma-Aldrich, St. Louis, MO, USA) rau 16 h ntawm 4 ◦C, ua raws li incubation nrog 20 µL ntawm protein A / G-agarose hlaws (Santa Cruz Biotechnology, Dallas, TX, USA) rau 3 h ntawm 4 ◦C. Precipitated proteins tau eluted nyob rau hauv SDS qauv tsis thiab ces phosphorylated MITF (Ser73) protein yog ntsuas los ntawm immunoblotting siv anti-p-MITF antibody (pSer73). Immunoblotting tau ua tiav, raws li tau piav qhia yav dhau los [4]. Luv luv, tag nrho cov qauv protein tau npaj siv lysis buffer, muaj 1 feem pua ​​​​NP-40 (Nonidet P-40), 150 mM NaCl, 50 mM Tris-HCl (pH 7.4), 10 mM NaF, thiab a protease inhibitor cawv. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) tau siv los cais cov proteins hauv txhua tus qauv raws li lawv qhov hnyav molecular. Cov protein sib cais tau raug xa mus rau polyvinylidene difluoride (PVDF) membrane (Millipore, Burlington, MA, USA). Membranes nrog cov protein hloov pauv tau raug tsim nrog thawj cov tshuaj tiv thaiv kab mob (1: 1000) thiab cov tshuaj tiv thaiv thib ob (1:10,000) ntawm 4 ◦C lossis chav tsev kub. Cov khoom siv Chemiluminescent ECL Prime (GE Healthcare, Pittsburgh, PA, USA) tau siv los ua kom pom cov kab lus protein.

4.4. Kev ntsuas ntawm Intracellular thiab Extracellular Melanin Cov ntsiab lus 

Intracellular thiab extracellular melanin cov ntsiab lus tau ntsuas thiab txheeb xyuas, raws li tau piav qhia yav dhau los [3]. Mouse melanogenic B16F10 cov hlwb tau coj los ntawm phenol-red-free DMEM. Cells raug kho ua ntej nrog -MSH (0.1 mM) rau 1 h los txhawb melanogenic stimulation, thiab incubated nrog zerumbone rau peb hnub. Tom qab incubation, cov kab lis kev cai nruab nrab tau hloov mus rau hauv cov hlab ntsha tshiab, thiab cov noob qoob loo tau sau thiab yaj hauv 1 N NaOH uas muaj 10 feem pua ​​​​DMSO ntawm 80 ◦C rau 1 h. Cov ntsiab lus melanin ntawm kab lis kev cai nruab nrab thiab cell rho tawm tau ntsuas ntawm 475 nm (OD475) siv tus nyeem ntawv absorbance. Cov ntsiab lus melanin ces normalized rau cellular protein concentration.

4.5. Quantitative RT-PCR

Quantitative real time-PCR tau ua raws li tau piav qhia yav dhau los [4]. Luv luv, lub peev xwm siab cDNA thim rov qab cov khoom siv (Applied Biosystems, Waltham, MA, USA) thiab tag nrho RNA (2 µg) tau siv rau cDNA synthesis. SYBR Green PCR Master MIX (Dynebio, Seongnam, Kauslim) tau siv rau ntau PCR. Qhov sib lawv liag ntawm PCR primers 50 thiab 30 yog raws li nram no: TCAAGTTTCCAGAGACGGGT thiab CATCATCAGCCTGGAATCAA rau MITF; ATAGGTGCATTGGCTTTGG thiab TCTTCACCATGCTTTTTGG rau tyrosinase; CTCATCAAAGATGGCGTCTG thiab CTTCCTGAATGGGACCAATG rau TYRP1.

4.6. Cellular Tyrosinase Activity Assay

Mouse melanogenic B16F10 hlwb raug incubated nrog 0.1 mM ntawm -MSH thaum tsis muaj los yog muaj zerumbone, arbutin, kojic acid, thiab Zingiber officinal (ZO) extract, raws li qhia. Cov hlwb raug ntxuav thiab lysed siv txias PBS uas muaj 1 feem pua ​​​​Triton X-100, thiab cov enzymatic kev ua ntawm tyrosinase raug ntsuas siv cov txheej txheem yav dhau los piav qhia [4].

4.7. Kev txheeb cais

5. Cov lus xaus

Qhov kev tshawb pom loj ntawm txoj kev tshawb no yog tias Zingiber officinal (ZO) extract thiab nws cov khoom xyaw nquag, zerumbone (ZER), (i) attenuates melanin tsub zuj zuj ntawm -MSH stimulation; thiab, (ii) txo qis kev qhia ntawm melanogenesis-uas cuam tshuam txog kev hloov pauv, MITF, thiab nws lub hom phiaj cov noob los ntawm kev ua kom ERK1/2 ywj siab ntawm PKA-CREB signaling pathway (Daim duab 6). Cov txiaj ntsig no, yog li ntawd, qhia tias Zingiber officinal (ZO) extract muaj ZER, ua ib qho khoom muaj txiaj ntsig, uas yuav muaj txiaj ntsig zoo hauv kev txhim kho cov tshuaj pleev ib ce thiab cov khoom siv tawv nqaij dawb.

Cov ntaub ntawv

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