Glyoxalase System hauv Cov Kab Mob Hnub Nyoog: Kev cuam tshuam noj zaub mov raws li Kev Tiv Thaiv Kev Laus Ntu 1

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

Abstract:Lub glyoxalase system yog qhov tseem ceeb rau kev tshem tawm cov tshuaj lom ntawm cov khoom kawg glycation (AGEs).AGEs yog cov tshuaj lom neeg uas ua los ntawm kev hloov pauv tsis yog enzymatic ntawm biomolecules los ntawm cov suab thaj lossis lawv cov metabolites los ntawm cov txheej txheem hu ua glycation. AGEs muaj qhov cuam tshuam tsis zoo rau ntau cov ntaub so ntswg, ua lub luag haujlwm pathogenic hauv kev loj hlob ntawm molecular thiab cellular aging. Vim lub hnub nyoog cuam tshuam txog kev poob qis hauv cov txheej txheem tiv thaiv AGE sib txawv, suav nrog cov txheej txheem detoxifying thiab proteolytic muaj peev xwm, glycated biomolecules tau sau thaum lub sijhawm laus hauv peb lub cev hauv cov ntaub so ntswg. Saib nyob rau hauv no txoj kev, anti-AGE detoxifying systems yog npaj raws li kev kho mob lub hom phiaj los tua pathological tsis ua hauj lwm txuam nrog AGE tsub zuj zuj thiab cytotoxicity. Ntawm no peb qhia txog lub xeev tam sim no ntawm kev paub txog kev tiv thaiv cov txheej txheem tiv thaiv kev ntxhov siab glycation, nrog rau qhov tshwj xeeb tseem ceeb ntawm glyoxalase system raws li lub hauv paus txheej txheem rau detoxifying cov reactive intermediates ntawm glycation. Qhov kev tshuaj xyuas no tsom mus rau glyoxalase 1 (GLO1), thawj enzyme ntawm glyoxalase system, thiab tus nqi txwv enzyme ntawm cov txheej txheem catalytic. Txawm hais tias GLO1 tau nthuav tawm thoob plaws lub ntiaj teb, qib protein thiab kev ua ub no tau tswj hwm hauv cov ntaub so ntswg. Peb muab kev sib piv ntawm GLO1 protein ntau hauv cov ntaub so ntswg sib txawv. Peb qhov kev tshawb pom qhia tias lub luag haujlwm rau glyoxalase system hauv homeostasis hauv lub qhov muag retina, cov ntaub so ntswg oxygenated nrog cov protein sai sai. Peb kuj piav qhia txog kev hloov pauv ntawm glyoxalase system raws li lub hom phiaj kho mob kom ncua kev loj hlob ntawm cov kab mob uas muaj hnub nyoog thiab sau cov ntaub ntawv uas piav qhia txog cov kev paub tam sim no txog cov khoom noj khoom haus nrog cov khoom los hloov kho glyoxalase system.

Ntsiab lus:glycation kev nyuaj siab; glyoxalase system; kev laus; proteotoxicity

Thov nias ntawm no kom paub ntxiv

1. Taw qhia: Glycative Stress thiab tsis noj qab haus huv laus

Ib lub cev loj hlob ntawm cov ntaub ntawv qhia tau hais tias kev sib sau ntawm cov proteins uas puas lawm yog cov cim tshwj xeeb ntawm kev laus thiab ntau yam kab mob uas muaj hnub nyoog, suav nrog hom 2 mob ntshav qab zib, mob qog noj ntshav, neurodegenerative, plawv, thiab mob qhov muag [1-7]. Aberrant proteins impair cellular homeostasis los ntawm kev tsim cov non-functional thiab lom aggregates thiab qhov no ua rau lub inactivation ntawm tsis tsuas yog aberrant proteins tab sis kuj yuav ua rau lub luag hauj lwm ntawm lwm yam tseem ceeb proteins vim kev nyuaj siab rau-los yog insufficiency ntawm-cov protein zoo tswj machinery. hauv cell. Ib qho tseem ceeb mechanism uas ua rau aberrant molecules yog kev hloov kho los ntawm qib siab glycation kawg-cov khoom (AGEs).

Dicarbonyl compounds yog generated

los ntawm cov txheej txheem metabolic sib txawv (Daim duab 1) uas koom nrog kev noj zaub mov qab zib thiab carbohydrate metabolism los tsim AGEs. Cov tshuaj dicarbonyl no cuam tshuam nrog biomolecules, xws li cov proteins, lipids, thiab nucleic acids hauv kev hloov pauv tsis yog enzymatic tom qab kev hloov pauv hu ua glycation. Cov glycating dicarbonyl tseem ceeb yog methylglyoxal (MG), glyoxal, los yog 3-deoxyglucosone [8]. Cov dicarbonyls no tau khaws cia nyob rau theem qis hauv cov xwm txheej hauv tsev, tab sis cov txheej txheem kev laus ua rau cov glycating reagents mus rau qib pathological, txhim kho kev tsim cov tshuaj lom AGEs thiab, thaum kawg, cuam tshuam cov ntaub so ntswg. Muab hais tias qhov tsim ntawm AGEs yog nyob ntawm cov piam thaj hauv cov ntshav, kev noj zaub mov glycemic siab lossis mob ntshav qab zib ua rau muaj kev cuam tshuam loj heev ntawm AGEs. Qhov no ncaj qha cuam tshuam nrog kev hloov pauv cov metabolism, nce o, thiab kev loj hlob ntawm cov mob hnyav. Hloov pauv, kev noj zaub mov tsawg glycemic txwv tsis pub muaj AGE thiab cuam tshuam nrog qeeb qeeb ntawm qee cov kab mob no [9-13]. Hauv cov ntsiab lus no, hyperglycemia ua rau muaj kev ntxhov siab ntxiv rau cov hnub nyoog sib txuas ntawm cov proteins glycated thiab ua rau muaj kev cuam tshuam loj heev ntawm AGEs deposits ntawm lub cev ua haujlwm.

Daim duab 1. Schematic daim duab ntawm -dicarbonyls tsim thiab detoxification txoj kev tiv thaiv AGE-derived kev puas tsuaj hauv kev laus. Kev tsim cov reactive heev -dicarbonyls xws li methylglyoxal (MG) yog los ntawm non-enzymatic degradation ntawm glycolytic intermediates, nrog rau dihydroxyacetone phosphate thiab glyceraldehyde 3-phosphate thiab lwm qhov chaw, nrog rau cov amino acid thiab lipid metabolism. Txhawm rau kom tsis txhob AGE puas tsuaj, glyoxalase system yog lub hauv paus txheej txheem uas txwv tsis pub cov synthesis ntawm AGEs, hloov cov biomolecules siab reactive, xws li MG, rau hauv tsawg reactive biomolecules (D-lactate). Cov txheej txheem no suav nrog cov haujlwm ua ntu zus ntawm ob lub enzymes GLO1 thiab GLO2 thiab txo daim ntawv ntawm glutathione (GSH). Lwm cov txheej txheem detoxifying implies qhov kev ua ntawm DJ-1, aldehyde dehydrogenases (ALDHs), Aldo-keto reductases (AKRs), thiab acetoacetate degradation enzymes. Thaum tsim, AGEs tuaj yeem raug tshem tawm los ntawm ob txoj hauv kev proteolytic: ubiquitin-proteasome (UPS) system thiab autophagy. Cov txheej txheem tiv thaiv no (tseem ceeb hauv ntsuab) poob qis hauv kev laus thiab pab txhawb rau qhov pib ntawm cov kab mob uas muaj hnub nyoog xws li neurodegeneration, kab mob qhov muag (AMD, cataract, DR), nephropathies, metabolic syndrome, thiab mob qog noj ntshav. GLO1: glyoxalase 1; GLO2: glyoxalase 2; GSH: glutathione.

Cistanche tuaj yeem tiv thaiv kev laus

Kev ntxhov siab ntau dhau ntawm glycation txhawb nqa cov protein insolubility, deregulating signaling thiab protein zoo tswj txoj hauv kev. AGEs-los ntawm kev hloov pauv hauv proteome perturb signaling pathways hauv cov nqaij mos physiology (MAP / ERK, JAK-STAT, thiab PI3K-AKT txoj hauv kev) uas ua rau muaj kev hloov pauv hauv nuclear ntawm kev hloov pauv hauv ntau lub xov tooj ntawm tes, suav nrog o, apoptosis, ER kev ntxhov siab , autophagy, oxidative kev nyuaj siab, mitochondrial muaj nuj nqi, thiab lwm yam. (saib hauv [2,14]). Glycated proteins kuj tseem tuaj yeem tshaj tawm lossis txwv kev ua haujlwm ntawm cov peev txheej proteolytic. Cov kev hloov no thaum kawg ua rau muaj qhov pib ntawm ntau yam mob uas muaj hnub nyoog.

Ntau qhov kev tshawb fawb tau pom tias qhov tsim ntawm MG thiab MG-derived AGEs yog ib qho tseem ceeb hauv cov kab mob ntshav qab zib thiab nws cov teeb meem, xws li retinopathy, nephropathy, thiab neuropathy [15-19]. Dicarbonyl kev nyuaj siab kuj yog ib qho kev sib kho ntawm kev rog thiab kab mob plawv [20,21]. MG tuaj yeem pab txhawb rau atherosclerosis los ntawm ntau lub tswv yim, suav nrog kev sib sau ntawm MG-derived AGEs hauv atherosclerotic plaques [22] thiab MG-induced low-density lipoprotein glycation [23]. Kev koom tes ntawm MG thiab ntshav siab kuj tau pom nyob rau hauv ntau txoj kev tshawb fawb, qhia txog MGlevels nyob rau hauv lub aorta thiab raum cov ntaub so ntswg [24,25]. Ntau qhov kev tshawb fawb tseem tau lees paub tias kev sib sau ntawm AGEs muaj feem cuam tshuam nrog ntau yam kab mob neurodegenerative, yog li cuam tshuam rau lub hlwb, xws li Alzheimer's disease, Parkinson's disease, thiab schizophrenia [26-28]. Ib qho piv txwv zoo tshaj plaws ntawm kev sib raug zoo ntawm AGE tsub zuj zuj thiab cuam tshuam txog kev laus tshwm sim tshwm sim hauv cov ntaub so ntswg qhov muag ua rau glycation-induced ocular cov nqaij mos, xws li cataracts, muaj hnub nyoog ntsig txog macular degeneration (AMD), thiab ntshav qab zib retinopathy (DR)[{ {15}}]. Hais txog cov kab mob cataracts, qhov ua rau qhov muag tsis pom kev thoob ntiaj teb, lub lens crystallins ua cov xim daj-xim av zuj zus nrog lub hnub nyoog raws li qhov tshwm sim ntawm kev sib sau ntawm AGEs byproducts [31]. Raws li lub lens, AGEs retinal nce nrog hnub nyoog thiab ntshav qab zib, tshwj xeeb tshaj yog nyob rau sab nrauv retina. AMD yog qhov ua rau qhov muag tsis pom ntawm cov neeg laus hauv cov tebchaws tsim kho. Cov qib AGE siab dua muaj nyob hauv AMD cov neeg mob piv rau kev tswj cov ntsiab lus nrog rau hauv AMD nas qauv [32-36]. DR yog tus cwj pwm los ntawm kev sib sau ntawm AGEs nyob rau hauv lub retina, inducing microvascular puas [37].micronized purified flavonoid feem 1000 mg sivCov kev hloov pauv pathological no ua rau tsis muaj kev puas tsuaj rau cov ntshav-retinal barrier, thiab macular edema, thaum kawg ua rau tsis pom kev. Hauv cov ntsiab lus, AGEs sau thoob plaws hauv lub cev thaum laus, tshwj xeeb, hauv cov neeg mob ntshav qab zib. Qhov no cuam tshuam cov kab mob homeostasis thiab pab txhawb rau qhov pib thiab kev loj hlob ntawm ntau yam kab mob uas muaj hnub nyoog.

Muaj ntau lub tshuab rau detoxify AGEs. Cov no suav nrog cov kab ke glyoxalase, qhov zoo tshaj plaws-tus yam ntxwv mechanism los tiv thaiv kev tsim ntawm AGEs, thiab ib txoj hauv kev tuaj yeem tshem tawm cov kab mob nruab nrab ntawm glycation. Txawm li cas los xij, lub peev xwm tiv thaiv AGEs poob qis nrog lub hnub nyoog ua rau kom nrawm nrawm ntawm AGEs hauv 'cov ntaub so ntswg qub. Txawm hais tias muaj cov txheej txheem tiv thaiv sib txawv los txwv kev sib sau ntawm AGEs hauv cov ntaub so ntswg, txhim kho lawv los tiv thaiv kev sib sau ntawm AGEs thiab cov kab mob cuam tshuam tseem tsis tau raug siv [38].Nyob rau ntu tom ntej, peb sau cov ntaub ntawv tam sim no txog kev tshem tawm cov txheej txheem tsom rau. lub glyoxalase system los txo cov tsub zuj zuj ntawm cov tshuaj lom byproducts nyob rau hauv lub hlwb thiab cov ntaub so ntswg. Thaum kawg, peb tham txog qhov muaj txiaj ntsig ntawm kev noj zaub mov zoo los txhawb lub zog glyoxalase raws li kev tiv thaiv kev laus.

2. Detoxifying Mechanisms tiv thaiv Glycative Stress: Lub luag haujlwm tseem ceeb ntawm Glyoxalase System

Ntau cov txheej txheem detoxifying tiv thaiv kev sib sau ntawm AGEs tau tshaj tawm. Daim duab 1 yog ib tug schematic txheej txheem cej luam ntawm -dicarbonyl tsim thiab sib txawv detoxification txoj kev tiv thaiv AGEs-derived kev puas tsuaj nyob rau hauv kev laus. Txoj hauv kev tseem ceeb ntawm AGEs synthesis koom nrog cov tshuaj tiv thaiv ntawm reactive dicarbonyls tau los ntawm cov piam thaj metabolism nrog cov thawj amines (N-terminal los yog lysine sab saw) los yog cov pab pawg neeg guanidine ntawm arginine sab saw [39]. Kev tsim cov reactive heev -dicarbonyls, xws li MG, yog los ntawm cov metabolism hauv glycolytic intermediates, xws li dihydroxyacetone phosphate thiab glyceraldehyde 3-phosphate, thiab lwm yam, nrog rau cov amino acid thiab lipid metabolism.

AGEs yog irreversible thiab, ib zaug tsim, tsuas yog tshem tawm los ntawm proteolyticpath-txoj kev [5,9,40,41]. Ob lub peev xwm loj proteolytic tau pom zoo los pab txhawb rau kev tshem tawm AGEs: ubiquitin-proteasome system (UPS) thiab autophagic lysosomal proteolytic system (ALPS) [5,9,40,41](Daim duab 1). UPS ua haujlwm feem ntau ntawm cov proteins uas tsis zoo sib xws. Nyob rau hauv UPS, substrates tau lees paub thiab tagged nrog ubiquitin thiab tsom mus rau proteasome rau degradation. ALPS muaj lub hom phiaj ntawm cov khoom thauj mus rau lysosomal compartment rau degradation. Autophagic cargo tuaj yeem muaj ntau haiv neeg, suav nrog cov proteins uas tsis muaj kuab lom, cov proteinaceous aggregates, thiab txawm tias tag nrho cov organelles. Ob txoj hauv kev proteolytic muaj kev sib koom ua ke thiab nce cov ntaub ntawv txhawb nqa kev sib tham ntawm ob txoj hauv kev nrog kev sib cuam tshuam ncaj qha thiab tsis ncaj[42-46]. Qhov crosstalk no tau lees paub lub tshuab thaub qab thiab, nyob rau hauv cov ntaub ntawv ntawm qhov tsis txaus ntawm ib qho ntawm txoj kev, lwm txoj hauv kev proteolytic nyhav kom them nyiaj rau kev tswj kom zoo thiab ua haujlwm proteome [47].

Cov hnub nyoog cuam tshuam txog kev hloov pauv ntawm cov protein degradation tau sau tseg rau ntau cov ntaub so ntswg ntau dua 3 xyoo dhau los, txawm tias ua ntej lub molecular characterization ntawm proteolytic pathways tau txhais [48]. Niaj hnub no, qhov kev poob qis ntawm cov molecular thiab cellular ntawm ob txoj kev loj proteolytic nrog lub hnub nyoog tau nkag siab zoo dua thiab muaj qhov sib txawv ntawm cov qib qis ntawm UPS thiab lysosomal systems. Ntau cov ntawv tshaj tawm tau pom tias cov ntaub so ntswg-dependant poob hauv UPS, thaum autophagic poob zoo li yog universal (saib hauv [49-51). Hais txog autophagy, ob qho tib si lysosomal thiab autophagosomal compartments tau txais kev hloov kho tsis zoo. Kev hloov pauv uas ua rau muaj qhov ua tsis tau zoo ntawm autophagy suav nrog kev txo qis hauv lysosomal stability, kev ua haujlwm ntawm hydrolase, tsub zuj zuj ntawm cov khoom siv tsis txaus (lipofuscin) hauv lysosomal lumen, dysfunctional lysosomal pH, txo qis transcriptional qib ntawm autophagy-txog cov proteins, txo chaperone stability. autophagy receptor LAMP2A nyob rau hauv lub lysosomal daim nyias nyias thiab txo kev koom tes ntawm lub cev muaj zog proteins nyob rau hauv lub autophagic compartments ([49,51,52]). Hauv kev sib piv rau autophagy, tam sim no tau lees paub tias kev hloov pauv hauv cov peev xwm proteasome proteolytic nrog lub hnub nyoog zoo li muaj txiaj ntsig ntau dua li qhov ntau.oteflavonoidKev hloov pauv hauv cov ntsiab lus ntawm proteasomal core catalytic kev ua ub no thiab modulatory subunits, txo qis proteasome qhia, nrog rau cov kev hloov hauv lub xeev oxidation ntawm cov proteasome subunits thiab proteasome substrates, pab txhawb rau lub hnub nyoog-txog inhibition ntawm UPS muaj peev xwm (saib xyuas hauv [53] , 54). Qee zaum, tsuas yog muaj peev xwm tsis txaus ntawm cov txheej txheem proteolytic los tuav kom thauj khoom. Hmoov tsis zoo, qhov kev ua tau zoo ntawm ob lub tswv yim no poob qis nrog lub hnub nyoog, ua rau muaj peev xwm tsis txaus los lees paub thiab tshem tawm cov protein uas puas lawm thiab, yog li ntawd, cov khoom sib txuam ntawm cov protein ntau thiab cov organelles tsis zoo [55,56]. Net AGEs theem yog txiav txim los ntawm qhov sib npaug ntawm tus nqi ntawm kev sib txuas lossis kev tsim thiab tus nqi ntawm kev tshem tawm. Qhov tshwm sim tam sim ntawm qhov poob ntawm qhov muaj peev xwm proteolytic yog qhov sib xyaw ntawm cov protein nyob ntev hauv cov kab mob uas muaj hnub nyoog, ntau yam uas ua rau glycation-derived kev puas tsuaj hauv lawv cov amino acid sequences. Kev sib sau ntawm AGEs tshwm sim nyob rau hauv lub hnub nyoog ntsig txog thiab -raws li ([4,9]) thiab kev soj ntsuam proteomic tsis ntev los no hauv kev tshawb fawb kev laus tau qhia tias AGEs biology muaj cov txheej txheem metabolic uas muaj kev cuam tshuam nrog cov hnub nyoog cuam tshuam nrog proteomes [57].

Txawm hais tias UPS thiab ALPS poob qis nrog lub hnub nyoog, muaj ntau txoj hauv kev tiv thaiv nrog lub peev xwm los txo cov synthesis ntawm AGEs. Hauv kev tshuaj xyuas no, peb tsom mus rau cov txheej txheem tiv thaiv no txwv cov biogenesis ntawm AGEs, nrog rau qhov tshwj xeeb ntawm glyoxalase system, thawj txoj hauv kev rau detoxifying reactive dicarbonyls [58]. Hauv seem no, peb yuav piav qhia txog glyoxalase system. Peb kuj piav qhia luv luv txog lwm cov txheej txheem hauv kev tshem tawm AGEs: Parkinson-associated protein DJ-1, aldehyde dehydrogenases (ALDHs), Aldo-keto reductases (AKRs), thiab acetoacetate degradation.

2.1.Glyoxalase System: Qhov Loj Detoxifying Txoj Kev rau Kev Tawm Tsam Dicarbonyls

Cov ntaub ntawv loj txhawb nqa glyoxalase system ua txoj hauv kev detoxifying tseem ceeb rau reactive dicarbonyls nyob rau hauv cytosol ntawm tag nrho cov kab mob mammalian [58]. Glyoxalase system yog txoj hauv kev zoo tshaj plaws rau cov metabolism hauv MG. Cov noob rau glyoxalases yog evolutionarily txuag thiab dav faib nyob rau hauv ntau yam nyob systems, xws li tib neeg, nroj tsuag, poov xab, kab mob, fungi, thiab protists. Lub xub ntiag nyob rau hauv ntau ntau haiv neeg taxa qhia txog qhov tseem ceeb ntawm glyoxalase enzymes nyob rau hauv lub physiological muaj nuj nqi ntawm lom lub neej. Kev ua haujlwm sib xyaw ua ke ntawm glyoxalases 1 thiab 2 (GLO1, GLO2) ua rau kev hloov pauv ntawm reactive, acyclic -oxoaldehydes rau hauv cov khoom sib xws -hydroxy acids [58]. Cov tshuaj tiv thaiv no kuj xav tau catalytic GSH. Nyob rau hauv thawj kauj ruam, GLO1 hloov nws cov substrate, hemithioacetal, tsim los ntawm ib tug spontaneous cov tshuaj tiv thaiv ntawm aldehyde ntawm dicarbonyl MG thiab GSH, rau hauv SD-lactoylglu zwm txwv. Tom qab ntawd, GLO2 hydrolyzes SD-lactoylglu tathione rau D-lactate thiab hloov kho GSH (Daim duab 1).puritans vitamin cCov haujlwm ntawm GLO1 yog ncaj qha proportional rau GSHconcentration. Cov haujlwm GLO1 txo qis thaum GSHis tshem tawm, xws li thaum oxidative kev nyuaj siab thaum GSH hloov mus rau GSSG [59].

MG yog tsim thaum lub sij hawm glycolysis thiab gluconeogenesis los ntawm degradation ntawm dihydroxyacetone phosphate thiab glyceraldehyde 3-phosphate, raws li zoo raws li catabolism ntawm threonine, oxidation ntawm ketone lub cev, thiab degradation ntawm glycated proteins. Lwm cov substrates, suav nrog glyoxal, phenylglyoxal, thiab hydroxypyru aldehyde, kuj metabolized ntawm txoj kev no [60]. GLO1, tus nqi-txheej enzyme nyob rau hauv glyoxalase system, catalyzes thawj detoxification kauj ruam [61], yog li kev hloov pauv ntawm GLO1 protein yog koom nrog ntau cov txheej txheem pathological hauv kev laus, xws li mob ntshav qab zib, kab mob neurodegenerative, mob qog noj ntshav, thiab qhov muag cuam tshuam. kab mob [20.

Txoj cai ntawm GLO1 kev qhia thiab kev ua haujlwm yog qhov nyuaj thiab tseem tsis nkag siab zoo (Daim duab 2). GLO1 cov txheej txheem txhawb nqa muaj cov hlau teb cov ntsiab lus (MRE), cov ntsiab lus teb cov tshuaj insulin (IRE), cov noob ntxov 2-factor isoform (E2F), thiab kev ua kom muaj zog-binding protein 2 (AP{{10). } } ), thiab ib qho tshuaj tiv thaiv kab mob antioxidant (ARE). Kev ua haujlwm ntawm IRE thiab MRE tau lees paub hauv cov neeg sau xov xwm kev soj ntsuam qhov twg kev kho tshuaj insulin thiab zinc chloride ua rau muaj kev hloov pauv ntau ntxiv 62]. Cov kev ua haujlwm zoo sib xws tau raug soj ntsuam rau E2F thiab AP-2 [63,64]. Lub ARE nyob rau hauv exon 1 ntawm Glo1 ua haujlwm koom nrog Glo1 rau cov khoom siv hluav taws xob nuclear erythroid 2-txog yam 2 (NRF2) kev ntxhov siab- teb cov lus teb [65]. Ob peb lub noob muaj feem xyuam rau MG metabolism thiab tiv thaiv oxidative kev nyuaj siab yog nyob rau hauv kev tswj ntawm NRF2-YOG txoj kev [66]. NRF2 yog complex nrog KEAP1, substrate adapter protein rau cullin-3-dependent E2 ubiquitin ligase complex, coj NRF2 rau degradation los ntawm 26S proteasome raws li physiological mob. Oxidative stress ua rau lub destabilization ntawm no complex, ua rau lub translocation ntawm NRF2 mus rau lub nucleus, thiab ua rau lub upregulation ntawm antioxidant noob [67,68]. Kev khi ntawm NRF2 rau lub Glo1-ARE ua kom cov basal thiab inducible qhia ntawm GLO1.[65]. NRF2 thiab cov lus teb antioxidant kuj tseem raug tswj hwm thaum MG ua rau lub dimerization ntawm KEAP liberating Nrf2 [69].

Ntau qhov kev tshawb fawb qhia tias NRF2 nce GLO1 kev ua haujlwm thiab txo qis kev ntxhov siab hauv MG; Yog li, qhov kev hloov pauv ntawm GLO1 los ntawm NRF2 agonists ua rau txo qis hauv MG thiab MG-derived protein adducts hauv ob lub hlwb thiab cov ntaub so ntswg [70-73]. Ntxiv mus, kab mob siab, hlwb, lub plawv, lub raum, thiab lub ntsws Glol mRNA thiab cov protein tau txo qis hauv NRF2 knockout nas [65]. Ua ke, cov ntawv ceeb toom no qhia tias GLO1 yog lub hom phiaj nqes nqes los ntawm txoj kev NRF2 / KEAP1 ua nws txoj haujlwm tiv thaiv los ntawm kev txo qis MG thiab dicarbonyl kev ntxhov siab. Txawm li cas los xij, kev ua kom mob ntawm NF-kB (nuclear factor kB) nrog NRF2 diminishes Glol qhia [74]. Glow qhia kuj tsis zoo tswj hwm los ntawm HIFl (hypoxia-inducible factor l) nyob rau hauv hypoxic mob, ib qho tseem ceeb physiological tsav tsheb ntawm dicarbonyl kev nyuaj siab [75].

Nrog rau kev tswj hwm kev hloov pauv, kuj tseem muaj kev cai tom qab kev txhais lus ntawm GLO1 protein (Daim duab 2). GLO1 yog acetylated los ntawm cytosolic sirtuin -2[76,77], thiab nws cov lus qhia yuav raug txo qis los ntawm kev ua kom RAGE (receptor rau qib siab glycation kawg-cov khoom lag luam); Txawm li cas los xij, cov txheej txheem no tsis to taub meej [78].sibKev tshawb fawb tsis ntev los no tau pom tias GLO1 protein tuaj yeem hloov kho los ntawm phosphorylation ntawm threonine 107 (T107) thiab nitrosylation ntawm cysteine ​​139 [79]. Hauv txoj kev tshawb no, phosphorylation ntawm T107 los ntawm calmodulin-dependent kinase II delta nyob rau hauv GLO1 protein tau tshaj tawm tias yog ib qho kev tswj hwm kev tswj hwm glyoxalase system. Tshwj xeeb, phosphorylation ntawm GLO1 ntawm T107 cuam tshuam rau kinetic efficiency ntawm MG detoxification thiab proteasomal degradation tus nqi. Yog li, nws cov xwm txheej hloov pauv yog txuam nrog kev loj hlob ntawm cov kab mob uas muaj hnub nyoog [79].

Daim duab 2. Mechanisms ntawm glyoxalase 1 (GLO1) kev tswj. GLO1 kev ua haujlwm tuaj yeem tswj hwm los ntawm ntau lub tswv yim, suav nrog kev tswj hwm kev hloov pauv thiab kev hloov pauv tom qab. Tus neeg txhawb nqa Glo1 muaj ntau yam kev tswj hwm, xws li cov lus teb antioxidant (ARE), hlau teb (MRE), thiab cov ntsiab lus ntawm cov tshuaj insulin (IRE), thiab cov chaw khi rau AP-2 thiab E2F. nuclear factor erythroid 2-related factor 2 (NRF2) is complexed with KEAP1, a substrate adapter protein for cullin-3-dependent E2 ubiquitin ligase complex, directing NRF2 for degradation by the ubiquitin-proteasome system (UPS). Oxidative stress ua rau lub destabilization ntawm complex NRF2-KEAP1, ua rau lub detachment ntawm NRF2 uas yog translocated mus rau lub nucleus uas ua rau lub upregulation ntawm txawv antioxidant noob. Kev khi ntawm NRF2 rau Glo1-ARE nce qhov kev qhia ntawm GLO1. Nyob rau hauv cov xwm txheej hypoxia, Glow qhia yog inversely tswj los ntawm hypoxia-inducible factor 1 (HIFlx). Kev hloov pauv tom qab sib txawv hauv cytosol tuaj yeem cuam tshuam GLO1 kev ruaj ntseg.

2.2. Alternative Detoxification Mechanisms li Putative Backup Systems los them rau qhov tsis muaj Glyoxalase Kev Ua Haujlwm

Thaum lub hauv paus txheej txheem rau detoxifying reactive dicarbonyls nyob rau hauv lub glyoxalase system, muaj lwm txoj kev uas muaj peev xwm mus detoxify dicarbonyls tsim thaum lub sij hawm qab zib metabolism. Cov no suav nrog ALDHs, AKRs, Parkinson-associated protein DJ-1, thiab khawb los ntawm acetoacetate los ua 3-hydroxy hexane-2, 5-dione (3-HHD Ib.) [80]. Qhov cuam tshuam ntawm lub cev ntawm cov tshuab no tseem tsis tau paub meej thiab nws tau raug nug seb puas muaj cov enzymes no tseem ceeb heev rau kev tshem tawm AGEs hauv cov ntaub so ntswg vim muaj kev ua haujlwm siab ntawm glyoxalase system. Lawv zoo li yog cov khoom ntawm cov txheej txheem thaub qab uas ua haujlwm hauv qhov tsis muaj glyoxalase kev ua haujlwm txawm tias lub luag haujlwm ntawm cov ntaub so ntswg ntawm cov kev tsis tuaj yeem txo qis.

DJ-1, tseem hu ua Parkinson's disease protein 7 (PARK7), ua lub luag haujlwm tseem ceeb hauv Parkinson's disease (PD). Qhov tsis ua haujlwm DJ-1 protein tau pom tias ua rau autosomal recessive PD [81,82]. DJ-1 tau tshaj tawm tias muaj ob txoj haujlwm sib txawv: (1) glyoxalase kev ua haujlwm hauv vitro, hloov MG rau hauv lactate thiab tiv thaiv MG-induced cov ntaub so ntswg puas hauv Caenorhabditis elegans [83], thiab (2) deglycase kev ua hauv vitro, txo Thaum ntxov-theem MG byproducts [84]. Tsis ntev los no, lwm cov kev tshawb fawb kuj tau pom tias DJ-1 plays lub luag haujlwm tseem ceeb hauv DNA deglycase [85-87].cistanche yog dab tsiLub peev xwm detoxifying ntawm DJ-1 thaum tsis muaj glutathione (GSH) ua rau qhov no yog lwm txoj hauv kev rau glyoxalase system, uas yuav tsum muaj GSH. Txawm li cas los xij, Pfaff et al.siv ob DJ-1 knockdowns hauv Drosophila hlwb thiab DJ-1 knockout nyob rau hauv tag nrho cov kab mob tau pom tsis muaj qhov sib txawv ntawm MG protein adducts [88].

AKRs yog ib tug superfamily ntawm cov proteins muaj peev xwm txo aldehydes thiab ketones rau hauv thawj thiab theem nrab cawv. AKRs metabolize MG rau hydroxy acetone los yog lactaldehyde. Qee qhov kev tshawb fawb tau pom tias qhov kev hloov pauv ntawm tib neeg thiab nas Aldo-keto reductases hauv nas fibroblast hlwb tiv thaiv MG-induced kev puas tsuaj, qhia tias AKRs tuaj yeem koom nrog MG detoxification thiab txo qis AGEs qib [89-91]. Kev ua haujlwm siab AKR1B3 tau kuaj pom hauv Glo1 knockout nas Schwann hlwb nrog rau kev nthuav tawm ntau ntxiv thaum lub sij hawm MG raug, qhia tias nws tuaj yeem yog ib qho kev them nyiaj yug los ntawm qhov tsis muaj glyoxalase system lossis ntau dhau glycation stress [92]. Interestingly, qhov tsis muaj AKR1B3 ua rau muaj ntau dua MG thiab AGEs nyob rau hauv lub siab ntawm cov nas mob ntshav qab zib [91].

LEDs yog lwm pab pawg ntawm -dicarbonyl metabolizing enzymes uas oxidize MG rau pyruvate. ALDH qhia tau nce ntxiv hauv nas Schwann cov hlwb qus thaum kho MG [92]. Nyob rau hauv tus qauv zebrafish, glo1 knockout ntses tau pom tias induced ALDH kev ua ub no pab them rau qhov tsis muaj GLO1 [93]. Txawm li cas los xij, tsawg kawg hauv cov nas, cov txheej txheem them nyiaj yog cov ntaub so ntswg-nyob, raws li kev nthuav qhia ntawm AKRs thiab ALDHs tau pom hauv daim siab cov ntaub so ntswg tab sis tsuas yog AKRs tau tshaj tawm hauv ob lub raum hauv Glo1 knockout nas [94]. Hauv kev tshawb fawb tib neeg, 3-DG metabolite tsim los ntawm aldehyde dehydrogenase 1A1 (ALDH1A1) kev ua haujlwm tau nce hauv cov ntshav thiab erythrocytes ntawm cov neeg mob ntshav qab zib [92]. Tsis ntev los no, nws kuj tau pom tias ketone lub cev acetoacetate txo MG concentration los ntawm cov tshuaj tiv thaiv tsis-enzymatic thaum mob ntshav qab zib thiab noj ketosis [95,96]. Lawv pom tias txoj hauv kev metabolic no cuam tshuam nrog kev tsis sib haum xeeb aldol-kev tshwm sim ntawm MG thiab ketone lub cev acetoacetate, ua rau 3-hydroxy hexane-2,5-dione, uas muaj nyob hauv cov ntshav. ntawm cov neeg mob ntshav qab zib insulin. Lwm txoj hauv kev uas yuav pab them rau qhov tsis muaj peev xwm ntawm glyoxalase system tuaj yeem tsim cov tshuaj lom molecules xws li y-diketones, uas cuam tshuam nrog peripheral axonal degeneration thiab testicular raug mob [97,98].

Txawm hais tias tsis muaj kev soj ntsuam kev laus ntawm cov proteins koom nrog GLO1- txoj kev ywj pheej, kev hloov pauv hnub nyoog ntawm cov molecular players tau raug tshaj tawm. Piv txwv li, muaj kev sib raug zoo ntawm D]-1 theem ntawm kev qhia thiab oxidative kev nyuaj siab, thiab cov ntaub ntawv sib txawv tau pom tias muaj kev nce hauv DJ-1 nrog hnub nyoog. DJ-1 mRNA thiab qib protein ntau ntxiv los ntawm 8 mus rau 20 lub lis piam ntawm hnub nyoog hauv nas [99] thiab DJ-1 qib tau nce ntxiv raws li kev ua haujlwm ntawm lub hnub nyoog hauv tib neeg cov kua cerebrospinal [100]. Hauv cov ntaub so ntswg, nws tau pom tias DJ-1 tau qhia nyob rau hauv retinal pigment epithelium thiab photoreceptors thiab cov lus qhia tau nce hauv qhov muag qub [101]. Nws tuaj yeem cuam tshuam cov txheej txheem them nyiaj vim qhov poob ntawm glyoxalase system kev ua haujlwm.

2.3. Tissue-Dependent Activity ntawm Glyoxalase System

Txawm hais tias GLO1 yog ib qho protein ntau, cov qib ntawm cov enzyme no tau tswj hwm hauv cov ntaub so ntswg. Txhawm rau ntsuas lub luag haujlwm ntawm glyoxalase system nyob rau hauv cov ntaub so ntswg sib txawv, peb tau tshuaj xyuas cov kev qhia thiab kev ua haujlwm ntawm GLO1 hauv cov hlab ntsha uas tsis yog-ocular (siab, hlwb, lub plawv, thiab lub raum) thiab cov ntaub so ntswg (retina, RPE / choroid, thiab lens) los ntawm hom tsiaj qus C57BL/6] nas. Siv cov tshuaj tiv thaiv uas tshwj xeeb paub txog GLO1, Western blotting thiab immunohistochemistry tau ua los ntsuas cov qib protein. GLO1 kev ua hauv cytosolic rho tawm tau txiav txim siab spectrophotometrically raws li tus nqi pib ntawm kev tsim ntawm SD-lactoylglutathione, raws li yav dhau los qhia [30,102]. Cov txiaj ntsig no tau sau tseg hauv daim duab 3.

Daim duab 3. Kev sib piv ntawm GLO1 protein thiab kev ua haujlwm hauv cov nqaij mos thiab cov nqaij mos. (A) GLO1 kev ua haujlwm tau raug tshuaj xyuas hauv cov ntaub so ntswg uas tsis yog lub qhov muag thiab cov ntaub so ntswg los ntawm WT nas raws li tau piav qhia yav dhau los [29] thiab kev ua haujlwm tau qhia raws li feem pua ​​​​(%) piv rau daim siab. (B) Daim siab thiab (C) retina tus neeg sawv cev Western blot tsom xam ntawm WT thiab Glow overexpression transgenic nas (Glo1 Tg ntxiv / ntxiv) siv cov tshuaj monoclonal antibody (tsis yog lag luam) thiab polyclonal antibody rau Glol (kev lag luam, GeneTex) [36,103,104]. (D) Tus sawv cev Western blot tsom xam ntawm cov ntaub so ntswg uas tsis yog-ocular rho tawm (50ug) ntawm WT nas siv monoclonal antibody rau Glo1 (tsis yog lag luam) thiab (E) protein ntau ntawm GLO1 normalized los tswj kev thauj khoom (Ponceau staining). (F) GLO1 kev ua haujlwm tau ua nyob rau hauv cov ntaub so ntswg (Retina, RPE / Choroid, thiab Lens) los ntawm WT nas raws li tau piav qhia yav dhau los [29] thiab kev ua haujlwm tau qhia tias yog milliunits ib milligram ntawm cov protein. Tus nqi yog txhais tau tias ± SEM. Tus qauv loj yog n{18}}los ntawm GLO1 protein thiab kev soj ntsuam kev ua haujlwm.

Cov ntaub ntawv luam tawm yav dhau los qhia tias retina thiab daim siab ua haujlwm siab tshaj plaws ntawm GLO1 ([30]; Daim duab 3A). Nco ntsoov tias kev ua haujlwm ntawm lub retinal yog tus nqi siab tshaj plaws thaum lub siab, lub raum, lub hlwb, thiab lub siab tsuas yog sawv cev rau 46 feem pua, 27 feem pua, 22 feem pua, thiab 11 feem pua ​​​​ntawm cov detoxifying retinal muaj peev xwm, feem. Peb tau soj ntsuam yog tias cov haujlwm ntawm GLO1 cuam tshuam nrog qib ntawm cov enzyme los ntawm kev ntsuam xyuas ntawm GLO1 protein ntau los ntawm Western blotting. Cov tshuaj tiv thaiv kab mob tiv thaiv GLO1 yav dhau los tau raug lees paub nyob rau hauv cov ntawv tshaj tawm dhau los thiab siv rau kev tshuaj xyuas ntawm GLO1 hauv cov qauv retinal [36,103,104]. Raws li kev tswj hwm zoo, kev sib piv kev soj ntsuam kuj tau ua nyob rau hauv retina thiab daim siab cov ntaub so ntswg los ntawm transgenic nas overexpressing GLO1 ntawm C57BL / 6J (B6) keeb kwm yav dhau [105]. Txhawm rau tshuaj xyuas qib ntawm GLO1, peb siv ob hom tshuaj tiv thaiv kab mob sib txawv: polyclonal luav antibody (kev lag luam antibody los ntawm GeneTex) thiab monoclonal nas antibody (tsis yog lag luam antibody) qhia nyob rau hauv cov tsiaj sib txawv rau kev kawm ntawm GLO1 biology [103,106]. Peb tuaj yeem kuaj pom GLO1 protein nyob rau hauv daim siab thiab retina cov ntaub so ntswg tsiaj qus los ntawm Western blotting, thiab peb pom qhov kev qhia siab tshaj plaws hauv cov nas transgenic hauv ob cov ntaub so ntswg (Daim duab 3B, C, thiab ntxiv daim duab S1). Ob pawg tau lees paub rau ob qho tshuaj tiv thaiv. Qhov sib txawv electrophoretic profiles ntawm GLO1- qhov zoo qhia tias kev hloov pauv tom qab tuaj yeem yog qhov tseem ceeb hauv lub luag haujlwm ntawm cov protein. Raws li, kev tshawb fawb tsis ntev los no tau qhia tias phosphorylated GLO1 muaj txiaj ntsig zoo thiab ruaj khov dua, txhawb cov kev hloov pauv tom qab hloov pauv raws li cov txheej txheem meej tswj hwm GLO1 kev ua haujlwm [79]. Txawm li cas los xij, muaj cov ntaub ntawv tsis txaus ntseeg txog yuav ua li cas tom qab kev hloov pauv hloov pauv hloov glyoxalase 1 kev ua haujlwm.

As expected, we found GLO1 protein in all non-ocular tissues analyzed, with the liver showing the highest expression. The relative order of GLO1 expression was liver>kidney>brain>lub plawv (Daim duab 3D, E). Qhov no corroborates cov txiaj ntsig ntawm kev kawm yav dhau los [30]. Muaj cov ntaub ntawv txwv txog lub luag haujlwm ntawm GLO1 hauv cov ntaub so ntswg. Raws li peb tau tshaj tawm yav dhau los, qhov kev ntsuam xyuas enzymatic tau qhia tias GLO1 kev ua haujlwm yog ~ 10 npaug siab dua hauv retina piv rau lub lens lossis RPE / choroid (Daim duab 3F, [30]). Lub overexpression ntawm glyoxalase kuv txhim kho tib neeg retinal pericyte ciaj sia nyob rau hauv hyperglycemic mob [107] thiab angiotensin receptor blocker uas restores GLO1 nyob rau hauv cov nas mob ntshav qab zib tau pom tias yuav txo tau cov retinal acellular capillaries [18]. Tsis tas li ntawd, qhov tsis muaj GLO1 hauv Zebrafish cuam tshuam rau cov neeg laus retina hlab ntsha architecture, txawm hais tias muaj zog angiogenic sprout tsim tsuas yog pom nyob rau hauv glo1-/- overfed zebrafish tab sis tsis nyob rau hauv ib txwm noj [93].

Lub retina yog ib qho nyuaj heev, cov ntaub so ntswg dynamic nrog ntau hom cell (Daim duab 4A). Ntshav ntws, thiab qhov tshwm sim raug rau xenobiotics thiab lwm yam kev ntxhov siab, yog qhov siab tshaj plaws hauv lub cev. Txhua tag kis sawv ntxov, 10 feem pua ​​​​ntawm cov lus qhia sab nrauv ntawm retina photoreceptors raug tshem tawm thiab yuav tsum tau muab tshem tawm los ntawm cov kab mob uas nyob ib sab ntawm cov kab mob epithelial. Peb tau ua qhov kev tshuaj ntsuam xyuas immunohistochemical los ua tus yam ntxwv thawj zaug ntawm qhov sib txawv ntawm GLO1 hauv retina. GLO1 protein muaj nyob rau hauv tag nrho cov cell hom nyob rau hauv lub retina, nrog cov theem siab nyob rau hauv lub cell lub cev ntawm lub puab nuclear txheej thiab ganglion cell laver. Photoreceptor cell lub cev nyob rau hauv txheej txheej nuclear tau qis dua. Nyob rau hauv photoreceptors, feem ntau GLO1 proteins tau pom nyob rau hauv sab hauv thiab sab nrauv. RPE kuj tseem muaj cov protein ntau ntawm GLO1, thaum choroid thiab sclera muaj qis dua ntawm GLO1 protein (Daim duab 4B, C).

Daim duab 4. Immunohistochemistry ntawm GLO1 nyob rau hauv nas retinal ntaub so ntswg. (A) Hla-sectional, cellular schematic ntawm lub retina qhia txog nws peb cov txheej txheem tseem ceeb suav nrog ganglion cell txheej (GCL), uas muaj cov hlwb hlwb hlwb (RGC), inner nuclear txheej (INL), hosting interneurons ntawm amacrine, bipolar thiab kab rov tav cov hlwb zoo li Müller glial hlwb, thiab txheej txheej nuclear (ONL), vaj tse pas nrig thiab lub khob hliav qab photoreceptors. Cov ntaub so ntswg, los yog neuroretina, txuas nrog lub retinal pigmented epithelium (RPE). Cov xub liab qhia txog RPE txheej. (B) Cov duab sawv cev ntawm GLO1 immunostaining hauv cov qauv retinal los ntawm WT nas. (C) Lub ntsiab lus siv fluorescence ntawm GLO1 normalized rau tus nqi hauv RPE. Cov ntaub ntawv qhia yog txhais tau tias ± tus qauv yuam kev ntawm txoj kev (SEM). Peb cov txiaj ntsig hauv retina yog qhov cuam tshuam vim tias retina yog qhov sib txawv ntawm cov ntaub so ntswg tom qab mitotic, qhov twg glycation-derived kev puas tsuaj tsis tuaj yeem txo los ntawm cellular faib [5,9]. Tsis tas li ntawd, kev hloov pauv hauv GLO1 tau cuam tshuam nrog kev puas tsuaj rau lub hlwb [108]. Ib qho xwm txheej zoo sib xws tuaj yeem tshwm sim hauv lwm cov ntaub so ntswg uas muaj cov hlwb uas tsis muaj peev xwm rov tsim dua tshiab, xws li lub hauv nruab nrab paj hlwb, qhov twg feem coob ntawm cov neurons yog post-mitotic. Kev ntsuam xyuas ntawm GLO1 qib nrog rau cov cim tshwj xeeb ntawm tes yuav tso cai rau peb los ntsuas qhov sib txawv ntawm cov xov tooj ntawm tes rau hauv cov ntaub so ntswg. Peb cov txiaj ntsig tau qhia tias qib siab ntawm retinal GLO1 protein thiab kev ua haujlwm yuav ua lub luag haujlwm tseem ceeb tiv thaiv AGE-los ntawm kev puas tsuaj nrog lub hnub nyoog.

Kab lus no yog muab rho tawm los ntawm Cells 2021, 10, 1852. https://doi.org/10.3390/cells10081852 https://www.mdpi.com/journal/cells