Qhov cuam tshuam ntawm Dietary Iron-Chelating Bioactive Compounds hauv Molecular Mechanisms Ntawm Oxidative Stress-Induced Cell Aging Part 2

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3.2. Cellular Senescence

Cellular senescence yog ib qho ntawm cov cim qhia ntawm kev laus ntawm lub cev. Cov yam ntxwv tseem ceeb tshaj plaws ntawm cov txheej txheem cellular tseem ceeb yog qhov raug ntes mus tas li ntawm lub voj voog ntawm tes, uas yog nrog los ntawm cov kab mob hauv lub cev ntawm cov macromolecules puas, nrog rau cov secretory phenotype thiab hloov pauv metabolism [55,56]. Ob hom cellular senescence tau pom nyob rau hauv mammalian hlwb; cov no yog hu ua "replicative senescence" thiab "stress-induced cellular senescence"[56]. Thawj zaug feem ntau tshwm sim tom qab qee qhov kev faib tawm hauv ntau hom hlwb. Nws tau piav ntau xyoo dhau los hauv kab lis kev cai tib neeg fibroblasts [57]. Qhov no tshwm sim tom qab raug ntaus nqi rau telomere attrition, maj mam shortening ntawm linear kawg ntawm chromosomes raws li txhua DNA replication [58]. Ntawm qhov tod tes, kev ntxhov siab vim yog cellular senescence feem ntau ywj siab ntawm qhov ntev telomere thiab sawv cev rau cov lus teb rau ntau yam kev ntxhov siab xws li oxidative stress, genotoxic stress, mitochondrial deterioration, hypoxia, nutrient deprivation, thiab aberrant activation of oncogenes |56, { {8}}. Interestingly, oxidative kev nyuaj siab yog ib tug ntau denominator rau tag nrho cov no vim hais tias nws yuav koom nrog rau tag nrho cov saum toj no-hais teeb meem kev nyuaj siab [62-65].

Cellular senescence yog undoubtedly txuas nrog organismal laus [55,56].Cov txiaj ntsig cynomorium,Txawm li cas los xij, senescent hlwb tsis tsuas yog kuaj pom hauv cov ntaub so ntswg laus; Lawv tuaj yeem raug kuaj pom nyob rau hauv txhua theem ntawm lub neej thiab tuaj yeem ua lub luag haujlwm muaj txiaj ntsig hauv ntau yam ntawm tib neeg lub cev thiab cov txheej txheem pathological suav nrog embryogenesis, kho qhov txhab, thiab qog nqaij hlav [56,61]. Txawm li cas los xij, qhov ruaj khov ntawm cov hlwb uas muaj hnub nyoog muaj kev cuam tshuam thiab tau txuas rau cov kab mob kev laus thiab kev mob nkeeg [56,59,66-69].

Thov nias ntawm no kom paub ntxiv

Hais txog lawv cov morphology, senescent hlwb qhia cov cim xws li loj, flattened, thiab irregularly-shaped cell lub cev; kev hloov pauv ntawm cov plasma membrane; poob ntawm nuclear condensation; thiab nce lysosomal cov ntsiab lus ntawm senescence-associated beta-galactosidase (SA- -gal)J70,71]. Lawv kuj ua rau muaj kev hloov pauv loj hauv lawv cov ntaub ntawv zais cia, nthuav tawm kev nthuav qhia ntxiv thiab tso tawm ntawm cov cytokines thiab chemokines, kev loj hlob yam, cov khoom ntawm extracellular matrix (matrix metalloproteinases, serine proteases), thiab ROS [59]. Tag nrho cov kev hloov pauv no kuj tau nrog los ntawm kev nce qib ntawm cov khoom hauv lub cev ntawm cov tshuaj lom neeg uas tsis yog-degradable "khoom siv khib nyiab" uas yog hu ua "lipofuscin" lossis "ceroid" lossis txawm tias "hnub nyoog pigment"[72-74].

Cov ntu tom ntej no piav qhia txog cov txheej txheem ntawm kev tsim lipofuscin thiab qhia tias muaj peev xwm ua tau los cuam tshuam lossis tiv thaiv nws cov khoom.

3.3. Lipofuscin tsim thiab tsub zuj zuj hauv cov cell senescent

Cov xim no hu ua "lipofuscin" tau tshawb pom thiab tshaj tawm xyoo 1842 los ntawm Dutch histologist Hannover [75]. Lo lus lipofuscin tau pib siv los ntawm Borst hauv nws cov lus qhuab qhia tab sis tau luam tawm thawj zaug los ntawm Hueck hauv 1912 [76,77]. Lub npe tau muab los ntawm Greek lo lus lipo (uas txhais tau tias rog) thiab lo lus Latin fuscus (uas txhais tau tias tsaus ntuj lossis dusky). Lipofuscin tsim thiab tsub zuj zuj yog cov yam ntxwv hloov nrog universal manifestation nyob rau hauv senescent hlwb [78-80] thiab muaj ntau heev nyob rau hauv lub neej ntev postmitotic hlwb, xws li neurons, cardiomyocytes, skeletal leeg hlwb, thiab retinal pigment epithelial (RPE) hlwb [ 74, 81] ib. Cov hlwb no txuas ntxiv ua neej nyob ntev ntev tom qab kev ua tiav ntawm lawv qhov kev loj hlob, tab sis lawv maj mam nce ntxiv ntawm lipofuscin uas tsis tuaj yeem degraded lossis exocytosed.

Cistanche tuaj yeem tiv thaiv kev laus

Los ntawm kev siv ntau yam txuj ci txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm Tshwj xeeb, tus nqi tau ceev ceev hauv cov tsiaj nyob luv thiab qeeb hauv cov neeg nyob ntev, qhia tau hais tias lipofuscin tsub zuj zuj feem ntau tej zaum muaj kev cuam tshuam rau cov cellular zog thiab txuas nrog lub luv luv ntawm lub cev lub neej [80,83,84] . Txawm hais tias qhov tseem ceeb ntawm qhov kev sib raug zoo no, qhov tseeb biochemical mechanisms hauv qab lipofuscin tsub zuj zuj, nrog rau nws qhov cuam tshuam ntawm kev ua haujlwm ntawm tes, tseem tsis to taub.

Lipofuscin feem ntau pom muaj nyob rau hauv lysosomes tab sis kuj muaj tsawg dua nyob rau hauv cytosol ntawm cov hnub nyoog hlwb [85,86]. Nws nthuav tawm dav spectrum ntawm nws pib-fluorescence nrog cov xim daj-xim av [80,87], tab sis nws cov qauv thiab cov ntsiab lus tseem tsis zoo. Txawm hais tias nws muaj pes tsawg leeg sib txawv hauv ntau hom ntawm tes, nws tau pom tias feem ntau yog tsim los ntawm oxidized proteins thiab lipids (xws li triglycerides, fatty acids dawb, roj cholesterol, thiab lipoproteins) thiab tsawg tsawg ntawm carbohydrates thiab nucleotide fragments txuas rau ib leeg. covalent bonds ntawm ntau hom [84]suab puam hyacinthQhov txuas ntawm hlau rau ntawm nws qhov chaw kuj yog ib qho kev sib txawv ntawm lipofuscin [88,89].

Txawm hais tias qhov kawg tshwm sim ntawm lipofuscin tsub zuj zuj ntawm cellular functions tseem tsis meej, nws tau pom tias nws tuaj yeem cuam tshuam cov haujlwm ntawm ob qho tib si proteasomal thiab lysosomal protein degradation systems. Tsis tas li ntawd, muaj kev sim ua pov thawj qhia tias nws tuaj yeem ua rau muaj kev cuam tshuam ntxiv ntawm cov dawb radicals los ntawm redox-active hlau ions (labile hlau) txuas rau nws qhov chaw [89].

3.4.Lipofuscin ua cov khoom siv oxidized tshaj hauv cov cell raug Oxidative Stress

Txij li thaum lipofuscin muaj cov oxidized sib sau ua ke feem ntau yog tsim los ntawm covalently cross-linked proteins thiab lipids|90], nws yog ib qho tsim nyog los postulate tias labile hlau - muaj peev xwm catalyze tiam ntawm tsis tshua muaj reactive dawb radicals - yog koom tes nyob rau hauv txoj kev ntawm nws tsim. [91]. Cov ntaub ntawv pov thawj tau los ntawm kev sim tshuab feem ntau tau pom tias qhov kis ntawm cov hlwb kom nce qib ntawm oxidative kev nyuaj siab invariably ua rau txoj kev loj hlob ntawm ib tug muaj zog senescent-phenotype nyob rau hauv ntau hom cell, nrog rau qhov sib npaug acceleration ntawm intracellular tsim thiab tsub zuj zuj ntawm lipofuscin-zoo li cov ntaub ntawv. [87,89,92,93]. Cov kauj ruam txuas ntxiv ua rau kev tsim lipofuscin yog qhia hauv daim duab 2.

Raws li tau hais los saum toj no, lub xub ntiag ntawm labile hlau yuav tsum muaj rau lub cim ntawm reactive ROS (HO degree thiab RO *), uas yog lub luag hauj lwm rau oxidation thiab over-oxidation ntawm cellular macromolecules (Daim duab 2A, B). Ntxiv mus, oxidatively modified macromolecules tuaj yeem cuam tshuam cov protein degradation thiab kho cell, yog li ua kom yooj yim rau lub voj voog ntawm kev nce oxidation (Daim duab 2C). Kev sib xyaw ua ke ntawm cov oxidized ntau dhau, uas tsis yog-degradable cellular Cheebtsam rau hauv cov hlwb ua rau lipofuscin tsim (Daim duab 2D), uas yog npaj los pab txhawb kev laus ntawm tes (Daim duab 2E).

Daim duab 2. Schematic sawv cev ntawm cov kauj ruam ua ntu zus uas ua rau lipofuscin tsim thiab pab txhawb kev laus ntawm tes. Nco ntsoov tias Fe2 ntxiv yog qhov yuav tsum tau muaj rau lub cim ntawm cov reactive ROS (HO thiab RO), uas yog lub luag hauj lwm rau oxidation thiab tshaj-oxidation ntawm cellular macromolecules (A, B). Tshaj-oxidized macromolecules tuaj yeem cuam tshuam cov txheej txheem kho cellular (tshwj xeeb tshaj yog 20S proteasome), yog li ua kom yooj yim rau lub voj voog tsis zoo ntawm kev nce qib oxidation (C). Oxidatively hloov kho, tsis-degradable cellular Cheebtsam yog maj mam sau mus rau hauv cov hlwb raws li covalently interconnected aggregates nyob rau hauv daim ntawv ntawm lipofuscin (D), qhov tseeb uas yog npaj los cuam tshuam cov txheej txheem ntawm cell aging (E). Arrowheads thiab flatheads qhia qhov induction thiab inhibition, feem, ntawm cov txheej txheem.Flavonoid extraction method pdfInterestingly, Marzabadi li al.[94] pom tias lipofuscin tsub zuj zuj tau tiv thaiv nyob rau hauv cov hlau-depleted hlwb los ntawm kev siv cov hlau-chelating tshuaj desferrioxamine, qhia tias lipofuscin tsim yuav tsum heev reactive dawb radicals xws li HO degree thiab RO degree (Daim duab 2). Obviously, cov reactive radicals tuaj yeem pib cov tshuaj tiv thaiv kab mob uas ua rau cov lipid peroxidation rhuav tshem cov khoom, uas provoke tsim cov undegradable, tsis tshwj xeeb cross-linking ntawm cellular Cheebtsam.

Ua ke, cov txiaj ntsig saum toj no qhia tau hais tias qhov sib npaug sib luag ntawm cov qib intracellular peroxide thiab cov muaj labile hlau txiav txim siab qhov tshwm sim ntawm ntau yam tshuaj lom uas ua rau cov lipofuscin tsub zuj zuj, nrog rau induction ntawm cellular senescence thiab cell tuag los ntawm ob qho tib si apoptosis. los yog necrosis [29,95].

Lub induction ntawm cellular senescence los ntawm peroxides tuaj yeem ua tiav los ntawm ntau txoj hauv kev. Piv txwv li, tus nqi nruab nrab ntawm H, O, cov hlwb tuaj yeem cuam tshuam ncaj qha rau kev ua haujlwm ntawm MAP kinases tshwj xeeb thiab kev hloov pauv ntawm cov teeb liab senescence, uas ua rau lub zog ntawm p16INK4aINK4A axis thiab ua rau induction ntawm cell senescence [64,65,92. , 96] ib. Ntawm qhov tod tes, siab dua HO, ntau dua, ib yam li cov ntaub ntawv hauv cov cheeb tsam uas muaj zog heev uas nyiam cov phagocytes, tuaj yeem ua rau cov hlau-catalyzed oxidation ntawm DNA uas tom qab ua rau muaj kev cuam tshuam rau cov teeb meem. Nyob rau hauv ob qho tib si, qhov sib npaug tsim thiab tsub zuj zuj ntawm oxidatively hloov cellular macro-molecules sawv cev rau qhov tshwm sim. Nws yuav tsum raug sau tseg, txawm li cas los xij, cov lus nug ntawm seb qhov lipofuscin tsub zuj zuj yog qhov ua rau muaj qhov tshwm sim ntawm cellular senescence los yog qhov tshwm sim ntawm nws tseem yog ib qho tseem ceeb tab sis tsis muaj lus nug.

3.5. Intracellular Iron Homeostasis thiab Lipofuscin Tsim

Raws li tau hais los saum toj no, hlau yog ib qho tseem ceeb rau cov hlwb thiab cov kab mob vim nws koom nrog ntau yam tshuaj lom neeg cov tshuaj lom neeg uas txhawb nqa cov haujlwm yooj yim xws li kev thauj oxygen, kev ua pa ntawm tes, thiab DNA synthesis thiab kho. Txawm li cas los xij, hlau kuj tuaj yeem koom nrog hauv cov tshuaj tiv thaiv uas ua rau muaj kev puas tsuaj ntawm cov dawb radicals, hu ua Fenton-types. Txhawm rau txo cov hlau toxicity, cov tsiaj nyeg tsim cov txheej txheem uas tswj hwm nws qhov muaj 35,37I. Txawm li cas los xij, ib qho me me thiab hloov kho kom zoo ntawm redox-active hlau feem ntau hu ua "labile iron" yog ib txwm muaj, txawm tias sawv cev ntawm cov hlau tiag tiag ntawm cov cell sib txawv [6,38]. Yog li, labile hlau sawv cev rau lub cev tsis muaj zog uas tuaj yeem teb rau ntau yam stimuli los ntawm kev hloov nws qib, aiming kom sib npaug ntawm kev tiv thaiv ntawm cell puas thiab lav cell xav tau.

Nyob rau hauv tej yam kev mob ntawm ib ntus elevated concentrations ntawm peroxides (conventionally hu ua oxidative kev nyuaj siab), labile hlau tuaj yeem kho cov xwm txheej hauv qab no: (a) pib thiab nthuav tawm ntawm lipid peroxidation chain reactions, (b) protein oxidation thiab cross-linking, (c) induction ntawm DNA kev puas tsuaj xws li ib leeg thiab ob-strand so, thiab (d) ua rau muaj ntau yam nyuaj redox signaling pathways [10,29,43]. Tag nrho cov hlau-catalyzed cov teebmeem no tuaj yeem ua rau cellular senescence nrog rau kev tsim thiab tsub zuj zuj ntawm lipofuscin.

Nws tsim nyog hais txog qhov no uas peb twb tau ua pov thawj hauv cov ntawv tshaj tawm txog kev tiv thaiv H2O2-induced DNA puas thiab apoptosis nyob rau hauv cov hlwb nrog depleted qib ntawm la-bile hlau los ntawm kev siv ntau yam hlau-chelating agents [11 29, 42, 43, 97] ib. Hauv cov kev tshawb nrhiav no, peb tau siv qhov kev sim hauv vitro cell culture-raws li kev sim uas sib txawv ntawm tib neeg lub hlwb tau raug oxidative kev nyuaj siab nyob rau hauv daim ntawv ntawm H, thiab O thiab kev puas tsuaj nyob rau hauv nuclear DNA tau kwv yees ntau npaum li cas los ntawm kev siv comet assay, a rhiab txoj kev uas kuaj DNA ib leeg-strand tawg tsim nyob rau hauv ib tug neeg lub hlwb. Txaus siab rau, ua ntej incubation ntawm hlwb nrog ib tug series ntawm paub muaj zog antioxidants xws li ascorbic acid, o -tocopherol, Trolox, N-acetylcysteine, thiab o -lipoic acid ua ntej raug H, O, tsis muaj kev tiv thaiv [7 ]. Txij li thaum lub peev xwm ntawm cov neeg ua haujlwm no los tawm tsam cov dawb radicals tau tsim nyob rau hauv ntau qhov kev tshawb fawb hauv vitro, cov txiaj ntsig tsis zoo uas tau hais los saum toj no tau raug ntaus nqi rau qhov tsis muaj peev xwm ntawm cov neeg ua haujlwm no txhawm rau txhawm rau tshem tawm cov dawb radicals reactive hauv lub hlwb.

Ib qho tseem ceeb ntawm cov hlau-catalyzed cross-linking tej zaum yuav yog qhov yooj yim ntawm covalent khi ntawm oxidized soluble cell Cheebtsam rau cov kab mob lom. Xws li ib qho kev tshwm sim yuav tsum hamper lub exocytosis ntawm daim nyias nyias cov ntaub ntawv, ua rau nws mus tas li intracellular tsub zuj zuj. Nws yog qhov tsim nyog los xav tias lysosomal daim nyias nyias yuav tsum yog lub hom phiaj tseem ceeb hauv qhov no vim lawv qhov sib thooj rau qhov chaw ntawm lipofuscin tsim. Tseeb, lipofuscin feem ntau tau kuaj pom hauv cov hlwb uas tau txais los ntawm lysosomal membrane ntu [98].

Muab qhov tseem ceeb ntawm muaj labile hlau rau kev tsim thiab tsub zuj zuj ntawm lipofuscin, cov kev cai ntawm nws intracellular homeostasis zoo li tseem ceeb tshaj plaws txog cov txheej txheem kev laus. Kev txaus siab ntawm labile hlau muaj raws li qhov tseem ceeb tshaj plaws uas txiav txim siab oxidation thiab dhau-oxidation ntawm cov khoom siv ntawm tes thiab kev sib sau ntawm lipofuscin hauv cov hlwb tuaj yeem qhib txoj hauv kev rau kev txhim kho cov tswv yim tshiab, aiming los cuam tshuam nrog thiab hloov kho lub moos lom neeg ntawm lub cev. kev laus.

3.6. Inactivation ntawm Kho Systems los ntawm Over-Oxidized Cell Cheebtsam

Cov tswv yim ntawm tes rau kev kho cov khoom sib txawv oxidized ntawm tes sib txawv, nyob ntawm seb qhov xwm txheej ntawm cov khoom. Piv txwv li, oxidized DNA nucleotides raug tshem tawm thiab hloov los ntawm ib txwm ua los ntawm cov txheej txheem hu ua "nucleotide excision kho, thaum oxidized proteins raug degraded rau ib qho amino acids uas tuaj yeem rov qab siv tau rau cov protein synthesis tshiab.

Muaj ntau ntau yam protein degradation systems: nyob rau hauv cov hlwb, muaj lysosomal enzymes; nyob rau hauv cytosol, muaj proteasomes thiab calpains; hauv mitochondrial matrix, muaj cov Lon proteases (ATP-dependent proteases); thiab hauv mitochondrial membrane, muaj triple-A proteases [78, 98-100]. Tsis tas li ntawd, ntxiv rau oxidatively modified proteins, lysosomes kuj tseem tuaj yeem nqa thiab degrade txawm tias hnyav organelles xws li mitochondria lossis ib feem ntawm cytoplasm hauv cov txheej txheem hu ua chaperon-mediated autophagy, macro-autophagy, thiab micro-autophagy [82,101].

Txawm tias muaj tseeb hais tias feem ntau oxidatively hloov biomolecules thiab organelles yuav zoo kho los yog degraded los ntawm cov hlwb, nws tau raug pom tias ib txhia ntawm lawv txuam nrog lub hnub nyoog, qhia hais tias lub inherent tsis txaus ntawm cellular turnover mechanisms.flavonoidsNws tau raug pom tias twb tau oxidized cell Cheebtsam tuaj yeem hloov kho oxidative ntxiv, ua rau cov khoom tsim tawm uas cell degradation systems tsis muaj peev xwm tiv nrog [34,84]. Lub tsub zuj zuj ntawm xws li tsis-degradable conglomerates yuav, nyob rau hauv lem, hamper lub functionality ntawm degradation systems, yog li aggravating teebmeem thiab ua rau ib tug vicious voj voog, raws li schematically illustrated nyob rau hauv daim duab 2.

Nyob rau hauv cov xwm txheej ntawm oxidative kev nyuaj siab ntau ntxiv thiab kav ntev, kev kho lub peev xwm ntawm cov hlwb feem ntau thiab cov protein degradation muaj peev xwm, tshwj xeeb tshaj yog, tuaj yeem ncav cuag qib saturation, yog li ua rau muaj cov oxidized tsis tu ncua. Qhov xwm txheej no ua rau muaj qhov tshwm sim ntxiv ntawm oxidation ntxiv ntawm cov khoom oxidized uas twb muaj lawm thiab tsim cov kev hloov kho oxidative ntxiv thiab muaj txiaj ntsig ntau dua, suav nrog kev sib koom ua ke thiab kev sib koom ua ke ntawm cov khoom sib txuas. Tag nrho cov complexity ntawm cov qauv tsim tshuaj ntau tshaj qhov degradation peev xwm ntawm cellular proteolytic systems (tshwj xeeb tshaj yog 20S proteasome), ua rau gradual tsub zuj zuj ntawm over-oxidized undegradable "khoom noj khoom haus" cov ntaub ntawv nyob rau hauv lub hlwb, feem ntau mus rau hauv lysosomes [82,102].

Kev sib xyaw ua ke, cov khoom sib xyaw ua ke ntawm cov khoom siv ntau tshaj oxidized hauv cov hlwb ua rau muaj qhov tshwm sim ntawm cov oxidation ntxiv ntawm cov khoom siv cell uas twb muaj lawm oxidized nyob rau lub sijhawm, yog li pab txhawb kev pib ntawm lub voj voog ntawm oxidation, dhau-oxidation, thiab tsub zuj zuj; Tag nrho cov no thaum kawg ua rau muaj kev cuam tshuam loj ntawm kev ua haujlwm ntawm tes, raws li pom tseeb hauv kev laus thiab senescence.

3.7. Lysosomes ua qhov chaw tseem ceeb ntawm Lipofuscin tsim

Raws li qhov tshwm sim ntawm ib txwm autophagic degradation, lub lysosomal compartment yog nplua nuj nyob rau hauv labile hlau vim ntau autophagocytized macromolecules thiab organelles muaj hlau. Kev sib xyaw ua ke ntawm redox-active hlau thiab pH qis hauv lysosomes pab txhawb kev tsim cov radicals tsis tshua muaj zog los ntawm cov peroxides tsis tshua muaj zog ntawm Fenton cov tshuaj tiv thaiv. Yog li ntawd, cov organelle no yog rhiab heev rau me ntsis oxidative kev nyuaj siab uas hlwb ib txwm muaj thaum lub sij hawm hloov pauv ntawm intracellular H, O, khov kho-xeev. Lub generated HO·s instantly induce chain oxidation ntawm lysosomal Cheebtsam, xws li cov proteins thiab membrane lipids, ua rau tsim cov lipofuscin-zoo li cov ntaub ntawv uas muaj tseeb tau pom tias yuav tau sau nyob rau hauv lysosomes.

Nyob rau hauv cov xwm txheej hnyav thiab ntev oxidative kev nyuaj siab, lub simultaneous muaj H2O2 thiab labile hlau induces ntxiv oxidation nyob rau sab saum toj ntawm twb oxidized au-to-phagocytosed biomolecules, ua rau ntau tshaj oxidized khoom uas yog cross-linked nrog ntau covalent bonds. .hesperidin sivCov khoom no, ntxiv rau kev tiv thaiv kev degradation, tuaj yeem cuam tshuam cov cell reparation systems, raws li tau raug pov thawj hauv proteasomes [85,102]. Cov lus pom zoo no tau txais kev txhawb nqa los ntawm kev soj ntsuam tias kev sib xyaw ntawm oxidative kev nyuaj siab nrog inhibition ntawm lysosomal proteases ncua kev degradation ntawm nws pib-phagocytosed macromolecules thiab muab sij hawm ntau rau lawv oxidation, dramatically accelerating lipofuscin tsim nyob rau hauv kab lis kev cai hlwb [7]. Lipofuscin nws tus kheej tuaj yeem tsim los ntawm ntau hom pib-lossis hetero-phagocytosed khoom. Nyob rau hauv ntau lub hlwb, tshwj xeeb tshaj yog nyob rau hauv aerobic sawv daws yuav xws li mob myocytes thiab neurons, auto-phagocytosed mitochondria yog ib feem ntawm intra-lysosomal undegradable khoom. Cov pov thawj muaj zog rau lub hauv paus chiv keeb mitochondrial ntawm ib feem tseem ceeb ntawm lipofuscin lub cev sawv cev rau kev soj ntsuam tias muaj ntau ATP synthase subunits muaj nyob rau hauv lipofuscin-loaded hlwb [103]. Txawm li cas los xij, hauv cov kab mob scavenger nrog cov nquag phagocytosis xws li macrophages, microglial hlwb, thiab retinal pigment epithelial hlwb, ib feem ntawm lawv cov ntsiab lus lipofuscin kuj tuaj yeem muab tau.

3.8. Kev kuaj pom ntawm Senescent Cells

Kev lees paub ntawm cov hlwb senescent yog qhov teeb meem tseem ceeb uas muab cov pov thawj ntxiv ntawm lub luag haujlwm ntawm senescence hauv tib neeg pathologies [56,104]. Tsis tas li ntawd, kev nthuav dav sai ntawm cov kws khomob yuav tsum tau kuaj pom tseeb ntawm cov hlwb senescent [105]. Ntau cov cim ntsuas pom cov sensors ntawm cellular senescence tau nthuav tawm hauv Table 1. Cov kev tshawb pom tsis ntev los no tau qhia txog qhov cuam tshuam ntawm kev laus hauv COVID-19, ua pov thawj rau kev siv tshuaj khomob rau kev kho lossis tiv thaiv COVID-19 cov neeg mob [106.

Kev sib sau ntawm lipofuscin tshiab tuaj yeem kuaj pom thiab ntsuas tau los ntawm kev siv electron, confocal, thiab fluorescence microscopy, nrog rau cov cytometry ntws [108,109]. Ntxiv mus, lipofuscin tuaj yeem kuaj pom ntawm lub hauv paus ntawm nws cov autofluorescence ua ke nrog ntau cov txheej txheem histochemical thiab cytochemical [68,87,110,111]. Tshwj xeeb tshaj yog, GL13, biotinylated Sudan Black-B (SBB) tshuaj analogues uas yog muag raws li "SenTraGorTM," cuam tshuam nrog lipofuscin thiab tso cai rau kev txheeb xyuas qhov tseeb ntawm senescent hlwb hauv vitro thiab ex vivo los ntawm kev siv cov tshuaj tiv thaiv kab mob nruab nrab ntawm kev kuaj pom [ 56, 107, 110] ib. Ua haujlwm qhov kev ntsuam xyuas no, qhov kev txiav txim siab ntau ntawm cov kua dej los yog rho tawm cov lipofuscin hauv cov kab lis kev cai ntawm tes supernatants, cov kua hauv lub cev, thiab cov ntaub so ntswg homogenates kuj ua tiav [112]. Qhov sib lawv liag ntawm cov xwm txheej ua rau lipofuscin tsub zuj zuj thaum lub sij hawm senescence thiab nws kev cuam tshuam nrog lipofuscin yog schematically nthuav tawm hauv daim duab 3A. Cov duab sawv cev ntawm Li-Fraumeni-p21WAF1/Cip1 Tet-OFF thiab ON(senescent) hlwb, stained nrog SenlraGor, tau nthuav tawm hauv daim duab 3B. Lub teeb liab cytoplasmic muaj zog yog pom tseeb hauv cov hlwb senescent ( duab sab xis), thaum tsis muaj cov hlwb induced tsis zoo (sab laug duab).

Kev txhim kho ntawm kev siv theranostic raws li nanotechnology yuav tso cai rau qhov tseeb lub hom phiaj ntawm senescent hlwb [113-115]. Daim phiajcim ntawm cov hlwb senescent hauv vivo tseem yog qhov nyuaj heev. Nyob rau hauv cov ntsiab lus no, cov tshiab GL13 compound tej zaum yuav enriched los ntawm kev koom ua ke ntawm quantum dots los yog lwm yam tsim nyog nano-carriers thiab ib tug hydrophilic hull rau encapsulate tag nrho cov system, rendering GL13 ib tug pheej neeg sib tw rau molecular imaging nyob rau hauv vivo [114].

Daim duab 3. (A)SenTraGorTM tshwj xeeb reacts tawm tsam lipofuscin, uas tsis yog-degradable byproduct ntawm cellular senescence, tso cai rau kom paub tseeb tseeb ntawm senescent hlwb nyob rau hauv vitro thiab ex vivo los ntawm kev siv ib tug antibody-mediated nrhiav kom tau txoj kev. (B) SenTraGor staining ntawm Li-Fraumeni-p21WAF1/Cip1 Tet-OFF (sab laug duab) thiab ON hlwb ( duab sab xis); Thawj qhov loj: × 200. 4. Kev Noj Qab Haus Huv Bioactive Compounds thiab Oxidative Stress

Ntau qhov kev tshawb fawb txog kev kis mob kis thoob qhov txhia chaw tau ua thaum lub sijhawm thib ob ntawm lub xyoo pua dhau los tau cuam tshuam txog kev noj zaub mov Mediterranean ib txwm (cov khoom noj uas muaj nyob rau sab qaum teb ntug dej hiav txwv Mediterranean) nrog qis qis ntawm qee cov kab mob ntev thiab txo qis kev mob thiab kev pheej hmoo tuag [{{0 }}]. Yog li ntawd, kev tshawb fawb hnyav tau ua tiav los txheeb xyuas cov neeg ua haujlwm noj zaub mov Mediterranean uas muaj peev xwm tiv thaiv lossis txo qis cov teebmeem ntawm oxidative kev nyuaj siab thiab txiav txim siab lawv hom molecular ntawm kev ua.

4.1.Dietary Bioactive Compounds: Dawb Radical Scavenging Antioxidants lossis Tsis muaj Hlau Chelators?

Kev noj zaub mov Mediterranean ib txwm muaj kev noj qab haus huv ntau ntawm cov roj txiv roj thiab cov zaub mov cog xws li txiv hmab txiv ntoo, zaub, cereals, thiab legumes; noj nruab nrab ntawm cov ntses, khoom noj siv mis, thiab cawv; thiab noj tsawg ntawm cov khoom noj nqaij [119]. Nws cov txiaj ntsig kev noj qab haus huv tau nquag raug ntaus nqi rau qhov ntau ntawm cov tshuaj tua kab mob ntawm cov dawb radical scavenger hom, uas muaj ntau nyob rau hauv cov khoom noj ntawm cov khoom noj no. Nws feem ntau xav tias cov dawb radical scavengers tuaj yeem cuam tshuam nrog thiab tshem tawm cov dawb radicals, yog li tiv thaiv oxidation hauv lub cev thiab ua rau ncua lossis tseem tiv thaiv qhov tshwm sim ntawm ntau yam kab mob, suav nrog kev laus [120-123].

Txawm li cas los xij, cov txiaj ntsig ntawm qhov kev sim loj tshaj plaws ntawm kev siv tshuaj tua kab mob antioxidant tau ua kom deb li deb tau ua tsis tau zoo los qhia kev tiv thaiv kev loj hlob ntawm cov kab mob ntev [124-137]. Tsis tas li ntawd, kev txhawj xeeb tau tshwm sim txog kev nyab xeeb ntawm kev noj tshuaj ntau ntxiv ntawm cov tshuaj antioxidants vim tias kev sib txuas nrog kev pheej hmoo ntawm kev noj qab haus huv tau pom nyob rau qee qhov xwm txheej [138,139]. Qhov kev ua tsis tiav no tuaj yeem piav qhia los ntawm qhov tseeb tias cov dawb radicals xws li HO degree thiab RO degree yog qhov muaj zog heev, tam sim ntawd thiab tsis tshwj xeeb tawm tsam thiab oxidizing txhua pawg tshuaj muaj nyob rau hauv ib puag ncig ntawm lawv tiam [140]. Yog li, thaum tsim tawm hauv cov hlwb, nws yog qhov ua tau tsis yooj yim rau cov khoom siv sab nraud uas tau txais dawb radical scavenger los ua rau lawv tsis zoo. Nws yuav tsum tau hais txog ntawm no tias tib txoj hauv kev los tiv thaiv cov khoom ntawm tes los ntawm oxidation thiab kev puas tsuaj nyob rau hauv oxidative kev nyuaj siab yog los tiv thaiv cov tiam ntawm xws li reactive dawb radicals. Lwm lub tswv yim ua kom tsis txhob muaj oxidation ntawm cov khoom siv roj ntsha tseem ceeb xws li DNA thiab cov proteins nyob rau hauv cov xwm txheej zoo li no tuaj yeem yog los tswj qhov chaw ntawm lawv qhov tsim los ntawm kev siv cov hlau chelating agents. Raws li tau hais hauv qab no, kev noj zaub mov feem ntau thiab Mediterranean noj zaub mov, tshwj xeeb, muaj ntau ntau ntawm cov hlau tsis muaj zog chelators, (Daim duab 4), uas, thaum muaj peev xwm dhau los ntawm cov cell membrane, tuaj yeem tshem tawm cov hlau tsis muaj zog los ntawm cov macromolecules tseem ceeb, yog li tiv thaiv lawv los ntawm qhov tsis xav tau oxidation txawm tias lawv inhibit Fenton cov tshuaj tiv thaiv los yog tsis

Daim duab 4. Schematic kev nthuav qhia qhia tau hais tias cov nroj tsuag-derived cov zaub mov ntawm Mediterranean noj zaub mov muaj ntau ntxiv ntawm cov hlau-binding tebchaw muaj peev xwm chelate intracellular labile hlau thiab tiv thaiv cov tiam ntawm heev reactive dawb radicals uas yog lub luag hauj lwm rau lub unregulated oxidation ntawm cell constituents. Cov khoom noj ntawm Mediterranean noj zaub mov muaj ntau lub tebchaw, suav nrog phenolic alcohols, phenolic acids, thiab flavonoids, uas tau rov hais dua los ua cov dawb radical scavenging antioxidants. Ib tug xov tooj ntawm cov tebchaw no tau raug tshuaj xyuas los ntawm peb pab pawg tshawb fawb, thiab peb tau pom muaj kev sib raug zoo ntawm kev tiv thaiv lub peev xwm ntawm txhua qhov sib xyaw thiab nws lub peev xwm los chelate intracellular labile hlau tab sis tsis nrog lawv lub peev xwm los tshem tawm cov dawb radicals hauv vitro [8,9, 12]. Ib qho cuab yeej tsim nyog ntxiv ntawm cov tebchaw uas yuav tsum tau siv lawv lub peev xwm tiv thaiv, yog lawv lub peev xwm ncav cuag lub cell sab hauv los ntawm diffusion lossis lwm yam kev thauj mus los ntawm cov plasma membrane [11,42,141]. Raws li cov kev soj ntsuam no, peb tau npaj siab tias bioactive compounds muaj nyob rau hauv Mediterranean noj zaub mov muab lawv cytoprotective teebmeem los ntawm detaching intracellular labile hlau los ntawm cov tseem ceeb cellular constituents, yog li txo lawv undesirable oxidation.

4.2.Puas Dietary Iron-Chelating Agents tiv thaiv lipofuscin tsim?

Raws li cov lus hais saum toj no, nws tsim nyog xav tias cov tshuaj bioactive hlau-chelates tam sim no nyob rau hauv cov zaub mov Mediterranean tuaj yeem sawv cev rau cov ntsiab lus tseem ceeb uas yog lub luag haujlwm rau kev tiv thaiv ntawm lipofuscin tsim thiab, yog li ntawd, txoj kev laus feem ntau. Raws li peb paub, kev siv zog ua haujlwm txhawm rau sim sim qhov kev xav tseem ceeb no tseem tsis tau ua tiav.

Ntau tus lej ntawm cov hlau-chelating molecules nrog cov qauv tshuaj sib txawv thiab cov yam ntxwv muaj nyob hauv cov khoom noj Mediterranean. Piv txwv li, peb tau tshawb fawb ntau cov nroj tsuag uas muaj ntau cov polyphenols thiab tau tsim cov phenolic tebchaw nrog ib pawg ortho-dihydroxyl tiv thaiv oxidative kev nyuaj siab, thaum cov uas tsis muaj ib hydroxyl los yog muaj nyob rau hauv ib tug meta-los yog para-txoj hauj lwm yog tag nrho ineffective. [8, 10-12]. Cov kev soj ntsuam no tau tsa cov lus nug ntxiv ntawm seb cov hlau-chelates muaj nyob rau hauv cov khoom noj puas muaj peev xwm nkag mus rau ntau yam teeb meem kom ncav cuag sab hauv ntawm lub hom phiaj. Hauv qhov no, cov khoom noj tshwj xeeb tuaj yeem raug suav hais tias yog "cov tshuaj tiv thaiv tsis ncaj ncees" vim tias lawv tiv thaiv cov tiam ntawm cov dawb radicals es tsis ua kom detoxifying lawv tom qab lawv cov khoom siv intracellular.

Qee lub sij hawm, intracellular labile hlau ions tuaj yeem ua tiav tsis tiav nrog cov neeg ua haujlwm noj zaub mov vim lawv qhov qis qis thiab muaj kev cuam tshuam loj heev hauv lub cev, yog li tso cai rau kev koom tes ntawm cov hlau hauv cov tshuaj tiv thaiv redox. Txawm li cas los xij, tib cov neeg ua haujlwm feem ntau muaj ob txoj haujlwm vim tias lawv tuaj yeem muaj ob qho tib si hlau-binding thiab dawb radical-scavenging zog nyob rau hauv tib lub molecule. Yog li ntawd, cov khoom noj khoom haus tau los ntawm cov hlau chelators tuaj yeem ua haujlwm nyob rau hauv ob qho tib si: txawm tias txo qis oxidative kev ntxhov siab vim kev puas tsuaj ntawm tes los ntawm kev tshem tawm cov hlau nplaum labile ntawm cov cellular macromolecules tsis muaj zog thiab ua rau nws tsis ua haujlwm lossis los ntawm kev sib koom ua tsis tiav ntawm cov hlau, uas ua rau nws tshem tawm ntawm cov hlau. nws txoj haujlwm qub tab sis tso cai rau nws nyob twj ywm redox-active thiab muaj peev xwm oxidize cov khoom noj uas tau txais los ntawm hlau chelators.

5. Cov lus xaus

Ib qho ntawm cov ntsiab lus tseem ceeb tshaj plaws hauv thaj tsam ntawm kev laus hnub no yog qhov hu ua "dawb radical txoj kev xav ntawm kev laus." Raws li qhov kev xav no, kev laus ntawm lub cev yog tshwm sim los ntawm kev puas tsuaj oxidative cuam tshuam los ntawm cov dawb radicals uas feem ntau tshwm sim los ntawm qhov tshwm sim. ntawm aerobic metabolism. Lub cim tsis tu ncua ntawm xws li reactive radicals tsis tshua muaj tshwm sim ua rau maj mam tsim thiab tsub zuj zuj ntawm non-repairable aggregates ntawm puas cell constituents. Cov khoom siv tsis muaj tshuaj lom neeg no, uas feem ntau muaj cov proteins thiab lipids thiab uas ua rau daj-xim av fluorescence, hu ua "lipofuscin," ceroid," lossis "hnub nyoog pigment," thiab nws suav tias yog lub cim ntawm kev laus ntawm tes.

Lipofuscin feem ntau yog tsim los ntawm kev tswj tsis tau thiab tsis muaj kev hloov kho oxidative ntawm cellular macromolecules. Cells tau nruab nrog ntau qhov kev tiv thaiv kab ke los soj ntsuam thiab kho oxidized macromolecules. Txawm li cas los xij, thaum muaj kev ntxhov siab oxidative hnyav ntxiv rau lub sijhawm ntev, nws tsis tas yuav ua rau lub cim ntawm cov dawb radicals heev thiab nyob rau hauv cov khoom siv oxidation dhau lawm, yog li tsim cov khoom uas tsis tuaj yeem kho, degraded, lossis txawm tias exocytosed. los ntawm cov txheej txheem cellular. Tsis tas li ntawd, nws tau pom tias cov khoom siv oxidized ntau dhau tuaj yeem ua rau tsis muaj zog ntawm cov cellular tiv thaiv thiab cov txheej txheem rov ua haujlwm, yog li ua rau lub voj voog tsis zoo ntawm qhov nce ntawm lipofuscin tsub zuj zuj.

Txij li thaum cov dawb radicals muaj zog heev tuaj yeem tsim nyob rau hauv cov txheej txheem oxidation hlau-catalyzed (Fenton cov tshuaj tiv thaiv), muaj cov hlau labile sawv cev rau qhov tsim nyog ua ntej rau lipofuscin tsim thiab tsub zuj zuj hauv cov hlwb. Raws li cov kev txiav txim siab no, nws muaj peev xwm kwv yees tias kev tswj hwm zoo ntawm cellular hlau homeostasis nyob rau hauv dav dav thiab labile hlau faib, tshwj xeeb, tuaj yeem sawv cev rau tam sim no tsis txaus siab rau retard intracellular lipofuscin tsim thiab ua rau cellular aging (senescence). Peb tau pom yav dhau los tias ntau cov hlau-chelating phytonutrients uas muaj nyob rau hauv Mediterranean-hom kev noj zaub mov muaj peev xwm nkag mus rau cov kab mob lom thiab ncav cuag cov cell sab hauv [8,9,11,12]. Cov neeg ua haujlwm chelate intracellular labile hlau (tsis tas yuav muaj kev sib raug zoo siab) thiab yog li txiav txim siab nws qhov kev faib tawm thiab, yog li ntawd, qhov chaw ntawm oxidative kev nyuaj siab vim oxidation. Raws li lub tswv yim txheej txheem, kev noj haus phytochemicals yuav tsum sib txuas cov yam ntxwv hauv qab no hauv lawv cov qauv txhawm rau tiv thaiv cov hlwb hauv cov xwm txheej ntawm oxidative kev nyuaj siab: lawv yuav tsum muaj peev xwm (a) nkag mus rau cellular daim nyias nyias; (b) chelate cellular labile hlau; thiab (c) nyob rau hauv rooj plaub ntawm kev sib cuam tshuam ntawm cov hlau khi nrog peroxides (kev ua haujlwm tsis tiav ntawm nws qhov chaw sib koom ua ke), txhawm rau txhawm rau txhawm rau tsim cov hluav taws xob reactive radical.

Ua kom tiav cov lus xaus los ntawm qhov kev nthuav qhia saum toj no, cov lus hauv qab no tuaj yeem ua tau: (a) labile hlau sawv cev rau tus neeg sawv cev tseem ceeb uas yog lub luag haujlwm rau kev tsim cov dawb radicals uas muaj peev xwm oxidize cellular constituents nyob rau hauv tej yam kev mob ntawm oxidative kev nyuaj siab, (b ) oxidized thiab tshwj xeeb tshaj yog tshaj-oxidized cell Cheebtsam muaj xws li lub ntsiab lub cev ntawm lipofuscin uas yog tsim thiab sau nyob rau hauv lub hlwb nyob rau hauv cov xwm txheej no, (c) depletion ntawm intracellular labile hlau los ntawm hlau-chelating agents tiv thaiv oxidation ntawm cellular Cheebtsam, thiab ( d) Peb cov khoom noj thiab tshwj xeeb tshaj yog cov khoom noj Mediterranean muaj ntau ntau ntawm cov tebchaw uas muaj peev xwm hloov kho intracellular hlau faib.

Xav txog cov kev txiav txim siab saum toj no ua ke, nws tsim nyog xav tias qhov kev txheeb xyuas ntawm cov khoom noj khoom haus bioactive nrog cov khoom siv tau tso cai rau lawv siv los ua cov cuab yeej tshuaj rau kev tiv thaiv kev tiv thaiv hauv cov xwm txheej ntawm kev ntxhov siab oxidative hauv hlwb, cov ntaub so ntswg, thiab tag nrho cov kab mob. Lub tswv yim no tuaj yeem qhib txoj hauv kev tshiab rau kev txhim kho cov tswv yim txhawm rau txo qis cov tsos mob thiab kev loj hlob ntawm cov kab mob uas muaj hnub nyoog.

Kab lus no yog muab rho tawm los ntawm Antioxidants 2021, 10, 491. https://doi.org/10.3390/antiox10030491 https://www.mdpi.com/journal/antioxidants