Kev Tshawb Fawb Cistanche: Pharmacologic Epigenetic Modulators Ntawm Alkaline Phosphatase nyob rau hauv Kab Mob Raum Ntev Part 1
Mar 12, 2022
Hu rau:joanna.jia@wecistanche.com/ WhatsApp: 008618081934791
Mathias Haarhausa,b,c, Dean Gilhamd, Ewelina Kulikowskid, Rau Magnussonbthiab Kamyar Kalantar-Zadehe,f,g
Lub hom phiaj ntawm kev tshuaj xyuas
Hauvmob raum mob, cuam tshuam ntawm ntau cov txheej txheem metabolic ua rau kev laus ntxov ntxov, nrawm nrawmkab mob plawv, thiab kev tuag. Cov kev cuam tshuam ib leeg tau rov ua tsis tiav los txhim kho qhov kev cia siab rau tus kab mob raum ntev cov neeg mob.EpigeneticCov kev cuam tshuam muaj peev xwm hloov kho ntau yam txheej txheem pathogenetic ib txhij.Alkaline phosphataseyog ib tug muaj zog kwv yees ntawm cov kab mob plawv thiab tag nrho cov-ua rau tuag thiab muaj feem xyuam rau cov txheej txheem pathogenic cuam tshuam nrog cov kab mob plawv hauvmob raum mob.
Kev tshawb pom tsis ntev los no
Hauv kev tshawb nrhiav kev sim,epigeneticmodulation ntawmalkalinephosphataselos ntawmmicroRNAslos yog bromodomain thiab ntxiv terminal (BET) protein inhibition tau pom cov txiaj ntsig tau zoo rau kev kho mob plawv thiab lwm yam kab mob metabolic. BET inhibitorapabetaloneTam sim no tau raug tshuaj xyuas rau kev txo qis ntawm cov hlab plawv hauv theem III kev tshawb fawb soj ntsuam hauv cov neeg mob uas muaj kab mob plawv, nrog rau cov neeg mob raum mob ntev. (ClinicalTrials.gov Identifier: NCT02586155). Phase II kev tshawb fawb qhia tau ib qhoalkalinephosphatase- txo qhov peev xwm ntawmapabetalone, uas tau cuam tshuam nrog kev txhim kho cov hlab plawv thiab lub raum.
Cov ntsiab lus
Alkaline phosphataseyog ib qho kev kwv yees ntawm kab mob plawv thiab kev tuag hauvmob raum mob. Epigeneticmodulation ntawmalkaline phosphatasemuaj peev xwm cuam tshuam rau ntau yam txheej txheem pathogenetic hauv cov kab mob raum ntev thiab yog li txhim khomob plawvqhov tshwm sim.
Ntsiab lus:
lub raum ua haujlwm, alkaline phosphatase, apabetalone, mob raum mob, epigenetic, microRNA, vascular calcification.
Taw qhia
Cov kab mob raum ntev (mob raum mob) yog lub xeev ntawm qhov tsis txaus ntseeg ntawm ntau lub cev kev tswj hwm lub cev tseem ceeb, ntawm lawv cov ntxhia nyiaj tshuav, acid-base tshuav nyiaj li cas, kev noj zaub mov zoo, thiab lub zog sib npaug, ua rau muaj kev mob plawv sai (kab mob plawv) thiab kev tuag. . Tsis tas li ntawd, mob raum mob kuj tseem cuam tshuam nrog kev mob ntev thiab zoo li tus qauv rau kev laus ntxov ntxov [1,2]. Hauv cov kab mob raum mob ntev, ntau txoj hauv kev tau raug kho uas cuam tshuam nrog kev tiv thaiv kab mob thiab o, oxidative kev nyuaj siab, endothelial dysfunction,vascular calcification, thiab coagulation [3]. Pharmacologicepigeneticmodulation muaj qhov zoo ntawm kev tsom mus rau ntau yam kab mob ntsig txog cov txheej txheem ib txhij. Vim nws cov lus qhia nyob rau hauv ntau cov ntaub so ntswg thiab lub cev, uas yog upregulated nyob rau hauv teb rau txawv pathogenic stimuli,alkaline phosphatase (alkalinephosphatase, EC 3.1.3.1) tej zaum yuav yog lub hom phiaj tsim nyog rauepigeneticmodulation (Daim duab 1).
Daim duab 1.Alkaline phosphataseyog ubiquitously qhia; txawm li cas los xij, qhov kev pab cuam ntawmalkaline phosphataselos ntawm cov ntaub so ntswg sib txawv mus rau circulatingalkaline phosphatasekev ua si yuav txawv. Raws li kev noj qab haus huv, daim siab thiab pob txha isoforms ntawm cov ntaub so ntswg nonspecific isozymealkaline phosphatasesuav nrog kwv yees li 50 feem pua ntawm tag nrho cov kev ncigalkaline phosphatasekev ua si. plab hnyuvalkaline phosphatasetuaj yeem muaj txog li 10 feem pua ntawm cov circulatingalkaline phosphatasekev ua si hauv cov neeg uas muaj ntshav pawg B lossis 0, tab sis tsawg dua 3 feem pua ntawm cov neeg uas muaj ntshav pawg A.alkaline phosphatasekwv yees cov txiaj ntsig ntsig txog kab mob, piv txwv li, kab mob plawv lossis kev tuag, tab sis mus rau qhov ntevalkaline phosphatasemuab tau los ntawm cov ntaub so ntswg tshwj xeeb contributes rau tag nrho cov circulatingalkalinephosphataseKev ua haujlwm hauv cov kab mob pathological tseem tsis tau txiav txim siab ntau. Tsim los ntawm Macrovector thiab Brgfx-Freepik.com.
cistancheua taukho mob raumtxhim kholub raum ua haujlwm
TSEEM CEEB
Kev ncigalkalinephosphataseyog ib qho kev pheej hmoo zoo rau cov kab mob plawv thiab tag nrho cov neeg tuag nyob hauv cov pej xeem thiab cov kab mob raum ntev.
Alkaline phosphataseyog ubiquitously nthuav tawm thiab koom nrog ntau cov txheej txheem pathophysiological cuam tshuam nrog kev mob plawv hauv cov kab mob raum, piv txwv li,vascular calcification, mob ntev, oxidative kev nyuaj siab, thiab fibrosis.
BET inhibitors thiabmicroRNAsyogepigeneticmodulators nrog lub peev xwm rau ib txhij tsom ntau yam pathogenic mechanisms upregulated nyob rau hauv cov kab mob ntev.
Qhov tshiabepigeneticmodulatorapabetalonehom phiaj pathogenetic txheej txheem txuam nrog induction ntawmalkalinephosphatasethiab txhim kho cov kab mob plawv hauv cov neeg mob uas muaj kev pheej hmoo siab, suav nrog cov neeg mob raum mob ntev thaum txo circulatingalkalinephosphatasekev ua si.
Cistanchetuaj yeem txhim kholub raum ua haujlwmthiab zammob raum mob.
ALKALINE PHOSPHATASENYOB HAUV LUB SIJ HAWM
Alkaline phosphataseyog ib qho ubiquitously nthuav tawm enzyme uas catalyzes hydrolytic tshem tawm ntawm phosphate pawg los ntawm biochemical compounds [4]. Plaub qhov sib txawv isozymes paub hauv tib neeg. Cov ntaub so ntswg-nonspecific isozyme (TN-alkalinephosphatase) yog qhia nyob rau hauv ntau yam kabmob, piv txwv li, pob txha, siab, ob lub raum, hlwb, hlab plawv system, thiab leukocytes, whereas cov ntaub so ntswg tshwj xeeb isozymes yog qhia nyob rau hauv txoj hnyuv (I-alkaline phosphatase), placenta, thiab testis (kab mob cellalkalinephosphatase) [5]. Nyob rau hauv feem ntau cov neeg noj qab haus huv, circulating tag nrhoalkalinephosphatase Kev ua haujlwm yog suav nrog kwv yees li 50 feem pua ntawm cov pob txha tshwj xeeb isoforms ntawm TN-alkalinephosphatase(B-alkalinephosphatase) thiab qhov sib npaug feem pua ntawm daim siab tshwj xeeb TN-alkalinephosphataseisoforms. Txawm li cas los xij, hauv cov neeg mob ntshav pawg B thiab 0, I-alkaline phosphatasetuaj yeem pab txhawb txog li 10 feem pua ntawm kev ncigalkalinephosphatasekev ua si. Hauv cov tib neeg uas muaj ntshav pawg A, I-alkalinephosphatasepab txhawb tsawg dua 3 feem pua ntawm tag nrhoalkalinephosphatasekev ua haujlwm, raws li cov ntshav pab pawg A cov qe ntshav liab khi I-alkaline phosphatasehauv kev ncig.alkalinephosphataseyog ib qho ectoenzyme txuas mus rau txheej txheej cell membranes. Nws raug tso tawm mus rau hauv kev ua ib homodimer soluble thiab tshem tawm ntawm kev ncig ntawm hepatic asialoglycoprotein receptors tom qab desialylation los ntawm circulating neuraminidase [6-8].
FIGURE 2. Cov ntsiab lus ntawm cov txheej txheem txuas dephosphorylation los ntawmalkaline phosphatasemus rau ib txwm thiab cov txheej txheem pathophysiological. LPS, lipopolysaccharides; MMP, metalloproteinase; OPN, osteopontin; Pi, phosphate; PL, pyridoxal; PLP, pyridoxal phosphate; PIB, pyrophosphate.
TN-alkalinephosphataseyog koom nrog hauv kev tswj hwm biomineralization, o, oxidative stress, endothelial dysfunction, fibrosis, thiab cellular hypertrophy [9&,10–12]. TN-alkaline phosphatasedephosphorylates tebchaw ntawm extracellular matrix heev unspecifically. Paub txog kev ua haujlwm lom neeg ntawmalkalinephosphatasesuav nrog cov inactivation ntawm calcification inhibitors, dephosphorylation ntawm nucleotides hauv purinergic signaling, ua kom cov matrix metalloproteinases (MMPs), thiab cov kev cai hauv zos ntawm vitamin B6 metabolism (Fig. 2). Kuv-Alkalinephosphatasepab txhawb rau kev tswj lub plab microbiome, kev noj zaub mov zoo, thiab kev tiv thaiv kab mob hauv lub cev [5].
FIGURE 3. Chromatin yog muaj DNA thiab cov proteins uas tsim kom muaj cov qauv kev cog lus tseem ceeb rau kev ntim khoom thiab ruaj khov ntawm eukaryotic chromosomes. Cov khoom tseem ceeb ntawm cov protein yog histones, nyob ib ncig ntawm qhov DNA tau raug mob los tsim cov nucleosome.Epigeneticssuav nrog covalent kev hloov kho rau chromatin uas tsis cuam tshuam rau DNA hauv kab ke. Covalent kev hloov kho rau chromatin cuam tshuam rau ob qho tib si chromatin qauv thiab kev nrhiav neeg ua haujlwm ntawm cov kev hloov pauv uas, qhov tshwm sim, hloov cov noob rau lossis tawm. Cov dynamicepigeneticCov kev hloov kho yog ua los ntawm kev ntxiv (sau) thiab tshem tawm (erasing) posttranslational modifications, ua raws li los ntawm 'nyeem', uas dictates noob qhia thiab qhov tshwm sim phenotypic teb.
Alkaline phosphatasemuaj nyob rau hauv ntau hom nrog rau tib neeg, thiab niaj hnub siv los ua tus cim rau kab mob siab lossis pob txha hloov pauv; Txawm li cas los xij, txog thaum tsis ntev los no, nws qhov cuam tshuam txog biologic tau nkag siab tsis zoo. Zoo ib yam li cov kev tshawb fawb evolutionary tom qab qhov tshwm sim ntawm C-reactive protein (CRP) los ntawm ib tug inflammatory modulator mus rau tam sim no ib tug tshiab kab mob plawv marker, nyob rau hauv lub dhau los 2 xyoo lawm,alkalinephosphatase, ib yam nkaus, tau tshwm sim nrog lub luag haujlwm tshiab tau pom hauv bio-homostasis [9&]. Cov ntaub ntawv pov thawj tam sim no qhia tias kev mus ncigalkalinephosphataseyog ib qho kev kwv yees muaj zog ntawm cov txiaj ntsig tsis zoo ntawm cov hlab plawv thiab txhua qhov ua rau tuag [9&]. Txawm hais tias nws yog ib qho tshiab ntawm kev pheej hmoo ntawm cov hlab plawv thiab muaj peev xwm kho lub hom phiaj rau kev pheej hmoo mob plawv, tsis muaj kev kho mob-theem kho mob txhawm rau txo cov ntshav qab zib.alkalinephosphatasemuaj nyob rau hnub no.
Alkaline phosphatasethiab biomineralization
Biomineralization yog tswj los ntawm kev sib cuam tshuam ntawm calcification promotors thiab inhibitors. Hauv cov kab mob hauv lub raum ntev, kev cuam tshuam ntawm qhov kev sib cuam tshuam no tshwm sim thiab tuaj yeem ua rau cov ntaub so ntswg calcification xws li medial artery calcification lossis calcification ntawm atherosclerotic plaques.alkalinephosphataseNws yog ib qho tseem ceeb rau cov pob txha mineralization, raws li pom los ntawm hypophosphatasia, ib tug kab mob nyob rau hauv cov kab mob uas tsis muaj peev xwm ntawm kev hloov pauv ntawm cov kab mob.alkalinephosphatasegene uas encodes TN-alkalinephosphatase[13]. Ntxiv rau,alkalinephosphataseplays lub luag haujlwm tseem ceeb hauv pathological soft-tissue calcification [14,15].Alkalinephosphataseyog nquag txhim kho nyob rau hauv matrix vesicles muab tau los ntawm mineralization-muaj peev xwm hlwb. Cov vesicles ua haujlwm li nidi rau matrix mineralization. Cov txheej txheem zoo sib xws hauv physiologically mineralizing cov ntaub so ntswg, xws li pob txha thiab dentin, thiab pathological soft-tissue calcification.Alkalinephosphatasetxhawb kev nthuav tawm ntawm matrix mineralization los ntawm dephosphorylation ntawm mineralization inhibitors xws li pyrophosphate thiab phosphoprotein osteopontin, thiab los ntawm tiam ntawm inorganic phosphate, rendering ib tug ntau procalcific extracellular milieu [16-18]. Lub luag haujlwm hauv kev tswj hwm ntawm phosphoproteins ntxiv hauv cov kab mob extracellular tuaj yeem kwv yees. Matrix Gla protein (MGP) yog ib qho tseem ceeb tshaj plaws physiological mineralization inhibitors [19]. Nws cov haujlwm yog txiav txim siab los ntawm kev txhais lus tom qab phosphorylation ntxiv rau vitamin K-dependent carboxylation [20,21]. Cov nyhuv ntawm MGP inhibition los ntawm pharmacological vitamin K antagonists ntawm kev nthuav tawm ntawm medial artery calcification thiab calcific uremic arteriolopathy hauv cov kab mob raum ntev. paub zoo [22,23]. Cov qib qis qis ntawm daim ntawv nonphosphorylated MGP yog txuam nrogvascular calcificationthiab kev tuag nyob rau hauv cov neeg mob dialysis, ywj siab ntawm nws cov xwm txheej carboxylation [24]. Txawm li cas los xij, cov txheej txheem ntawm MGP dephosphorylation tseem tsis tau paub thiab lub luag haujlwm raualkalinephosphatase nyob rau hauv cov txheej txheem no tsuas yog hypothesized.
Alkaline phosphatase thiab fibrosis
Ib lub tswv yim tshiab tau pom zoo rau alkaline phosphatase hauv fibrosis thiab mob plawv fibro calcification, uas yog ib qho ntawm congestive plawv tsis ua hauj lwm [25]. Lub upregulation ntawm alkaline phosphatase hauv plawv myocytes ua rau muaj zog fibrosis ntawm dephosphorylation ntawm metalloproteinases 2 thiab 9 [26]. Qhov tseeb, kev ua kom muaj zog ntawm alkaline phosphatase tau pom nyob rau hauv cov neeg mob raum mob ntev nrog myocardial hypertrophy thiab congestive plawv tsis ua haujlwm [27-29]. Tsis tas li ntawd, alkaline phosphatase hauv bronchoalveolar lavage tau raug txheeb xyuas tias yog tus cim ntawm pulmonary fibrosis, txuas alkaline phosphatase rau cov txheej txheem fibrotic hauv lub ntsws [30].
Alkaline phosphatase thiab o
Ntau cov txheej txheem txuas Alkaline phosphatase rau o. Circulating alkaline phosphatase correlates zoo nrog circulating CRP, thiab alkaline phosphatase tau raug pom tias yog ib feem ntawm cov kab mob siab-theem mob [31]. Tsis tas li ntawd, circulating I-alkaline phosphatase yog txhim kho hauv cov mob inflammatory [32]. Txawm li cas los xij, CRP thiab inflammatory cytokines muaj qhov cuam tshuam rau kev ua haujlwm ntawm alkaline phosphatase hauv osteoblasts [33,34] raws li circulating CRP tsuas yog cuam tshuam nrog tag nrho cov alkaline phosphatase, tsis yog B-alkaline phosphatase, nyob rau hauv ntau pawg ntawm cov neeg mob dialysis [35], qhia. ib qho ntxiv-skeletal qhov chaw rau qhov nce circulating alkaline phosphatase kev ua si thaum lub sij hawm o. Nyob rau hauv sib piv rau cov nyhuv ntawm o ntawm alkaline phosphatase nyob rau hauv cov pob txha, inflammatory mediators yuav ua rau kom alkaline phosphatase kev ua ub no nyob rau hauv vascular du leeg hlwb (VSMCs) thiab mesenchymal qia hlwb [36,37], uas yog concordant nrog kev soj ntsuam kev tshawb pom ntawm opposing teebmeem ntawm o. ntawm pob txha tiv thaiv vascular mineralization nyob rau hauv mob raum kab mob [38]. Alkaline phosphatase modulates cellular inflammatory teb ntawm purinergic signaling los ntawm kev pab txhawb rau lub enzymatic hloov dua siab tshiab ntawm proinflammatory extracellular adenosine triphosphate rau anti-inflammatory adenosine [39]. Alkaline phosphatase kuj tau qhia los ntawm cov kab mob inflammatory hauv phab ntsa vascular thiab tuaj yeem kho qhov sib txuas ntawm qhov mob thiab vascular calcification, feem ntau pom hauv atherosclerotic plaque thiab kab mob ntawm cov kab mob metabolic, xws li hom 2 mob ntshav qab zib mellitus thiab mob raum mob [40-43. ].
Sepsis-induced o tuaj yeem ua rau mob raum raug mob thiab ua rau lub raum tsis ua haujlwm uas ua rau mob hnyav thiab tuag [44]. Serum alkaline phosphatase kwv yees kev kis kab mob ntsig txog kev tuag [45] thiab tau raug tsim los ua ib feem ntawm kev soj ntsuam kev kwv yees tus qauv rau cov kab mob bacteremia hauv cov kab mob raum ntev 5D cov neeg mob [46]. Circulating alkaline phosphatase muaj peev xwm ua kom tsis muaj zog endotoxins thiab lwm yam phosphorylated proinflammatory tebchaw [31,32]. plab hnyuv alkaline phosphatase detoxifies lipopolysaccharide (LPS) kom txo nws cov inflammatory zog thiab kev cuam tshuam nrog tus xov tooj zoo li receptors thiab tiv thaiv o nyob rau hauv zebrafish teb rau lub plab microbiota [47]. Tseeb tiag Resolvin E1-induced plab hnyuv alkaline phosphatase txhawb kev daws teeb meem ntawm o los ntawm LPS detoxification [48]. Lub tswv yim no tau sib tw hauv kev sim tshuaj. Piv txwv li, nyob rau hauv cov neeg mob uas mob raum raug mob thiab sepsis, txhaj tshuaj recombinant alkaline phosphatase txhawb ib tug txo nyob rau hauv tag nrho cov ua rau tuag, txhawb lub physiological luag hauj lwm rau alkaline phosphatase nyob rau hauv mitigating lub deleterious thiab morbid ua tshwm sim los ntawm sepsis [49]. Yog li ntawd, zoo ib yam li CRP, muaj lub luag haujlwm lom neeg rau kev nce qib ntawm alkaline phosphatase nyob rau hauv cov xwm txheej pathologic, uas yuav ua rau muaj qhov tshwm sim tsis zoo. I-alkaline phosphatase kuj tseem tuaj yeem tiv thaiv kev tiv thaiv kab mob ntawm cov kab mob ntshav qab zib mellitus hom 1, xws li kab mob plawv lossis ntshav qab zib nephropathy [50].
Alkaline phosphatase thiab oxidative kev nyuaj siab Ua rau muaj kev ntxhov siab oxidative cuam tshuam nrog kev mob plawv tsis zoo [51]. Oxidative stress induces alkaline phosphatase thiab calcification hauv calcifying vascular cells [52]. Kev nce oxidative kev nyuaj siab kuj tseem cuam tshuam nrog osteoporosis [53] vim mineralization yog inhibited hauv osteoblasts [52]. Kev txo qis ntawm cov hlab plawv oxidative kev ntxhov siab hauv cov neeg mob raum mob ntev los ntawm kev kho mob qoj ib ce yog cuam tshuam nrog kev txo qis ntawm alkaline phosphatase [54]. Txawm li cas los xij, lub hauv paus chiv keeb ntawm kev nce ntshav alkaline phosphatase kev ua haujlwm hauv cov neeg mob oxidative kev nyuaj siab tseem tsis tau txiav txim siab.
Alkaline phosphatase thiab kub siab alkaline phosphatase pab txhawb kev tswj ntshav siab thiab vascular tone. Inhibition ntawm alkaline phosphatase nyob rau hauv cais perfused raum thiab cov tsiaj sim hauv vivo txo cov ntshav siab (BP) cov lus teb rau norepinephrine [55]. Cov nyhuv yog piav qhia ib nrab los ntawm lub luag haujlwm ntawm alkaline phosphatase hauv purinergic signaling thiab nce adenosine ntau lawm. Circulating alkaline phosphatase kev ua ub no yog inversely correlated mus rau lub siab tshaj plaws vasodilatory teb rau acetylcholine, qhia txog endothelial dysfunction [56]. Ib qho ntxiv txheej txheem txuas alkaline phosphatase rau BP tswj yog kev koom tes nrog cov hlab ntsha khov [57], tej zaum piav qhia los ntawm vascular calcification [58]. Ib qho kev koom tes ntawm Alkaline phosphatase rau qhov nce fibrotic transformation ntawm cov hlab ntsha muaj peev xwm kuj tau speculated [59].
Alkaline phosphatase thiab kev paub tsis meej
Circulating alkaline phosphatase yog txuam nrog kev paub tsis meej [60–62]. Kev paub tsis meej yog ib qho teeb meem loj hauv kev laus thiab kab mob raum ntev. Cov kev txawv txav hauv qab muaj xws li cov txheej txheem neurodegenerative thiab impaired microcirculation. Hauv Alzheimer tus kab mob, alkaline phosphatase nyob rau hauv lub hlwb thiab kev ncig yog inversely correlated nrog kev txawj ntse muaj nuj nqi, thiab dephosphorylation ntawm tau tau pom zoo raws li ib tug putative pathomechanism [63]. Kev nce ntxiv ntawm alkaline phosphatase kuj tseem cuam tshuam nrog cerebral me hlab ntsha kab mob, ib qho cim ntawm vascular kev paub tsis meej [64]. alkaline phosphatase pab txhawb rau kev tswj hwm ntawm gamma-amino butyrate thiab lwm yam neurotransmitters [65]. Lub koom haum ntawm kev txo qis alkaline phosphatase tom qab parathyroidectomy hauv cov neeg mob raum mob ntev nrog kev paub txog kev paub zoo qhia tau hais tias muaj peev xwm kho tau rau alkaline phosphatase txo qis hauv kev paub tsis meej [66].
Alkaline phosphatase hauv cov kab mob raum ntev
Hauv cov kab mob hauv lub raum ntev, circulating alkaline phosphatase feem ntau yog siv ua ke nrog cov tshuaj parathyroid rau qhov kwv yees ntawm cov pob txha hloov vim nws koom nrog cov pob txha tsim [10,67]. Thaum tsis muaj kab mob siab, kev hloov pauv ntawm tag nrho cov alkaline phosphatase feem ntau tshwm sim los ntawm B-alkaline phosphatase thiab tuaj yeem txheeb xyuas qhov siab thiab qis pob txha hloov pauv [68]. Tsis tas li ntawd, circulating alkaline phosphatase yog qhov kev kwv yees zoo dua ntawm qhov xwm txheej tawg hauv cov neeg mob lim ntshav dua li cov pob txha pob txha pob txha [69]. Circulating alkaline phosphatase kuj yog ib qho muaj zog thiab ywj siab kwv yees ntawm kev tuag thiab mob plawv hauv cov kab mob raum ntev [9&]. Hauv cov neeg tsis muaj mob raum mob, kev sib koom ua ke ntawm alkaline phosphatase thiab o yog kwv yees ntawm kev tuag [35]. Nyob rau hauv sib piv, circulating B-alkaline phosphatase theem nyob rau hauv cov neeg mob uas muaj mob raum mob siab heev yog ib tug txawm muaj zog kwv yees ntawm kev tuag tshaj tag nrho cov alkaline phosphatase [70]. Qhov no tuaj yeem yog vim nws txoj kev koom tes nrog kev nthuav dav vascular calcification tshwm sim hauv cov neeg mob uas muaj kab mob raum ntev ntawm kev lim ntshav [71]. Raws li tag nrho cov pathomechanisms tau tham saum toj no yog upregulated nyob rau hauv mob raum kab mob [3], qhov kev koom tes ntawm alkaline phosphatase rau cov mob raum kab mob uas muaj feem xyuam rau kev tuag, mob plawv, thiab impaired kev txawj ntse yog suav tias yog multifactorial.
Kev cai ntawm Alkaline phosphatase L GENE EXPRESSION
Tib neeg TN-alkaline phosphatase yog encoded los ntawm alkaline phosphatase L gene (accession naj npawb, NM_000478), uas nyob rau ntawm caj npab luv ntawm chromosome 1, 1p36.12 [72–74]. Cov alkaline phosphatase L noob ntau tshaj 50 kb thiab muaj 12 exons. Thawj exon yog ib feem ntawm 50- cheeb tsam tsis txhais lus ntawm TN-alkaline phosphatase mRNA, uas muaj xws li exon 1A lossis 1B uas teb rau cov neeg txhawb nqa sib txawv thiab ua rau ob mRNAs, txhua tus encoding ib qho polypeptide zoo tib yam, tab sis nrog sib txawv 50 - cheeb tsam tsis tau txhais [75]. Kev qhia ntawm TN-alkaline phosphatase yog ubiquitous; Txawm li cas los xij, kev hloov pauv ntawm ob qhov sib txawv ntawm exon 1 ua rau muaj qhov tshwj xeeb ntawm tes thiab cov ntaub so ntswg tshwj xeeb. Ib qho ntawm cov ntawv sau tseg no yog hu ua 'pob txha alkaline phosphatase L transcript' inactive osteoblasts suav nrog exon 1A, whereas exon 1B yog tsav los ntawm ib qho kev txhawb nqa tshwj xeeb hauv daim siab thiab lub raum cov ntaub so ntswg [75,76].
The regulation of alkaline phosphatase L expression is best studied in osteoblast-like cells. Bone formation by cells from the osteoblast lineage and functional actions, for example, biomineralization, involve multiple developmental signals such as hormones, growth factors, cytokines, Wingless-related integration site (WNT) ligands, and bone morphogenetic proteins. In addition, several transcription factors regulate the expression of a variety of osteoblast-specific genes expressing proteins pivotal for biomineralization, for example, collagen type I, bone-specific alkaline phosphatase, and osteocalcin [77]. The bone essential transcription factor runt-related transcription factor 2 (Runx2) has been identified as the master regulator for osteoblast differentiation [78]. Osterix (Osx; Sp7 gene), a zinc-finger containing transcription factor with a Runx2-binding sequence, is also essential for osteoblast differentiation and bone mineralization. Osx is not expressed in Runx2-deficient mice, whereas the expression of Runx2 is not affected in Osx-deficient mice [79], which implies that Osx regulates osteoblast differentiation downstream of Runx2 [80].
Lwm yam tseem ceeb ntawm kev hloov pauv hauv kev sib txawv ntawm osteoblast yog homeobox gene Msx2 thiab cov tswv cuab ntawm tsev neeg distal-tsawg homeobox (Dlx). Msx2 txwv tsis pub cov lus qhia ntawm alkaline phosphatase L los ntawm kev khi ncaj qha rau nws tus neeg txhawb nqa, thaum Dlx5 ua kom alkaline phosphatase L qhia los ntawm kev cuam tshuam nrog kev ua ntawm Msx2 [81]. Dlx3 yog lwm lub zog tswj hwm ntawm Runx2 ua kom lub sijhawm osteogenic sib txawv [82]. Nws kuj tau pom tias overexpression ntawm Dlx2 tsis cuam tshuam rau RUNX2, DLX5, thiab MSX2 qhia raws li osteogenic induction, tab sis stimulates alkaline phosphatase L thiab osteocalcin qhia [83]. Yog li, Dlx2 yuav ncaj qha upregulate alkaline phosphatase L los txhawb osteoblastogenesis.
NyemNtawm norau Part 2.
