Autophagy Raws li Cov Txheej Txheem Muaj Peev Xwm Ua Raws Li Cov Khoom Siv Hluav Taws Xob Ntawm 1,25-Dihydroxyvitamin D3 Ntawm Periodontitis: Kev Tshawb Xyuas Narrative
Dec 08, 2023
Abstract
Daim ntawv tseem ceeb ntawm vitamin D, 1, 25-dihydroxyvitamin D3 (1,25D3), paub txog nws cov bioactivity dav hauv cov ntaub so ntswg. Txawm hais tias cov txheej txheem muaj tseeb hauv qab nws qhov kev tiv thaiv tiv thaiv kab mob hauv lub cev tseem tsis tau meej, cov kev tshawb fawb tsis ntev los no tau pom tias 1,25D3 tswj autophagy. Autophagy yog ib qho tseem ceeb rau kev tswj cov kab mob intracellular, kev tswj kev mob, thiab cov pob txha metabolic tshuav nyob rau hauv cov ntaub so ntswg homeostasis, thiab nws cov kev cai yuav yog ib txoj hauv kev nthuav rau yav tom ntej periodontal kev tshawb fawb. Txij li thaum vitamin D tsis txaus yog ib qho teeb meem kev noj qab haus huv thoob ntiaj teb, nws lub luag haujlwm ua tus tswj hwm lub peev xwm ntawm autophagy muab kev nkag siab tshiab rau cov kab mob hauv lub cev. Raws li lub hauv paus ntsiab lus no, qhov kev tshuaj xyuas cov ntaub ntawv piav qhia no tsom los tshawb xyuas qhov sib txuas ntawm 1,25D3 thiab autophagy hauv pre-odontitis. Kev tshawb nrhiav cov ntaub ntawv nthuav dav tau ua nyob rau hauv PubMed siv cov ntsiab lus hauv qab no (xws li vitamin D, autophagy, periodontitis, kab mob, epithelial hlwb, kev tiv thaiv kab mob, o, thiab pob txha poob). Hauv qhov kev tshuaj xyuas no, cov kev tshawb fawb tshiab tshaj plaws ntawm kev tiv thaiv kev ua haujlwm ntawm 1,25D3 tiv thaiv kab mob thiab kev tswj hwm ntawm autophagy los ntawm 1,25D3 tau sau tseg, thiab lub luag haujlwm muaj peev xwm ntawm 1,25D3- qhib autophagy nyob rau hauv lub pathogenesis ntawm periodontitis yog soj ntsuam. 1,25D3 tuaj yeem tiv thaiv kev tiv thaiv kab mob los ntawm kev sib txawv ntawm cov cim qhia hauv cov kab mob ntawm cov kab mob ntawm cov kab mob, thiab tsawg kawg yog ib feem ntawm cov kev tswj hwm no tau ua tiav los ntawm kev ua kom cov lus teb autophagic. Qhov kev tshuaj xyuas no yuav pab qhia meej txog kev sib raug zoo ntawm 1,25D3 thiab autophagy hauv homeostasis ntawm cov ntaub so ntswg thiab muab kev xav rau cov kws tshawb fawb los txhim kho cov tswv yim tiv thaiv thiab kev kho mob yav tom ntej.
Cov txiaj ntsig ntawm cistanche tubulosa- ua kom muaj zog tiv thaiv kab mob
Ntsiab lus
Vitamin D, Autophagy, Periodontitis, Epithelial barrier, Kev tiv thaiv kab mob, Inflammation, Alveolar pob txha poob
Keeb kwm
Periodontitis yog ib hom kab mob sib kis uas rhuav tshem cov ntaub so ntswg thiab muaj ntau yam etiological thiab pab txhawb. Nws yog qhov nthuav dav hauv cov neeg thoob ntiaj teb [1]. Kev sib cuam tshuam ntawm cov kab mob sib kis ntawm cov kab mob polymicrobial nyuaj thiab kev puas tsuaj ntawm lub cev tiv thaiv kab mob yog qhov tseem ceeb ntawm cov kab mob pathogenic ntawm cov kab mob periodontitis [1, 2]. Kev txhim kho ntxiv hauv kev kuaj mob thiab kev kho mob ntawm periodontitis tseem xav tau, thiab cov kev kho tshiab nrog cov nqi qis thiab kev cuam tshuam siab yuav tsum tau tsim [1]. Muaj ntau tshaj li ib txhiab tus neeg thoob ntiaj teb raug kev txom nyem los ntawm vitamin D (VD) tsis txaus, uas yog qhov teeb meem kev noj qab haus huv thoob ntiaj teb uas tsis tuaj yeem kwv yees [3]. Serum 25-hydroxyvitamin D [25(OH)D] qib qis dua 20 ng/mL (50 nmol/L) txhais tau tias yog deficiency thiab 21–29 ng/mL (52.5–72.5 nmol/L) tsis txaus [4 ]. VD tsis muaj peev xwm cuam tshuam nrog kev pheej hmoo ntawm periodontitis [5, 6]. Yog li, kev kawm txog lub luag haujlwm ntawm VD hauv kev noj qab haus huv ntawm lub cev yog qhov tseem ceeb heev. VD yog cov vitamin fat-soluble thiab precursor ntawm steroid hormones. Tom qab ob lub hydroxylations feem ntau hauv daim siab thiab lub raum (lossis qee cov ntaub so ntswg) [7], nws tau hloov mus rau nws daim ntawv tseem ceeb, 1,25-dihydroxy vitamin D3 (1,25D3), uas tswj ntau yam ntawm Cov txheej txheem lom neeg hauv lub hom phiaj cov ntaub so ntswg los ntawm genomic thiab non-genomic pathways [8] (Fig. 1). Interestingly, lub zos vitamin D3 hloov mus rau 25 (OH) D3 thiab 1,25 (OH) 2D3 nyob rau hauv lub qhov ncauj keratinocytes, human gingival fibroblasts (HGFs) thiab periodontal ligament cells (HPDLCs) tau pom [9, 10]. Kev tswj hwm ntawm cov vitamin D3 tsis ua haujlwm tau pom tias muaj kev tiv thaiv zoo ib yam li 1,25 (OH) 2D3 tau ua, qhia txog qhov muaj peev xwm ntawm kev thov ncaj qha ntawm cov vitamin D3 tsis muaj zog rau cov gingiva [10]. Tsis tas li ntawd, kev ua haujlwm lom neeg ntawm 1,25D3 feem ntau yog ua tiav los ntawm kev khi rau cov vitamin D receptor (VDR), ib tug tswv cuab ntawm lub nuclear receptor superfamily uas kho cov transcription ntawm cov hom phiaj (Fig. 1). Nws tau pom tias VDR tsis tsuas yog muaj nyob rau hauv cov kab mob me me hauv plab hnyuv epithelial, cov pob txha hlwb, thiab lub raum hlwb, tab sis kuj muaj ntau lub cev tiv thaiv kab mob, qog hlwb, thiab cov hlwb epithelial, qhia txog lub luag haujlwm tseem ceeb ntawm 1,25D3 hauv ntau cov kab mob ntxiv. 8, 11] ib. Tsis ntev los no, 1,25D3 tau dhau los ua lub ntsiab lus kub hauv kev tshawb fawb txog kab mob. Nws lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob microbial thiab hloov kho lub cev tiv thaiv kab mob hauv lub qhov ncauj ib puag ncig tau sib tham. Txawm li cas los xij, qhov tseeb hauv qab molecular mechanism tseem tsis meej.
Autophagy, cov txheej txheem lysosomal degradation zoo heev, yog lub hauv paus rau kev tswj hwm lub cev homeostasis. Kev hloov pauv hauv autophagy tau cuam tshuam nrog ntau yam kab mob, nrog rau cov kab mob periodontitis [12]. Nws lub luag haujlwm muaj peev xwm hauv pathogenesis ntawm periodontitis tau tshaj tawm [13]. Yog li ntawd, ua kom autophagy homeostasis yog qhov tseem ceeb. Nyob rau hauv xyoo tas los no, txoj kev loj hlob ntawm autophagy modulators tau txais kev txaus siab thoob plaws; cov modulators no tau pom muaj peev xwm kho tau zoo rau qee yam kab mob [14]. Cov pov thawj ntxiv qhia tau hais tias 1,25D3 tuaj yeem txhawb nqa autophagy los tiv thaiv kev txhim kho ntawm cov kab mob sib kis thiab mob [15]. Tsis tas li ntawd, kev sim kev tshawb fawb ntawm kev koom tes ntawm 1,25D3 thiab autophagy nyob rau hauv periodontitis tseem nyob rau hauv lawv cov me nyuam mos thiab tsis muaj kev ntsuam xyuas tau luam tawm los soj ntsuam qhov muaj peev xwm hais tias autophagy kev cai muaj feem xyuam nrog 1,25D3-kev tiv thaiv kev sib kho. periodontitis. Muab qhov tseem ceeb ntawm kev sib cuam tshuam ntawm 1,25D3 thiab autophagy, qhov kev tshuaj xyuas no qhia txog cov pov thawj tseeb ntsig txog (1) kev tiv thaiv kev tiv thaiv ntawm 1,25D3 tiv thaiv kab mob uas tau tshawb pom txog tam sim no, (2) kev sib txuas ntawm 1,25D3 thiab autophagy, thiab (3) ua tau lub luag haujlwm ntawm 1,25D3-modulated autophagy hauv kev tua cov kab mob, kev hloov kho ntawm lub cev tiv thaiv kab mob thiab cov lus teb tsis zoo, thiab txo cov pob txha.
![Fig. 1 Metabolism of vitamin D and biological response with genomic and non-genomic effects. VD is formed mainly through exposure to solar ultraviolet B (UVB) radiation by 7-dehydrocholesterol (7-DHC) in the human skin and can also be derived from the diet. The amount of VD obtained from diets and supplements is very low. VD is delivered in circulation in combination with VD-binding proteins (VDBPs) to the liver, where it is converted to 25(OH)D by the action of vitamin D-25-hydroxylase (25-OHase). After the binding of 25(OH)D to VDBPs, it subsequently reaches the kidney or other tissues (such as epithelial cells) [7], where it is converted to the active form 1,25(OH)2D by 25-hydroxyvitamin D-1 hydroxylase (1-Ohase, CYP27B1). The most biologically active metabolite of VD is 1,25(OH)2D3 (1,25D3), which is derived from vitamin D3 (cholecalciferol) and exerts its biological effects mainly by binding to the VDR. In the nucleus, 1,25D3 can bind successively to the nuclear receptor VDR, retinoid X receptor (RXR), and VD response elements (VDREs), which affect the transcription of target genes, ultimately affecting protein synthesis and decomposition. In addition, 1,25D3 can bind to the membrane receptor membrane-associated, rapid response steroid (MARRS)-binding protein to exert a non-genetic effect by interacting with other signaling pathways](/Content/uploads/2023842169/20231205105210d4cda7d7a3874b599f14a1f59289e531.png "Fig. 1 Metabolism of vitamin D and biological response with genomic and non-genomic effects. VD is formed mainly through exposure to solar ultraviolet B (UVB) radiation by 7-dehydrocholesterol (7-DHC) in the human skin and can also be derived from the diet. The amount of VD obtained from diets and supplements is very low. VD is delivered in circulation in combination with VD-binding proteins (VDBPs) to the liver, where it is converted to 25(OH)D by the action of vitamin D-25-hydroxylase (25-OHase). After the binding of 25(OH)D to VDBPs, it subsequently reaches the kidney or other tissues (such as epithelial cells) [7], where it is converted to the active form 1,25(OH)2D by 25-hydroxyvitamin D-1 hydroxylase (1-Ohase, CYP27B1). The most biologically active metabolite of VD is 1,25(OH)2D3 (1,25D3), which is derived from vitamin D3 (cholecalciferol) and exerts its biological effects mainly by binding to the VDR. In the nucleus, 1,25D3 can bind successively to the nuclear receptor VDR, retinoid X receptor (RXR), and VD response elements (VDREs), which affect the transcription of target genes, ultimately affecting protein synthesis and decomposition. In addition, 1,25D3 can bind to the membrane receptor membrane-associated, rapid response steroid (MARRS)-binding protein to exert a non-genetic effect by interacting with other signaling pathways")
Fig. 1 Metabolism ntawm vitamin D thiab cov lus teb lom nrog cov genomic thiab non-genomic teebmeem. VD yog tsim los ntawm kev raug rau hnub ci ultraviolet B (UVB) hluav taws xob los ntawm 7-dehydrocholesterol (7-DHC) hauv tib neeg daim tawv nqaij thiab tuaj yeem muab tau los ntawm kev noj haus. Tus nqi ntawm VD tau los ntawm kev noj zaub mov thiab tshuaj ntxiv yog tsawg heev. VD yog xa mus rau hauv kev sib txuas nrog VD-binding proteins (VDBPs) rau lub siab, qhov twg nws hloov mus rau 25 (OH)D los ntawm kev ua ntawm vitamin D-25-hydroxylase (25-OHase). Tom qab kev khi ntawm 25 (OH)D rau VDBPs, nws tom qab ntawd mus txog rau lub raum lossis lwm cov ntaub so ntswg (xws li cov hlwb epithelial) [7], qhov uas nws hloov mus rau daim ntawv 1,25 (OH) 2D los ntawm {{13} }hydroxyvitamin D-1 hydroxylase (1-Ohase, CYP27B1). Cov tshuaj lom neeg lom neeg tshaj plaws ntawm VD yog 1,25 (OH) 2D3 (1,25D3), uas yog muab los ntawm vitamin D3 (cholecalciferol) thiab ua rau nws cov teebmeem lom lom neeg feem ntau los ntawm kev khi rau VDR. Nyob rau hauv lub nucleus, 1,25D3 tuaj yeem khi txuas ntxiv mus rau nuclear receptor VDR, retinoid X receptor (RXR), thiab VD cov ntsiab lus teb (VDREs), uas cuam tshuam rau kev hloov pauv ntawm cov hom phiaj, thaum kawg cuam tshuam rau protein synthesis thiab decomposition. Tsis tas li ntawd, 1,25D3 tuaj yeem khi rau daim nyias nyias receptor membrane-koom nrog, cov lus teb ceev ceev steroid (MARRS)-binding protein kom ua rau muaj kev cuam tshuam tsis zoo los ntawm kev cuam tshuam nrog lwm cov kev taw qhia.
Kev tiv thaiv ntawm 1,25D3 tiv thaiv kab mob
Kev tua kab mob
Piv nrog rau cov tshuaj tua kab mob uas yuav ua rau cov kab mob tsis zoo thiab qee qhov kev tsis haum tshuaj, 1,25D3 muaj qhov kev nyab xeeb siab vim tias nws hloov kho lub cev tiv thaiv kab mob (xws li tshuaj tiv thaiv kab mob peptides (AMPs) thiab autophagy) kom siv tshuaj tua kab mob thiab tuaj yeem ua ncaj qha rau cov kab mob (Fig. . 2A). AMPs, suav nrog cathelicidin, -defensins, thiab S100 proteins, feem ntau yog tsim los ntawm lub cev tsis muaj zog thiab epithelial hlwb [16]. LL-37, tib neeg tib neeg ntawm tsev neeg cathelicidin, muaj cov tshuaj tua kab mob tiv thaiv ntau yam kab mob hauv qhov ncauj [17]. Cathelicidin antimicrobial peptide (CAMP) noob yog lub hom phiaj ncaj qha ntawm VDR-mediated transcription [18]. Cov tshuaj tua kab mob ntawm 1,25D3 tawm tsam Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) kuj tuaj yeem tshwm sim los ntawm 1,25D3-induced LL-37 [19]. Thaum lub concentration ntawm cov vitamin D biomarker 25 (OH) D3 nyob rau hauv cov ntshav yog qis dua 30 ng / mL nyob rau hauv cov neeg mob uas muaj kab mob caries, cov theem ntawm secretory immunoglobulin A (sIgA), LPS binding protein (LBP), cathelicidin thiab tag nrho cov tshuaj antioxidant. txo. Tom qab VD supplementation (VDS), cov qib rov qab mus rau qhov qub [20], thiab qaub ncaug LL-37 qib tau cuam tshuam rau cov ntshav cov vitamin D hauv cov menyuam hnub nyoog rau xyoo [21]. Cov txiaj ntsig no qhia tau hais tias lub luag haujlwm tseem ceeb ntawm 1,25D3-induced AMPs, qhia txog kev sib koom ua ke ntawm VD tsis muaj peev xwm thiab raug rau cov kab mob microbial.
Tsis ntev los no, ob peb txoj kev tshawb fawb tau tshaj tawm qhov cuam tshuam ncaj qha ntawm 1,25D3 ntawm qee cov kab mob. Vim nws muaj zog lipid solubility, cell membrane kev ncaj ncees yuav raug hloov, thiab permeability rau lwm yam tshuaj, xws li tshuaj tua kab mob, tej zaum yuav nce [22, 23]. 1,25D3 exerts an inhibitory nyhuv ntawm Fusobacterium nucleatum (F. nucleatum), A. actinomycetemcomitans, Solobacterium moorei, thiab Streptococcus mutans (S. mutans) ntawm siab concentrations (Ntau tshaj los yog sib npaug rau 100 ug / mL), whereas 1,25D3 tau pom tias muaj cov kab mob tshwj xeeb tiv thaiv Porphyromonas gingivalis (P. gingivalis) ntawm qhov tsis tshua muaj siab (tsawg kawg inhibitory concentration [MIC]: 3.125 txog 6.25 ug / mL, MBC: 6.25 txog 25 ug / mL). Tsis tas li ntawd, 1,25D3 tuaj yeem txo qis cov noob qhia ntawm cov kab mob virulence cuam tshuam nrog cov kab mob colonization (fmA, hagA, thiab hagB) thiab cuam tshuam rau cov ntaub so ntswg puas (rgpA, rgpB, thiab kgp) [24]. Tsis zoo li cov tshuaj tua kab mob uas tsom rau hauv vitro viability ntawm cov kab mob, tsom rau cov kab mob virulence factor noob uas tseem ceeb rau hauv vivo viability tuaj yeem txo cov kab mob tiv thaiv kab mob - lwm qhov tseem ceeb ntawm kev siv tshuaj tua kab mob. Interestingly, 1,25D3 tau pom los ua ib feem kev sib koom ua ke tawm tsam P. gingivalis thaum ua ke nrog metronidazole. Hauv kev sib xyaw nrog tetracycline, 1,25D3 tau pom muaj cov nyhuv ntxiv [24].
Daim duab 2 Muaj peev xwm ua tau los ntawm 1,25D3 exerts lom los ntawm cov ntaub so ntswg. A 1,25D3 muaj cov tshuaj tiv thaiv kab mob ncaj qha tawm tsam cov kab mob tshwj xeeb los ntawm nws cov kev ua haujlwm lytic thiab inhibition ntawm P. gingivalis virulence yam, thiab nws kuj tau nce qib kev qhia ntawm LL-37 thiab sIgA hauv cov qaub ncaug. Tom qab P. gingivalis ntxeem tau, 1,25D3 induces functional autophagy kom degrade P. gingivalis thiab upregulates AMP noob qhia los tua kab mob, exerting indirect antimicrobial ua. B 1,25D3 impedes TNF- -NF-κB signaling thiab upregulates VHL signaling los tiv thaiv epithelial barrier los ntawm pathogen ntxeem tau rau hauv cov ntaub so ntswg sib sib zog nqus. Nws lub luag haujlwm tiv thaiv suav nrog kev txhawb nqa kev sib txuas ntawm tes, txo qis cov lus teb (txo qis ntawm TNF, IL-6, IL-12, IFN, IL-1 , thiab HIF-1 ), thiab txo keratinocyte apoptosis. Tsis tas li ntawd, 25 (OH) D3 tau hloov mus rau 1,25D3 nyob rau hauv gingival epithelial hlwb thiab tom qab ntawd nthuav tawm nws cov teebmeem lom los ntawm kev khi rau VDR. C 1,25D3 tuaj yeem siv nws cov tshuaj tiv thaiv kab mob tiv thaiv kab mob P. gingivalis los ntawm kev tswj cov kev taw qhia sib txawv hauv macrophages/monocytes (xws li NF-κB thiab MAPK) thiab ua kom cov polarization ntawm Th hlwb mus rau Th2 / Treg phenotype, nrog rau los ntawm downregulation ntawm ib co pro-inflammatory cytokines (xws li IL-17 thiab IL-6) thiab upregulation ntawm AMPs, AhR, IL-4, thiab IL-10. D 1,25D3 tuaj yeem ua rau nws cov nyhuv ntawm cov pob txha alveolar los ntawm kev tiv thaiv kab mob, inhibition ntawm osteoclastogenesis, induction ntawm osteogenic sib txawv, thiab transcriptional kev cai ntawm osteogenesis ntsig txog yam. Txawm li cas los xij, nws cov lus teb rau cov pob txha poob, xws li kev tswj hwm ntawm osteogenesis ntsig txog yam, yuav raug txo qis hauv zos los ntawm inflammatory stimuli.
Epithelial barrier
Lub qhov ncauj epithelial barrier cais tus tswv tsev ntawm lub qhov ncauj ib puag ncig, thiab lub cev lub cev physiological barrier tiv thaiv kab mob thiab exogenous tshuaj nkag mus rau hauv cov ntaub so ntswg sib sib zog nqus. Nyob rau hauv lub gingival epithelium, qhov ncauj keratinocytes yog thawj hom cell txuas los ntawm ntau yam transmembrane proteins nrog cov qauv tshwj xeeb thiab kev ua haujlwm, xws li nruj junctions, adherens junctions, thiab gap junctions [25]. Tight junctions yog semi-permeable barriers muaj xws li claudin, occludin, thiab zonula occludens (ZO)-1-3. Adherens junctions muaj transmembrane cadherin (tsuas yog E-cadherin) thiab intracellular catenin [25]. VDR tau qhia nyob rau hauv tag nrho cov gingival epithelial txheej [26]. 1,25D3/VDR signaling tswj cov kev qhia ntawm cov proteins sib txawv koom nrog hauv kev sib txuas ntawm lub cev (xws li claudin, occludin, ZO-1/2, E-cadherin, thiab -catenin) kom tswj tau cov kab mob epithelial barrier kev ncaj ncees [27, 28]. Hauv tib neeg lub qhov ncauj keratinocytes, E-cadherin intercellular junctions (ECJs) tuaj yeem cuam tshuam los ntawm matrix metalloproteinase 9 (MMP-9) induced los ntawm qog necrosis factor- (TNF- ) [26]. Tsis tas li ntawd, 1,25D3 tuaj yeem txo MMP-9 ntau lawm los ntawm inhibiting nuclear factor-κB (NF-κB) signaling, yog li attenuating downregulation ntawm ECJs thiab txhim kho intercellular junctions [26]. Kev nce apoptosis ntawm lub qhov ncauj epithelial hlwb tuaj yeem cuam tshuam cov mucosal barrier thiab ua kom cov kab mob nkag mus sai. 1,25D3/VDR txo qhov ncauj keratinocyte apoptosis los ntawm inhibiting qhov ua kom ntawm NF-κB-dependent p53-upregulated modulator of apoptosis (PUMA), uas yog ib qho tseem ceeb pro-apoptotic regulator. Tsis tas li ntawd, lwm yam apoptogenic yam tshwm sim los ntawm Escherichia coli LPS, suav nrog phospho-p65 (p-p65) thiab active caspase 3/9, kuj raug txo los ntawm 1,25D3 [29]. 1,25D3/VDR tuaj yeem txo cov lus teb inflammatory hauv ob qho tib si von Hippel-Lindau (VHL)- thiab NF-κB-dependent pathways [29, 30]. Tib neeg lub qhov ncauj keratinocytes txhawb nqa los ntawm LPS tuaj yeem tsim ntau yam ntawm hypoxia-inducible factor-1 (HIF-1), thiab plaub lub ntsiab cytokines (interferon- [IFN], interleukin-1 [IL{ {59}} ], TNF , and IL-6) [30]. HIF-1 nce cytokine transcription thiab accelerates inflammatory teb [31]. Lub overexpression ntawm HIF-1 thiab inflammatory cytokines nyob rau hauv tib neeg lub qhov ncauj keratinocytes tau pom tias yuav rov qab los ntawm 1,25D3 kev kho mob los ntawm impeded NF-κB signaling txoj kev thiab upregulated VHL qhia; Txawm li cas los xij, seb 1,25D3 puas muaj kev tswj hwm ncaj qha rau HIF-1 tseem tsis paub. IFN thiab IL-1 kev qhia tuaj yeem raug txo los ntawm 1,25D3 hauv HIF-1 - txoj hauv kev nyob, thaum lub downregulation ntawm TNF- thiab IL-6 yuav tshwm sim los ntawm inhibition ntawm NF-κB teeb liab txoj kev [30]. Ib qho kev tshawb fawb hauv vivo pom tias qhov tsis muaj 1,25D3 nyob rau hauv lub qhov ncauj epithelial hlwb exacerbates inflammatory teb induced los ntawm LPS nyob rau hauv lub gingival epithelium. Tsis tas li ntawd, IL-1 qib mRNA raug txwv hauv qhov ncauj keratinocytes kho nrog 10 nM ntawm 1,25D3 [10]. Kev qhia ntawm lwm cov pro-inflammatory cytokines IL-8 thiab IL-12 tau txo los ntawm 1,25D3 kev kho mob hauv tib neeg cov gingival epithelial cells (HGECs) kis nrog P. gingivalis, thaum nyob rau hauv lwm cov ntaub so ntswg hauv lub cev, xws li raws li HGFs thiab HPDLCs, 1,25D3 kuj tau pom los txo cov qib inflammatory [32, 33]. Tese tshawb pom tau hais tias qhov inhibition ntawm NF-κB signaling los ntawm 1,25D3 plays lub luag haujlwm tseem ceeb hauv kev txhim kho intercellular junctions, txo apoptosis, thiab txo cov inflammatory teb nyob rau hauv lub qhov ncauj epithelial hlwb (Fig. 2B).
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
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Kev tiv thaiv kab mob thiab kab mob
Txoj kev loj hlob ntawm periodontitis tshwm sim los ntawm qhov ncauj kab mob muaj feem xyuam rau cov inflammatory mediators hauv zos uas tsim thaum lub sij hawm tus tswv lub cev tiv thaiv kab mob. Hais txog VDS, nws raug pom zoo tias cov neeg mob uas muaj VD tsis txaus yuav tsum tau muab VDS ua ntej kev phais mob kom tsis txhob muaj qhov tsis zoo ntawm qhov kev kho mob tshwm sim [34]. Tsis ntev los no, hauv qee qhov kev tshawb fawb vivo, VDS txo qis cov lus teb thiab cov pob txha alveolar poob [10, 35, 36]. Txawm li cas los xij, qhov cuam tshuam me me ntawm 1,25D3 ntawm cov kab mob ntawm cov kab mob hauv lub cev tsis muaj qhov cuam tshuam rau kev kho mob kuj tau tshaj tawm [37], uas tej zaum yuav tshwm sim los ntawm cov txheej txheem sib txawv, kev kawm cov pej xeem, lub sijhawm luv luv, thiab kev tsim qauv. Yog li, kev ua tau zoo mus sij hawm ntev thiab cov qauv txheej txheem ntawm VDS raws li kev kho mob ntxiv rau kev kho mob yuav tsum tau kawm ntxiv. Ntxiv rau HGECs, HGFs, thiab HPDLCs tau hais los saum no, 1,25D3 / VDR teeb liab nyob rau hauv ntau lub cev tiv thaiv kab mob kuj koom nrog kev tiv thaiv kev tiv thaiv tiv thaiv kab mob ntxeem tau thiab inflammatory teb (Fig. 2C). Nyob rau hauv cov ntaub ntawv ntawm innate tiv thaiv kab mob, 1,25D3 tswj cov kev taw qhia sib txawv thiab cytokine kab lus nyob rau hauv monocytes / macrophages kom exert tshwj xeeb anti-inflammatory zog tiv thaiv kab mob P. gingivalis. 1,25D3 inhibits kev ua kom NF-κB [24], p38 mitogen-activated protein kinase (MAPK), thiab extracellular signal-regulated kinase-1/2 (ERK-1/2) signaling pathway [ 38] ib. 1,25D3 tseem tuaj yeem cuam tshuam qhov kev qhia ntawm IL-6 thaum txhawb nqa qhov kev qhia ntawm IL-10 [38, 39]. Tsis tas li ntawd, cov kev tshawb fawb tau pom tias nyob rau hauv cov neeg mob uas muaj hom 2 mob ntshav qab zib mellitus thiab periodontitis, 1,25D3 tuaj yeem txhawb nqa neutrophil apoptosis los ntawm p38-MAPK txoj kev [40]. Tsis tas li ntawd, nyob rau hauv cov ntaub ntawv ntawm adaptive tiv thaiv, 1,25D3 tswj qhov sib txawv ntawm T lymphocytes, tso tawm ntawm immunoglobulin, thiab zus tau tej cov inflammatory cytokines [41]. 1,25D3 kev cuam tshuam tuaj yeem tswj T cell polarization mus rau cov khoom sib txawv. Polarized subsets, tshwj xeeb tshaj yog T1, T17, T2, thiab Treg subsets, ua ke nrog secreted cytokines, yog cov tseem ceeb players nyob rau hauv lub puas thiab reparative theem ntawm periodontitis [42]. 1,25D3 txo cov proportions ntawm T1 thiab T17 hlwb, nce qhov proportions ntawm T2 thiab Treg subsets, downregulated IL-17 qib, thiab upregulated IL-4 thiab IL-10 theem [42, 43 ].
Txo cov pob txha alveolar poob
1,25D3 tuaj yeem siv nws cov teebmeem ntawm cov pob txha alveolar los ntawm nws cov nyhuv immunomodulatory, inhibition ntawm osteoclastogenesis, induction ntawm osteogenic sib txawv, thiab transcriptional regulation ntawm osteogenesis ntsig txog yam (Fig. 2D). Ib txoj kev tshawb fawb tau tshaj tawm cov pob txha alveolar resorption nrog VD noj tsawg dua 400 IU / d thiab txo qis kev pheej hmoo ntawm mob ntev ntev nrog VD noj ntau dua 800 IU / d [44]. Hauv kev sim vivo, qhov sib ntxiv ntawm 1,25D3 txo cov pob txha poob, tej zaum vim yog qhov inhibition ntawm inflammatory teb [36, 45, 46]. Hauv gingival epithelium, tom qab 1,25D3 ntxiv, qhov kev qhia ntawm VDR thiab aryl hydrocarbon receptor (AhR) signaling tau upregulated, thiab tom qab ntawd, LPS-induced activation ntawm NF-κB thiab nucleotide-binding oligomerization domain-zoo li receptor tsev neeg pyrin domain muaj. 3 (NLRP3) inflammasome tau suppressed [36]. AhR tau nthuav dav hauv cov kab mob tiv thaiv kab mob thiab tau raug txheeb xyuas tias yog lub hom phiaj rau kev tiv thaiv kab mob [47]. NLRP3 inflammasome yog cuam tshuam nrog kev puas tsuaj rau lub cev. Nyob rau hauv macrophages, activated AhR signaling blocks lub activation ntawm NLRP3 inflammasome los ntawm NF-κB, thiab tom qab zus tau tej cov inflammatory cytokines yog inhibited [48]. Cov kab lus ntawm IL-1 thiab IL-6 raug downregulated, tejzaum nws yog vim txoj cai ntawm inflammasome txoj kev los ntawm 1,25D3. Raws li tau hais yav dhau los, 1,25D3 kev tswj hwm inhibited alveolar pob txha resorption kev ua haujlwm los ntawm kev hloov pauv cov polarization ntawm T hlwb hauv kev sim tshuaj tiv thaiv kab mob [43]. Cov kev tshawb fawb ntxiv tau pom tias muaj kev sib koom ua ke ntawm cov txiaj ntsig ntawm 1,25D3 ntawm T hlwb thiab kev ua kom osteoclast. Nyob rau hauv ib puag ncig inflammatory, cov kab lus ntawm cov cim qhia txog osteoclastogenesis (xws li MMP-9) thiab RANKL hauv vitro raug txo qis los ntawm 1,25D3 los ntawm kev tswj hwm ntawm T cell subsets [42]; Yog li, osteoclastogenesis yog inhibited. Tsis tas li ntawd, 1,25D3 tau pom tias muaj txiaj ntsig zoo txhawb kev sib txawv ntawm kev sib txawv ntawm tib neeg lub cev ligament stromal hlwb / qia hlwb (PSCs) thiab ua rau kom muaj kev cuam tshuam ntawm osteogenesis (osteocalcin thiab osteopontin) [49, 50]. Txawm li cas los xij, tsis ntev los no tau pom tias muaj kev mob tshwm sim los ntawm kev txo qis 1,25D3-induced qhia ntawm osteocalcin thiab osteopontin hauv hPDLSCs [49], uas tej zaum yuav yog los ntawm inhibited transcriptional kev ua ntawm VDR [51]. Txoj kev tshawb no muaj qee qhov kev txwv vim qhov sib ntxiv ntawm cov khoom siv dag zog, xws li dexamethasone, mus rau osteogenic induction nruab nrab, uas yuav cuam tshuam cov txiaj ntsig. Kev tshawb fawb yav tom ntej hauv qhov tob ntawm cov txheej txheem uas cov lus teb inflammatory cuam tshuam rau bioactivity ntawm 1,25D3 tuaj yeem pab txhim kho qhov ua tau zoo ntawm VDS raws li kev kho mob ntxiv.
cistanche cog-nce kev tiv thaiv kab mob
1,25D3 thiab autophagy
Autophagy
Autophagy yog cov txheej txheem loj hauv cov cellular degradation nyob rau hauv uas cytoplasmic Cheebtsam (misfolded proteins, internalized pathogens, thiab puas organelles) raug xa mus rau lysosomes rau degradation [52]. Autophagy tsim lub zog rau kev kho dua tshiab ntawm tes, tswj hwm cellular homeostasis, thiab koom nrog ntau yam txheej txheem lom neeg. Hauv cov tsiaj txhu, raws li txoj hauv kev sib txawv uas cov khoom siv ntawm tes raug xa mus rau lysosomes, autophagy feem ntau muab faib ua peb pawg: macroautophagy, microautophagy, thiab chaperone-mediated autophagy. Txij li thaum macroautophagy yog txoj hauv kev tseem ceeb ntawm kev tswj hwm lub cev ntawm lub cev, hauv qhov kev tshuaj xyuas no, peb tsuas yog xa mus rau macroautophagy li "autophagy." Cov txheej txheem autophagy suav nrog tsib kauj ruam tseem ceeb (Daim duab 3): pib, elongation, maturation, fusion nrog lysosomes, thiab degradation [53]. Cov txheej txheem nyias nyias uas qhwv lub hom phiaj cov ntsiab lus maj mam nthuav mus rau ib qho tshwj xeeb ob txheej txheej membrane, uas yog autophagosome. Tom qab ntawd, lysosomes thiab autophagosomes fuse los ua ib qho autolysosome, uas dhau los ua monolayer membrane qauv, thiab lub hom phiaj cov ntsiab lus yog degraded los ntawm lysosomal hydrolases kom tau raws li qhov xav tau ntawm cell metabolism, rov ua dua ntawm cov organelles, thiab tshem tawm cov kab mob [52].
Kev tswj cov nyhuv ntawm 1,25D3 ntawm autophagy
Nyob rau hauv xyoo tas los no, ntau cov kev tshawb fawb tau pom tias ntxiv rau kev cuam tshuam cov calcium thiab phosphorus metabolism thiab tswj kev tiv thaiv kab mob thiab kev kis kab mob, 1,25D3 kuj kho autophagy ntawm genomic thiab non-genomic signaling txoj hauv kev los cuam tshuam lub cev kev ua haujlwm ntawm lub cev sib txawv [15]. VD tsis muaj peev xwm kuj cuam tshuam rau autophagy [54]. Txawm li cas los xij, nws cov txheej txheem tshwj xeeb ntawm kev txiav txim tseem tsis meej. Tam sim no, kev tshawb fawb ntsig txog tau tsom mus rau kev tswj hwm cytosolic calcium ntau ntau, autophagy-hais txog cov noob qhia, AMPs, thiab lysosomes. 1,25D3-induced autophagy signaling tau raug tshaj tawm los ua lub luag haujlwm tiv thaiv ntau yam kab mob los ntawm nws cov tshuaj tua kab mob antioxidant, tshuaj tiv thaiv kab mob, tshuaj tiv thaiv kab mob, thiab tshuaj tiv thaiv kab mob [15]. Hauv kev nthuav dav, 1,25D3 / VDR tuaj yeem ua rau autophagy los ntawm kev nce qib ntawm cytosolic dawb calcium thiab down-regulating kev qhia ntawm mammalian lub hom phiaj ntawm rapamycin (mTOR) thiab Bcl-2 uas represses Ca2+ tso tawm [ 15]. Kev cai ntawm chav kawm III phosphoinositide 3-kinase (PI3KC3)/Beclin-1 txoj hauv kev los ntawm 1,25D3 hauv cov hlwb sib txawv thiab cov ntaub so ntswg cuam tshuam rau autophagosome nucleation [55, 56]. Beclin-1, ib qho tseem ceeb ntawm P13K complex koom nrog hauv autophagosome nucleation thiab maturation, yog tus tswj hwm ntawm autophagy thiab cuam tshuam los ntawm NF-κB, Bcl-2, 1,25D3, thiab 1,25D3 Analogs [57]. Tsis tas li ntawd, 1,25D3 / VDR induces CAMP synthesis thiab activates autophagy hauv Mycobacterium tuberculosis (Mtb)-mob monocytes. Catelicidin LL-37 yog lub hom phiaj qis qis uas txhawb nqa kev sib xyaw ntawm autophagosomes thiab lysosomes los ua autolysosomes [58]. Ntxiv mus, 1,25D3-induced human cathelicidin LL-37 tau pom los txhawb tib neeg monocyte autophagy ntawm transcriptional activation ntawm Beclin-1 thiab autophagy-related (ATG) 5 [58]. Lwm qhov kev tshawb fawb tsis ntev los no tau nthuav tawm 1,25D3-VDR-PTPN6 axis-regulated autophagy hauv macrophages. Protein tyrosine phosphatase non-receptor type 6 (PTPN6), a cytoplasmic phosphatase, yog induced los ntawm 1,25D3 thiab tswj autophagy-txog cov noob los txhawb 1,25D3-mediated autophagy [59]. Tsis tas li ntawd, 1,25D3 / VDR tau pom los txhawb qhov kev hloov pauv hloov pauv ntawm ATG16L1 kom cuam tshuam rau autophagy [60]. Kev kho mob nrog 1,25D3 nce basal theem ntawm autophagy los ntawm de-repressing qhov tseem ceeb autophagy noob LC3B (MAP1LC31B) uas yog constitutively repressed los ntawm VDR [61] (Fig. 3). Interestingly, 1,25D3 kuj tseem tuaj yeem txo autophagy los ntawm kev txo qis ntawm NF-κB, TNF- , lossis IFN- [62], uas qhia tau hais tias kev tswj hwm ntawm autophagy los ntawm 1,25D3 / VDR signaling yog bidirectional thiab tej zaum yuav txawv ntawm cov kab mob sib txawv. . Nws tau pom tias piv rau cov ntaub so ntswg noj qab haus huv, qhov chaw mob los ntawm cov kab mob tshwm sim ntawm cov kab mob rhesus liab tau pom tias muaj kev hloov pauv tseem ceeb hauv kev qhia ntawm qee cov noob caj noob ces, qhia tias autophagy tuaj yeem ua rau tsis zoo hauv cov kab mob hauv lub cev thiab koom nrog cov kab mob ntawm cov kab mob periodontitis [12] ]. Lwm cov kev tshawb fawb soj ntsuam tib neeg kuj tau pom qhov sib txawv tseem ceeb hauv cov theem ntawm autophagy ntawm cov neeg noj qab haus huv thiab cov neeg mob uas muaj kab mob periodontitis. Piv txwv li, peripheral ntshav mononuclear hlwb (PBMCs) los ntawm cov neeg mob uas muaj kab mob periodontitis tau pom tias muaj kev txo qis ntawm cov proteins uas cuam tshuam nrog autophagy ATG5-12 conjugate, ATG16L1, thiab ATG7. Cov kev cai ntawm autophagy yog li ntawd lub hom phiaj kho mob rau periodontitis yav tom ntej. Ib txoj kev tshawb nrhiav pom tias cov vitamin D supplementation txhim kho autophagy los ntawm upregulating cov kev qhia ntawm cov proteins nyob rau hauv PBMCs thiab upregulating cov kev qhia ntawm ATG5 thiab ATG16L1 nyob rau hauv cov ntaub so ntswg gingival los ntawm cov neeg mob nrog periodontitis [35]. Txoj kev tshawb no muaj kev txwv ntawm tus qauv me me thiab xaiv cov neeg mob uas tsis muaj qhov tsis txaus VD thawj zaug. Tsis tas li ntawd, cov kev tshawb fawb soj ntsuam kuj tau pom tias cov ntaub so ntswg inflammatory thiab peripheral cov ntshav nyob rau hauv cov neeg mob uas muaj kab mob peripheral pom muaj ntau dua LC3 II / I piv piv rau kev noj qab haus huv periodontium [63, 64]. Ib qho kev tshawb fawb hauv vitro pom tias kev ntxiv cov vitamin D3 ntxiv ntxiv rau LC3 II / I piv txwv los ntawm Pg [65]. Nws tau raug hais tias cov txiaj ntsig dav dav ntawm vitamin D ntawm autophagy yog bidirectional. Yog li ntawd, yuav tsum muaj kev sim ntau dua hauv vivo thiab hauv vitro txhawm rau txheeb xyuas qhov sib koom ntawm vitamin D thiab autophagy hauv periodontitis txhawm rau txhim kho cov tswv yim kho tshiab rau cov kab mob.
Daim duab 3 General regulatory mechanism ntawm 1,25D3/VDR ntawm autophagy. Cov txheej txheem macroautophagic classic yog tshwm sim los ntawm cov cim kev ntxhov siab sib txawv thiab muaj cov kauj ruam fve: (1) Phagophore (los yog cais membrane) pib los ntawm endoplasmic reticulum (ER), thiab lwm yam cellular daim nyias nyias, nrog rau cov Golgi complex, mitochondria, thiab ntshav daim nyias nyias. kuj tseem tuaj yeem xa phospholipids rau phagophore; (2) phagophore nucleation; (3) phagophore elongation tsim ib qho autophagosome tom qab kaw; (4) fusion ntawm autophagosome thiab lysosome tsim ib qho autolysosome; thiab (5) degradation ntawm cytoplasmic Cheebtsam nyob rau hauv lub autolysosome. Los ntawm txoj kev genomic thiab non-genomic, 1,25D3 induces autophagy ntawm cov kauj ruam sib txawv. 1,25D3 nce cytosolic-dawb calcium uas tso tawm los ntawm ER thiab inhibited los ntawm Bcl{17}}, thiab nws downregulates mTOR qhia kom pib autophagy induction, tswj PI3KC3/Beclin-1 txoj kev cuam tshuam rau phagophore nucleation, thiab upregulates human cathelicidin (LL-37) los txhawb kev sib xyaw ntawm lysosome thiab autophagosome. Tsis tas li ntawd, 1,25D3 tuaj yeem hloov kho cov kab lus ntawm cov noob ntawm ATG16L1, PTPN6, LC3, thiab CAMP kom induce autophagy. 1,25D3 de-represses LC3B noob (MAP1LC31B) los ntawm VDR. Cov txheej txheem no pom nyob rau hauv ntau hom cell thiab cov ntaub so ntswg induce autophagy thiab ua lub luag haujlwm tiv thaiv kab mob sib txawv los ntawm antioxidant, tiv thaiv kab mob, tiv thaiv kab mob, thiab tshuaj tiv thaiv kab mob.
Ua tau lub luag haujlwm ntawm 1,25D3 ntawm autophagy modulation hauv periodontitis
Txawm hais tias cov txheej txheem tshwj xeeb tseem tsis tau paub meej, twb tau muaj qee qhov hauv vivo thiab hauv vitro kev tshawb fawb txhawb nqa qhov kev xav ntawm kev koom tes ntawm kev tswj hwm autophagy hauv kev tiv thaiv cov vitamin D hauv lwm cov kab mob sib kis thiab mob xws li Salmonella colitis [66], UV- kev kho mob ntawm tshav kub thiab mob [67], kev tsis haum ntawm cov hlab ntsws [68], thiab osteoarthritis [69]. Lub luag haujlwm muaj peev xwm ntawm 1,25D3-induced autophagy signaling nyob rau hauv ntau hom cell thiab cov ntaub so ntswg tau tham hauv kev tshuaj xyuas tsis ntev los no [15]. Txawm li cas los xij, muaj cov ntaub ntawv me me txog nws lub luag haujlwm hauv kev noj qab haus huv ntawm qhov ncauj. Cov kev tshawb fawb uas twb muaj lawm muab pov thawj txaus los txhawb lub luag haujlwm ntawm ntau qhov kev tswj hwm ntawm autophagy nyob rau hauv lub pathogenesis ntawm periodontitis, nrog rau cov kev cai ntawm pathogen ntxeem tau, tiv thaiv kab mob, o, thiab alveolar pob txha homeostasis. 1,25D3, tus tswj hwm tseem ceeb ntawm autophagy, qhia tau hais tias muaj peev xwm zoo hauv kev tiv thaiv thiab txo cov kab mob hauv cov kab mob hauv lub cev, uas yog kho, yam tsawg kawg hauv ib feem, ntawm kev hloov kho ntawm autophagy.
cistanche cov txiaj ntsig rau txiv neej-ua kom muaj zog tiv thaiv kab mob
Barrier
Autophagy activated nyob rau hauv cov kab mob muaj feem xyuam rau intracellular antimicrobial tiv thaiv mechanisms ntawm ib tug lysosomal degradation txoj kev [70]. Active 1,25D3 mediating autophagy txhim kho Salmonella tshem tawm hauv plab hnyuv epithelia thiab zoo li yog ib qho kev cog lus kho mob rau kev tswj tus kab mob Mtb [71]. Nyob rau hauv cov ntaub so ntswg, P. gingivalis, ib tug loj opportunistic pathogen, yuav induce autophagy nrog txawv zog nyob rau hauv phagocytic (macrophages thiab dendritic hlwb) thiab non-phagocytic hlwb (GECs, endothelial hlwb, thiab gingival fibroblasts) tom qab internalization [72–75]. Autophagy txhim kho qhov tshem tawm ntawm P. gingivalis internalized los ntawm macrophages thiab dendritic hlwb. Txawm li cas los xij, txhawm rau zam kev tshem tawm los ntawm tus tswv tsev tiv thaiv kab mob, P. gingivalis tau tsim cov tswv yim tseem ceeb ntawm kev ciaj sia tawm tsam GECs. Hauv GECs thiab tib neeg coronary artery endothelial hlwb (HCAECs), P. gingivalis impairs tsim autolysosomes kom dim lysosomal degradation thiab replicate nyob rau hauv autophagosome vacuoles rau persistent intracellular survival [70, 75]. P. gingivalis-induced autophagy muab ib qho chaw zoo rau microenvironment rau replication, ciaj sia taus, thiab kev tshaj tawm hauv GECs thiab HCAECs, qhia nws lub luag haujlwm tseem ceeb hauv kev loj hlob ntawm periodontitis thiab atherosclerosis [70, 76]. Interestingly, nyob rau hauv active 1,25D3 kev kho mob, cov neeg tsis taus autophagy induced los ntawm P. gingivalis nyob rau hauv epithelial hlwb yuav ua tau zoo los ntawm ib tug ntau ntawm cov autophagosome vacuoles thiab txhawb fusion ntawm autophagosomes thiab lysosomes. 1,25D3 txo qis tus naj npawb ntawm cov neeg nyob P. gingivalis internalized rau hauv HeLa cell subline KB hlwb thiab U937 hlwb los ntawm kev txhawb nqa autophagy nyob rau hauv ib koob tshuaj (Daim duab 4A). Cov tshuaj tua kab mob ntawm 1,25D3 poob qis heev tom qab autophagy inhibition nrog 3-methyladenine ({26}}MA) kho [65]. A. actinomycetemcomitans kab mob induced autophagy nyob rau hauv tib neeg junctional epithelium keratinocytes (JEKs); Cov txheej txheem no inhibits intracellular ciaj sia taus ntawm cov kab mob thiab txo tus naj npawb ntawm JEKs nyob rau hauv cell tuag [77]. 1,25D3 kev kho mob txhim kho cov kab mob tua kab mob kom txo tau tus naj npawb ntawm cov cheeb tsam siv tau ntawm A. actinomycetemcomitans hauv kab lis kev cai GEC [19]. Txawm li cas los xij, seb nws cov tshuaj tua kab mob puas cuam tshuam nrog kev tswj hwm ntawm autophagy thiab seb 1,25D3 ua lub luag haujlwm tiv thaiv kev tuag ntawm tes ntawm autophagy induction yuav tsum tau tshawb nrhiav ntxiv. Interestingly, ntau dhau autophagy lossis tsis txaus ua rau autophagy tuaj yeem ua rau cellular puas lossis tuag [78]. Butyrate yog ib qho metabolite ntawm qee cov kab mob anaerobic periodontal uas ua rau cell tuag ntawm autophagy hauv GECs thiab gingival fibroblasts. Nws yog cov concentrated nyob rau hauv lub hnab tshos periodontal thiab ua lub luag haujlwm tseem ceeb hauv kev pib thiab kev loj hlob ntawm cov kab mob periodontal [79, 80]. Txawm li cas los xij, butyrate kuj muaj kev tiv thaiv kab mob hauv plab. Butyrate tsim los ntawm plab microbes upregulated VDR qhia nyob rau hauv ib koob tshuaj raws li nyob rau hauv tib neeg txoj hnyuv epithelial hlwb, thiab ib tug txo nyob rau hauv proliferation ntawm butyrate-ua cov kab mob tau pom nyob rau hauv nas plab hnyuv epithelia tsis muaj VDR [81]. Cov laj thawj tom qab cov haujlwm sib txawv ntawm butyrate ntawm cov chaw sib txawv tseem tsis meej (Daim duab 4A). Kev soj ntsuam kev sib raug zoo ntawm 1,25D3 thiab butyrate hauv qhov ncauj kab noj hniav tuaj yeem pab peb nkag siab zoo txog kev tswj hwm lub luag haujlwm ntawm 1,25D3 hauv kev loj hlob ntawm cov kab mob hauv lub cev.
![Fig. 4 Possible role of 1,25D3 via autophagy modulation in the pathogenesis of periodontitis. A P. gingivalis-induced autophagy provides a favorable microenvironment for its replication and survival, whereas 1,25D3 could convert this impaired autophagy into a functional one by promoting fusion with lysosomes. Butyrate activates cell death via excessive autophagy in GECs and gingival fibroblasts. Whether there is an interaction between 1,25D3 and butyrate in periodontal tissue remains unknown. B TLR activation by bacteria (such as Mtb) on monocytes upregulates the expression of VDR and 1-hydroxylase genes (CYP27B1), thereby leading to CAMP production and subsequent antimicrobial activity. The VD pathway was first described by Liu et al. in [91]. Similarly, 1,25D3-mediated autophagy was required for IFN-γ-induced antimicrobial activity. C 1,25D3 has been found to upregulate AhR expression, thus blocking NF-κB and NLRP3 which lead to tissue destruction, promote autophagy-mediated degradation of NLRP3, and downregulate IL-1β expression mediated by the NLRP3 inflammasome. Autophagy protects cells from apoptosis under inflammatory conditions, reduces ROS accumulation, and promotes angiogenesis in patients with periodontitis; however, whether 1,25D3 can induce autophagy in patients with periodontitis to exert such an effect is still unknown. D An increase in autophagy can promote the differentiation, survival, and normal functions of osteoblasts, osteoclasts, and osteocytes. 1,25D3 restores PA-mediated impaired autophagy to protect osteoblasts from lipotoxicity of PA and inhibits cell death of osteocytes in an mTOR pathway-dependent manner under hypoxic conditions. 1,25D3 plays a dual role in regulating the autophagy of OCPs, a process dependent on the RANKL intervention status; it inhibits autophagy of OCPs in the absence of RANKL and enhances RANKL-induced autophagy if the OCPs to exert a pro-osteoclastogenesis effect](/Content/uploads/2023842169/202312051055187aadcfed04974d7cbcc390df8447bb8d.png "Fig. 4 Possible role of 1,25D3 via autophagy modulation in the pathogenesis of periodontitis. A P. gingivalis-induced autophagy provides a favorable microenvironment for its replication and survival, whereas 1,25D3 could convert this impaired autophagy into a functional one by promoting fusion with lysosomes. Butyrate activates cell death via excessive autophagy in GECs and gingival fibroblasts. Whether there is an interaction between 1,25D3 and butyrate in periodontal tissue remains unknown. B TLR activation by bacteria (such as Mtb) on monocytes upregulates the expression of VDR and 1-hydroxylase genes (CYP27B1), thereby leading to CAMP production and subsequent antimicrobial activity. The VD pathway was first described by Liu et al. in [91]. Similarly, 1,25D3-mediated autophagy was required for IFN-γ-induced antimicrobial activity. C 1,25D3 has been found to upregulate AhR expression, thus blocking NF-κB and NLRP3 which lead to tissue destruction, promote autophagy-mediated degradation of NLRP3, and downregulate IL-1β expression mediated by the NLRP3 inflammasome. Autophagy protects cells from apoptosis under inflammatory conditions, reduces ROS accumulation, and promotes angiogenesis in patients with periodontitis; however, whether 1,25D3 can induce autophagy in patients with periodontitis to exert such an effect is still unknown. D An increase in autophagy can promote the differentiation, survival, and normal functions of osteoblasts, osteoclasts, and osteocytes. 1,25D3 restores PA-mediated impaired autophagy to protect osteoblasts from lipotoxicity of PA and inhibits cell death of osteocytes in an mTOR pathway-dependent manner under hypoxic conditions. 1,25D3 plays a dual role in regulating the autophagy of OCPs, a process dependent on the RANKL intervention status; it inhibits autophagy of OCPs in the absence of RANKL and enhances RANKL-induced autophagy if the OCPs to exert a pro-osteoclastogenesis effect")
Daim duab 4 Muaj peev xwm ua tau lub luag haujlwm ntawm 1,25D3 ntawm autophagy modulation nyob rau hauv lub pathogenesis ntawm periodontitis. A P. gingivalis-induced autophagy muab ib qho chaw zoo rau microenvironment rau nws replication thiab ciaj sia taus, whereas 1,25D3 yuav hloov no impaired autophagy mus rau ib tug ua hauj lwm los ntawm kev txhawb fusion nrog lysosomes. Butyrate activates cell tuag ntawm ntau dhau autophagy hauv GECs thiab gingival fibroblasts. Txawm hais tias muaj kev cuam tshuam ntawm 1,25D3 thiab butyrate hauv cov ntaub so ntswg tsis paub meej. B TLR activation los ntawm cov kab mob (xws li Mtb) ntawm monocytes upregulates cov kev qhia ntawm VDR thiab 1-hydroxylase genes (CYP27B1), yog li ua rau CAMP ntau lawm thiab cov tshuaj tiv thaiv kab mob tom ntej. Txoj kev VD tau piav qhia thawj zaug los ntawm Liu li al. hauv [91]. Ib yam li ntawd, 1,25D3-kev kho mob autophagy yog xav tau rau IFN{18}}induced antimicrobial kev ua. C 1,25D3 tau pom los txhim kho AhR kev qhia, yog li thaiv NF-κB thiab NLRP3 uas ua rau cov ntaub so ntswg puas tsuaj, txhawb autophagy-mediated degradation ntawm NLRP3, thiab downregulate IL-1 qhia kho los ntawm NLRP3 inflammasome. Autophagy tiv thaiv cov hlwb los ntawm apoptosis nyob rau hauv cov mob inflammatory, txo ROS tsub zuj zuj, thiab txhawb nqa angiogenesis hauv cov neeg mob uas muaj kab mob; Txawm li cas los xij, txawm tias 1,25D3 tuaj yeem ua rau mob autophagy hauv cov neeg mob uas muaj kab mob periodontitis kom ua tau zoo li no tseem tsis tau paub. D Kev nce hauv autophagy tuaj yeem txhawb kev sib txawv, kev muaj sia nyob, thiab kev ua haujlwm ntawm osteoblasts, osteoclasts, thiab osteocytes. 1,25D3 restores PA-mediated impaired autophagy los tiv thaiv osteoblasts los ntawm lipotoxicity ntawm PA thiab inhibits cell tuag ntawm osteocytes nyob rau hauv ib tug mTOR txoj kev-raws li nyob rau hauv hypoxic tej yam kev mob. 1,25D3 plays ob lub luag haujlwm hauv kev tswj cov autophagy ntawm OCPs, cov txheej txheem nyob ntawm RANKL kev cuam tshuam; Nws inhibits autophagy ntawm OCPs thaum tsis muaj RANKL thiab txhim kho RANKL-induced autophagy yog tias OCPs ua rau muaj kev cuam tshuam rau cov nyhuv osteoclastogenesis.
Kev tiv thaiv kab mob
1,25D3 plays lub luag haujlwm tseem ceeb hauv kev tswj kev tiv thaiv kab mob los ntawm autophagy, muab kev tiv thaiv kab mob tiv thaiv kab mob tiv thaiv kab mob uas cuam tshuam rau lub cev tiv thaiv kab mob. 1,25D3-induced autophagy yog ib qho tseem ceeb rau kev tshem tawm ntawm intracellular Mtb nyob rau hauv tib neeg monocytes / macrophages [71], thiab cathelicidin yog suav tias yog ib qho tseem ceeb mediator ntawm 1,25D3-induced autophagy [58]. Interestingly, txoj hauv kev uas IFN- txhawb nqa cov tshuaj tiv thaiv kab mob yog nyob ntawm 1,25D3 signaling-induced autophagy hauv tib neeg macrophages [82]. 1,25D3 tau tshaj tawm tias ua rau autophagy nyob rau hauv ib qho kev ywj pheej ntawm cathelicidin rau inhibition ntawm tib neeg immunodeficiency virus hom-1 (HIV-1) replication hauv macrophages [83]. 1,25D3 muab cov tswv yim kho mob rau cov kab mob kis, xws li tus kab mob khaub thuas, los ntawm kev kho cov kab mob autophagic, yog li tiv thaiv apoptosis [84]. Hauv cov kab mob periodontal, qhov induction ntawm autophagy txhim kho kev tua ntawm cov kab mob hauv lub cev uas cuam tshuam cov macrophages thiab dendritic hlwb. Hauv THP-1- muab tau los ntawm macrophages, qhov kev ciaj sia ntawm intracellular ntawm P. gingivalis thiab A. actinomycetemcomitans yog inhibited los ntawm kev txhim kho autophagy [73, 85]. Nws tau raug tshaj tawm tias tom qab 1,25D3 kev kho mob, tus nqi ntawm P. gingivalis hauv U937- tau txais cov macrophages poob qis hauv cov koob tshuaj. Nws cov txheej txheem ntawm kev ua haujlwm yuav cuam tshuam nrog kev degradation ntawm P. gingivalis nyob vim yog 1,25D3- txhawb kev sib koom ua ke ntawm P. gingivalis nrog autophagosome thiab lysosomal cov cim [86]. Ntxiv mus, kev ciaj sia ntawm P. gingivalis nyob rau hauv cov hlwb dendritic yog impaired los ntawm rapamycin-induced autophagy [72]. Kev lees paub ntawm P. gingivalis los ntawm cov hlwb dendritic ua rau muaj ob qhov xwm txheej: thaiv autophagy rau kev ciaj sia thiab txhawb nqa autophagy rau kev degradation. Siv cov neeg txhawb nqa autophagy tuaj yeem pab txhawb kev tua cov kab mob thiab kev daws teeb meem ntawm lub cev, yog li muab kev nkag siab rau hauv txoj kev kho tshiab [87].
Tsis tas li ntawd, autophagy tau dhau los ua kev cuam tshuam nrog TLR signaling. TLR signaling stimulated los ntawm TLR ligands yog qhov tseem ceeb rau kev pib thiab kev tswj hwm ntawm autophagy activation [88]. Tsis tas li ntawd, 1,25D3 / VDR signaling yog koom nrog TLR-induced autophagic pathway. 1,25D3-dependent autophagy yog induced los ntawm TLR signaling. Piv txwv li, TLR2 / 1 / CD14 stimulation los ntawm mycobacterial lipoprotein LpqH nce mRNA qhia ntawm Cyp27b1 hydroxylase thiab kev ua haujlwm VDR ua rau lub sijhawm, yog li inducing autophagy hauv tib neeg monocytes [89]. Kev sib cuam tshuam ntawm 1,25D3 / VDR-AMP axis thiab autophagy tam sim no yog lub ntsiab lus tshawb fawb kub [90]. Xyoo 2006, Liu et al. thawj lub npe hu ua cov tshuaj tiv thaiv hauv monocytes tshwm sim los ntawm kev ua haujlwm ntawm Tus Xov Tooj Zoo li receptors (TLRs) los ntawm cov kab mob thaum lub sij hawm tsim CAMP raws li txoj hauv kev VD. Kev ua kom TLR los ntawm cov kab mob ntawm macrophages tuaj yeem txhim kho qhov kev qhia ntawm VDR thiab 1-hydroxylase genes, yog li ua rau CAMP ntau lawm thiab cov tshuaj tua kab mob tom qab [91]. Txoj kev no kuj muaj nyob hauv HGECs, HGFs, thiab HPDLCs kis los ntawm P. gingivalis [32, 92, 93]. Cov txiaj ntsig no qhia txog txoj hauv kev uas TLRs ua rau 1,25D3- nyob ntawm cov kab mob tua kab mob tiv thaiv kab mob hauv lub cev. Tsis txaus 1,25D3 qib hauv lub cev tuaj yeem ua rau txo qis hauv TLR-induced antibacterial kev ua si, yog li ua rau muaj kev pheej hmoo ntawm periodontitis (Fig. 4B). Autophagy kuj suav hais tias yog tus tswj hwm ntawm T hlwb, cuam tshuam rau T cell ua haujlwm, sib txawv, thiab cov metabolism [94]. Hauv cov neeg mob uas muaj lub cev tsis muaj zog lupus erythematosus, qhov tsis txaus VD hnyav cuam tshuam rau kev qhia ntawm ATG proteins (mTOR thiab LC3) thiab ua rau muaj kev nce ntxiv hauv CD4+ T cell suav thiab txo qis hauv CD8+ T cell. suav [54].
Kev cai o
Autophagy activation tuaj yeem txwv kev mob ntau dhau hauv cov ntaub so ntswg los ntawm inhibiting IL-1 secretion, NLRP3 inflammasome tsim, thiab reactive oxygen hom (ROS) tsub zuj zuj [73, 95–97], tiv thaiv hlwb los ntawm apoptosis nyob rau hauv inflammatory mob [63] thiab txhawb nqa angiogenesis [98–101] (Fig. 4C).
IL-1 amplifies periodontal o thiab ua lub luag haujlwm tseem ceeb hauv kev rhuav tshem cov ntaub so ntswg. LPS-induced p-p65 activates NLRP3 inflammasome hauv lub cev tiv thaiv kab mob los ntawm kev khi rau NF-κB qhov chaw hauv cheeb tsam txhawb nqa ntawm NLRP3 [102]. Te NLRP3 inflammasome, uas yog lub luag haujlwm rau IL-1 tso tawm, ua rau muaj txiaj ntsig zoo rau cov pob txha alveolar resorption los ntawm kev txhawb nqa kev sib txawv ntawm osteoclast, thiab NLRP3 knockout txo cov pob txha alveolar poob hauv kev sim ua ntu zus [103, 104]. Raws li tau hais hauv SubSect. 1, 1,25D3 tau pom tias inhibit NLRP3 thiab NLRP3-kev kho IL-1 kev qhia kom txo qis kev sim kab mob hauv nas thiab txo qhov ncauj keratinocyte apoptosis. Tsis paub me ntsis txog seb puas yog autophagy mediates 1,25D3-induced anti-inflammatory thiab anti-apoptotic teebmeem nyob rau hauv periodontal kab mob. Txawm li cas los xij, qee qhov kev sib txuas kuj tau pom nyob rau hauv lwm yam kab mob. Hauv LPS-primed thawj peritoneal macrophages hauv tus qauv nas, 1,25D3 tau pom los txhawb autophagy-mediated degradation ntawm NLRP3 thiab downregulate IL-1 qhia tawm los ntawm NLRP3 inflammasome [105] (Fig. 4C). ROS, ib qho tseem ceeb hauv kev ua kom NLRP3, tau pom tias txo qis tom qab 1,25D3 kev kho mob hauv peritoneal macrophages [105]. 1,25D3 kev kho mob tsub kom autophagy nyob rau hauv daim tawv nqaij flaps, uas yuav ua rau kom txo tau ntawm oxidative kev nyuaj siab, li no ho txhim kho daim tawv nqaij fap ciaj sia taus [106]. Tsis tas li ntawd, 1,25D3 paub tias ua rau autophagy inhibit apoptosis hauv qee cov kab mob. Piv txwv li, 1,25D3 tiv thaiv tus kab mob khaub thuas-induced cellular apoptosis los ntawm kev kho cov autophagic flux, muab cov tswv yim kho mob rau tus kab mob kis [84] (Fig. 4C).
Txij li thaum VDR muaj dav nyob rau hauv vascular endothelial hlwb thiab cov leeg nqaij du, lub luag haujlwm tswj hwm ntawm 1,25D3 hauv angiogenesis thiab vascular cell ua haujlwm tau tshaj tawm [107]. Cov kev tshawb fawb tau qhia txog kev txhawb nqa vascularization los ntawm 1,25D3 hauv daim tawv nqaij flaps [106]. Txawm li cas los xij, 1,25D3 kuj tau tshaj tawm los txo cov retinal thiab corneal neovascularization hauv nas [108]. Cov txiaj ntsig no qhia tias lub luag haujlwm ntawm 1,25D3 hauv kev tswj hwm ntawm angiogenesis txawv ntawm cov kab mob sib txawv. Tsis tas li ntawd, qhov pro-angiogenic muaj peev xwm ntawm autophagy tau raug tshawb xyuas nyob rau hauv lub periodontium. Autophagy txhawb nqa angiogenesis kho los ntawm cov qia mesenchymal, suav nrog PDLSCs [99, 100]. Kev ua kom autophagy los ntawm rapamycin hauv PDLSCs tau pom tias yuav ua rau kom muaj kev tso tawm ntawm angiogenesis-txhawb cytokines xws li angiogenin thiab cov txheej txheem fibroblast loj hlob, qhov inhibition ntawm autophagy nrog knockdown ntawm Beclin1 coj mus rau kev tawm tsam ntawm pro-angiogenic muaj peev xwm [101]. Cov txiaj ntsig saum toj no muab kev nkag siab tshiab rau hauv lub peev xwm autophagy-mediated angiogenesis los ntawm 1,25D3 hauv lub sijhawm (Fig. 4C).
cistanche cov txiaj ntsig-ua kom muaj zog tiv thaiv kab mob
Pob txha homeostasis
Alveolar pob txha homeostasis yog nruj tswj los ntawm qhov sib npaug ntawm osteoclastogenesis thiab osteoblastogenesis. Nyob rau hauv periodontitis, ib qho tsis txaus nyiam cov pob txha resorption ua rau pathological resorption ntawm pob txha alveolar [109]. Autophagy, tus neeg ua si tshiab, txheeb xyuas nyob rau xyoo tas los no, ua lub luag haujlwm tseem ceeb hauv cov pob txha homeostasis thiab koom nrog kev tswj hwm ntawm cov pob txha alveolar metabolism hauv cov kab mob periodontitis [13, 110]. Feem ntau, autophagy yog qhov tseem ceeb rau kev sib txawv, kev ciaj sia, thiab kev ua haujlwm ntawm cov pob txha (xws li osteoclasts, osteoblasts, thiab osteocytes); Yog li, qhov tsis zoo autophagy tuaj yeem ua rau cov pob txha pathologies [111–114]. Piv txwv li, autophagy pab tsis tau tsuas yog rau kev ciaj sia ntawm osteoblasts nyob rau hauv oxidative kev nyuaj siab [113, 114] thiab muab lub zog qhov chaw rau osteoblast txawv [115] tab sis kuj rau osteoclast reabsorption [114]. Autophagy tseem koom nrog hauv qhov sib txawv ntawm qhov sib txawv ntawm osteoblasts rau hauv osteocytes thiab ua lub luag haujlwm tseem ceeb hauv osteocyte ciaj sia [116]. Thaum lub sij hawm tus txheej txheem no, autophagy kho qhov loj thiab cov ntsiab lus ntawm organelles thiab pab cov hlwb hloov mus rau hypoxia thiab noj zaub mov tsis zoo thiab khaws lub zog, yog li cuam tshuam cov pob txha poob [111]. Ntxiv mus, txhim kho autophagy hauv osteoblasts tau pom tias txo cov pob txha resorption txuam nrog o, xws li apical periodontitis [117].
Cov kev tshawb pom saum toj no qhia tias kev tswj hwm ntawm autophagy hauv cov pob txha pob txha yuav muaj kev cuam tshuam rau kev kho mob [110]. 1,25D3, ib qho tseem ceeb autophagy regulator, txhawb nqa osteoblast ntau lawm thiab tiv thaiv osteoblasts los ntawm apoptosis [118, 119]. Autophagy tej zaum yuav yog ib qho kev tawm tswv yim uas 1,25D3 tswj cov pob txha ntawm tes sib txawv thiab ua haujlwm (Fig. 4D). Cov kev tshawb fawb tsis ntev los no tau tshawb xyuas lub luag haujlwm ntawm 1,25D3 hauv cov pob txha metabolism los ntawm kev tswj hwm ntawm autophagy. Piv txwv li, 1,25D3 tiv thaiv osteoblasts los ntawm palmitate-induced lipotoxicity nyob rau hauv vitro los ntawm kev tswj tsis tau autophagy rau kev ua haujlwm autophagy, yog li txhim kho cell ciaj sia taus thiab ua haujlwm [119]. 1,25D3 plays ob lub luag haujlwm hauv autophagy ntawm osteoclasts. Thaum tsis muaj RANKL, 1,25D3 ncaj qha cuam tshuam qhov autophagy ntawm osteoclast precursors (OCPs). Txawm li cas los xij, vim nws qhov kev cuam tshuam zoo ntawm RANKL signaling, 1,25D3 tuaj yeem ua rau RANKL-induced autophagy ntawm OCPs, nws thiaj li ua rau muaj txiaj ntsig zoo rau osteoclastogenesis. RANKL-induced osteoclastogenesis tau poob qis los ntawm qhov sib ntxiv ntawm autophagy inhibitors, ntxiv txhawb cov pro-osteoclastogenesis nyhuv ntawm 1,25D3 ntawm autophagy [120]. 1,25D3 kuj tau pom tias inhibit osteocyte tuag nyob rau hauv hypoxic tej yam kev mob nyob rau hauv ib tug mTOR txoj kev-nyob ntawm seb. Qhov no nce qhov muaj peev xwm ntawm kev siv 1,25D3 raws li kev kho mob rau cov xwm txheej uas osteocyte tuag tshwm sim hauv hypoxia [121]. Tsis tas li ntawd, ntshav qab zib mellitus tau paub tias yog ib qho tseem ceeb ntawm kev pheej hmoo rau kab mob periodontal, thiab cov xwm txheej no tau ntseeg tias muaj kev cuam tshuam nrog kev sib deev. Mob ntshav qab zib mellitus yog txuam nrog qhov tshwm sim ntawm cov pob txha tawg thiab txo cov pob txha ceev. 1,25D3 exerts ib qho kev tiv thaiv osteoprotective los ntawm kev txo cov ntshav qabzib ntau dhau los ntawm PI3K/Akt/FoxO1 txoj kev qhia, muab kev nkag siab tshiab ntawm cov tswv yim rau cov ntshav qab zib-vim cov pob txha poob [122].
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
Cov lus xaus
Kev tiv thaiv lub luag haujlwm ntawm 1,25D3 nyob rau hauv pathogenesis ntawm periodontitis, nrog rau kev tshem tawm ntawm cov kab mob hauv lub cev, kev saib xyuas ntawm epithelial barrier, nyem los ntawm o, thiab txo cov pob txha alveolar, tej zaum yuav ua tiav, ib feem, los ntawm kev tswj ntawm autophagy. 1,25D3 signaling tswj autophagy, thiab cov kev cai ntawm autophagy yog ib qho tseem ceeb rau periodontal noj qab haus huv. Muab hais tias autophagy koom nrog kev tiv thaiv ntawm 1,25D3 ntawm kev kis kab mob, mob, thiab cov pob txha metabolism hauv ntau yam kab mob, ntxiv kev tshawb fawb txog kev sib txuas ntawm 1,25D3 thiab autophagy hauv periodontitis tuaj yeem qhia txog kev kho mob ntawm 1,25D3 thiab cov tswv yim tshiab. rau kev tiv thaiv kab mob thiab kev kho mob.
Cov ntaub ntawv
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