Qhov cuam tshuam ntawm vitamin D rau ntawm daim tawv nqaij laus

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

Abstract:Cov nquag metabolites ntawm vitamin D3 (D3) thiab lumisterol (L3) siv ntau yam kev tiv thaiv kev laus thiab kev tiv thaiv kev tiv thaiv ntawm daim tawv nqaij. Cov no tau ua tiav los ntawm immunomodulation thiab suav nrog kev tiv thaiv kab mob, kev tswj hwm ntawm keratinocyte proliferation, thiab cov kev pab cuam sib txawv los tsim cov kab mob epidermal uas tsim nyog rau kev tswj cov tawv nqaij homeostasis. Tsis tas li ntawd, lawv ntxias cov tshuaj tiv thaiv oxidative, inhibit DNA puas thiab ua rau DNA kho cov txheej txheem kom txo cov tawv nqaij laus ntxov thiab mob qog noj ntshav. Cov txheej txheem ntawm kev txiav txim yuav koom nrog kev sib cuam tshuam nrog ntau lub receptors nuclear suav nrog VDR, AhR, LXR, thim rov qab agonism ntawm ROR thiab- , thiab kev ua tsis zoo los ntawm 1,25D3-MARRS receptor thiab kev cuam tshuam nrog qhov chaw tsis muaj kev sib txuas ntawm VDR. Yog li, cov ntaub ntawv nquag ntawm vitamin D3 suav nrog nws cov canonical (1,25 (OH), D3) thiab noncanonical (CYP11A1- pib) D, derivatives thiab L3 derivatives yog cov neeg ua haujlwm cog lus rau kev tiv thaiv, txo qis, lossis kev kho mob. ntawm cov tawv nqaij ntxov ntxov. Lawv tuaj yeem raug tswj hwm qhov ncauj thiab / lossis tshuaj pleev ib ce. Lwm hom kev siv parenteral ntawm vitamin D3 precursor yuav tsum raug txiav txim siab kom tsis txhob muaj cov metabolism hauv 25 (OH) D: uas tsis tau lees paub los ntawm CYP11A1 enzyme. Qhov kev ua tau zoo ntawm cov tshuaj pleev ib ce vitamin D3 thiab L3 derivatives xav tau kev soj ntsuam ntxiv hauv kev sim yav tom ntej.

Ntsiab lus:tawv nqaij laus; kev yees duab; daim tawv nqaij tiv thaiv kab mob; vitamin D; vitamin D metabolites; kev tiv thaiv kev yees duab

1. Taw qhia

Daim tawv nqaij, zoo li lwm yam khoom nruab nrog cev, tau poob qis hauv nws lub cev, morphological, thiab kev ua haujlwm zoo thaum laus [1-4]. Qhov tshwm sim ntawm kev laus yog natural thiab genetic predisposed. Cov haujlwm ntawm daim tawv nqaij yog qhov tseem ceeb rau homeostasis thiab ciaj sia. Raws li lub cev loj tshaj plaws hauv tib neeg lub cev, daim tawv nqaij, ua ke nrog hypodermis (subcutaneous rog), yog ob qho tib si lub hauv paus thiab lub hom phiaj rau ntau cov tshuaj hormones thiab neuromodulators [5-17l, ua rau nws muaj kev ywj pheej peripheral endocrine organ [5 , 18] ib. Cov tawv nqaij kuj tseem muaj peev xwm tsim cov prohormone vitamin D thiab hloov nws mus rau hauv cov metabolites nquag [19-25], uas tuaj yeem ua rau muaj kev cuam tshuam ntau yam ntawm cov tawv nqaij loj (keratinocytes thiab fibroblasts) [20, 25-29 ] thiab lub cev tiv thaiv kab mob [4,28,30,31] ntawm kev ua kom lub zog ntawm cov vitamin D receptor (VDR)[29,{12}}].poob teb chaws Ottoman cistancheVitamin plays lub luag haujlwm tseem ceeb hauv daim tawv nqaij homeostasis uas ua rau nws txoj haujlwm tsis muaj zog [20,29,36-38]. Tsis tas li ntawd, ua ib feem tseem ceeb ntawm kev ua haujlwm ntawm lub cev tiv thaiv kab mob, cov ntaub ntawv nquag ntawm vitamin D modulate cutaneous immunity [8,30,39].

Thov nias ntawm no kom paub ntxiv

Tus qauv kub ntawm kev txheeb xyuas cov vitamin D raws li txoj cai yog los ntawm kev ntsuas nws cov metabolite loj circulating metabolite, 25-hydroxyvitamin D3 (25(OH)D3), los ntawm high-performance kua chromatography (HPLC) los yog kua chromatography-tandem mass spectrometry (LC -MS/MS)[40-42] Tsis ntev los no, ib qho tshiab rhiab, thiab tshwj xeeb LC-MS/MS txoj kev ntawm kev ntsuas ib txhij ntawm 13 cov metabolites ntawm cov vitamin D, thiab D, tau nthuav tawm [43].

Qhov tseem ceeb, subclinical ({0}} nmol/L) thiab kev kho mob vitamin D deficiency (<30 nmol/l)in="" the="" general="" population="" have="" become="" a="" global="" problem="" worldwide="" [44-48].="" several="" physiological="" factors="" may="" influence="" vitamin="" d="" statuses,="" such="" as="" age,="" body="" mass="" index(bmd,="" skin="" type,="" pregnancy,="" and="" exclusive="" breastfeeding="" [49-53].="">micronized purified flavonoid feem 1000 mg sivCov genetic polymorphisms ntawm qee cov genes koom nrog hauv daim tawv nqaij pigmentation (TYR, TYRP1, EXOC2, thiab DCT) kuj txuam nrog 25 (OH) D3 serum concentration [54]. Ntau yam ntawm ib puag ncig ua rau muaj vitamin D tsis txaus, xws li lub caij ntuj no, lub hnub tsis txaus, thiab qhov chaw nyob siab [55,56]. Kev zam lub hnub thiab huab cua muaj kuab paug yog qhov tseem ceeb ua rau tsis txaus UVB. Ntxiv mus, ozone thiab cov teeb meem me me (PM) tuaj yeem cuam tshuam ncaj qha rau kev tsim cov vitamin D [57]. Tsis tas li ntawd, cov pa phem hauv huab cua, cov pa phem tsis tu ncua, thiab cov hlau hnyav tuaj yeem coj zoo li cov tshuaj endocrine cuam tshuam (EDCs), uas yuav ua rau tsis muaj vitamin D ncaj qha lossis tsis ncaj. Qhov kawg yuav yog qhov thib ob rau qhov hnyav nce, qhov tsis zoo ntawm parathyroid hormone thiab calcium homeostasis, thiab thyroid tsis ua haujlwm [57,58]. Cov pov thawj ntxiv qhia tias kev haus luam yeeb tuaj yeem txo cov ntshav qab zib ntawm 25 (OH) D3 [57].

Nrog rau cov hnub nyoog dhau los, lub peev xwm ntawm daim tawv nqaij los tsim cov vitamin D, txo qis (tsis hais lub caij nyoog), thiab degradation ntawm nws cov ntaub ntawv nquag nce [59,60]. Nws tau pom tias qhov concentration ntawm cov vitamin D ua ntej ntawm daim tawv nqaij, 7-dehydrocholesterol (7-DHC), poob li ntawm 50 feem pua ​​​​ntawm hnub nyoog 20 txog 80 xyoo [59]. Ob peb lwm yam ua rau lub xeev tsis muaj vitamin D nyob rau hauv lub hnub nyoog nrawm, suav nrog kev raug tshav ntuj tsawg, kev noj zaub mov tsis txaus ntawm vitamin D, lossis kab mob ua rau malabsorption. Tsis muaj vitamin D, uas yog ib txwm muaj nyob rau hauv lub hnub nyoog siab, tuaj yeem txo cov haujlwm tseem ceeb ntawm daim tawv nqaij xws li kev tiv thaiv ib puag ncig thiab tiv thaiv kev mob qog noj ntshav [25,39,{10}}]. Hauv kev tshuaj xyuas no, peb tsom los tham txog qhov tseem ceeb ntawm cov vitamin D hauv cov txheej txheem ntawm daim tawv nqaij laus.

2. Kev laus ntawm daim tawv nqaij—Koj daim tawv nqaij tuaj yeem nthuav tawm cov dab neeg

Kev laus ntawm daim tawv nqaij yog cov txheej txheem nyuaj uas cuam tshuam los ntawm tag nrho cov cuam tshuam ntawm ob qho tib si sab hauv thiab sab nraud ntawm tib neeg lub neej (tawv nqaij exposome), uas yog lub luag haujlwm rau kev hloov pauv ntawm cov tawv nqaij thiab kev ua haujlwm ntawm cov laus [167-69]. Lub ntsiab tseem ceeb sab hauv uas cuam tshuam rau lub caij nyoog (physiological) ntawm daim tawv nqaij laus muaj xws li hormonal poob thiab kev hloov pauv ntawm cov noob caj noob ces nrog rau cov hnub nyoog nce qib [1]. Tsis tas li ntawd, qhov cutaneous regenerative tej zaum yuav txo qis nrog lub hnub nyoog vim yog ntau dhau senescence ntawm keratinocytes, fibroblasts, thiab melanocytes dhau sij hawm, uas ua rau cov tawv nqaij laus [70-72]. Lub hnub nyoog ntawm daim tawv nqaij yog tus cwj pwm los ntawm nplua wrinkles thiab atrophy nrog txo elasticity. Qhov kev laus ntawm lub sijhawm no cuam tshuam rau txhua qhov chaw ntawm daim tawv nqaij tab sis qhia tau hais tias phenotypic sib txawv ntawm cov cheeb tsam anatomical sib txawv, thiab nws txawv ntawm cov neeg sib txawv [67,73]. Ib qho nucleotide polymorphisms (SNPs) ntawm MC1Rgene (lub ntsiab tswj hwm ntawm melanin pigmentation [74]) tau txuas nrog lub hnub nyoog ntawm lub ntsej muag, muab lub hauv paus tshiab ntawm cov hluas zoo nkauj [75].

Cistanche tuaj yeem tiv thaiv kev laus

Qhov tseem ceeb tshaj plaws sab nraud kev ntxhov siab cuam tshuam rau ntawm daim tawv nqaij thiab ua rau nws cov laus ntxov ntxov muaj xws li ultraviolet (UV) hluav taws xob [76,77], ambient pollutants [{2}}], thiab haus luam yeeb [57,83]. Kev tsis tu ncua ntawm daim tawv nqaij rau cov kev thuam ib puag ncig no txhawb kev tsim cov pa oxygen reactive (ROS) thiab ua rau oxidative kev nyuaj siab [84,85]. Cov xwm txheej ib puag ncig kuj tuaj yeem ua rau muaj kev puas tsuaj ntawm epidermal barrier muaj nuj nqi [69] thiab kev hloov pauv ntawm daim tawv nqaij microflora [86,87], ua rau muaj kev mob hnyav [2,88].

Cov hluav taws xob hluav taws xob ultraviolet (UVR) yog qhov teeb meem sab nraud tshaj plaws uas ua rau muaj kev puas tsuaj ntawm daim duab nyob rau hauv qhov chaw raug tshav ntuj. Photoaged daim tawv nqaij yog nthuav tawm raws li qhuav, sib sib zog nqus-wrinkled daim tawv nqaij nrog ntxhib ntxhib los mos, dyschromia, senile lentigines, vascular teeb meem, thiab lwm yam. [68,89]. UVR txo qis qhov kev qhia ntawm filaggrin uas ua rau muaj kev cuam tshuam ntawm epidermal hydration, yog li nws cov downregulation los ntawm UVR tuaj yeem piav qhia cov tawv nqaij xerosis hauv kev yees duab [90]. Ob leeg UVA (315-400 nm) thiab UVB(280-315 nm) tau pom tias muaj txiaj ntsig zoo rau kev yees duab, los ntawm kev tsim khoom tsis zoo ROS lossis los ntawm kev puas tsuaj DNA ncaj qha [83]. Txawm li cas los xij, UVA tau suav tias yog lub luag haujlwm tseem ceeb hauv kev laus. UVA sawv cev ntau dua 80 feem pua ​​​​ntawm tag nrho cov niaj hnub UV irradiation thiab tuaj yeem nkag mus rau 5-10 lub sij hawm tob rau hauv cov dermis reticular, qhov uas nws tuaj yeem ua rau cov cellular matrix (ECM) ntau dua li UVB [91]. Ntxiv mus, UVA raug tsub kom qhov kev qhia ntawm matrix metalloproteinases (MMPs), tshwj xeeb tshaj yog cov kev qhia ntawm collagenolytic enzyme MMP-1 nyob rau hauv dermal fibroblasts, uas ua raws li ib tug tseem ceeb regulator nyob rau hauv kev yees duab [92,93] Tsis tas li ntawd, tus mob UVA irradiation. inhibits hyaluronan synthesis, yog li hloov cov muaj pes tsawg leeg ntawm proteoglycans nyob rau hauv lub dermis [94]. Kev raug UVA ntev yog cuam tshuam nrog kev yees duab thiab yees duab mob qog noj ntshav vim muaj ntau dhau ntawm ROS thiab reactive nitrogen hom (RNS), uas tuaj yeem cuam tshuam rau ob qho tib si nuclear thiab mitochondrial DNA [95,96]. UVB tuaj yeem nkag mus tsuas yog los ntawm cov epidermis tab sis muaj kev lom zem ntau dua. Nws kuj txhawb kev hloov pauv ntawm 7-DHC rau vitamin D:[97,98]. UVB absorbed los ntawm DNA thiab RNA induces ib tug tsim ntawm cyclobutane pyrimidine dimers (CPDs) thiab lwm yam photoproducts [99], yog li inducing ntau yam hnub ci kos npe hloov pauv nyob rau hauv tej genes, nrog rau cov qog suppressor noob p53 [100,101]. UVR induces ib tug tsub zuj zuj ntawm p53 protein nyob rau hauv lub nucleus uas nyob rau hauv lem activates lub transcription ntawm noob lub luag hauj lwm rau cell voj voog ntes cia DNA kho, thiab ua rau induction ntawm apoptosis ntawm lub hlwb nrog unrepaired DNA puas [102,103]. Cov kev hloov pauv tshwj xeeb p53 tuaj yeem pom nyob rau hauv cov nqi siab, tsis yog hauv actinic keratosis (precancerous xeev) thiab squamous cell carcinomas (60-90 feem pua) nrog UV kos npe tab sis kuj nyob rau hauv ib txwm tsos ntawm UV-tso tawv nqaij (txog 75 feem pua) ), piv nrog tus nqi qis dua ntawm cov kev hloov pauv hauv cov tawv nqaij noj qab haus huv tiv thaiv hnub ci (5 feem pua ​​​​ntawm tag nrho cov mob) [104].

Kev tshav ntuj ntev ntev, ua ke nrog kev pheej hmoo ntawm cellular senescence, tuaj yeem ua rau lub cev tsis muaj zog ntawm daim tawv nqaij, mob ntev, thiab kev yees duab, uas cuam tshuam nrog kev pheej hmoo mob qog noj ntshav[77,105-107]. Yog li ntawd, photoaging ua rau cov tawv nqaij laus ntxov ntxov. Txawm hais tias qee cov txheej txheem kev laus muaj ntau qhov zoo sib xws lossis sib tshooj, cov duab ntawm daim tawv nqaij txawv ntawm daim tawv nqaij laus hauv ECM. Photoaged daim tawv nqaij yog tus yam ntxwv los ntawm degraded collagen thiab accumulated aberrant elastin fibers thiab glycosaminoglycans, whereas physiologically laus daim tawv nqaij yog nthuav tawm los ntawm atrophy ntawm dermal lug [108].

Qhov cuam tshuam tsis zoo ntawm cov pa phem nyob ib puag ncig rau tib neeg kev noj qab haus huv thiab tib neeg cov tawv nqaij yog qhov kev txhawj xeeb zuj zus [109]. Ozone (O3) los ntawm cov smog thiab PM, feem ntau tiv nrog daim tawv nqaij, muaj peev xwm txhawb ROS ntau lawm thiab tsim oxidative kev nyuaj siab, ua rau phenotypic nta ntawm extrinsic laus [69]. Nws tau pom tias qhov kis tau ntev mus rau PM ua rau cov xim xim thiab qhov tob nasolabial folds [110,111]. Ntxiv mus, ultrafine hais (<0.1 μm）="" can="" penetrate="" tissues="" and="" localize="" in="" the="" mitochondria,="" causing="" an="" aberrant="" mitochondrial="" function="" because="" of="" the="" oxidative="" processes="" [1121.="" additionally,="" photo-pollution="" exposure="" may="" aggravate="" uvr-mediated="" skin="" aging="">

UVR, feem ntau yog UVA, los ntawm cov nyiaj ntau dhau ntawm ROS ua rau cov mitogen-activated protein kinases (MAPKs) thiab cov ntaub ntawv hloov pauv xws li nuclear erythroid 2-zoo li (Nrf2), c-Jun-N-terminal kinase(INK) , thiab nuclear factor-K (NF-kB), thiab ua kom cov ntaub ntawv ntawm MMPs [114]. Activated MMPs, ua ke nrog kev txo qis ntawm MMP inhibitors (TIMP), ua rau muaj kev cuam tshuam ntawm ECM homeostasis thiab kev puas tsuaj ntawm collagen thiab elastin [115]. Tsis tas li ntawd, UVR cuam tshuam cov endogenous antioxidant enzymes, ua rau muaj zog oxidative puas ntawm collagen. Kev puas tsuaj ntawm ECM kev ncaj ncees yog pom raws li qhov pom ntawm daim tawv nqaij puas tsuaj [93]. Kev ua kom cov redox-sensitive transcription yam, activator protein-1 (AP-1) thiab NF-k, koom nrog hauv kev tsim wrinkle thiab o, plays lub luag haujlwm tseem ceeb hauv kev laus ntawm daim tawv nqaij [88]. Ob qho xwm txheej, NF-k thiab AP-1, tau nce siab nyob rau hauv cov sij hawm tom qab raug txiav rau cov tshuaj UVB tsawg. Kev tswj hwm ntawm AP -1 suppresses qhov hloov pauv loj hlob (TGF- ) receptors, uas ntxiv thaiv cov synthesis ntawm procollagen [116,117]. Tsis tas li ntawd, activated AP -1 stimulates degradation ntawm collagen los ntawm MMPs thiab ua rau lub ntsiab activator ntawm inflammatory teb NF-k [118]. NF-k signaling yog ib qho kev paub zoo ntawm cov ntaub so ntswg homeostasis thiab nws lub luag haujlwm tseem ceeb hauv kev laus ntawm daim tawv nqaij tsis ntev los no tau piav qhia [119]. ROS-induced activation ntawm NF-k tsav ib qho kev nce ntawm proinflammatory cytokines thiab MMPs thiab txo TGF- thiab hom I collagen synthesis [119]. Cov proinflammatory cytokines (interleukin (IL)-1, IL-6, thiab qog necrosis factor (TNF)-c) txhawb cov inflammatory teb thiab txhim khu kev ua kom NF-k 93]. Nws tau pom tias NF-k kev qhia tuaj yeem nce hauv mitochondrial DNA (mtDNA)-depleter nas thiab tom qab rov ua haujlwm mitochondrial, NF-k qhia tuaj yeem txo qis. Cov ntaub ntawv no tau lees paub tias NF-k signaling yog ib qho tseem ceeb mechanism uas ua rau cov tawv nqaij thiab plaub hau follicle pathologies[120]. Vim lub wavelength ntev dua, UVA nce mus txog dermal fibroblasts hauv vivo nrog rau kev ua haujlwm ntawm Nrf2-kev nthuav qhia ntawm cov noob caj noob ces antioxidant. Tsis zoo li UVA, UVB tsis qhib Nrf2 hauv daim tawv nqaij lossis txawm tias zoo li muaj cov nyhuv inhibitory [121]. Txawm li cas los xij, vitamin D: derivatives, uas yog cov khoom ntawm UVB kev txiav txim, ua kom Nrf2 signaling [122]. Lub endogenous Nrf2 yog qhov tseem ceeb rau kev tiv thaiv ntawm daim tawv nqaij hlwb tiv thaiv oxidative insults thiab rau kev tswj cov redox tshuav nyiaj li cas thaum lub sij hawm ntawm daim tawv nqaij laus [123,124]. Ntau qhov kev tshawb fawb hauv vitro thiab hauv vivo tau lees paub qhov tseem ceeb ntawm qhov kev hloov pauv ntawm Nrf2 thiab nws cov kev taw qhia qis hauv kev tiv thaiv UV [125,126].

Qhov tseeb, tib neeg cov tawv nqaij laus feem ntau yog tsav los ntawm oxidative txheej xwm. Ib qho ROS ntau lawm thiab tsis txaus kev ua si los yog mitochondrial dysfunction yog cov xwm txheej tseem ceeb hauv oxidative stress-induced tawv nqaij laus. Cov qib siab ntawm ROS ua rau oxidative kev puas tsuaj ntawm lipids, proteins, genomic, thiab mtDNA, thiab tseem tuaj yeem deplete thiab ua rau lub cev tiv thaiv antioxidant ntawm daim tawv nqaij (ob leeg tsis yog enzymatic thiab enzymatic ib qho) [85,127].

Cov ntaub ntawv pov thawj txhawb nqa kev sib txuas ntawm mitochondrial dysfunction thiab cov txheej txheem kev laus [126]. Ntau cov kev tshawb fawb pom tau tias qhov txo qis hauv mtDNA cov ntsiab lus thiab mitochondrial tus naj npawb thaum laus. Nws tau xav tias mitochondrial tsis ua haujlwm ua lub luag haujlwm hauv kev ua kom cov cellular senescence, pom nyob rau hauv lub hnub nyoog nce qib [128-130]. Tsis tas li ntawd, mitochondria tau ntseeg tias yuav pab txhawb rau 90 feem pua ​​​​ntawm cov tsim ROS hauv cov hlwb [95]. mtDNA, raws li lub hom phiaj tseem ceeb rau ROS, yog qhov yooj yim heev rau oxidative puas tsuaj thiab muaj cov txheej txheem kho DNA tsis zoo [96,131]. Kev ua haujlwm poob qis ntawm mitochondria ua rau lub voj voog tsis zoo uas ua rau muaj kev txhim kho ntxiv ntawm ROS ntau lawm [127,132].

3. Cov teebmeem ntawm Vitamin D3 ntawm daim tawv nqaij

3.1. Impact Paths on 1 the Skin

Kev raug ntau dhau rau hnub ci UVR ua kom cov tawv nqaij laus thiab tuaj yeem ua rau mob qog noj ntshav [133].oteflavonoidTxawm li cas los xij, UVR ua lub luag haujlwm muaj txiaj ntsig hauv kev tswj hwm ntawm ntau cov tawv nqaij ua haujlwm [56,/7,134]. Tib yam UVB, lub luag hauj lwm rau qhov nce ntawm cov qog nqaij hlav tsis-melanoma, yuav tsum muaj vitamin D: ntau lawm hauv daim tawv nqaij uas muab ntau tshaj 90 feem pua ​​​​ntawm cov vitamin D: lub cev xav tau [44,55,135].Nyob rau hauv daim tawv nqaij, vitamin D3 Nws yog ib qho tseem ceeb rau kev tsim cov kab mob epidermal barrier thiab cov hauv paus plaub hau, thiab nws qhov tsis muaj peev xwm tau txuas rau ntau yam kab mob proliferative thiab inflammatory cutaneous disorders [20,2944,136].

Raws li kev nqus ntawm UVB, 7-DHCis hloov mus ua vitamin D; nyob rau hauv daim tawv nqaij, ib tug txheej txheem accelerated thermal zog. Kev raug UVB ntev kuj tuaj yeem tsim tachysterol (T3) thiab lumisterol (L3) 24,97]. Cov tshuaj tiv thaiv no tsis yog-enzymatic thiab nyob ntawm UVB koob tshuaj thiab qhov kub thiab txias. Vitamin D3 tuaj yeem qhib tau los ntawm txoj hauv kev canonical thiab non-canonical nrog kev ua kom zoo sib xws ntawm L3 rau cov tshuaj lom neeg lom neeg metabolites (Daim duab 1). Nyob rau hauv txoj kev classical, vitamin Da yog hydroxylated rau 25-hydroxyvitamin D; (25(OH)D3) los ntawm CYP2R1 thiab/los yog CYP27A1 hauv daim siab nrog ntxiv hydroxylation los ntawm CYP27B1 hauv lub raum, tawv nqaij, thiab lwm yam ntaub so ntswg rau nws. Cov tshuaj lom neeg muaj zog metabolite 1,25 (OH), D3 [20,21,137].

In the alternative (non-canonical) pathway, vitamin D3 can be activated by CYP11A1 with further modification by other cytochrome enzymes leading to the production of a large number of metabolites in humans [21,36,138-142](Figure 1), some of which are non-or low-calcemic at high, therapeutic, doses[143-146]. The major CYP11A1-derived vitamin D3products are 20(OH)D;and 20,23(OH)>D:[23,139,147,148].Ntxiv mus, 20(OH)D3 tuaj yeem txhais tau tias yog ib yam khoom ntuj vim nws muaj nyob rau hauv zib mu [149]. L kuj tseem tuaj yeem metabolized rau biologically active derivatives [150-152], uas tsis tau lees paub los ntawm 7-DHC reductase [153].

Cov teebmeem genomic tseem ceeb thiab cov lus teb lom neeg ntawm vitamin D metabolites hauv daim tawv nqaij yog kho los ntawm lawv txoj kev khi rau nuclear VDR [32,61,154-156]. Qhov tseem ceeb, VDR tau raug tshaj tawm los tswj txog 3 feem pua ​​​​ntawm cov tsiaj txhu genome vim nws txoj kev nthuav dav hauv txhua cov ntaub so ntswg [4,34,157,158]. Cov tawv nqaij kuj qhia txog VDR thiab ua haujlwm tsis yog tsuas yog ib qho chaw xwb tab sis kuj yog qhov chaw rau kev ua ntawm vitamin D3 [28,39]. Tsis tas li ntawd, VDR tau qhib los ntawm classical 1,25 (OH), D: tuaj yeem ua rau cov lus teb sai sai los ntawm cov txheej txheem uas tsis yog-genomic, daim nyias nyias-txuas raws li lwm qhov ligand-binding site [159] lossis los ntawm kev ua ntawm 1,25D{ {19}}MARRS receptor [156,160,161]. Cov dej num uas tsis yog-genomic zoo sib xws rau CYP11A1- muab cov hydroxyderivatives tau los tseem tsis tau tsim.SNPs tuaj yeem cuam tshuam rau VDR cov dej num txhawb kev loj hlob ntawm melanoma thiab cov qog nqaij hlav tsis-melanoma [162,163]. VDR ua haujlwm raws li cov qog qog nqaij hlav [164] thiab qhov txo qis hauv nws qhov kev qhia yog cuam tshuam nrog kev loj hlob ntawm cutaneous melanoma |165,166].puritans vitamin cNtawm qhov tsis sib xws, cov lus qhia ntawm nuclear VDR tau pom tau nce siab (nruab nrab mus rau qhov muaj zog) hauv squamous cell carcinomas (SCCs) thiab basal cell carcinomas (BCCs) piv rau hauv cov tawv nqaij ib txwm [167,168]. Yog li, tsom VDR nrog vitamin D secosteroids (tshwj xeeb tshaj yog cov calcemic qis) yuav muaj txiaj ntsig hauv kev tiv thaiv kab mob qog noj ntshav, txo qis, lossis kho [62,64,169].

Daim duab 1. Txoj hauv kev uas tsis yog vitamin D; thiab lumisterol(L3) ua kom (reprinted los ntawm [61] nrog kev tso cai los ntawm Springer). D, L, thiab 7-DHC yog cov substrates rau CYP11A1 uas tsim cov hydroxyderivatives sib raug. Nyob rau hauv cov ntaub ntawv ntawm L, thiab 7-DHC, sab saw yuav cleaved los ntawm CYP11A1 los tsim 7DHP los yog pL uas yuav tsum tau ntxiv metabolized los ntawm steroidogenic enzymes (ES).Nyob rau hauv daim tawv nqaij, UVB ua 5, {{ 11}}dienes tuaj yeem ua rau kev tsim khoom ntawm D, La, thiab T3 derivatives nrog rau cov saw ntev ntev thiab PD, pL, thiab pT derivatives nrog cov saw hlau luv. Thaum qhov kev txiav tawm rau UVC / UVB yog 280 nm, peb qhia qhov ntau ntawm 290-315 nm vim lub wavelengths qis dua 290 nm yog lim los ntawm ozone txheej, thiab tsis muaj pre-D ntxiv; yog tsim los ntawm 315 nm [170]. 7DHC, 7-dehydrocholesterol; 7DHP, 7-dehydropregnenolone; PD, preganalciferol; pL, preganalumisterol; D3, vitamin D3; L3, lumisterol; T3, tachysterol; OH, pawg hydroxyl; tus lej ua ntej OH, carbon tooj nrog OH; tus lej hauv subscripts tom qab (OH), tus lej ntawm pawg hydroxyl.

CYP11A1-derived hydroxyderivatives tuaj yeem tswj qee cov tawv nqaij ua haujlwm los ntawm lwm cov khoom siv hluav taws xob xws li retinoic acid-related orphan receptors (ROR) thiab y, uas tau qhia hauv daim tawv nqaij [171]. Lub endogenously tsim nonclassical vitamin D; hydroxy derivatives, 20 (OH) D3: thiab 20,23 (OH) 2D3 tuaj yeem ua tsis muaj zog RORa thiab Rory inverse agonists [155,171,172]. Ntxiv mus, cov hydroxyderivatives no tuaj yeem ua rau muaj kev tiv thaiv kab mob thiab tuaj yeem tiv thaiv qog nqaij hlav hauv daim tawv nqaij los ntawm ROry-mediated mechanism [173].

Xwb, cov classical 1,25(OH)2D3 thiab CYP11A1- pib vitamin D3 derivatives tuaj yeem ua agonists ntawm aryl hydrocarbon receptor (AhR) [174] thiab siab X receptors (LXR) [175]. Ntxiv mus, qhov ua kom ntawm AhR nyob rau sab saum toj canonical txoj kev rau 20,23(OH)2D3[174]. Qhov receptor no tswj cov cellular proliferation, o, thiab melanogenesis nyob rau hauv daim tawv nqaij [176]. Txawm hais tias muaj ntau yam ligands tuaj yeem tsom mus rau AhR. qee qhov kev tshawb fawb txog kev ua haujlwm thiab kev ua qauv molecular tuaj yeem kwv yees tias cov teeb liab secosteroid hloov mus ntxiv ua rau txo qis ntawm cov lus teb proinflammatory [177], detoxification, thiab antioxidative action [61,174].

Ua kom tiav, cov tshuaj lom neeg muaj txiaj ntsig classical thiab tshiab vitamin D; metabolites exert sib txawv affinities rau ntau receptors nyob rau hauv daim tawv nqaij, thiab los ntawm lawv cov kev hloov kho, lawv muaj peev xwm cuam tshuam cov kab mob sib txawv cutaneous. Tsis tas li ntawd, txhawm rau ua rau VDR, cov ntaub ntawv nquag ntawm cov vitamin D tuaj yeem ua rau lwm cov khoom siv nuclear xws li RORs, AhR, LXR, thiab 1,25D3-MARRS receptors. Cov ntaub ntawv nquag ntawm vitamin D3 muaj ntau yam haujlwm, uas ib feem sib tshooj hauv lawv cov tshuaj tiv thaiv kab mob, tshuaj tua kab mob, tshuaj tiv thaiv kab mob, kev sib txawv, tshuaj tua kab mob, thiab tshuaj tiv thaiv kab mob ntawm daim tawv nqaij [20,38,63,141,145,178].sibNrog rau cov yam ntxwv zoo tshaj plaws 1,25(OH), D, CYP11A1- muab cov khoom lag luam ntawm vitamin D, thiab L3 nthuav tawm cov khoom tiv thaiv kev tiv thaiv UVR-vim cov tawv nqaij puas tsuaj (Daim duab 2) [37,61,{{9} }].

3.2.Qhov cuam tshuam ntawm Cutaneous Immune Function

Vitamin D; thiab nws cov analogues thiab precursors ua lub luag haujlwm tseem ceeb hauv kev tswj hwm; kev tswj hwm ntawm ob qho tib si hauv lub cev thiab lub cev tiv thaiv kab mob, suav nrog hauv daim tawv nqaij [8,184,185] Muaj kev sib raug zoo ntawm vitamin D tsis txaus thiab qhov tshwm sim ntawm kev kis kab mob thiab kev tiv thaiv kab mob ntawm daim tawv nqaij. [31, 186-188]. Qhov kev qhia ntawm VDR tau pom nyob rau hauv yuav luag txhua lub cev tiv thaiv kab mob suav nrog T- thiab B-lymphocytes (Lym), macrophages, mast cells, natural killer (NK) hlwb, thiab tswj T hlwb (Tregs), tab sis nws txawv ntawm kev tswj hwm [ 189] ib. Monocytes, piv txwv li, poob VDR qhia theem thaum sib txawv ntawm macrophages thiab dendritic cells (DCs) [190,191]. Immunomodulatory kev ua ntawm active vitamin D3 metabolites muaj xws li induction ntawm Tregs [192] thiab T-helper-2(Th2)-Lym, ua ke nrog downregulation ntawm proinflammatory Th1/Th17/Th9-Lym [193] 1,25(OH)2D3 tuaj yeem muaj qhov cuam tshuam ncaj qha thiab tsis ncaj rau T-Lym [194]. Qhov cuam tshuam ncaj qha yog raws li DC-derived cytokines, uas hloov kho Th-Lym teb [30]. Ncaj nraim, 1,25 (OH) D3 tuaj yeem cuam tshuam lub cev tsis muaj zog ntawm cov cytokines xws li interferon-gamma (IFN-y), TNF-x, thiab IL-2 (Th1 cytokines), IL{{38} }/21 (Th17 cytokines), thiab Th9 cytokines[193,195,196], thaum nws txhim kho qib ntawm cov tshuaj tiv thaiv IL-10 los ntawm Tregs[197] lossis Th2- muab los ntawm IL-4 [198]. Raws li qhov tshwm sim, vitamin D hloov Cov inflammatory teb rau ib tug ntau tolerogenic Th2 teb nrog nce CD4 ntxiv rau CD25 ntxiv Tregs pom nyob rau hauv ib tug hloov nyob rau hauv cytokine profile nyob rau hauv daim tawv nqaij [19]. Tsis tas li ntawd, 1,25 (OH) 2D: cuam tshuam lub tshuab ua haujlwm B-Lym los ntawm inducing apoptosis [200], suppressing immunoglobulin E (IgE)-dependent mast cell activation [201,202], thiab upregulating IL -10 ntau lawm [203] Enhanced IL-10 synthesis ua rau muaj kev cuam tshuam ntawm mast cell-mediated o thiab IgE-txog kev tsis haum tshuaj [201].1,25(OH)2D; thiab nws cov analogs ncaj qha tswj cov tshuaj tiv thaiv kab mob peptide (AMP) cov noob qhia hauv lub cev tsis muaj zog [204,205]. Ntxiv mus, nws tau pom tias vitamin D muaj peev xwm ua kom muaj qhov tseem ceeb rau kev tiv thaiv kab mob, kev tsim cov cathelicidin (LL37) [204] thiab los hloov cov kev ua phagocytic ntawm macrophages thiab NK hlwb [193]. Tsis tas li ntawd, vitamin D exerts immunosuppressive los ntawm kev hloov kho ntawm epidermal Langerhans hlwb [206] thiab proliferation ntawm Tregs tooj [184,185,197].

CYP11Al tau qhia kuj nyob rau hauv lub cev tiv thaiv kab mob [207], qhov twg vitamin D tuaj yeem ntxiv metabolized rau hauv cov khoom siv roj ntsha hydroxyderivatives [31,39]. Los ntawm kev ua kom VDR los yog los ntawm kev inhibition ntawm Rory-mediated activation, 20 (OH) D3 thiab 20,23 (OH) 2D3, zoo li 1,25 (OH) 2D3, tuaj yeem txo qhov sib txawv ntawm Th17, nrog rau kev tsim thiab kev ua haujlwm. ntawm inflammatory cytokine IL-17 los ntawm lub cev tiv thaiv kab mob[155,208,209]. Yog li, Th17-txog qhov mob ntawm daim tawv nqaij tuaj yeem ua tiav los ntawm Rory inverse agonists xws li CYP11A1- muab tau los ntawm Dg-hydroxy derivatives, ua rau kev tswj hwm ntawm lub cev tiv thaiv kab mob thiab tiv thaiv autoimmunity [210,211]. Qhov tsis ntev los no inhibition ntawm collagen-induced autoimmune mob caj dab los ntawm CYP11A1- muab 20(OH)D3 tau tshaj tawm [212]. 3.3.Ib feem ntawm daim tawv nqaij laus

A normal vitamin D; status is important for the general prevention of premature aging and maintaining a healthful skin aging [213,214]. Vitamin D3 metabolites including its classical (1,25(OH)2Dg) and novel(CYP11Al-initiated) Dg hydroxyderivatives exert many beneficial protective effects on the skin, which could influence the process of premature aging via many different mechanisms, leading to a delay or attenuation of both chronological skin aging and photoaging. Skin-resident cells (keratinocytes, fibroblasts, and sebocytes) are capable of locally activating vitamin D3 [23,36,215] and exhibiting a diverse biological effects such as photoprotection and immunosuppression, similar to the UVR-induced one[179,216]. The process of chronological aging is associated with immunological alteration and the imbalance between inflammatory and anti-inflammatory mechanisms, leading to a chronic low-grade inflammation, known as "inflammaging" state [217,218]. The"inflammaging'phenotype of the skin and hair follicles is a result of both chronic antigen stimulation and continued exposure to oxidative stress caused by ROS and RNS [219,220]. With advancing age, skin is affected by the profound remodeling of the immune system, leading to a decline in its adaptive capacity [221,222]. Th1-and Th17-related markers, together with the number of epidermal DCs are increased as a function of age [223-225]. DCS during aging appear to be functionally impaired, which contributes to the initiation of inflammatory and autoimmune skin disorders and a loss of their protective role against cutaneous infections. The active forms of vitamin D, are able to decrease the proliferation and cytotoxicity of T-Lym, as well as suppress the differentiation of B-Lym and the maturation of DCs [193]. Therefore, vitamin D: hydroxyderivatives exert potent anti-inflammatory activities including the inhibition of TNF-α, INF-γ, and IL-1/6/9/17 production 【4,38,185】, suggesting their implication in the modulation of skin inflammation. Moreover, the nonacademic and nontoxic 20(OH)D3 has shown a similar anti-inflammatory property in vivo to 1,25(OH)>D3 (hypercalcemic nyob rau hauv cov koob tshuaj siab) los ntawm kev tawm tsam ntawm lub cev tiv thaiv kab mob los ntawm T- thiab B-lym [155,212].

Active vitamin D metabolites tuaj yeem tiv thaiv daim tawv nqaij tiv thaiv kev phom sij ntawm cov tawv nqaij ua rau cov neeg laus, suav nrog UVR, muaj kuab paug, thiab kab mob microbial [179,226-230]. Nws tau raug pom tias kev tswj hwm qhov ncauj ntawm cov koob tshuaj vitamin D: tsis ntev tom qab UVB raug tuaj yeem thim rov qab sai sai ntawm cov duab tsim los ntawm kev puas tsuaj los ntawm kev txo qis qhov mob thiab induction ntawm kev kho cov txheej txheem ntawm epidermal barrier [38]. Muaj cov pov thawj muaj zog ua pov thawj tias cov vitamin D thiab L hydroxyderivatives tuaj yeem ua rau, nyob rau hauv koob tshuaj, cov tshuaj tiv thaiv oxidative thiab thim rov qab UVB-mediated ROS ntau lawm hauv keratinocytes los ntawm kev ua kom Nrf2 uas ua haujlwm rau cytoprotection thiab detoxification, yog li attenuating photoaging [ 122] ib. Yog li ntawd, lawv ua hauj lwm los tiv thaiv UVB-induced oxidative kev nyuaj siab nyob rau hauv hlwb, pre-kho nrog txhua yam ntawm cov nquag metabolites rau 24 teev ua ntej UVB irradiation (50 mJ / cm²) 【122】. Cov hydroxyderivatives no txhawb kev nthuav tawm ntawm cov tshuaj tiv thaiv kab mob antioxidant hauv qab ntawm Nrf2 (GR, HO-1, CAT, SOD-1, thiab SOD-2) nrog rau kev qhia ntawm HO{{20 }}, CAT, thiab MnSOD ntawm qib protein[122]. Nrf2 ua lub luag haujlwm tseem ceeb hauv kev tshawb pom ntau dhau ROS thiab RNS thiab hauv kev cuam tshuam ntawm cov txheej txheem tiv thaiv kev puas tsuaj oxidative thiab tawv nqaij pigmentations uas tsim los ntawm UVA [121,125,231].

Chronic UVR irradiation, mainly UVB [232] and UVA [233] induce DNA damage and the formation of CPDs that potentially lead to premature skin aging and carcinogenesis. CYP11A1-derived D, and L hydroxyderivatives, along with 1,25(OH),D,, demonstrate photoprotective and reparative properties by increasing the expression and phosphorylation of p53 with its translocation to the nucleus [61,229,234,235]. The P53 gene family, in particular its isoform p63, might be an important molecular target for vitamin D action in premature aging and cancer [236], which are promoted by similar mechanisms [237]. Moreover,1,25(OH),D, and 1,25(OH),L, inhibit DNA damage and facilitate DNA repair by the reduction of CPDs [182,235,238,239] and RNS [178,234]. The photoprotection by 20(OH)D, and 20,23(OH), D; is comparable to 1,25(OH)>D, txo cov UVB-induced CPDs thiab DNA fragmentation hauv vivo [181,182] thiab hauv vitro [178]. Tsis tas li ntawd, ob qho tib si 20 (OH) D, thiab 20,23 (OH), D, txhawb kev sib txawv, inhibit proliferation, thiab txo qis cov lus teb proinflammatory hauv keratinocytes los ntawm kev txo qis ntawm NFk kev ua [240,241]. Nws tau pom tsis ntev los no tias tsis yog tsuas yog kev kho mob ua ntej xwb, tab sis kuj yog kev kho tom qab ntawm keratinocytes nrog CYP11A1- muab tau los ntawm D, thiab L3 derivatives tuaj yeem thim rov qab lawv qhov kev puas tsuaj UVB-induced [37,230].

Tsis tas li ntawd, 1,25 (OH) 2D: tuaj yeem ua rau muaj qhov txo qis ntawm daim tawv nqaij apoptosis, thiab nws tuaj yeem txhim kho CPD thiab txo cov oxidative DNA puas tsuaj los ntawm cov khoom siv hluav taws xob uas tsis yog genomic txuag autophagy thiab mitophagy [227], yog li pab txhawb rau lub cev ntawm daim tawv nqaij photoprotection mechanism [242].

4. Cov lus xaus thiab cov kev xav yav tom ntej

Vitamin D: thiab nws cov metabolites nquag siv ntau yam kev tiv thaiv kev laus thiab (duab) tiv thaiv cov teebmeem ntawm daim tawv nqaij. Cov no tau ua tiav los ntawm immunomodulation uas suav nrog cov tshuaj tiv thaiv kab mob thiab kev tswj hwm ntawm keratinocytes proliferation thiab kev sib txawv los tsim cov kab mob epidermal uas tsim nyog los tswj cov tawv nqaij homeostasis. Tsis tas li ntawd, lawv ntxias cov tshuaj tiv thaiv oxidative, inhibit DNA puas thiab ua rau DNA kho cov txheej txheem kom txo cov tawv nqaij laus ntxov thiab mob qog noj ntshav. Cov kev ua zoo sib xws tuaj yeem raug xa mus rau lumisterol metabolites. Yog li, cov ntaub ntawv nquag ntawm vitamin D: suav nrog nws cov canonical (1,25 (OH), D,) thiab noncanonical (CYP11A1- pib) D3-hydroxyderivatives, nrog rau L3- derivatives, yog cov neeg cog lus rau kev tiv thaiv, txo qis, lossis kev kho mob ntawm daim tawv nqaij ntxov ntxov thaum siv tshuaj pleev. Nws cia siab tias lawv yuav txo qis kev yees duab thiab tej zaum kho qhov kev puas tsuaj uas twb muaj los ntawm kev ntxhov siab sab nraud. Cov txheej txheem ntawm kev txiav txim yuav koom nrog kev sib cuam tshuam nrog cov receptors nuclear nrog rau VDR. AhR, LXR, thim rov qab agonism ntawm ROR thiab Rory, thiab cov kev ua tsis zoo los ntawm 1,25D3-MARRS receptor thiab kev cuam tshuam nrog qhov chaw tsis sib xws ntawm VDR. Cov txheej txheem tswj kev cuam tshuam los ntawm D: thiab L3 derivatives yuav suav nrog kev ua haujlwm ntawm Nrt2 thiab p53 thiab kev txo qis ntawm NFk signaling pathways lossis kev tswj hwm ntawm mitochondrial functions. Txhawm rau tiv thaiv kev laus ntawm daim tawv nqaij, vitamin D3 thiab lumisterol lossis lawv cov derivatives tuaj yeem muab tshuaj rau qhov ncauj thiab / lossis tshuaj pleev. Lwm cov ntaub ntawv ntawm kev siv parenteral ntawm vitamin D3 precursor yuav tsum raug txiav txim siab kom tsis txhob xa nws cov metabolism mus rau 25 (OH)D, uas tsis tau lees paub los ntawm CYP11A1enzyme[243]. Kev ua tau zoo ntawm cov tshuaj pleev ib ce vitamin D; thiab L3 derivatives xav tau kev tshuaj ntsuam xyuas ntxiv hauv kev sim yav tom ntej.

Kab lus no yog muab rho tawm los ntawm Int. J. Mol. Sci. 2021, 22, 9097. https://doi.org/10.3390/ijms22169097 https://www.mdpi.com/journal/ijms