Carvedilol, Adrenergic Blocker, Suppresses Melanin Synthesis Los Ntawm Inhibiting CAMP/CREB Signaling Pathway in Human Melanocytes Thiab Ex Vivo Human Skin Culture
Mar 20, 2022
Hu rau:joanna.jia@wecistanche.com/ WhatsApp: 008618081934791
myoung Eun Choi 1, †, Hanju Yoo 1,2, †, Ha-Ri Lee 2,3, Ik Joon Moon 1, Woo Jin Lee 1, Youngsup Song 3,*,‡ and Sung Eun Chang 1.
Abstract:Catecholamines ua haujlwm ntawm G protein-coupled receptors, ua rau muaj kev nce hauv intracellular theem ntawm 30, 50-cyclic adenosine monophosphate (cAMP) hauv ntau lub hlwb. Catecholaminebiosynthesis thiab -adrenergic receptor muaj nyob hauvmelanocytes; Yog li, catecholamines tuaj yeem ua lub luag haujlwm tseem ceeb hauv daim tawv nqaij pigmentation. Txawm li cas los xij, lawv cov kev ua thiab cov txheej txheem kho melanogenesis ntawm tib neeg daim tawv nqaij tseem tsis tau tshawb xyuas. Yog li ntawd, peb tau tshuaj xyuas qhov muaj peev xwm los tiv thaiv melanogeneticeffect ntawm carvedilol, ib qho tsis xaiv -blocker nrog tsis muaj zog 1- thaiv kev ua ub no. Carvedilol txo melanin cov ntsiab lus thiab cellular tyrosinase kev ua haujlwm yam tsis muaj kev cuam tshuam cellular viability hauv tib neeg.melanocyteszoo li hauv Mel-Ab immortalized nas melanocytes. Carvediloldownregulated microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-relatedprotein (TRP)-1, thiab TRP-2. Kev kho Carvedilol coj mus rau kev txo qis ntawm phosphor-cAMPresponse element-binding protein (CREB). Ntxiv mus, qhov nce hauv qib cAMP thaum kho nrog forskolin thim rov qab cov tshuaj tiv thaiv melanogenic ntawm carvedilol. Tsis tas li ntawd, carvedilol remarkably txo melanin Performance index nyob rau hauv ultraviolet-irradiated tib neeg daim tawv nqaij kab lis kev cai. Ua ke, peb cov txiaj ntsig qhia tau hais tias carvedilol zoo suppresses melanogenesis hauv tib neegmelanocytesthiab ex vivohuman daim tawv nqaij los ntawm inhibiting cAMP/protein kinase A/CREB signaling. Cov tshuaj tiv thaiv melanogenic ntawm carvedilol muaj qhov tseem ceeb rau daim tawv nqaijntxuav hniav dawbtus neeg sawv cev.
Ntsiab lus:carvedilol; adrenergic blocker;melanin synthesis; cAMP/CREB signaling
CistancheNws muaj peev xwm inhibit melanin synthesis
1. Taw qhia
Ntau yam ntawm cov tawv nqaij pigmentary muaj qhov cuam tshuam rau kev puas siab puas ntsws thiab kev sib raug zoo rau cov neeg mob. Ntau yam kev kho mob, nrog rau cov kab mob thiab cov tshuaj pleev ib ce nrog rau kev kho laser, tau tsim [1-3]. Txawm li cas los xij, cov txiaj ntsig feem ntau tsis txaus siab thiab tsis zoo, xws li post-inflammatory hyperpigmentation (PIH) thiab hypopigmentation, los ntawm kev kho mob yog ib txwm muaj. Tsis tas li ntawd, kev kho mob yog kim thiab siv sij hawm ntau [4–6].
Catecholamines, uas muaj xws li dopamine, epinephrine, thiab norepinephrine, yog signalingmolecules uas ua raws li neurotransmitters thiab endocrine hormones. Nyob rau hauv daim tawv nqaij, biosynthesis thiab degradation ntawm catecholamines tshwm sim nyob rau hauv tib neeg keratinocytes, tab sis catecholamine synthesis nyob rau hauv melanocytes yog me ntsis txawv [7-9]. Catecholamines ua haujlwm ntawm G protein-coupled receptors (GPCRs). Kev khi ntawm catecholamines rau GPCRs ua rau kev ua kom lub cev ntawm intracellular adenylatecyclase, uas ua ke 30, 50-cyclic adenosine monophosphate (cAMP) los ntawm ATP [10]. Tus tub txib thib ob cAMP siv nws txoj haujlwm los ntawm kev khi R-subunit ntawm protein kinase A (PKA), uas ua rau phosphorylation ntawm cAMP teb cov ntsiab lus-binding protein (CREB). GPCRs yog activated byamines thiab peptides, suav nrog glucagon, parathyroid hormone, secretin, thiab calcitonin [10].
Adrenergic receptor antagonists suav nrog -receptor thiab -receptor antagonists. -Receptorantagonists yog subcategorized rau tsis xaiv, 1- xaiv, thiab 2- xaiv tus neeg sawv cev, whereas -receptor antagonists yog subclassified li tsis xaiv, 1- xaiv, thiab 2- xaiv cov neeg ua haujlwm raws li lawv cov kev xaiv thaiv cov haujlwm. Tsis zoo li thawj tiam uas tsis yog xaiv -receptive antagonists, xws li propranolol, timolol, thiab nadolol, carvedilol yog ib tiam thib peb uas tsis xaiv -blocker uas qhia txog vasodilator ua los ntawm thaiv 1-adrenoreceptors ( 1-ARs) [11]. Yog li, carvedilol yog anonselective -blocker nrog tsis muaj zog 1- thaiv kev ua ub no [12]. Nws yog tsuas yog siv los ua cov tshuaj hauv qhov ncauj los tswj cov ntshav siab thiab kab mob plawv, zoo ib yam li lwm yam -blockers [12]. Txawm li cas los xij, tiam thib peb -blockers muaj angiogenic, antioxidant, anti-proliferative, anti-hypertrophic, thiab anti-apoptotic kev ua ub no uas yuav tsum tau ntxiv elucidation [11]. Hauv daim teb dermatologic, vim nws cov tshuaj tiv thaiv oxidant thiab cov tshuaj tiv thaiv kab mob, carvedilol feem ntau yog siv rau hauv qhov ncauj formulations rau kev kho mob rosacea (13,14). Tsis tas li ntawd, kev ua haujlwm antioxidant ntawm carvedilol ua rau muaj kev tiv thaiv ntawm ultraviolet (UV) ua rau daim tawv nqaij carcinogenesis, ua rau nws yog ib tus neeg saib xyuas kev noj qab haus huv ntawm cov kab mob ntawm daim tawv nqaij [15-18]. Txawm li cas los xij, chemopreventive teebmeem ntawm carvedilolare tsis kho ncaj qha los ntawm ARs. [19] Txawm hais tias qhov tseeb mechanism kuj tsis paub, cAMP/PKA thiab PKC-δ txoj kev taw qhia yuav cuam tshuam rau cov khoom ntawm carvedilol tiv thaiv daim tawv nqaij metastasis [20].
Nyob rau theem pib ntawm kev tshawb nrhiav pigmentation, tib neegmelanocytestau pom los qhia -1-AR signaling tom qab extracellular induction nrog norepinephrine. Txawm li cas los xij, -ARs tsis tau pom tom qab stimulation nrog adrenergic signaling nyob rau hauvmelanocytes[8]. Conversely, Cillbro et al. tom qab ntawd qhia tau tias muaj kev ua haujlwm tshwj xeeb 2-AR teeb liab muaj nyob hauv tib neeg melanocytes thiab tias 2-ARstimulation ua rau pigmentation los ntawm 2-AR/cAMP txoj kev [7]. Yog li, lub luag haujlwm ntawm catecholamines hauv kev tswj cov pigmentation tau pom zoo, thiab cAMP yog suav tias yog lub ntsiab axis rau catecholamine tswj ntawm melanogenesis.
Melanogenesis yog txheej txheem nyuaj uas muaj ntau txoj hauv kev. Tyrosinase, tyrosinase-related protein 1 (TRP-1), thiab TRP-2, kuj hu ua dopachrome tautomerase (DCT), yog peb lub ntsiab melanocyte-specific enzymes koom nrog hauvmelanin synthesis[21]. Melanogenesis yog induced los ntawm ntau yam, nrog rau cov tshuaj hormones, cytokines, neurotransmitters, loj hlob yam, thiab microolecules [21-23].
Qhov tseem ceeb tshaj plaws zoo regulator yog melanocortin -1 receptor thiab nws ligands, melanocortinsand adrenocorticotropic hormone [23]. Txawm li cas los xij, lwm yam tseem ceeb hauv melanogenesis yog -endorphin, estrogens, androgens, vitamin D3, thiab catecholamines [23]. Cov ntaub ntawv pov thawj tau pom zoo tias L-tyrosine thiab L-DOPA, uas yog cov substrates thiab nruab nrab ntawm melanogenesis, ua asinducers thiab zoo regulators ntawm txoj kev melanogenic, ntxiv rau cov tswj hwm ntawm lwm cov cellularfunctions [24]. Ntxiv mus, Jeff Howe et al. qhia tias induction thiab kev tswj ntawm melanogenesisby L-tyrosine yog kho los ntawm kev ua kom ncaj qha ntawm adrenergic receptors los ntawm L-tyrosine, es tsis yog los ntawm nws cov khoom metabolic xws li catecholamines [25]. Hauv lawv cov kev tshawb fawb, norepinephrine thiab epinephrinestimulated tyrosinase kev ua haujlwm, tab sis lawv cov nyhuv inductive raumelanin synthesistau muab piv qis dua L-tyrosine [25].
Catecholamines tuaj yeem ua lub luag haujlwm tseem ceeb hauv daim tawv nqaij pigmentation system; Txawm li cas los xij, lawv cov teebmeem ntawm melanogenesis hais txog qhov kev txiav txim ntawm thib peb tiam uas tsis yog xaiv -blocker tseem tsis tau tshawb pom. Yog li ntawd, hauv txoj kev tshawb no, peb tsom los tshawb xyuas seb carvedilol puas cuam tshuam rau melanogenesis thiab tshawb nrhiav nws cov txheej txheem ntawm kev ua haujlwm hauv tib neeg.melanocytesthiab ex vivo tib neeg skinand nws muaj peev xwm siv raws li ib tugntxuav hniav dawbkhoom.
inhibit melanin tsim nrogherba cistanches
2. Cov txiaj ntsig
2.1. Carvedilol txo qis Melanogenesis
Lub cytotoxicity ntawm carvedilol tawm tsam tib neeg ib txwmmelanocytes(NHMs) thiab Mel-ab cells raug soj ntsuam los ntawm WST cell proliferation assay. Ib qho carvedilol concentration ntawm 10 µM pib qhia cytotoxicity tawm tsam NHMs thiab Mel-ab hlwb (Daim duab 1A, B). Yog li ntawd, hauv kev ntsuam xyuas ntxiv, peb siv 8 µM ntawm carvedilol, uas tsis yog cytotoxic rau NHMs.
Kev kho mob nrog carvedilol txo qis melanin cov ntsiab lus nyob rau hauv koob tshuaj raws li yam tsis muaj kev cuam tshuam rau kev ua tau zoo ntawm NHMs (Daim duab 1C). Cov ntsiab lus melanin tau txo qis los ntawm 28.36 feem pua tom qab 96 hof 8 µM carvedilol kho (Daim duab 1C). Qhov sib ntxiv ntawm 100 mg / mL arbutin txo cov ntsiab lus melanin kom tsawg dua li carvedilol (Daim duab 1C). Tom qab 4 hnub ntawm kev kho mob carvedilol, cov ntsiab lus melanin poob qis hauv lub sijhawm (Daim duab 1D). Txawm li cas los xij, kev kho mob nrog forskolin (FSK) rau 4 hnub tom qab kev kho mob ua ntej nrog carvedilol ua rau muaj kev nce hauv melanin cov ntsiab lus (Daim duab 1E).FSK nce cov ntaub ntawv ntawm MITF mus rau qib siab tshaj plaws ntawm 2 h hauv NHMs thiab ntseeg tias tofunction ntawm cAMP /PKA/CREB pathway (Daim duab 1F).
2.2. Carvedilol inhibits qhov kev nthuav qhia ntawm MITF thiab Nws Cov Hom Phiaj thiab Txo Phospho-CREB Levelsin NHMs
Vim tias carvedilol txo melanin tsub zuj zuj zuj zus, peb tau tshawb xyuas cellular tyrosinase kev ua haujlwm.Kev kho mob nrog carvedilol txo qis cellular tyrosinase kev ua haujlwm nyob rau hauv koob tshuaj nyob rau hauv NHMs (Daim duab 2A). Tyrosinase kev ua haujlwm txo qis los ntawm 28.48 feem pua tom qab 96 h ntawm 8 µM carvedilol kho (Daim duab 2A). Tom ntej no peb txiav txim siab seb carvedilol cuam tshuam rau kev qhia ntawm MITF, uas ua lub luag haujlwm tseem ceeb hauv kev tswj hwm ntawm tyrosinase thiab cov noob melanogenic hauv qab. FSK kev kho mob tau nce intracellular cAMP qib thiab thim rov qab cov tshuaj tiv thaiv melanogenic ntawm carvedilol. Carvedilol tau txo qis cov protein ntau ntawm MITF, qhov tseem ceeb ntawm kev hloov pauv ntawm melanogenesis, ntawm 72 h (Daim duab 2B). Tsis tas li ntawd, qhov kev qhia ntawm nws cov hom phiaj, xws li tyrosinase thiab TRP{10}}, tau txo qis tom qab kho carvedilol (Daim duab 2B). Cov txiaj ntsig no qhia tias carvedilol inhibits melanogenesis los ntawm kev tswj MITF signaling.
Tom ntej no, peb tau tshawb xyuas cov kev taw qhia intracellular ntawm melanogenesis, uas tswj MITFtranscription, los ntawm kev ntsuas qhov qhia theem ntawm phospho-CREB thiab phospho-ERK. Phospho-ERKlevels tsis hloov lub sijhawm tom qab kho carvedilol; Txawm li cas los xij, qib phospho-CREB tau txo qis (Daim duab 2B). Raws li kev soj ntsuam yav dhau los, peb cov txiaj ntsig tau qhia tias carvedilolinhibits melanogenesis los ntawm inhibiting cAMP / PKA / CREB txoj kev taw qhia. Ntxiv mus, FSK kev kho mob thim rov qab cov tshuaj tiv thaiv melanogenic ntawm carvedilol los ntawm kev nce qib cAMP.
2.3. Melanin Index thiab Immunohistochemical Staining hauv Ex Vivo Tib Neeg Daim tawv nqaij kab lis kev cai
Lub epidermal melanocyte density thiab melanin index nyob rau hauv ex vivo tib neeg daim tawv nqaij kab lis kev cai cov ntaub so ntswg tau kuaj pom los ntawm Melan-A thiab Fontana-Masson qhov staining, raws li. Carvedilol tsis cuam tshuam rau tus naj npawb ntawm Melan-A (ntxiv rau)melanocytesnyob rau hauv cov qauv kho nrog carvedilol ntxiv rau UVradiation (UVR) piv nrog rau hauv cov qauv kho nrog UVR ib leeg (Daim duab 3A). HMB45 (ntxiv rau) melanocytes tuaj yeem qhia tau tias kev ua haujlwm melanocytic tau nce ntxiv thaum kho UVR thiab tau rov qab tswj xyuas tom qab kev kho carvedilol (Daim duab 3B). Txawm li cas los xij, cov ntsiab lus melanin tau txo qis hauv cov qauv kho nrog carvedilol ntxiv rau UVR piv nrog rau hauv UVR-ib leeg kho cov qauv (Daim duab 3C). Rau kev xam cov melanin Performance index, qhov feem ntawm Fontana-Masson's stainedarea tshaj tag nrho cheeb tsam ntawm ib qho piv txwv raug rau UVR thiab qhov ntawd rau carvedilol ntxiv rau UVR raug xam thiab piv (Daim duab 3D). Cell lysates ntawm txhua tus qauv tau txheeb xyuas los ntawm Western blotassay, uas qhia tias tyrosinase, TRP1, thiab DCT tau nce los ntawm UVR thiab txo qis kev kho bycarvedilol (Daim duab 3E). Raws li qhov tshwm sim, carvedilol zoo kawg li txo qis melanin Performance index thiab melanogenesis-txog cov proteins, uas qhia nws cov nyhuv anti-melanogenic ntawm UVR-kho tib neeg daim tawv nqaij.
3. Kev sib tham
Melanin yog lub luag haujlwm rau cov tawv nqaij thiab cov plaub hau xim thiab yog synthesized hauv melanosomes los ntawmmelanocytes. Txawm hais tias epidermal melanin ua lub luag haujlwm tseem ceeb tiv thaiv UVR, melaninoverproduction thiab tsub zuj zuj ntawm daim tawv nqaij ua rau muaj teeb meem ntawm daim tawv nqaij hyperpigmentary disorders, xws li PIH, photoaging-associated dyspigmentation, melasma, thiab hnub ci lentigines [18,26]. Yog li, qhov inhibition ntawm melanogenesis tau ua kom pom tseeb ntawm kev kho mob thiab kho kom zoo nkauj rau daim tawv nqaij thiab kev noj qab haus huv. Kev siv zog ntau tau ua los txheeb xyuas cov tshuaj tiv thaiv pigmentation tshiab thiab muaj txiaj ntsig zoo. Txawm li cas los xij, cov txheej txheem los tiv thaiv melanogenesis ntawm cov neeg ua haujlwm tshwj xeeb yog tam sim no tsis paub meej thiab feem ntau tau raug soj ntsuam hauv cov hlwb nas, uas ua rau cov txiaj ntsig tsis zoo ib yam nrog tib neeg cov tawv nqaij sim [27,28]. Tsis tas li ntawd, raws li melanogenesis ntawm melanocytes yog nruj tswj hwm los ntawm keratinocytes thiab lwm cov hlwb nyob sib ze, cocultured tib neeg cov hlwb los yog ex vivo tib neeg cov tawv nqaij muaj kev ntseeg siab dua qhov chaw sim rau kev tshawb nrhiav kev ua tau zoo.ntxuav hniav dawbcov neeg sawv cev [29]. Feem ntau cov neeg ua kom tawv nqaij dawb, txawm tias yog los yog tshuaj lom neeg, tuaj yeem ua rau tawv nqaij toxicity lossis khaus, uas tuaj yeem kwv yees tau qee yam siv hauv vitro cell viability assays nrog melanocytes. Hauv peb txoj kev tshawb fawb, carvedilol tsis tau qhia cytotoxicity thaum siv cov koob tshuaj me me.
cistanche bienfaits
Hydroquinone tshuaj pleev ib ce tuaj yeem ua rau muaj qhov tsis xav tau hypopigmentation mob thiab tawv nqaij [30–32]. Tsis tas li ntawd, qee qhovntxuav hniav dawbtshuaj pleev ib ce muaj kev puas tsuaj los ntawm inducinghypopigmentation los ntawm degradation ntawm tyrosinase proteins [33-35]. Cov tshuaj ntxuav hniav dawb tuaj yeem siv tau ntawm cov koob tshuaj ntau dua nyob ntawm tus neeg siv kom ua kom lub ntsej muag dawb ntawm cov kab mob hyperpigmentary.Yog li ntawd, kev siv zog los tshawb pom kev nyab xeeb thiab noj qab haus huv ntawm daim tawv nqaij ua kom tawv nqaij ua kom zoo nkauj tsis tu ncua hauv kev tshawb nrhiav.
Yog li ntawd, qhov kev tshawb fawb tam sim no tau tsim los ua hauv tib neeg lub cev thiab ex vivohuman daim tawv nqaij. Tsis tas li ntawd, raws li catecholamines 'tsim kev ua haujlwm ntawm G signaling, uas ua rau nce qib ntawm cellular cAMP, peb ntseeg hais tias ib qho adrenergic blocker tuaj yeem txo qis cAMP qib thiab inhibit qhov UVR / cAMP / CREB signaling pathway, uas yog lub ntsiab mechanism rau UV-induced tawv nqaij hyperpigmentation. [36, 37]. Yog li ntawd, peb xav tias adrenergic blockers uas txo cov qib cAMP txomelanin synthesis.
Ntxiv rau, txhawm rau txhim kho kev nyab xeebntxuav hniav dawbCov neeg sawv cev, txhim khu kev qha thiab rov tsim dua cov txheej txheem ntawm kev tiv thaiv melanogenesis yuav tsum tau ua raws tib lub sijhawm. Qhov tseem ceeb tshaj plaws physiologically stimulus yog UV, thiab ntawm UVR signaling rau epidermalmelanocytes, CREB axis yog txoj hauv kev tsim tshaj plaws rau kev tswj hwm ntawm melanogenesis hauv tib neeg epidermis [29]. Kev cuam tshuam rau UV ua tiav activatescAMP ntau lawm, PKA, thiab qhov kev hloov pauv ntawm CREB, uas, dhau los, ua rau muaj kev qhia ntawm MITF thiab downstream lub hom phiaj melanogenic noob [38,39]. Ntxiv rau CREB phosphorylation los ntawm PKA, cov kev tshawb fawb tsis ntev los no tau pom tias kev nrhiav neeg ua haujlwm ntawm CREB-regulated transcription coactivator (CRTC) 3 mus rau CREB transcription complex kuj yuav tsum tau rau cAMP-stimulated MITF. MITF ua lub luag haujlwm tseem ceeb tshaj plaws hauv kev tswj hwm ntawmmelanin synthesisthiab cov txiaj ntsig tau hloov pauv ntawm melanogenic enzymes [26,40,41]. Thaum lub sij hawm no intracellular signaling txheej txheem, melanogenesis yog tswj los ntawm ib tug tseem ceeb enzyme, tyrosinase, thiab ntxiv enzymatic proteins, xws li TRP-1 thiab DCT [1–4].Nyob rau hauv txoj kev tshawb no, carvedilol zoo txo cov phosphorylation ntawm CREB, uas. qhia tias nws txo MITF thiab tyrosinase proteins los ntawm inhibiting MITF transcription (Daim duab 4). Xav txog tias MITF mRNA noob kev tswj hwm yog tswj hwm nruj thiab cawm tau los ntawm lwm cov intracellular signalingmolecules thiab coactivators, kev tswj hwm qib ntawm MITF yog ib lub tswv yim zoo rau kev tshawb nrhiav cov tawv nqaij noj qab haus huv cov khoom xyaw vim tias txoj sia nyob ntawm MITF yog khaws cia thiab cawm [1,38,40]. Tseeb tiag, thaum peb tshawb xyuas FSK-induced MITF transcription, MITF mRNAwas pom muaj nws tus kheej ncov teb nkhaus rau melanogenesis thiab cellular ciaj sia taus cellularhomeostasis. Kev ua haujlwm lom neeg ntawmmelanocyteszoo li yuav intrinsically tswj los ntawm lwm cov lus teb cov lus qhia nyob rau hauv tib neeg melanocytes. Tsis tas li ntawd, carvedilol muaj qhov pheej hmoo tsawg dua ntawm cov xwm txheej tsis zoo ntawm hypopigmentation vim nws txo qis kev ua haujlwm ntawm cov cellular tyrosinase dhau sijhawm, tsis yog sai sai.
Catecholamines suav nrog dopamine, epinephrine, thiab norepinephrine thiab yog synthesized los ntawm kev noj haus tyrosine los ntawm kev ua ntawm enzymes [42]. Lub biosynthesis thiab degradation ntawm catecholamines tshwm sim nyob rau hauv ntau lub hlwb, nrog rau cov neurons ntawm sympathetic qab haus huv thiab lub hlwb, adrenomedullarycells, endothelial hlwb, neutrophils, thiab mononuclear hlwb [43-45]. Hauv tib neeg daim tawv nqaij, catecholaminesynthesis tshwm sim hauv keratinocytes. Conversely, melanocytes kuj qhia mRNA thiab enzymes rau autocrine synthesis ntawm norepinephrine tab sis tsis epinephrine [7,42]. Hauv tib neegmelanocytes, -1-AR tuaj yeem yog qhov tseem ceeb hauv cov tshuaj tiv thaiv norepinephrine, tab sismelanin synthesiskuj cuam tshuam los ntawm kev ua haujlwm 2-ARsignaling [7,8]. Interestingly, cov neeg mob uas muaj vitiligo tau nce 2-AR ceev hauv keratinocytes [46].Nroj tsuag norepinephrine ntau ntau pom nyob rau hauv cov zis thiab plasma ntawm cov neeg mob uas tsis yog-segmentalvitiligo, txhais tau hais tias catecholamine metabolism yuav cuam tshuam nrog kev loj hlob thiab kev loj hlob ntawm vitiligo. [47]. Tsis tas li ntawd, ntxiv rau classical kev ntxhov siab neurotransmitters, melanocytesproduce neuropeptides thiab cov tshuaj hormones, xws li corticotropin-releasing factor thiab proopiomelanocortin.Qhov ntau lawm yog stimulated los ntawm UVR thiab lwm yam tshuaj uas ua nyob rau hauv daim tawv nqaij neuroendocrinesystem [48]. Yog li ntawd, qhov kev txiav txim ntawm catecholamines thiab melanocytic muaj nuj nqi yog zoo sib xws nyob rau hauv ntau yam complex txoj kev. Tsis tas li ntawd, carvedilol tuaj yeem cuam tshuam cov tshuaj lom neeg hauv txoj hauv kev melanogenic thiab qhov ua tau no yuav tsum tau kawm ntxiv. Carvedilol tej zaum yuav muaj qhov zoo vim nws muaj kev tiv thaiv kab mob ib txhij, vim tias feem ntau cov kab mob hyperpigmentary yog PIH chaw kho mob lossis sub-clinically hauv cov neeg mob tawv nqaij tawv. Txij li thaum permeation ntawm carvedilol los ntawm daim tawv nqaij tau kawm ob qho tib si hauv vitro thiab ex vivo, carvedilol tuaj yeem tsim los ua cov tshuaj pleev ib ce.ntxuav hniav dawbtus neeg sawv cev yav tom ntej [49–51].
Kev tswj hwm carvedilol tuaj yeem ua rau bradycardia, kiv taub hau, hypotension, mob taub hau, thiab lub teeb taub hau. Cov tshuaj pleev ib ce ntawm carvedilol feem ntau tsis ua rau cov tsos mob tshwm sim; txawm li cas los xij, peb yuav tsum ua tib zoo saib xyuas cov tsos mob no thaum siv rau cov neeg mob uas muaj teeb meem ntawm daim tawv nqaij, xws li cov neeg mob atopic dermatitis. Ntxiv mus, eczema, pruritus, thiab lichenoid eruption raug tshaj tawm nyob rau hauv tsawg zaus thaum noj carvedilol. Cov kev mob tshwm sim ntawm cov kab mob dermatological no nrog rau cov kab mob hu ua contactdermatitis yuav tsum tau coj mus rau hauv tus account thaum siv carvedilol ua tshuaj pleevntxuav hniav dawbtus neeg sawv cev.
Hauv kev xaus, peb tau pom tias carvedilol txo qis melanogenesis hauv tib neegmelanocytesthiab ex vivo tib neeg daim tawv nqaij los ntawm inhibiting cAMP / CREB / MITF txoj hauv kev, uas qhia tias nws muaj peev xwm siv tau los ua tus neeg sawv cev zoo. Kev tshawb nrhiav ntxiv ntawm kev ua haujlwm ntawm kev koom tes ntawm adrenergicreceptor los ntawm carvedilol hauv tib neeg melanocytes yuav tsum ua raws.
4. Cov ntaub ntawv thiab cov txheej txheem
4.1. Khoom siv
Carvedilol, 3,4-dihydroxy-L-phenylalanine (L-DOPA), cholera toxin (CT), thiab 12-Otetradecanoylphorbol-13-acetate (TPA) tau muas los ntawm Sigma-Aldrich Co. (St. Louis, MO, USA).Dulbecco's Modified Eagle's Medium (DMEM) thiab Dulbecco's phosphate-buffered saline waspurchased from WelGENE (Daegu, Kauslim). Fetal bovine serum (FBS), tshuaj tua kab mob-antimycotic, thiab trypsin-EDTA tau yuav los ntawm Gibco (Grand Island, NY, USA). Medium 254 (CascadeBiologics, Portland, OR, USA) thiab FSK ([3R-(3 ,4a ,5 ,6 ,6a ,10 ,10a ,10b )]-5-(Acetyloxy)-3-ethenyldodecahydro{ {24}},10,10b-trihydroxy-3,4a,7,7,10a-pentamethyl-1H-naphtho[2,1-b]pyran-1-ib ) tau yuav los ntawm Tocris Bioscience (Bristol, UK).
4.2. Cell Kab thiab Cell Culture
Thawj NHMs tau txais los ntawm Invitrogen (Carlsbad, CA, USA) tau khaws cia hauv Medium 254 (Thermo Fisher, Waltham, MA, USA) ntxiv nrog Human Melanocyte Growth Supplement (Thermo Fisher). Mel-ab hlwb, tus nas-derived spontaneously immortalized melanocyte cell kab, tau txais los ntawm Kauslim Cell Line Bank (KCLB, Seoul, Kauslim Teb) thiab khaws cia hauv DMEM ntxiv nrog 10 feem pua FBS, penicillin-streptomycin, 100 nM TPA, thiab 1 nM CT. Txhua lub hlwb raug khaws cia nyob rau ntawm 37 ◦C nyob rau hauv ib cheeb tsam humidified ntawm 5 feem pua CO2.
4.3. Antibodies thiab Western Blots
Cov hlwb raug ntxuav ib zaug nrog txias PBS thiab lysed nyob rau hauv protein lysis buffer (1 feem pua SDS hauv 10 mMTris thiab 5 mM EDTA, pH 7.4), tom qab ntawd incubation ntawm 98 ◦C rau 10 min. Cov qauv protein tau sib cais los ntawm 8 feem pua SDS-polyacrylamide gel electrophoresis, blotted rau nitrocellulose daim nyias nyias (GE Healthcare Life Sciences, Chicago, IL, USA), thiab tom qab ntawd thaiv nrog Tris-buffered saline uas muaj 0.5 feem pua Tween 20 thiab 5 feem pua BSA, thiab raug rau immunoblotting. Tyrosinase thiab TRP{14}} cov tshuaj tiv thaiv tau yuav los ntawm Santa Cruz Biotechnology (Dallas, TX, USA), thiab MITF tau yuav los ntawm Abcam (Cambridge, UK). -tubulin (Gentex, Holland, MI, TEB CHAWS USA) tau siv los ua kev tswj hwm kev thauj khoom sab hauv.
4.4. Melanin Cov ntsiab lus
Cov nyhuv cytotoxic ntawm carvedilol tau soj ntsuam siv Ez-Cytox Cell Viability Assay Kit (Dogen-Bio Co., Ltd., Seoul, Kauslim Teb) raws li cov chaw tsim khoom cov lus qhia.Mel-Ab hlwb thiab NHMs tau cog rau hauv 6-zoo daim hlau. ntawm qhov ceev ntawm 6 × 105 thiab 3 × 105 cells / zoo, feem. Cells raug kho nrog carvedilol, raws li qhia nyob rau hauv cov duab, rau 3 los yog 5 hnub (d).Ua ntej ntsuas cov ntsiab lus melanin, cov hlwb raug soj ntsuam nyob rau hauv ib theem-zoo microscope thiab yees duab (Olympus, Tokyo, Nyiv). Cells tau yaj hauv 550 µL ntawm 1 N NaOH ntawm 100 ◦C rau 30 min thiab centrifuged ntawm 13, 000 rpm rau 5 min. Kev nqus ntawm cov supernatants tau ntsuas 405 nm los ntawm tus nyeem ntawv microplate. Cov ntsiab lus melanin intracellular tau nthuav tawm raws li qhov feem pua ntawm cov hlwb 'kev tswj tsis tau. Arbutin (100 mg / mL) tau siv los tswj qhov zoo.
4.5. Cellular Tyrosinase Kev Ua Haujlwm
Cov kev ua tyrosinase raug soj ntsuam los ntawm kev ntsuas tus nqi ntawm dopachrome tsim ntawm L-DOPA.Tom qab incubation nrog carvedilol, cov hlwb raug ntxuav nyob rau hauv dej txias PBS thiab lysed nyob rau hauv tyrosinase lysis tsis (phosphate buffer, pH 6.8, muaj {1 feem pua Triton), {5}}) nrog rov qab khov/thaw cycles.Cov lysates tau qhia meej los ntawm centrifugation ntawm 15, 000 rpm ntawm 4 ◦C rau 10 min. Tom qab ntsuas cov protein ntau ntawm lysate thiab kho cov protein ntau nrog lysis tsis, 90 µL ntawm supernatant tov nrog 10 µL ntawm 10 mM L-DOPA hauv tyrosinase lysis tsis yog incubated ntawm 37 ◦C.Cellular tyrosinase kev nyeem ntawv tau ntsuas ntawm 475 nm siv lub microplatereader txhua 10 min rau tsawg kawg 1 h. Arbutin (100 mg / mL) tau siv los ua tus neeg saib xyuas zoo.
herba cistanches
4.6. Immunohistochemical Analysis
Paraffin-embedded tib neeg cov ntaub so ntswg raug txiav rau hauv 6-µm-thick seem thiab stained nrog Melan-A (Novocastra, Newcastle, UK), Fontana-Masson cov khoom siv (ID labs, London, ON, Canada), thiab HMB45 (Santa Clara , CA, USA), raws li cov neeg tsim khoom cov lus qhia. Qhov ntsuas melanin tau txiav txim siab los ntawm kev ntsuas qhov feem pua ntawm thaj chaw stained rau tag nrho cov ntaub so ntswg siv ImageJ 1.52asoftware (National Institutes of Health, Bethesda, MD, USA).
4.7. Kev txheeb cais
Cov ntaub ntawv raug nthuav tawm raws li qhov txhais tau hais tias ± tus qauv yuam kev ntawm qhov nruab nrab (SEM), thiab qhov ntsuas qhov tseem ceeb tau txiav txim siab los ntawm tus tub ntxhais kawm tsis muaj kev sib tw t-test siv GraphPad Prism5 software (San Diego, CA, USA). Hauv txoj kev tshawb no, p < 0.05,="" p="">< 0.01,="" thiab="" p="">< 0.001="" tau="" suav="" tias="" yog="" qhov="" tseem="" ceeb="" thiab="" raug="" sawv="" cev="" los="" ntawm="" *,="" **,="" thiab="" ***,="">
Cov ntaub ntawv
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