Oxidative Stress Thiab Ischemia / Reperfusion Injury nyob rau hauv lub raum Transplantation: tsom rau Ferroptosis, Mitophagy Thiab Tshiab Antioxidants Ⅱ
Nov 13, 2023
4. Antioxidants thiab Ferroptosis / Mitophagy Regulators
Muaj ntau cov tshuaj pharmacological nroganti-oxidant muaj peev xwmtau raug npaj rau kev kho mob ntawm I / R raug mob, suav nrog rau cov hom phiaj ntawm cov teeb meem nuclear erythroid 2-txog yam 2 (Nrf2), hydrogen sulfide (H2S), mitochondria-targeting antioxidants, tshuaj muaj peev xwm tiv thaiv oxidant, thiab lwm yam tshwj xeeb ferroptosis. thiab mitophagy regulators (Table 1).
Table 1. Antioxidant molecules nrog lawv cov chav kawm, mechanism, thiab lub hom phiaj
4.1. Kev cai ntawm Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)
Lub nuclear erythroid 2-txog yam 2 (Nrf2) yog ib qho inducible transcription yam uas tswj cov kev qhia ntawm antioxidant teb cov ntsiab lus [66] (Daim duab 2).
Nyob rau hauv physiological tej yam kev mob, Nrf2 khi rau Kelch-zoo li ECH-koom nrog protein-1 (Keap1) nyob rau hauv lub cytoplasm thiab degraded los ntawm ubiquitin-proteasome txoj kev [67]. Nyob rau hauv oxidative kev nyuaj siab, Nrf2 dim los ntawm degradation ua tsaug rau qhov inactivation ntawm Keap1, cov ntaub ntawv dimers nrog ib tug tswv cuab ntawm cov me me Maf proteins nyob rau hauv nuclei, khi rau anti-oxidant teb cov ntsiab lus, thiab activates transcription ntawm antioxidant noob [68].
Thaum lub raum I/R, qhov hyperactivation ntawm Nrf2 los ntawm 1-[2-cyano-3-, 12-dioxolane- 1,9(11)-dien -28-oyl] imidazole (CDDO) nyob rau hauv thawj theem ntawm cov txheej txheem ischemia tiv thaiv kev loj hlob ntawm ROS-mediated tubular kev puas tsuaj los ntawm inducing cov kev qhia ntawm noob koom tes nyob rau hauv anti-oxidant teb [NADPH: quinone acceptor oxidoreductase 1 (Nqo1) , Sulfiredoxin-1 (Srxn1) thiab Thioredoxin Reductase 1 (Txnrd1)], glutathione metabolism [Glutamate-Cysteine Ligase Modifier Subunit (Gclm) thiab Glutathione S-Transferase Mu 1 ({Gstm1)], thiab NADPH synthe 22}}Phosphate Dehydrogenase (G6pd) thiab Phosphogluconate Dehydrogenase (Pgd)] [69].
Daim duab 2. Mechanism ntawm Nrf2 kev cai hauv kev kho mob raum I/R. Nyob rau hauv physiological tej yam kev mob, Nrf2 khi rau Kelch-zoo li ECH-koom nrog protein-1 (Keap1) nyob rau hauv lub cytoplasm thiab degraded los ntawm ubiquitin-proteasome txoj kev. Thaum lub raum I / R lub hyperactivation ntawm Nrf2 los ntawm CDDO, H2S, thiab dej-soluble H2S tus neeg pub dawb (xws li GYY4137) ua rau muaj kev hloov pauv ntawm Nrf2 uas khi rau cov lus teb antioxidant thiab ua rau kev hloov pauv ntawm cov noob encoding proteins koom nrog hauv cov txheej txheem antioxidant thiab hlau metabolism yog li tiv thaiv ROS-mediated tubular puas thiab ferroptosis cascade
NYEM QHOV NO TUAJ SAIB HNUB NYOOG CISTANCHE FOR KIDNEY
Nrf2 tseem tswj cov kev qhia ntawm cov noob encoding rau cov proteins mediating hlau metabolism thiab tuaj yeem tiv thaiv ferroptosis cascade, xws li ferritin lub teeb thiab cov saw hnyav (FTL/FTH1), ferroportin (SLC40A1) [70,71], GPX4, thiab HO{{7 } }, los ntawm qhov uas ferroptosis yog inhibited thiab I / R-koom haum raum raug mob alleviated (7273]. Contrarily, silencing Nrf2 nyob rau hauv cov nas raug mob I / R, ua rau lub raum tsis ua hauj lwm thiab elevated histological tubular kev puas tsuaj, nce lub raum vascular permeability oxidative kev nyuaj siab, thiab apoptosis piv rau cov nas qus [74-76].
4.2. Antioxidant Effects ntawm Hydrogen Sulfide (H2S)
Hydrogen sulfide (1S) yog ib qho membrane-permeable, gaseous mediator uas inhibits oxidative puas tsuaj los ntawm kev tshem tawm dawb radicals thiab ROS los ntawm kev nce qib ntawm GSHand thioredoxin thiab ua kom Nrf2 signaling los ntawm inactivation ntawm Keap1 (77,78). Ntau qhov kev tshawb fawb tau tshaj tawm txog kev tiv thaiv ntawm cov ntaub ntawv soluble ntawm HS (xws li sodium hydrosulfide lossis sodium sulfide) hauv cov qauv tsiaj ntawml/R raug mob (79-84] (Table 2)
Thaum lub raum I / R raug mob, qhov kev qhia ntawm enzyme cystathionine gamma-lyase uas catalyzes H2S tsim yog nce-tswj thiab yog li, H2S ntau lawm, nrog rau nws cov plasmatic concentration, nce [80]. Qhov no tuaj yeem sawv cev rau kev tiv thaiv lub raum tiv thaiv I / R. Qhov tseeb, kev tswj hwm ntawm exogenous NaHS (15 min ua ntej ischemia thiab 5 min ua ntej reperfusion) tiv thaiv I / R-induced activation ntawm caspase-3 nrog rau kev poob qis hauv kev qhia ntawm apoptotic markers Bid thiab Bcl{ {9}} [79] nrog kev ua haujlwm zoo thiab cov teebmeem histological.
Lwm qhov kev tiv thaiv kev sib kho los ntawm H2S yog raws li nws lub peev xwm los ntxias hypometabolism (50% txo qis hauv oxygen noj thiab 60% hauv cov pa roj carbon dioxide tawm) [85]. Qhov kev thov rau O2 txo qis rau qhov uas H2S-kho nas tuaj yeem muaj sia nyob hauv 5% O2 rau ntau dua 6 h [86].
Hauv tus qauv nas ntawm lub raum I / R raug mob, H2S tau tswj hwm ua ntej qhov kev thuam ntawm ischemic yuav khaws lub raum ua haujlwm, tiv thaiv apoptosis, thiab txwv tsis pub cov leukocytes thiab granulocytes nkag mus rau hauv lub raum interstitium [82]. Piv txwv li, kev kho mob tom qab ischemic nrog H2S yuav tsis muaj kev tiv thaiv. Cov txiaj ntsig no tau pom tias qhov txo qis hauv O2 xav tau thaum lub sijhawm hypoxia tiv thaiv kev ua kom tsis zoo ntawm txoj kev cuam tshuam nrog I / R [82].
Raws li cov kev tshawb pom no, Han et al. ua qauv qhia, hauv tus qauv ischemic raum nas, muaj peev xwm ntawm NaHS kev kho mob txhawm rau txhawm rau ua kom rov tsim dua cov hlwb puas los ntawm kev ua kom muaj zog.anti-oxidant cuam tshuam [83].
Tsis ntev los no Zhao et al. kuj pom tau hais tias ib tug dej-soluble H2S pub (GYY4137) muaj peev xwm txo tau qhov deterioration ntawm lub raum muaj nuj nqi thiab morphology nyob rau hauv lub raum I / R qauv los ntawm kev ua kom lub nuclear localization ntawm Nrf2 [84].
Cov kev tshawb pom no qhia tias H2S-tsim system tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev rov qab los ntawmmob raum raug mobthiabtiv thaiv kev loj hlob mus rau mob raum mob.
4.3. Mitochondria-Targeting Antioxidants
Feem ntau siv cov tshuaj antioxidants tuaj yeem ua tsis tau zoo hauv kev txwv mitochondrial ROS ntau lawm, vim lawv tsis tshua nkag mus rau mitochondria sab hauv. Txhawm rau kov yeej cov kev txwv no, mitochondria-targeting anti-oxidants tau tsim los muab lawv xa mus rau mitochondrion sab hauv [87]. Cov molecules no tau siv ntau yam kev tshawb fawb ua ntej thiab kho mob (Table 3) [88–102].
MitoQ: a quinone suav nrog lipophilic triphenylphosphonium (TPP) cation covalently txuas los ntawm aliphatic 10-carbon saw mus rau antioxidant ubiquinone moiety [103]. TPP lipophilic cation kis tau sai heev los ntawm cov kab mob lom thiab nws cov nqi zoo ua rau cov khoom sib txuam ntawm cov molecules mus rau mitochondria qhov twg nws ua raws li cov saw-tshuaj tiv thaiv oxidant los tiv thaiv oxidative puas tsuaj [104]. Hauv cov qauv nas ntawm ob sab raum ischemia, ua raws li 24 teev rov ua dua, kev tswj hwm ntawm MitoQ 15 min ua ntej ischemia txo qhov hnyav ntawm I / R raug mob rau lub raum los ntawm kev txo qis oxidative puas tsuaj [88,89].
Nws muaj peev xwm khaws cia mitochondrial kev ncaj ncees thiab kev ua haujlwm txwv tsis pub ferroptosis tshwm sim los ntawm kev poob ntawm GPX4 lossis raug rau RSL3 [105]. Szeto-Schiller peptide SS-31 (tseem hu ua MTP-131, elamipretide, thiab bendavia) yog peptide tus neeg sawv cev uas cuam tshuam nrog cardiolipin [106] nyob rau hauv lub mitochondrial membrane thiab exerts muaj zog anti-oxidant propriety [ 107] ib.
Hauv cov qauv nas ntawm lub raum I / R raug mob, kev kho mob nrog SS{{0}} tiv thaiv mitochondrial qauv thiab ua pa thaum ntxov reperfusion, ceev rov qab ntawm ATP, txo apoptosis thiab necrosis ntawm tubular hlwb, thiab abrogated tubular dysfunction [ 93] ib. Tsis tas li ntawd, SS-31 zoo li tuaj yeem hloov kho qhov kev qhia ntawm cov tswv cuab ntawm RAS system (ib qho tseem ceeb ntawm kev tswj hwm lub raum ua haujlwm), tshwj xeeb yog aminopeptidase A (APA) thiab Ang receptors (AT2R) [94]. Hauv Phase 2a tsis ntev los no, ntau qhov chaw, randomized, ob qhov muag tsis pom kev, kev tshawb fawb placebo-tswj Saad li al., soj ntsuam kev nyab xeeb, kev zam, thiab kev ua tau zoo ntawm IV-tswj elamipretide (kev kho mob tsim ntawm SS-31) kom txo tau ntawm reperfusion raug mob nyob rau hauv cov neeg mob uas hnyav atherosclerotic lub raum hlab ntsha stenosis nyob rau hauv revascularization nrog ib tug cutaneous transluminal raum angioplasty (PTRA) [95]. Cov neeg mob tau kho ua ntej thiab thaum lub sij hawm PTRA nrog elamipretide (0.05 mg / kg ib teev intravenous infusion) lossis placebo. Piv nrog rau cov placebo pab pawg, cov neeg mob uas tau txais elamipretide pom tau tias muaj kev nce qib ntawm GFR thiab cov ntshav siab systolic poob qis tom qab 3 lub hlis.
Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl lossis 4-hydroxy-tempo) yog ib qho ruaj khov piperidine nitroxide uas tshem tawm cov superoxide anions thiab txo cov intracellular concentrations ntawm Fe2+ thiab, li no, tsim hydroxyl radicals ntawm Fenton los yog Haber-Weiss cov tshuaj tiv thaiv [108,109]. Hauv cov qauv nas ntawm lub raum I / R raug mob, kev tswj hwm ntawm tempol ua ntej thiab thoob plaws hauv reperfusion attenuated lub raum tsis ua haujlwm tsawg kawg yog ib feem los ntawm kev txo qis raum ntawm myeloperoxidase (MPO) thiab qib ntawm malondialdehyde (MDA) [100].
Cov tshuaj no tam sim no nyob rau hauv kev tshawb nrhiav hauv kev sim tshuaj ntsuam xyuas nws lub peev xwm los tiv thaiv ntau yam tshuaj lom uas cuam tshuam nrog cisplatin thiab kev kho hluav taws xob (suav nrog kev tiv thaiv mucositis, nephrotoxicity, thiab ototoxicity) hauv cov neeg mob qog noj ntshav hauv taub hau thiab caj dab (NCT03480971). Mito-TEMPO yog ib qho kev sib xyaw ua ke ntawm cov tshuaj tiv thaiv kab mob hauv lub cev los tiv thaiv oxidant piperidine nitrox ide TEMPO (2,2,6,6-tetramethylpiperidin-1-} yloxy) thiab TPP cation uas pab txhawb 1000-fold tsub zuj zuj mus rau hauv mitochondrial matrix thiab xaiv lub hom phiaj mitochondrial ROS [110]. Kev tswj hwm ntawm mito-TEMPO hauv cov nas tom qab rov ua dua thiab rau 3 lossis 5 hnub sib law liag tom qab kev phais rov qab kho lub raum mtDNA qib, mitochondrial loj, thiab ATP ntau lawm nrog rau qhov txo qis qhov mob thiab mob raum [101].
XJB peptides yog tsim los ntawm 4-NH2-TEMPO, ib tug ruaj khov nitroxide radical nrog anti-oxidant zog conjugated rau ib tug pentapeptide fragment los ntawm gramicidin S (Leu-d-Phe ProVal-Orn), ib tug natural membrane- active cyclopeptide tshuaj tua kab mob nyob rau hauv lub puab mitochondrial membrane [111]. Qhov feem ntau kawm ntawm tag nrho cov XJB peptides yog XJB-5-131. Cov nas txhaj tshuaj intraperitoneally nrog XJB-5-131 (10 mg / kg) 30 min ua ntej ischemia thiab rau 3 hnub sib law liag tom qab kev phais tau pom tias txo qis raum mob, rov tsim kho thiab kho cov kab mob raum raug mob tsawg kawg yog ib feem los ntawm inhibition ntawm I / R induced ferroptosis [102].
4.4. Tshuaj nrog Antioxidant Properties
Dexmedetomidine yog ib qho kev xaiv heev thiab tshwj xeeb 2-adrenoreceptor agonist nrog cov nyhuv sedative. Hauv cov qauv nas ntawm I / R, dexmedetomidine, muab tshuaj intraperitoneally ntawm ntau npaum li cas (los ntawm 10 mus rau 100 ug / kg) thaum pib ntawm ischemia lossis reperfusion lossis tom qab phais, txo qis lub raum tsis ua haujlwm, mob hlab ntsha necrosis thiab inflammatory teb yam tsawg kawg ntawm ib feem ntawm nce lub raum p38 MAPK, tiv thaiv oxidant, thiab kev saib xyuas ntawm autophagy [112–115].
Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-ib qho) yog ib qho tshuaj tua kab mob muaj zog ntawm hydroxyl thiab peroxyl radicals. Raws li tsis ntev los no tau tshaj tawm nyob rau hauv cov ntaub ntawv, kev tswj hwm ntawm edaravone (los ntawm 3 mus rau 10 mg / kg) intravenously nyob rau hauv ib tug nas qauv ntawm I / R raug mob (los ntawm clamping ntawm lub raum hlab ntsha) tiv thaiv lub raum puas los ntawm kev txo oxidative kev nyuaj siab, inhibiting apoptosis, thiab kev txhim kho. mitochondrial raug mob los ntawm JAK/STAT signaling [116,117]. Nyob rau hauv lub neej yav tom ntej, edaravone yuav muaj peev xwm ua hauj lwm nyob rau hauv kev kho mob lub cev thiab kev hloov pauv.
4.5. Ferroptosis thiab Mitophagy Specific Agents:
Dhau li ntawm cov lus hais saum toj no cov tshuaj tiv thaiv antioxidant uas tuaj yeem muaj lub luag haujlwm tsis ncaj rau ob qho tib si ferroptosis thiab mitophagy, cov molecules tshwj xeeb tau raug npaj rau kev tswj hwm ntawm ob txoj hauv kev, suav nrog ferrostatin -1 thiab liproxstatin, ob qho tshwj xeeb inhibitors ntawm ferroptosis vim lawv reactivity raws li radical trapping antioxidants yuav tso cai kom txo tau cov tsub zuj zuj ntawm lipid hydroperoxides [118]. Liproxstatin-1 tau tshaj tawm tias tuaj yeem tiv thaiv ferroptosis hauv tib neeg lub raum proximal tubule epithelial hlwb, hauv Gpx4−/− raum, thiab hauv I / R-induced cov ntaub so ntswg raug mob [37]. Txawm li cas los xij, kev tshawb fawb ntxiv (nrog rau kev sim tshuaj kho mob) yuav tsum tau ua kom zoo dua rau kev siv tshuaj kho mob ntawm cov neeg ua haujlwm no.
5. Cov lus xaus
Tsis muaj cov tswv yim kho mob muaj nyob rau hauv kev kho mob kom qeeb qhov pib thiab kev loj hlob ntawm allograft puas tsuaj los ntawm I / R raug mob. Txawm li cas los xij, cov ntaub ntawv tau txais hauv vitro thiab hauv cov qauv tsiaj qhia tias kev hloov pauv ntawm ferroptosis thiab mitophagy tuaj yeem sawv cev rau cov cuab yeej kho mob yav tom ntej los tiv thaiv lossis ua kom qeeb ntawm kev raug mob ntawm allograft I / R. Tsis tas li ntawd, qee qhov ntawm ob qho tib si kev siv tshuaj lom neeg tuaj yeem raug npaj ua tshiab (thiab tsis cuam tshuam) thaum ntxov kuaj biomarkers rau I / R raug mob-vim cov teeb meem allograft (feem ntau qeeb graft muaj nuj nqi).
Tus Sau Kev Koom Tes: SG, VV, FS, VC, thiab GZ tau tshawb nrhiav cov ntaub ntawv thiab sau cov ntawv sau. ER, GSN, thiab GS tau pab txhawb rau kev txheeb xyuas cov ntaub ntawv thiab kho cov ntawv sau. Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.
Kev Them Nyiaj: Qhov kev tshawb fawb no tsis tau txais nyiaj txiag sab nraud.
Kev tsis sib haum xeeb ntawm kev txaus siab: Cov neeg sau ntawv tshaj tawm tsis muaj teeb meem ntawm kev txaus siab.
Cov ntaub ntawv
1. Tonelli, M.; Wieb, N.; Knoll, G.; Bello, UA; Browne, S.; ib. Jadhav, D.; Klarenbach, S.; Gill, J. Systematic Review: Raum Transplantation Piv nrog Dialysis hauv Clinically Relevant Outcomes. Am. J. Hloov. 2011, 11, 2093–2109. [CrossRef] [PubMed]
2. Serrano, OK; Vock, DM; Chinnakotla, S.; Dunn, TB; Kandaswamy, R.; Pruett, TL; Feldman, R. Matas, AJ; Ntiv tes, EB Qhov Kev Sib Raug Zoo Ntawm Lub Sijhawm Txias Ischemia, Lub Raum Hloov Lub Sijhawm Ntev ntawm Kev Nyob, thiab Kev Hloov Kho Tus Nqi. Kev hloov pauv 2019, 103, 401–411. [CrossRef] [PubMed]
3. Qureshi, F.; Raub, H.; Kasiske, BL Silent acute rejection thaum lub sij hawm ncua ncua graft muaj nuj nqi txo lub raum allograft ciaj sia taus. Transplantation 2002, 74, 1400–1404. [CrossRef] [PubMed]
4. Yarlagadda, SG; Coca, SG; Formica, RN, Jr.; Poggio, ED; Parikh, CR Association ntawm ncua sij hawm graft muaj nuj nqi thiab allograft thiab cov neeg mob ciaj sia: Kev tshuaj xyuas thiab kev tshuaj xyuas meta. Nephrol. Hu rau. Transpl. Xyoo 2009, 24, 1039–1047. [CrossRef]
5. Perico, N.; Cattaneo, D.; Sayegh, MH; Remuzzi, G. Ncua kev ua haujlwm ntawm lub raum hloov pauv. Lancet 2004, 364, 1814–1827. [CrossRef]
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