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IL-22- kho lub raum metabolic reprogramming ntawm PFKFB3 los kho lub raum raug mob

Wei Chen, et al

Graphical Abstract

IL-22 attenuatesraumraug mobLos ntawm metabolic reprogramming ntawm lub raum TECs, tswj mitochondrial muaj nuj nqi thiab glycolysis nyob rau hauv puas TECs, thiab alleviates lub tsub zuj zuj ntawm mitochondrial ROS thiab dysfunctional mitochondria ntawm induction ntawm AMPK / AKT thiab PFBFK3 kev ua ub no. Amelioratingraumraug mobofIL-22 los ntawm kev tswj cov metabolism hauv cov teeb liab cuam tshuam tau lees paub hauv cisplatin-vim raum puas thiab mob ntshav qab zib nephropathy tsiaj qauv.

Abstract

Kev puas tsuaj rau lub raum pib ua rau cov txheej txheem metabolic tsis zoo nyob rau hauv tubule hlwb uas ua rau muaj kab mob raum kawg (ESTD). Interleukin-22 (IL- 22) yog ib qho tshuaj tua kab mob zoo rauraumraug moblos ntawm kev txhawb rau lub raum rov qab, tab sis me ntsis paub txog lub hauv paus molecular mechanisms. Ntawm no, peb xub muab pov thawj tias IL -22 attenuatesraumraug moblos ntawm metabolic reprogramming ntawm lub raum tubular epithelial hlwb (TECs). Tshwj xeeb, peb cov ntaub ntawv qhia tias IL-22 tswj hwm mitochondrial muaj nuj nqi thiab glycolysis hauv TECs puas lawm. Cov kev soj ntsuam ntxiv qhia tau hais tias IL-22 alleviates tsub zuj zuj ntawm mitochondrial reactive oxygen hom (ROS) thiab dysfunctional mitochondria ntawm induction ntawm AMPK/AKT signaling thiab PFBFK3 kev ua ub no. Hauv nas, amelioration ntawmraumraug mobthiab necrosis thiab txhim kho lub raum ua haujlwm los ntawm kev tswj hwm ntawm cov metabolism hauv cov teeb meem cuam tshuam thiab mitochondrial kev nyab xeeb ntawm recombinant IL-22 tau ntawv pov thawj hauv cisplatin-induced raum puas thiab mob ntshav qab zib nephropathy (DN) tsiaj qauv. Sib koom ua ke, peb qhov kev tshawb pom tau nthuav tawm cov tswv yim tshiab tshiab rau hauv kev tiv thaiv kev tiv thaiv ntawm IL-22 ntawm ob lub raum thiab qhia txog cov hauv kev kho mob ntawm IL-22 thiab cov kev cuam tshuam cov tshuaj metabolic hauv ntau yam kab mob raum.

KEYWORDSinterleukin -22,raumraug mob, mitochondrial dysfunction, metabolic reprogramming

Cistanchetubulosativ thaiv kab mob raum, nyem qhov no kom tau txais cov qauv

1 QHOV TSEEB

Mob hnyavraumraug mob(AKI), ib qho kev txhawj xeeb txog kev noj qab haus huv rau pej xeem cuam tshuam nrog kev tuag siab thiab mob hnyav, cuam tshuam rau ntau lab tus neeg mob hauv tsev kho mob thoob ntiaj teb thiab qhia tias muaj qhov tshwm sim sai sai.1–3 Cov kab mob hauv qab ntawm AKI tsis nkag siab tag nrho tab sis cuam tshuam txog kev puas tsuaj thiab apoptosis ntawm lub raum. tubular epithelial hlwb (TECs), tshwj xeeb tshaj yog nyob rau hauv lub proximal tubule.4–7 Ntau hom ntaub ntawv txhawb nqa uas lawv cov kev puas tsuaj loj thiab ruaj khov feem ntau ua rau cov ntaub so ntswg kho tsis tiav thiab tsis zoo, ua rau cov lus teb inflammatory, tubular degeneration, raum fibrosis, thiab kev loj hlob mus rau qhov kawg. Kab mob hauv lub raum kawg (ESTD).8–10 Hmoov tsis zoo, uas tsis yog kev pab kho mob ntshav qab zib, tsis muaj kev kho mob zoo rauraumraug mobmuaj. Yog li ntawd, kev kho mob zoo yog qhov xav tau ntau los txo cov kev txom nyem uas nws ua rau cov neeg mob thiab cov teeb meem nyiaj txiag tseem ceeb ntawmraumraug mobrau tib neeg thiab tib neeg.

Interleukin-22 (IL-22), tus tswv cuab tseem ceeb ntawm IL-10 tsev neeg cytokines, tsis ntev los no tau nyiam cov neeg muaj sia nyob hauv ntau yam kab mob uas tau tsav los ntawm epithelial puas.11–13 IL -22 tshem tawm cov ntaub so ntswg tiv thaiv thiab homeostasis feem ntau los ntawm kev ua kom lub STAT3 teeb liab txoj hauv kev thiab kev txhawb nqa ntawm epithelial proliferation.14,15 Tseem ceeb, cov kev tshawb fawb tau pom tias qhov kev qhia ntawm IL-22R1 yog txwv rau lub raum proximal TECs. , thiab kev kho mob nrog IL-22 tuaj yeem tiv thaiv lub raum epithelial raug mob thiab ua kom cov tubular regeneration.16,17 Txawm li cas los xij, txawm tias cov ntaub ntawv pov thawj qhia tau tias IL- 22 yog ib qho tshuaj tua kab mob zoo rauraumraug mob, me ntsis paub txog cov txheej txheem hauv qab ntawm IL- 22-induced TECs rov qab. Kev nkag siab txog lub hauv paus molecular ntawm IL-22 yog qhov tseem ceeb rau kev tshawb nrhiav seb IL-22 ua li cas los tiv thaiv AKI lossis ESTD thiab nrhiav pom cov tshuaj hloov pauv molecular nrog rau cov txheej txheem tseem ceeb cuam tshuam los tiv thaiv lub raum puas.

Kev kho lub raum tom qab kev puas tsuaj yog cov txheej txheem metabolically nyob ntawm thiab nyuaj.18 Cov pov thawj tsis ntev los no qhia tias cov kab mob metabolic ntawm tes tuaj yeem tswj lub raum cell ciaj sia thiab plasticity thiab yog li muab cov txiaj ntsig zoo rau kev nkag siab txog yuav ua li cas cov txheej txheem metabolic tswj cov ntaub so ntswg kho.19,20 Tshwj xeeb, cov kev tshawb pom no qhia tias metabolic reprogramming los ntawm PGC1 lossis S-nitroso-CoA reductase system tiv thaivraumraug mob. Mechanistically, nce glycolysis thiab oxidative phosphorylation (OXPHOS) tuaj yeem txhawb txoj kev loj hlob thiab kev tiv thaiv kab mob los yog tuaj yeem muab cov kev xav tau siab dua ntawm mitosis thiab anabolic biosynthesis thaum kho lub cev.19,21 Tsis ntev los no, peb cov kev tshawb fawb tau pom tias IL-22 alleviates. mitochondrial dysfunction nyob rau hauv daim siab, uas muaj xws li cellular metabolic dab.22,24 Yog li, peb nug seb IL-22 tiv thaiv lub raum puas thiab apoptosis ntawm regulating lawv metabolic xeev. Txhawm rau txiav txim siab cov txheej txheem ntawm IL-22 kho lub raum kho, peb kho tib neeg cov kab mob hauv lub cev (PTECs) nrog kev ntxhov siab. Peb xav tias IL-22 tsav cov metabolic reprogramming los txhim kho glycolysis thiab OXPHOS, uas tiv thaiv TECs tsis ua haujlwm. Peb qhia ntxiv tias IL-22 tau ntxias qhov kev pab cuam no los ntawm kev ua kom muaj AMPK / AKT signaling thiab nws cov molecular modifiers los txo cov kev ua haujlwm mitochondrial. Peb cov kev soj ntsuam tau pom lub teeb pom kev ntawm kev tswj hwm lub xeev metabolic rau kev kho thiab tiv thaiv kab mob raum thiab muab kev nkag siab tshiab rau kev tsim cov kev cuam tshuam tshiab rau kev raug mob ntawm lub cev.

Cistanche tuaj yeem khoraumraug mob

2 Cov Khoom Siv thiab Cov Txheej Txheem

2.1 Reagents

Oligomycin, rotenone, thiab cyanide p-trifluoromethoxy phenyl-hydrazone (FCCP) tau txais los ntawm Sea horse Biosciences; recombinant IL-22 tau muab los ntawm Novoprotein (Tuam Tshoj); Cisplatin (Crisp.), MitoTrackerGreen, LY294002, 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanineiodide (JC-1), thiab compound C tau txais los ntawm Beyotime Biotechnology (Tuam Tshoj); cov tshuaj tiv thaiv tsom rau Glut1, -Actin, p-AMPK, AMPK, thiab GAPDH tau yuav los ntawm Abcam; antibodies forSTAT3, p-STAT3 (Y705), AKT, p-AKT (S473), PFKFB3, thiab Caspase-3 tau muas los ntawm Cell SignalingTechnology; rapamycin, palmitic acid (Palm.), Z-VAD-FMK thiab qabzib tau txais los ntawm Sigma-Aldrich; MitoSOX, Hoechst33342, MitoTracker Liab, thiab PKH26 tau txais los ntawm Invitrogen.

2.2 Cell kab lis kev cai

Tib neeg cov tubule epithelial cell (HK{{0}}}) tau txais los ntawm Cell Bank ntawm Shanghai Institute of Biochemistry thiab Cell Biology, Suav Academy ntawm Kev Tshawb Fawb, thiab khaws cia raws li cov qauv kev cai. HK-2 tau muab noob rau hauv daim phiaj rau lub qhov dej (1 × 106 cell/well) los yog 96-cov phaj zoo (1 × 105 cell/well) thiab kab lis kev cai hauv 90 feem pua ​​​​RPMI1640 nruab nrab (Gibco) ntxiv nrog 100 U / ml penicillin, 100 µg / ml streptomycin, thiab 10 feem pua ​​​​fetal bovine serum (FBS) (Gibco). Peb xub incubated HK{13}} nrog IL-22 (0.5 µg/ml) rau 0.5 h, ces 50 mM d-glucose los yog 5 µg/ml cisplatin los yog 0.2 mM palmitic acid los yog 4 µM doxorubicin (DOX ) rau 24 h. Qee zaum, cov hlwb raug coj los ntawm Z-VAD-FMK (10 µM), compound C (5 µM), LY294002 (20 µM), lossis rapamycin (50 nM) rau lub sijhawm qhia.

2.3 Seahorse kev sim

Peb tau txheeb xyuas TECs siv Seahorse XF96 Extracellular Flux-Analyzer rau kev hloov pauv ntawm cov kua qaub ntxiv (ECAR) thiab tus nqi oxygen noj (OCR). Luv luv, HK-2 (1 × 105) tau loj hlob ntawm 96-zoo Seahorse-plates hmo ntuj. Tom qab ntawd, peb ntxuav cov hlwb nrog cov tshuaj ntsuam xyuas seahorse nruab nrab uas muaj 1 mM pyruvate, 10 mM qabzib, thiab 2 mM glutamine (lossis tsis muaj piam thaj rau kuaj ECAR) hauv qhov chaw tsis muaj CO2 ntawm 37◦C rau {{18} }}.5 h. Cov ntaub ntawv sim tau raug kaw tom qab cov tshuaj tiv thaiv tsis tau raug txhaj tshuaj ntawm qhov zoo tshaj plaws ntawm FCCP (1.0 µM), oligomycin (1.0 µM), rotenone / antimycin A (0.5 µM), 2-DG (50 mM), los yog qabzib (10 mM).

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2.4 Nas thiab tsiaj qauv

Txiv neej BALB/c nas (6-8 lub lis piam) tau yuav los ntawm Slaccas Experimental Animal Co. (Shanghai, Suav). Db/db thiab Db/m nas tau muab los ntawm Model Tsiaj Research Center ntawm Nanjing University (Nanjing, Suav). Txhua tus nas tau khaws cia rau hauv cov chaw tshwj xeeb tsis muaj kab mob (SPF) thiab loj hlob raws li cov txheej txheem kev cai. Rau cov qauv AKI, BALB / c nas tau txais cisplatin (20} mg / kg) lossis kev tswj hwm saline los ntawm kev txhaj tshuaj intraperitoneal. Db / db nas tau noj nrog kev noj zaub mov muaj roj ntau (HFD) ntawm lub sijhawm qhia cov ntsiab lus los ua rau mob ntshav qab zib nephropathy (DN). Db/m nas tau noj nrog chow-diets raws li pawg tswj hwm. Hauv AKI tsiaj sim, IL-22 tau txhaj tshuaj intraperitoneally ntawm koob tshuaj 0.5 mg / kg / hnub lossis 1.5 mg / kg / hnub rau 4 hnub sib law liag. Hauv DN kev sim tsiaj, IL-22 tau txhaj tshuaj intraperitoneally ntawm koob tshuaj 2.5 mg / kg ob zaug ib lub lim tiam rau yim lub lis piam sib law liag. Cov nas tswj tau txais qhov tsim nyog ntawm PBS. Peb cov txheej txheem kev sim tsiaj tau ua raws li cov txheej txheem soj ntsuam thiab pom zoo los ntawm Pawg Saib Xyuas Tsiaj thiab Siv Kev Ncaj Ncees ntawm Tsev Kawm Ntawv Pharmacy, Fudan University. Immunohisto tshuaj staining, ntsuas ntawm mitochondrial membrane muaj peev xwm, histological, thiab reactive oxygen hom (ROS) staining ntawm lub raum seem tau ua raws li yav tas los piav.22–24

2.5 Real-time PCR

Peb tau txais tag nrho-RNA los ntawm TRNzol reagents (Beyotime Biotechnology, Tuam Tshoj) los ntawm cov qauv ntawm tes lossis cov ntaub so ntswg thiab tom qab ntawd muab lawv mus rau cDNA siv MMLV-reverse transcriptase test kit (Beyotime Biotechnology). Kev qhia theem ntawm mRNA tau txheeb xyuas los ntawm lub sijhawm tiag tiag PCR cov cuab yeej (BioRad) siv SYBR ntsuab qPCR-mix cov khoom ntsuas (Beyotime Biotechnology) thiab ua qauv rau GAPDH.

2.6 Flow cytometry

Lub raum hlwb tau loj hlob thiab kho raws li tau piav qhia saum toj no. MitoSOX (mitochondrial ROS), MitoTracker Green (tag nrho mitochondrial mass), thiab MitoTracker Liab (mitochondrial membrane muaj peev xwm) staining tau ua raws li cov chaw tsim khoom cov lus qhia thiab kev tshawb fawb yav dhau los.22–24 Peb tau txais cov txiaj ntsig los ntawm Beckman Coulter Flow Cytometer thiab cov CytExpert software (BD Biosciences).

2.7 Glucose nce ntxiv

Peb ntsuas cov piam thaj hauv cov cell kab lis kev cai supernatant los ntawm kev kuaj ntshav qabzib raws li cov chaw tsim khoom raws tu qauv thiab kev tshawb fawb yav dhau los (GAHK20; Sigma). Cov txiaj ntsig normalization tau ua raws li cov xov tooj ntawm tes.

2.8 Gene swb

Peb siv qhov cuam tshuam me me RNA (siRNA; RiboBio, Tuam Tshoj) los tsoo cov noob tshwj xeeb. Ua ntej, Lipofectamine RNAiMAX thiab siRNA (100 pmol) tau maj mam sib xyaw ntawm pipetting thiab incubated ntawm 37◦C rau 0.5 teev. Tom qab ntawd peb hloov cov txheej txheem cell kab lis kev cai nruab nrab mus rau ib qho transfection cocktail thiab incubated lub hlwb rau 6 h rau siRNA noob transfection. Tom ntej no, peb hloov pauv hloov pauv cocktail mus rau qhov nruab nrab ntawm cov kab lis kev cai tshiab. Tom qab 48 teev, lub raum hlwb raug incubated nrog IL-22 rau kev kawm ntxiv.

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2.9 Western blot

Peb muab tag nrho cov proteins los ntawm cov hlwb los yog cov ntaub so ntswg los ntawm RIPA lysis buffer (Beyotime Biotechnology, Tuam Tshoj). Tom qab ntawd, peb sau cov lysates los ntawm centrifugation ntawm 4◦C ntawm 12 000 rpm rau 10 min. Tom qab ntawd, cov lysates tau rhuab nrog cov qauv buffers ntawm 100◦C rau 15 min, raug sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS– PAGE), thiab electrotransferred rau polyvinylidene difluoride (PVDF) membrane (Millipore, Lub teb chaws Yelemees). Tom qab ntawd cov ntaub so ntswg raug thaiv nrog 5 feem pua ​​​​bovine serum albumin (BSA) rau 2 h thiab co-incubated nrog thawj cov tshuaj tiv thaiv ntawm 4◦C thaum hmo ntuj. Tom qab ntxuav peb zaug, cov membranes tau incubated nrog horseradish peroxidase-conjugated secondary antibodies (CST, USA). Cov protein blots tau pom los ntawm kev txhim kho chemiluminescence imaging system.

2.10 Immunofluorescence

Lub raum hlwb raug kho los ntawm 3 feem pua ​​– 4 feem pua ​​paraformaldehyde thiab permeabilized nrog 0.1 feem pua ​​Triton X-100. Tom qab ntawd, peb thaiv cov hlwb nrog 5 feem pua ​​BSA rau 2 teev. Cells raug incubated ib hmos nrog anti-GLUT1 antibody ntawm 4◦C, ntxuav plaub zaug, thiab ces stained nrog PKH26. Tom qab ntawd, lub raum hlwb tau stained nrog Hoechst 33342 thiab mounted rau slides. Cov ntaub ntawv tau txais los ntawm confocal microscopy.

2.11 RNA-seq thiab bioinformatics

TEC cov qauv (2 × 107) tau lysed thiab tag nrho RNA raug rho tawm siv RNeasy mini cov khoom siv, raws li cov chaw tsim khoom raws tu qauv (Beyotime, Shanghai, Suav). Eukaryotic RNA-seq tau ua tiav los ntawm kev siv thev naus laus zis ntawm kev sib txuas txuas ntxiv tom ntej (NGS) ntawm Illumina HiSeq sequencing system, muab qhov 50-puag nyeem ntev. Kev sib txuas ntawm kev nyeem ntawv tau ua tiav siv TopHat v2.0.12 tawm tsam UCSC mm10 Assembly. Kev txheeb xyuas qhov sib txawv tau suav nrog siv DESeq2 (http://www.bioconductor.org/packages/release/ bioc/html/DESeq2.html) pob thiab cov kev txheeb xyuas qhov tseem ceeb tau ua hauv R (v3.1.1; http://www. .r-project.org/). Pathway overrepresentation tau ua tiav siv R pob ReactomePA.

2.12 Kev txheeb cais

Cov ntaub ntawv tau qhia raws li qhov txhais tau tias ± tus qauv sib txawv (SD) thiab tau qhia siv GraphPad Prism 5.0. Rau cov txiaj ntsig sib piv ob lossis ntau pab pawg, qhov sib txawv tau suav nrog siv Tus Tub Kawm Ntawv t-test lossis ib txoj kev tsom xam ntawm qhov sib txawv (ANOVA): ***p < 0.00="" 1,="" **p=""><0.01, thiab="" *p=""><>

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3 TSEEM CEEB

3.1 IL-22 khaws cov cellular metabolism hauv TECs

Vim hais tias mitochondria tau raug qhia tias yog cov organelles tseem ceeb uas koom ua ke ntawm cellular metabolism thiab cov txheej txheem apoptotic, peb tau soj ntsuam mitochondrial kev ua haujlwm hauv TECs uas tau txhawb nqa nrog.raumraug mobyam tseem ceeb thiab kho nrog IL-22.25 Raws li pom hauv daim duab 1A–D, mitochondrial basal oxygen noj tus nqi (OCR), lub peev xwm ua pa siab tshaj plaws (MRC), thiab kev ua pa tau thaiv ntau heev hauv TECs nyob rau hauv cov xwm txheej ntxhov siab. Qhov tseem ceeb, cov kev txawv txav no feem ntau tiv thaiv los ntawm IL- 22 kev kho mob. Glycolysis nyob rau hauv TEC puas lawm, pov thawj los ntawm extracellular acidification tus nqi (ECAR), kuj tseem ceeb heev txwv, piv nrog IL-22 ntxiv rau stimuli-them TECs (Daim duab 1B thiab E). Peb tau ua pov thawj ntxiv tias kev cuam tshuam oxidative phosphorylation (OXPHOS) thiab glycolysis hauv TECs puas tsis yog qhov cuam tshuam thib ob ntawm apoptosis los ntawm kev sib koom ua ke nrog pan-caspase inhibitor (Daim duab S1). Thiab IL-22-kev kho cov teebmeem ntawm cov teebmeem metabolic yog tshwj xeeb rau lub raum TECs (Daim duab S2). Tsis tas li ntawd, IL-22 txhawb nqa HK2 hlwb OXPHOS thiab glycolysis thaum tsis muaj stimuli, qhia tias IL-22's cuam tshuam rau txoj kev metabolic tsis yog tshwj xeeb rau TECs puas lawm (Daim duab S3). Ntxiv mus, peb cov txiaj ntsig kuj tau qhia tias IL-22 tau txhawb nqa qhov kev qhia thiab kev hloov pauv ntawm IL-22R1. Lub caij no, phosphorylation ntawm STAT3 thiab metabolic reprogramming cuam tshuam ntawm IL-22 raug tshem tawm tag nrho los ntawm IL-22R1 knockdown (Daim duab S4). Cov kev tshawb pom no tau qhia tias IL-22 rov qab kho lub xeev metabolic ntawm TECs los ntawm kev ua kom IL-22R1 ncaj qha. Vim tias ntau daim ntawv pov thawj tau qhia tias Glut1 ua lub luag haujlwm tseem ceeb hauv glycolysis thiab glucose homeostasis,26 peb, yog li ntawd, nug seb IL-22 cuam tshuam Glut1 kev hloov pauv lossis kev qhia. Raws li kev cia siab, peb tau pom tias IL-22 tsis yog tsuas yog txhawb nqa cov translocated Glut1 mus rau lub cell membrane nto (PKH26) thiab Glut1 qhia, tab sis kuj txhim kho cov piam thaj (Daim duab 1F thiab G). Zuag qhia tag nrho, cov kev soj ntsuam no tau qhia tias IL-22 tuaj yeem txhim kho OXPHOS thiab glycolysis hauv TECs raug mob.

Daim duab 1 IL-22 khaws cia mitochondrial lub zog thiab glycolysis hauv TECs. (A thiab B) Peb siv Seahorse XF96 Extracellular Flux Analyzer los ntsuas cov kev hloov pauv ntawm cov kua qaub ntxiv (ECAR) thiab tus nqi oxygen noj (OCR) ntawm TECs. OCR thiab ECAR hauv TECs incubated nrog 50 mM qabzib, los yog 5 µg/mL cisplatin, los yog 0.2 mM palmitic acid, los yog 4 µM DOX nyob rau hauv lub xub ntiag los yog tsis muaj IL{{8} }. (C) Lub peev xwm ua pa siab tshaj plaws (MRC) ntawm TECs soj ntsuam los ntawm kev hloov pauv hauv lub sijhawm hauv OCR. (D thiab E) Curves hauv OCR thiab ECAR ntawm TECs tom qab incubated nrog oligomycin, FCCP, qabzib, rotenone, thiab {{10}}DG. (F) Localization thiab kev qhia ntawm nuclear (xiav), Glut1 (ntsuab), thiab plasma membrane (liab) hauv TECs. (G) Glucose noj hauv TECs tom qab IL-22 kev kho mob rau 24 teev. n=3; scale bars, 20 µm; Cov tub ntxhais kawm ntawv t-test (tsis ua khub); ***p <0.001, **p=""><0.01, *p=""><>

3.2 IL-22 ameliorates cov tsub zuj zuj ntawm dysfunctional mitochondria hauv TECs los ntawm kev ua kom mitophagy

tsim ntawm LC3 puncta hauv TECs tom qab raug stimuli (Daim duab 2F). Peb mam li depleted mitophagy los soj ntsuam nws txoj haujlwm ntawm tubule cell metabolism ntawm siRNA-ATG5 (Daim duab S6). Peb cov ntaub ntawv qhia tias kev txo qis ntawm mitophagy hauv TECs cuam tshuam qhov kev tiv thaiv ntawm IL-22 hauv kev pabcuam mitochondrial ua ntej (Daim duab 2E), qhia tias IL-22 tiv thaiv mitochondrial dysfunction ntawm kev ua haujlwm ntawm mitophagy.

Daim duab 2 IL-22 inhibits mitochondrial dysfunction thiab mitochondrial ROS tsub zuj zuj ntawm induction ntawm mitophagy. (A) Mitochondrial loj tau stained thiab soj ntsuam los ntawm MitoTracker Green thiab ntws cytometry. Mitochondrial ROS raug soj ntsuam hauv TECs stained nrog MitoSOX (B). Mitochondrial membrane muaj peev xwm raug soj ntsuam hauv TECs stained nrog MitoTracker Green thiab MitoTracker Liab (C); mitochondrial ROS tsub zuj zuj raug soj ntsuam los ntawm MitoTracker Green thiab MitoSOX (D). (E) Confocal duab tshwm sim qhia mitochondrial ROS ntau lawm sau nrog MitoSOX. (F) Tus sawv cev cov duab microscopic qhia LC3-GFP punctate tsim nyob rau hauv lub xub ntiag los yog tsis muaj IL-22 TECs stimulated li (A) rau 24 teev. (E) OCR raug soj ntsuam thaum muaj lossis tsis muaj IL-22 thiab siRNA-ATG5 rau 24 teev. n=3; Cov tub ntxhais kawm ntawv t-test (tsis ua khub); ***p < 0="" 001,="" **p="">< 0.01,="" *p=""><>

3.3 IL-22 tuav mitochondrial kev ncaj ncees ntawm TECs los ntawm kev ua kom lub AMPK/AKT signaling

AMPK signaling, raws li ib tug tseem ceeb signaling hub txuas cell ciaj sia taus thiab metabolism, tswj qabzib metabolism, lipid synthesis, thiab mitochondrial muaj nuj nqi.28 Raws li lub raum tiv thaiv nyhuv ntawm interleukin -22 kho los ntawm metabolic reprogramming ntawm TECs, peb soj ntsuam seb puas. IL-22 tswj mitochondrial kev ncaj ncees los ntawm kev ua kom AMPK signaling transduction. Peb pom tias IL-22 nce kev ua haujlwm ntawm STAT3/AMPK/AKT signaling transduction hauv TECs raug mob, ua pov thawj los ntawm phosphorylation ntawm STAT3, AMPK, thiab AKT (Daim duab 3A). Tsis tas li ntawd, cov txheej txheem no tau raug thaiv hauv tubular hlwb tsis muaj STAT3, uas pom tau tias IL-22 tswj AMPK/AKT signaling los ntawm STAT3 (Daim duab 3B thiab C; Daim duab S7). Peb ntxiv incubated TECs nrog compound C thiab LY294002 kom ncaj qha inhibit AMPK / AKT signaling transductions, thiab tom qab ntawd soj ntsuam lawv cov mitochondrial zog thiab cov metabolism hauv xeev. Cov txiaj ntsig tau tshaj tawm tias kev kho mob nrog cov cim qhia no cuam tshuam qhov kev txhim kho OXPHOS thiab glycolytic flux tshwm sim los ntawm IL-22 kev kho mob (Daim duab 3D-I), uas qhia tias IL-22 txhawb nqa TECs metabolism los ntawm kev ua kom AMPK. / AKT signaling txoj kev.

Daim duab 3 Induction ntawm AMPK/AKT signaling los ntawm IL-22 tuav mitochondrial zog. TECs tau txhawb nqa 50 mM qabzib, lossis 5 µg/mL cisplatin, lossis 0.2 mM palmitic acid, lossis 4 µM DOX nyob rau hauv lub xub ntiag lossis tsis muaj IL-22, Compound C , los yog LY294002 rau lub sijhawm qhia. (A thiab B) AMPK/AKT signaling pathway activation in TECs or STAT3-WT thiab STAT3–KD TECs raug soj ntsuam los ntawm western blot tsom xam. (C thiab D) Kev hloov pauv hauv OCR thiab ECAR ntawm TECs tau txheeb xyuas. (E) AMPK/AKT signaling pathway activation nyob rau hauv TECs tau soj ntsuam los ntawm western blot tsom xam. (F–I) Kev hloov pauv hauv OCR thiab ECAR ntawm TECs tau ntsuas hauv TECs piv rau Compound C thiab LY294002 kho TECs. Cov tub ntxhais kawm ntawv t-test (tsis ua khub); n=3; ***p <0.001, **p=""><0.01, *p=""><>

3.4 IL-22 khaws cia cellular metabolism thiab mitochondrial kev ncaj ncees ntawm TECs ntawm induction ntawm PFKFB3

Tsis tas li ntawd, txhawm rau tshawb xyuas seb TECs 'mitochondrial Fitness thiab metabolism tau txhim kho li cas, peb siv RNA sequencing tsom xam (RNA-seq) los ntsuas cov noob qhia tom qab stimuli raug mob thiab IL-22 kho. Peb tau pom tias ntau lub noob tau hloov pauv hauv TECs tom qab IL-22 incubation (Daim duab 4A). Siv cov ntaub ntawv muaj nyob, cov gene teeb tsa kev tsom xam ntawm cov noob tau tswj hwm tau ua, uas tau qhia tias muaj txiaj ntsig zoo ntawm cov noob hauv AMPK taw qhia txoj hauv kev thiab MYC lub hom phiaj qhia txoj hauv kev (Daim duab S8). Qhov tseem ceeb, PFKFB3 tau raug cuam tshuam los ntawm IL-22 los ntawm cov noob thaum lub sijhawmraumraug mobyam stimulation (Daim duab 4A). Cov kev soj ntsuam no kuj tau qhia los ntawm cov duab confocal, Q-PCR, thiab sab hnub poob blot. Kev qhia siab ntawm PFKFB3 yog AMPK / AKT signaling nyob ntawm (Daim duab 4B thiab C; Daim duab S9).

Cov kev tshawb fawb yav dhau los tau qhia tias PFKFB3 tuaj yeem tswj hwm los ntawm ntau lub teeb liab hloov pauv kom nrawm nrawm ntawm epithelial regeneration thiab kho tom qab raug mob.29,30 Yog li, peb xav tias IL-22 induced PFKFB3 los khaws cov cellular metabolism ntawm TECs thiab tswj lawv cov mitochondrial zog. . Peb pom tias qhov inhibition ntawm AMPK / AKT signaling txo PFKFB3 qhia (Daim duab 4D). Yog li, peb ntsiag to PFKFB3 los kawm ntxiv txog nws cov haujlwm hauv TECs tom qab IL-22 incubation. Peb qhov kev tshawb pom tau qhia tias silenced PFKFB3 alleviated metabolic reprogramming cuam tshuam ntawm IL-22 ntawm kev kho ECAR thiab OCR (Daim duab 4E thiab F), thiab tiv thaiv cov piam thaj nce ntxiv nrog rau kev ua haujlwm tsis zoo ntawm mitochondria (Daim duab 4G thiab H). Ntxiv mus, peb tau ua pov thawj ntxiv tias cov teebmeem metabolic reprogramming ntawm IL-22 raug tshem tawm tag nrho los ntawm STAT3-knockdown thaum lub overexpression ntawm PFKFB3 tuaj yeem tuaj yeem cawm cov phenotypes, qhia IL-22 rov qab los. metabolic lub xeev ntawm lub raum puas hlwb epithelial ntawm lub hom phiaj STAT3-AMPK/AKT-PFKFB3 signaling ncaj qha (Daim duab S10). Ua ke, cov kev tshawb pom no tau qhia tias kev ua kom PFKFB3 ua lub luag haujlwm tseem ceeb hauv kev noj qab haus huv mitochondrial thiab dysfunctional mitochondria tshem tawm tom qab.raumraug mob.

FIGURE 4 IL-22 tswj mitochondrial kev ncaj ncees thiab cellular metabolism ntawm TECs ntawm induction ntawm PFKFB3. (A) Volcano zaj duab xis rau cov noob qhia nyob rau hauv TECs stimulated nrog qabzib, los yog cisplatin, los yog palmitic acid, los yog CCl4 nyob rau hauv lub xub ntiag los yog tsis muaj IL-22 rau 24 teev. (B) Confocal microscopic cov ntaub ntawv qhia PFKFB3 overexpression nyob rau hauv TECs tom qab IL-22 kev kho mob, uas yuav tsum tau AMPK/AKT signaling activation. (C) Cov txiaj ntsig PCR ntawm lub sijhawm tiag tiag qhia tau tias IL-22 ntxias PFKFB3 overexpression hauv TECs, uas tuaj yeem cuam tshuam los ntawm AMPK / AKT signaling block. (D) Lub AMPK/AKT/ PFKFB3 qhia txoj hauv kev ua kom muaj zog hauv TECs tom qab kev kho mob nrog Compound C thiab LY294002. (E thiab F) ECAR thiab OCR hauv TECs thaum muaj lossis tsis muaj IL-22, lossis si-PFKFB3 rau 24 teev. (G) Glucose noj hauv TECs tom qab IL-22 lossis si-PFKFB3 kev kho mob rau 24 teev. (H) Mitochondrial dysfunction raug soj ntsuam hauv TECs stained nrog MitoTracker Liab thiab MitoTracker Green. Cov tub ntxhais kawm ntawv t-test (tsis ua khub); n=3; ***p < 0.001,="" **p="">< 0.01,="" *p=""><>

3.5 IL-22 alleviates raum raug mob hauv cisplatin-induced AKI los ntawm kev tawm tsam ntawm lub raum ROS txuam thiab mitochondrial tsis ua haujlwm

Txhawm rau kuaj peb qhov kev xav tias IL-22 tswj lub raum metabolic profiles txhawm rau txhawm rau lub raum tubule raug mob hauv vivo, peb pib ntsuas lub raum ua haujlwm hauv IL-22- kho cov nas uas tau muab tshuaj nrog cisplatin (Daim duab 5A). Plaub hnub tom qab txhaj tshuaj cisplatin, IL-22 tsis tsuas yog txo cov tubular cellular puas thiab hemorrhage; Lawv lub raum tsis ua haujlwm kuj tau txo qis, uas tau soj ntsuam los ntawm cov ntshav urea nitrogen (BUN) thiab creatinine (Cr) (Daim duab 5B-D). Peb tau hais ntxiv tias IL-22 tiv thaivraumraug moblos ntawm kev txhim kho lub raum rov tsim dua tshiab thiab ua kom AMPK/AKT signaling thiab PFKFB3 (Daim duab 5E thiab F; Daim duab S11). Tom ntej no, peb ua haujlwm MitoSOX (mitochondria-specific ROS dye) thiab JC-1 (mitochondrial membrane tej zaum-dependent dye) los soj ntsuam cov mitochondrial dysfunction koom nrog hauv cellular metabolism thiab apoptosis. Hauv lub raum ntawm cov nas uas tau kho nrog cisplatin, muaj cov khoom sib piv ntawm ROS. Nco ntsoov, nyob rau plaub hnub tom qab IL-22 kev kho mob, theem ntawm ROS tau txo qis hauv lub raum raug mob piv rau ROS los ntawm cov nas tom qab kev kho PBS (Daim duab 5G). Ua ke, cov kev soj ntsuam no tau muab pov thawj tias IL-22 ua lub luag haujlwm tiv thaiv hauv cisplatin-induced AKI los ntawm kev tswj cov mitochondrial.

Daim duab 5 IL-22 alleviates raum puas nyob rau hauv cisplatin-induced AKI los ntawm inhibition ntawm lub raum ROS txuam thiab dysfunctional mitochondria. (A) Schematic daim duab ntawm kev sim cov txheej txheem los ntsuas qhov kev tiv thaiv ntawm IL-22 hauv cisplatin (20 mg/kg) ua rau lub raum puas. PBS raws li pawg tswj hwm tsheb thiab N-acetyl-l-cysteine ​​(NAC, 150 mg/kg) raws li pawg tswj hwm zoo. (B thiab C) Qib BUN, qib Cr qib, lub raum hnyav, thiab lub cev hnyav tau raug ntsuas. Tus neeg sawv cev HE (D), Ki-67 staining (E), MitoSOX (G), thiab JC{{10}} (G) cov duab ntawm lub raum seem tau nthuav tawm. (F) Kev sib piv ntawm STAT3/AMPK/AKT/PFKFB3 ua kom lub raum rho tawm los ntawm IL-22-cov nas kho tau raug tshuaj xyuas los ntawm cov kab mob sab hnub poob. Cov tub ntxhais kawm ntawv t-test (tsis ua khub); n=3; ***p <0.001, **p=""><0.01, *p=""><>

3.6 IL-22 ameliorates ntshav qab zib ua rau lub raum raug mob los ntawm inhibition ntawm mitochondrial tsis ua haujlwm los ntawm kev ua kom muaj AMPK/AKT signaling thiab PFKFB3

Peb thiab lwm tus tau ua pov thawj tias IL-22 tuaj yeem siv zog tiv thaiv kab mob ntshav qab zib nephropathy (DN), uas yog qhov laj thawj tseem ceeb ntawm ESTD.31–33 Txhawm rau kawm ntxiv txog cov txheej txheem hauv qab, peb tau pub db/db nas nrog siab- cov zaub mov muaj roj (HFD) thiab tom qab ntawd kho lawv nrog IL-22 (2.5 mg / kg, IP) rau 8 lub lis piam (Daim duab 6A). Thaum cov nas tau noj nrog HFD nkaus xwb, peb pom lub raum tubular fibrosis thiab dilatation, ntxiv rau atrophy. Hauv qhov sib piv, thaum cov nas tau kho nrog IL-22, lub raum fibrosis thiab histopathology tau txhim kho zoo, nrog rau lub raum ua haujlwm. Txhim kho lub raum ua haujlwm kuj tau pom los ntawm kev txo qis hauv cov ntshav Cr, BUN qib, thiab tag nrho cov zis albumin / 24 h (UAE) qib (Daim duab 6B-E). Txhawm rau kawm seb cov haujlwm no puas cuam tshuam nrog mitochondria, peb tau soj ntsuam cov haujlwm mitochondrial koom nrog hauv cellular metabolism thiab apoptosis. Cov txiaj ntsig tau qhia tias qhov nce mitochondrial ROS ntau ntau thiab kev ua haujlwm tsis zoo ntawm mitochondria tau txo qis los ntawm IL-22 kev kho mob (Daim duab 6F thiab G). Txhawm rau kawm ntxiv seb puas muaj kev tiv thaiv kev ua haujlwm ntawm IL-22 hauv lub raum tau kho los ntawm PFKFB3, peb tau txhaj cov nas nrog PFKFB3 shRNA adenovirus txhawm rau txhawm rau PFKFB3. Peb cov ntaub ntawv qhia tau hais tias cov txiaj ntsig zoo ntawm IL-22 ntawm HFD-vim lub raum raug mob, necrosis, steatosis, mitochondrial tsis ua haujlwm, thiab ROS tsub zuj zuj thiab ua kom muaj feem cuam tshuam cov kev taw qhia tau cuam tshuam los ntawm PFKFB3 knockdown (Daim duab 6B–G) . Kev nthuav qhia ntau ntxiv ntawm AMPK/AKT signaling kuj tau pom tom qab kev kho mob nrog IL-22 (Daim duab 6H). Nrog rau kev txo qis ntawm lub raum tsis ua haujlwm, cov lus qhia ntawm PFKFB3 thiab cov enzymes tseem ceeb hauv cellular metabolism kuj tau txhim kho hauv ob lub raum ntawm IL-22- kho cov nas (Daim duab 6H thiab kuv). Tsis tas li ntawd, kev tshuaj xyuas histological ntawm cov kabmob loj qhia tias tsis muaj kev raug mob morphological tom qab IL -22 txhaj tshuaj, qhia tias IL-22 tuaj yeem yog tshuaj tua kab mob zoo yam tsis muaj kev phiv loj lossis tshuaj lom rauraumraug mobkev puas tsuaj (Daim duab 12S). Zuag qhia tag nrho, peb cov ntaub ntawv qhia tias IL- 22 txo qis raum kev puas tsuaj los ntawm kev ua haujlwm ntawm AMPK / AKT signaling transduction, inhibition of ROS commulation, thiab mitochondrial function regulation los ntawm PFKFB3.

FIGURE 6 IL-22 alleviates diabetes-induced renal damage by AMPK/AKT signaling and inhibition of dysfunctional mitochondria by activation of PFKFB3. (A) Schematic daim duab ntawm kev sim cov txheej txheem los ntsuas qhov kev tiv thaiv los ntawm IL-22 hauv ntshav qab zib ua rau lub raum puas. Db/m ua pab pawg tswj tsheb. (B-D) Qib BUN, qib Cr qib, thiab UAE raug soj ntsuam. Tus neeg sawv cev HE (E), MitoSOX (F), thiab JC-1 (G) cov duab ntawm lub raum seem tau nthuav tawm. (H thiab I) Kev sib piv ntawm STAT3/AMPK/AKT/PFKFB3 kev ua kom lub raum rho tawm los ntawm IL-22-cov nas kho tau raug soj ntsuam los ntawm western blot. Cov tub ntxhais kawm ntawv t-test (tsis ua khub); n=3; ***p < 0="" 001,="" **p="">< 0.01,="" *p=""><>

4 Kev sib tham

IL-22 yog secreted los ntawm lub cev tiv thaiv kab mob, xws li NK hlwb, neutrophils, innate lymphoid cells (ILCs), thiab T hlwb, tab sis tsis ncaj qha rau cov hlwb no. Nws feem ntau tswj cov haujlwm ntawm cov hlwb epithelial vim yog txwv tsis pub IL-22R1 qhia ntawm cov hlwb epithelial suav nrog TECs.15,34 Cov kev tshawb fawb yav dhau los tau qhia tias IL-22 tuaj yeem tiv thaiv lub raum epithelial raug mob thiab ua kom cov tubular regeneration. los ntawm inhibition ntawm NLRP3 inflammasome thiab activating STAT3 thiab AKT signaling.16,31 Txawm li cas los xij, cov txheej txheem ntawm kev tiv thaiv no tseem tsis tau piav qhia. Txhawm rau txiav txim siab ntxiv molecular hauv paus ntawm IL- 22's ua haujlwm hauvraumraug mob, peb thawj zaug tshawb xyuas seb IL -22 puas tuaj yeem txo cov kab mob hauv lub raum tsis ua haujlwm thiab apoptosis tom qab los ntawm kev tswj hwm lawv cov xeev metabolic. Ntxiv mus, peb kawm ob tus qauv ntawmraumraug mobkab mob (AKI thiab DN) nrog IL-22 kev tswj hwm thiab sib piv cov kev soj ntsuam nrog cov pab pawg tswj hwm. Peb qhia tias IL-22 kho metabolic reprogramming kom tswj mitochondrial kev ncaj ncees, txo qis mitochondrial ROS tsub zuj zuj hauv TECs raug mob, thiab alleviates lub raum puas thiab necrosis. Tsis tas li ntawd, peb qhov kev tshawb pom qhia tias IL- 22 tuaj yeem qhib AMPK / AKT-txoj kev taw qhia txoj hauv kev hauv TECs thiab ob lub raum, tus neeg nruab nrab tseem ceeb ntawm kev kho mob epithelial thiab kev ciaj sia ntawm tes, txhawm rau txhim kho mitochondrial dysfunction thiab cov txheej txheem metabolic tsis zoo thiab qhib qhov tshiab. teb rau IL-22 mediated raum tiv thaiv mechanism. Zuag qhia tag nrho, peb cov txiaj ntsig qhia tau hais tias lub raum tiv thaiv cov teebmeem ntawm IL-22 yog kho los ntawm cov txheej txheem metabolic reprogramming.

Lub luag haujlwm tseem ceeb ntawm OXPHOS thiab glycolysis hauv kev tiv thaiv lub raum tau raug nthuav tawm hauv cov kev tshawb fawb yav dhau los, uas ntsuas kev siv roj los ntawm inhibitory S-nitrosylation ntawm pyruvate kinase M2 (PKM2) tiv thaiv.raumraug mob.19 Peb cov txiaj ntsig, tawm tswv yim txog kev txhawb nqa OXPHOS thiab glycolysis los ntawm IL-22 los ntawm kev nce metabolic regulators qhia thiab qabzib uptake, qhia tau tias IL-22 thim rov qab cov xeev metabolic tsis zoo cuam tshuam nrograumraug mob. Cov kev soj ntsuam no zoo ib yam nrog rau lub raum kev tiv thaiv kev ua haujlwm ntawm recombinant irisin thiab kuj nyob rau hauv txoj kab nrog kev tshawb pom los ntawm hepatocytes, qhov twg ob qho tib si OXPHOS thiab glycolysis xav tau rau kev ua haujlwm ntawm tes, tab sis yog tias cov no yog inhibited, ces cov thawj tubule hlwb thiab hepatocytes ua dysfunctional.35, 36

Mitochondrial dysfunction tau tshwm sim raws li lub hauv paus tseem ceeb molecular uas ua ke nrog metabolic profiles thiab cell tuag. Nyob rau hauv no, peb qhia hais tias raws li kev raug mob stimulation, TECs kev kho mob nrog IL-22 tau ameliorated tsub zuj zuj ntawm mitochondrial ROS thiab dysfunctional mitochondria raws li piv nrog txo qis mitochondrial kev ncaj ncees thiab ua hauj lwm nyob rau hauv cov pab pawg neeg tswj. Qhov tseem ceeb, AMPK teeb liab txoj hauv kev, lub zog tseem ceeb sensors, hloov cov txheej txheem metabolic kom tswj hwm cellular homeostasis thiab tiv thaiv cov cell lossis cov ntaub so ntswg puas.37–39 Hauv txoj kev tshawb fawb tam sim no, peb cov kev soj ntsuam qhia tias IL-22 khaws cia mitochondrial kev ncaj ncees thiab kev ua haujlwm ntawm kev ua kom cov AMPK/AKT teeb liab qhia tias IL-22 tiv thaiv mitochondrial tsis ua haujlwm hauv txoj hauv kev ncaj qha, uas yog qhov tseem ceeb rau kev tuav TECs ua pa muaj peev xwm. Tsis tas li ntawd, peb pom tau hais tias IL-22 kev taw qhia los ntawm STAT3 muaj kev cuam tshuam ncaj qha rau kev khaws cia mitochondrial kev nyab xeeb, raws li cov tau tshawb fawb yav dhau los uas tau ntxias STAT3 phosphorylation yog qhov tseem ceeb rau kev khaws cia mitochondrial kev ncaj ncees.40,41.

Ntau hom ntaub ntawv yav dhau los tau qhia tias PFKFB3 ua si ib feem ntawm lub hauv paus modulator hauv cell metabolism.29–30,42 Ntawm no, peb thawj zaug qhia tias IL-22 txhawb nqa PFKFB3 ua kom dhau los ntawm AMPK/AKT signaling hauv TECs, qhia IL{ {6}} tswj cov xeev metabolic los ntawm kev koom nrog kev tswj hwm ntawm PFKFB3. Ntxiv mus, cov kev tshawb fawb yav dhau los qhia ntxiv tias PFKFB3 tseem ceeb heev los tswj cov OXPHOS thiab glycolysis ntau ntawm cov hlwb lossis cov ntaub so ntswg.42,43 Raws li cov kev tshawb fawb no, peb cov kev soj ntsuam kuj qhia txog kev txhawb nqa OXPHOS thiab glycolysis hauv IL-22- kho TECs los ntawm kev ua kom PFKFB3. Ntawm ntau qhov kev hloov pauv hauv qab ntawm IL-22 uas tau tshawb xyuas, peb cov ntaub ntawv qhia tau hais tias PFKFB3 yog qhov muaj txiaj ntsig zoo tom qab IL{15}} kev kho mob thaum TECs puas thiab STAT3-AMPK/AKT PFKFB3 axis yog qhov tseem ceeb rau kev khaws cia. ntawm mitochondrial kev ncaj ncees thaum lub sij hawmraumraug mob(Daim duab 7). Lawv tseem yuav raug tshuaj xyuas yog tias IL-22 tseem tswj hwm lwm cov kev tswj hwm cov metabolism thiab cov txheej txheem cuam tshuam nrog rau lub raum raug mob los ntawm kev ua kom STAT3–AMPK/AKT-PFKFB3 txoj kev taw qhia.

FIGURE 7 Peb qhov kev tshawb pom qhia txog lub luag haujlwm tseem ceeb ntawm IL-22 hauv kev tswj lub raum cell metabolism los kho lub raum kev puas tsuaj los ntawm kev ua kom STAT3-AMPK/AKT-PFKFB3 axis. Cov txiaj ntsig no qhia tau tias txoj hauv kev kho mob ntawm IL-22 thiab tsom mus rau kev cuam tshuam cov teeb meem metabolic tuaj yeem ncaj qha rau kev kho mob rau ntau lub raum lossis kev tiv thaiv.

5 Cov lus xaus

Hauv kev xaus, peb tau pom cov kev kho mob muaj peev xwm thiab cov txheej txheem hauv qab ntawm IL-22 hauv lub raum puas. IL -22 tswj lub raum cell metabolism ntawm metabolic reprogramming kom khaws cia mitochondrial kev ncaj ncees. Inhibition ntawm lawv cov regulators (piv txwv li, AMPK, Akt, thiab PFKFB3) tuaj yeem ua rau cov kab mob metabolic tsis zoo thiab tsis muaj zog mitochondrial, raws li qhia hauv TECs nrog spontaneous -22 kev kho mob, uas tau nce dysfunctional mitochondria thiab mitochondrial ROS accumulation. Qhov tseem ceeb tshaj plaws, lub raum kev puas tsuaj los ntawm mitochondrial dysfunction thiab ROS tsub zuj zuj hauv cov qauv nas tau txo qis los ntawm IL-22 kev kho mob los ntawm kev ua kom STAT3-AMPK-AKT-PFKFB3 signaling. Yog li, peb txoj kev tshawb fawb tau qhia tias kev tsom xam cov teeb meem metabolic tuaj yeem ncaj qha ncaj qha rau ntau cov kab mob hauv lub raum puas thiab IL-22 yog tus kws kho mob muaj peev xwm tiv thaiv thiab kho cov kab mob no.

Cov khoom cistanche tuaj yeem khomob raum

Los ntawm: 'IL-22- kho lub raum metabolic reprogramming ntawm PFKFB3 los khoraumraug mob'los ntawmWei Chen, et al

---Clin. Txhais lus. Med. 2021; 11: e324.

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