Pyroptosis: A New Frontier in Kidney Diseases Part 1

Pyroptosis yog ib qho qauv ntawm programmed cell tuag uas txawv ntawm apoptosis thiab autophagy nyob rau hauv cov nqe lus ntawm cell morphology thiab kev ua haujlwm. Cov txheej txheem ntawmpyroptosisyog tus cwj pwm feem ntau los ntawm kev tsim ntawm gastrin protein tsev neeg-mediated membrane perforation, cell collapse, thiab tso tawm ntawm inflammatory yam, xws li IL-1 thiab IL-18. Nyob rau hauv xyoo tas los no, nrog kev nce ntawmKev tshawb nrhiav pyroptosis, cov kws tshawb fawb tau mob siab rau lub sijhawm los kawm txog cov txheej txheem ntawm pyroptosis hauv cov kab mob hauv lub raum.Pyroptosistej zaum yuav muaj feem cuam tshuam rau cov kab mob raum los ntawm ob txoj hauv kev: lub caspase-1- txoj kev sib haum xeeb canonical thiab caspase-4/5/11- txoj kev sib haum xeeb uas tsis yog txoj hauv kev. Tsis tas li ntawd, qee cov kws tshawb fawb tau txheeb xyuas lub hom phiaj rau kev kho mob ntawm lub raum kab mob los ntawm kev pom ntawmpyroptosisthiab tsim cov tshuaj sib xws, uas yuav dhau los ua kev pom zoo rau kev kuaj mob, kev kho mob, thiab kev kuaj mob ntawm cov kab mob raum. Cov ntaub ntawv no tsom mus rau kev nce qib tshiab hauv thaj chaw ntawmpyroptosis, tshwj xeeb tshaj yog nyob rau hauv lub luag haujlwm tseem ceeb pathogenic ntawmpyroptosisnyob rau hauv kev loj hlob thiab kev loj hlob ntawm cov kab mob raum. Nws nthuav tawm kev nkag siab ntau ntxiv ntawm cov kab mob hauv lub raum thiab qhia txog cov hom phiaj kho mob tshiab rau kev tiv thaiv thiab kho mob raum kab mob.

1. Taw qhia

Cov kab mob raum yog qhov teeb meem kev noj qab haus huv thoob ntiaj teb, cuam tshuam ntau dua 750 lab tus tib neeg thoob ntiaj teb; lawv yog cov kab mob uas muaj qhov tshwm sim thiab kev tuag. Cov kab mob raum sawv cev muaj xws li mob raum raug mob (AKI) thiab mob raum mob (CKD). Nws kwv yees tias AKI ua rau kwv yees li 1.7 lab tus neeg tuag txhua xyoo thoob ntiaj teb, thiab qhov tshwm sim ntawm CKD thoob ntiaj teb yog kwv yees li 11-13 feem pua. Kev pheej hmoo ntawm cov kab mob hauv lub raum tseem nce ntxiv. Txawm li cas los xij, vim muaj qhov sib txawv loj ntawm cov teb chaws hauv kev lag luam kev noj qab haus huv, kab lis kev cai, thiab kev nom kev tswv, muaj ntau qhov sib txawv ntawm cov txheej txheem kuaj thiab cov phiaj xwm kev ntsuam xyuas, ua rau cov kev kho mob tsis zoo thiab lub nra hnyav.

Programmed cell tuag plays lub luag haujlwm tseem ceeb hauv kev saib xyuas ntawm cellular homeostasis.Pyroptosisyog hom proinflammatory programmed cell tuag; Nws yog qhib los ntawm ib tug mob ntsig txog caspase tsev neeg, uas cleaves gasdermin kom nthuav tawm nws NT davhlau ya nyob twg, translocates mus rau daim nyias nyias, thiab perforates daim nyias nyias, hloov intracellular osmotic siab thiab thaum kawg ua rau cell vau.PyroptosisFeem ntau tshwm sim hauv myeloid-derived phagocytes, xws li macrophages, dendritic cells, thiab neutrophil granulocytes. Cov kev tshawb fawb tsis ntev los no tau qhia tiaspyroptosisNws kuj tseem pom nyob rau hauv CD4 ntxiv rau T hlwb, keratinocytes, epithelial hlwb, thiab neurons.Pyroptosisfeem ntau yog tswj hwm los ntawm caspase-1-txoj kev sib haum xeeb canonical thiab caspase-4/5/11- txoj kev sib haum xeeb uas tsis yog txoj hauv kev.

Cov kev tshawb fawb tob tob tau qhia tiaspyroptosisyog koom nrog hauv kev tshwm sim thiab kev loj hlob ntawm ntau yam kab mob, tshwj xeeb tshaj yog kab mob raum. Qhov kev tshuaj xyuas no qhia txog qhov kev nce qib hauv kev tshawb fawb txog kev sib raug zoo ntawmpyroptosisthiabraumkab mobthiab tham txog lub peev xwm kho lub hom phiaj hais txog lub mechanism ntawmpyroptosishauvraumkab mob.

Raws li cov kev tshawb fawb cuam tshuam, nyob rau xyoo tas los no, kev tshawb fawb txog kev siv cov qia hlwb thiab tshuaj ntsuab suav tshuaj rau kev kho mobraumkab mobtau txais txiaj ntsig zoo. Lub ntsiab mechanism ntawm ob txoj kev kho mob yog los txhawb kev kho cov mob raum cov ntaub so ntswg thiab tiv thaiv lub raum tshuav nyiaj li cas.

Suav tshuaj ntsuab kho mob,cistanche, tau siv hauv tshuaj suav tshuaj los kho ntau yammob ntevraumkab mobtxij thaum ub los. Nws tau tshaj tawm tias cistanche muaj peev xwm txo qhov mob, txoraumfibrosis, thiab txhawb cov synthesis ntawm extracellular matrix Cheebtsam. Nws tau raug tshaj tawm tias cov teebmeem no yog vim nws cov khoom siv bioactive, suav nrog ntau cov tshuaj phenolic, triterpenoids, thiab coumarins.

Ntawm qhov tod tes, stem cell technology tau ua rau muaj kev hloov pauv hauv kev kho mob. Kev tshawb fawb tau pom tias cov qia hlwb tuaj yeem sib txawv rau ntau hom ntawm lub raum hlwb thiab ua cov haujlwm kho mob, suav nrog kev tiv thaiv cov ntaub so ntswg raum, ua kom cov nqaij mos fibrosis, thiab kho cov ntaub so ntswg puas.

Nyem rau Cistanche Tubulosa Supplement Rau raum Kab Mob

Nug ntxiv:

david.deng@wecistanche.com WhatApp:86 13632399501

Thaum kawg, kev sib xyaw ntawm cov tshuaj suav tshuaj suav nrog kev tshawb fawb niaj hnub tuaj yeem yog tus yuam sij rau kev kho ntau yamraumkab mob. Cov tswv yim no tau maj mam lees txais los ntawm cov kws kho mob hauv zej zog thiab cov kev tshawb fawb tau pom tias kev sib koom ua ke ntawm kev kho mobcistanchethiab kev kho mob qia cell yuav txo tau qhov kev tuag ntawmraumkab mob. 

Hauv kev xaus, kev siv cistanche thiab qia cell kho hauv kev kho mob ntawmraumkab mobqhia tau hais tias muaj peev xwm zoo thiab xav tau kev tshawb fawb ntxiv. Kev sib xyaw ua ke ntawm ob txoj kev kho mob tuaj yeem muab kev kho mob zoo dua rau cov neeg uas tab tom ntsibraumkab mob.

2. Pyroptosis

Brennan thiab Cookson pom tias Salmonella typhi tuaj yeem ua rau macrophage tuag los ntawm caspase-1-dependent mechanism, uas txawv ntawm qhov kev paub dhau los ntawm apoptosis. Hom kev tuag ntawm tes no yog hu uapyroptosis. Pyroptosistxawv ntawm apoptosis thiab necrosis nyob rau hauv cov nqe lus ntawm morphology thiab mechanism (Table 1). Thaumpyroptosis, cell membrane yuav puas thiab ib tug 1.1-2.4 nm perforation yog tsim; Vim yog kev hloov pauv hauv intracellular thiab extracellular osmotic siab, cov hlwb ua qog thiab tawg, daim nyias nyias yuav ploj, thiab cov teeb meem inflammatory raug tso tawm. Txawm li cas los xij, thaum lub sijhawm txheej txheem no, cov qauv thiab kev ua haujlwm ntawm mitochondria tseem nyob twj ywm.

3. Kev taw qhia txoj kev cuam tshuam nrog Pyroptosis

Cov ntaub ntawv pov thawj tau txheeb xyuas ob txoj hauv kev ntsig txogpyroptosis(Daim duab 1): lub caspase-1-txoj kev kho mob canonical uas yog induced los ntawm inflammatory lub cev thiab cov caspase-4/5/11-txoj kev kho uas tsis yog canonical uas yog qhib los ntawm lipopolysaccharide (LPS).

3.1. Canonical Pyroptosis Txoj Kev.Lub canonicalpyroptosistxoj kevyog kho los ntawm inflammatory lub cev, feem ntau nucleotide-binding oligomerization domain-like (NOD) receptor NLR tsev neeg thiab PYHIN protein tsev neeg. Lub cev muaj zog tuaj yeem qhib tau los ntawm cov kab mob sib txuas nrog cov qauv molecular (PAMPs) lossis kev puas tsuaj rau cov qauv molecular (DAMPs). Kev ua kom cov caspase-1 los ntawm lub cev inflammatory yuav ua raupyroptosis.

NLR protein tsev neeg yog tsim los ntawm cov nucleotide-binding oligomerization domain (NOD/- NACHT), C-terminal uas muaj leucine-nplua nuj rov ua dua (LRRs), thiab N-terminal recruiting caspase domain (CARD) lossis Pyrin domain (PYD ). NOD/NACHT domain yog sib koom los ntawm NLR tsev neeg, thiab nws cov teeb liab downstream yog qhib los ntawm ATP-dependent oligomerization. Lub luag haujlwm tseem ceeb ntawm LRRs yog cuam tshuam nrog ligand kev nkag siab thiab kev tswj hwm kev tswj hwm, qhov CARD thiab PYD domains yog tus neeg nruab nrab tseem ceeb ntawm kev sib cuam tshuam ntawm cov proteins zoo sib xws hauv cov teeb liab qis.

Feem ntau pom lub cev mob hauv tsev neeg NLR suav nrog NLRP3, NLRP1, NLRP6, thiab NLRP6; lawv inducepyroptosislos ntawm kev nrhiav neeg ua haujlwm ntawm caspase-1 ntawm lub adapter protein ntawm CARD-PYRIN [19]. Kev saib xyuas ntau tau them rau lub cev inflammatory NLRP3; Raws li ib qho intra-cellular sensor, nws tuaj yeem qhib tau los ntawm feem ntau ntawm cov kev pheej hmoo endogenous thiab ib puag ncig stimulants [20]. Tam sim no, nws paub tias NLRP3 tuaj yeem qhib tau ob txoj hauv kev: ib qho yog nyob ntawm microbial molecules lossis endogenous cytokines; Lwm qhov yog induced los ntawm APT, pore-forming toxins, viral RNA, thiab particulates [21]. Ib txoj kev tshawb fawb ntxiv tau qhia tias kev ua kom NLRP3 tuaj yeem ua rau kev tso tawm ntawm caspase-1-kho proinflammatory cytokines, xws li IL-1 thiab IL-18, thiab inducepyroptosis[20]. Nws tau tshaj tawm tias anthrax lethal toxin (LT) tuaj yeem qhib tau caspase -1-kev kho mob macrophagepyroptosis, whereas caspase-1 tau qhib los ntawm LT-mediated cleavage ntawm 10 loci ntawm NLPR1 thiab ua kom lub cev inflammatory [22]. Yog li ntawd, kev ua kom lub NLRP1 inflammatory lub cev plays lub luag haujlwm tseem ceeb hauv kev tso tawm ntawm IL-induced inflammatory yam, xws li IL-1 thiab IL-18, thiabpyroptosis[23, 24] ib. Lub NLRP6 inflammatory lub cev feem ntau yog qhib los ntawm microbiota-kawg metabolites xws li taurine los yog Porphyromonas gingivalis. Nws tseem tuaj yeem tswj cov caspase-1- kho kom haumpyroptosisntawm txoj hnyuv epithelial hlwb los yog tib neeg gingival fibroblasts [25, 26]. Nyob rau hauv 2017, Zhu et al. [27] pom tias NLRP9 tuaj yeem lees paub qhov luv luv ob-stranded RNA txuas ntxiv los ntawm RNA helicase Dhx9 thiab tsim cov kab mob sib kis nrog cov adapter proteins ASC thiab caspase-1, yog li txhawb kev tso tawm ntawm IL-1 thiab IL-18 thiab inducingpyroptosis.

Covpyroptosishais los saum toj no hais txog kev sib cuam tshuam ntawm adapter protein ASC thiab caspase-1. Yog li, nws tau raug tshuaj xyuas seb lub adapter protein ASC puas tsim nyog thaum lub sij hawm tag nrho cov txheej txheem ntawm inflammatory lub cev-mediatedpyroptosis. Kev tshawb fawb yav dhau los ntawm macrophages tau pom tias thaum NAIP1/2 thiab NAIP5/6, ob tug tswv cuab ntawm NLR apoptosis-inhibition protein (NAIP) tsev neeg, tau qhib los ntawm hom III secretion system (T3SS) thiab flagelellin, lawv tuaj yeem tsim NLRC{ {6}}NAIP1/2 complex, los yog NLRC4-NAIP5/6 complex, thiab nrhiav caspase-1 los ntawm CARD-CARD kev sib cuam tshuam los ua raupyroptosis[28–30]. ASC tsis koom nrog txoj haujlwm no. Hloov chaw, NLRC4 ncaj qha recruits caspase-1 los uapyroptosis. Qhov no yog tej zaum vim NLRC4 muaj CARD domain [31].

Ntxiv rau NLR tsev neeg, lwm lub cev inflammatory kuj koom nrog qhov tshwm sim thiab kev loj hlob ntawmpyroptosis. Piv txwv li, cytoplasmic dsDNA thiab dsDNA cov tshuaj tiv thaiv kab mob tuaj yeem khi rau HIN200 domain thaum tsis muaj melanoma 2 (AIM2), ua rau kev ua kom PYD ntawm AIM2 thiab tsim cov protein complex nrog AIM2, ASC, thiab caspase{ {5}} thiab thaum kawg inducingpyroptosis[32, 33] ib. Lub mechanism rau kev cai ntawmpyroptosislos ntawm pyrin, cov protein encoded los ntawm MEFV, zoo ib yam li AIM2. Tib neeg pyrin protein muaj plaub lub luag haujlwm ua haujlwm, pyrin domain (PYD), zinc ntiv tes sau (lub thawv), coiled-coil domain (CC), thiab B30.2 / SPRY domain. Nas pyrin muaj peb lub npe: PYD, bBox, thiab CC. Raws li tus qauv lees paub receptor, pyrin tsis ncaj qha paub txog qhov muaj feem cuam tshuam ntawm cov kab mob lossis cov tswv. Hloov chaw, qhov tsis ua haujlwm ntawm RhoA GTPase induced los ntawm cov kab mob tuaj yeem ua rau muaj kev cuam tshuam ntawm pyrin thiab caspase-1 thiab PYD, uas thaum kawg induces caspase-1- kho lub cev tiv thaiv kab mob.pyroptosis[34].

Kev nrhiav neeg ncaj lossis tsis ncaj ntawm caspase-1 los ntawm lub cev inflammatory los tswjpyroptosistau kawm zoo. Txawm li cas los xij, cov txheej txheem los ntawm kev qhib lub caspase- 1 mediatespyroptosistseem tsis paub. Xyoo 2015, Shao et al. pom, nyob rau hauv ib qho kev sim hauv vitro, tias thaum caspase-1 tau qhib rau hauv nas marrow macrophages, nws tuaj yeem cais cov gastrin-N thiab gastrin-C tawg ntawm gasdermin (GSDMD) [35]. Nws tau raug lees paub ntxiv tias GSDMD-N ntu tuaj yeem ua rau muaj kev tuag ntawm tes, uas yog ze rau ntau dua.pyroptosis. Kev kuaj hauv vitro qhia tias GSDMD-NT tsim thiab ua kom cov caspase-1 tshwm sim ib txhij thiab tias ASC tsis tsim nyog rau kev ua kom GSDMD. Qhov no txhais tau hais tias cleaved caspase -1 tuaj yeem tsis tsuas cleave GSDMD tab sis kuj ncaj qha qhib GSDMD [36]. Thaum GSDMD yog cleaved rau hauv ib pawg ntawm GSDMD-NT, cov fragments no tsiv mus nyob rau hauv daim nyias nyias thaum sib sau ua ke thiab perforating daim nyias nyias, ua rau tso tawm ntawm inflammatory yam, xws li IL-1 thiab IL-18. Raws li tus naj npawb ntawm qhov nce, daim nyias nyias tawg, thiab cov ntsiab lus ntawm tes xws li IL-1 thiab cov pab pawg neeg muaj zog siab lub thawv 1 protein (HMGB1) raug tso tawm, ua rau cov yam ntxwv hloov pauv ntawmpyroptosis[37, 38].

3.2. Noncanonical Pyroptosis Signaling Pathway.Ntxiv rau qhov canonicalpyroptosissignaling pathway, lub noncanonicalpyroptosiskev taw qhia txoj kev kuj tau kawm zoo. Hauv xyoo 2011,pyroptosisnyob rau hauv macrophages kis E. coli, Citrobacter corynii, los yog Vibrio cholera tsis yog nyob ntawm inflammatory lub cev, tab sis ntawm caspase -11 [39]. Lipopolysaccharide (LPS) yog lub hauv paus tseem ceeb ntawm cov kab mob gram-tsis zoo, thiab cov kab mob LPS tuaj yeem raug lees paub los ntawm Tus Xov Tooj Zoo li receptor 4 (TLR-4) los txhawb kev hloov pauv ntawm cytokines. Nws tau pom tias LPS hauv macrophages tuaj yeem qhib tau caspase-11 thiab, thaum lub sijhawm ua haujlwm, tus kab mob cholera toxin B yog cytoplasmic carrier ntawm LPS thiab LPS tuaj yeem qhib caspase-11 ntawm nws tus kheej ntawm TLR4, qhia tias caspase{{ 9}} ncaj qha teb rau cytoplasmic LPS [40–42]. Nws kuj tau pom tias caspase -11 thiab homologous rau tib neeg caspase -4 thiab caspase -5 tuaj yeem khi ncaj qha rau LPS kom nws tus kheej qhib, yog li inducingpyroptosis, txawm hais tias lub luag haujlwm ntawm LPS hauv kev ua kom cov caspase-11 thiab tib neeg caspase homology xav tau kev tshawb nrhiav ntxiv [43]. Nws kuj tau pom tias GSDMD yog qhov tsim nyog raupyroptosisnyob rau hauv caspase-4/5-mediated nas macrophages [44]. Ib yam li ntawd, Aglietti et al. [45] tau tshaj tawm tias p30 protein fragments muab tau los ntawm GSDMD cleavage tom qab caspase -11 ua kom muaj peev xwm khi rau daim nyias nyias, ua rau tus yam ntxwv morphology ntawmpyroptosisthiab membrane perforation. Ib txoj kev tshawb fawb tshiab tau pom tias Asp289/285 loci ntawm caspase- 4/11 yog qhov tseem ceeb rau kev cuam tshuam ntawmpyroptosis, uas rov nthuav peb txoj kev paub ntawmpyroptosis[46].

Yog li ntawd, nws yuav tsum tau txiav txim siab seb caspase -11- kho mobpyroptosistau hais txog caspase-1. Pannexin -1 yog ib qho membrane channel protein uas tau nthuav tawm dav dav hauv txhua yam ntaub so ntswg thiab hlwb thiab tuaj yeem cleaved thiab lysed los ntawm caspase -11, ua rau cov channel rau cov membrane me me molecule tso, ua rau efflfflfflux ntawm intracellular ATP. , ua kom cov ligand-gated ion channels (P2X7) ntawm purinergic receptor P2X, thiab kev kho kom haum xeebpyroptosislos ntawm macrophages [47] Nws kuj tau pom tias exogenous APT tuaj yeem qhib P2X7 los ua ib txoj hauv kev rau K ntxiv rau efflfflfflux, uas yog qhov tseem ceeb rau kev ua kom lub cev ua rau NLRP3. Yog li ntawd, nws zoo li caspase-11- txoj kev kho mob uas tsis yog kev kho mob tuaj yeem txhawb nqa K ntxiv rau efflfflfflux ntawm pannexin-1, yog li ua rau NLRP3 inflammatory lub cev thiab caspase-1 thiab thaum kawg ua raupyroptosis, maturation, thiab tso tawm inflammatory yam [48, 49].

Ntau qhov kev tshawb fawb tau pom tias caspase-8 plays lub luag haujlwm tseem ceeb hauv cov kab mob tshwm sim los ntawm cov kab mob macrophages. Hauv xyoo 2018, nws tau pom tias tau txais cov caspase-8 tuaj yeem ua rau cov cell membrane puas thiab K ntxiv rau cov neeg sab nraud, uas ntxiv rau NLRP3 inflammasome thiab ua rau oligomerization ntawm ASC. Yog li ntawd, IL-1 raug tso tawm, thiab thaum lub sijhawm ua haujlwm no, GSDMD ua lub luag haujlwm tseem ceeb [50]. Hauv tib lub xyoo, lwm pab pawg kuj pom tias caspase-8 tuaj yeem ua rau lysis ntawm GSDMD thiab GSDME hauv murine macrophages, ua rau IL-1 tso tawm thiabpyroptosis. Ntxiv mus, nyob rau hauv tus qauv nas ntawm colitis, cov lus teb inflammatory kuj tau pom tias muaj feem xyuam nrog caspase-8- khopyroptosis[51]. Yog li, nws tau hais tias caspase -8 yog qhov hloov pauv raupyroptosis[52]. Txawm li cas los xij, nws tseem tsis tau paub meej tias caspase -8 cais-cleaves GSDMD ncaj qha lossis seb puas yuav tsum muaj cov khoom nruab nrab. Txog rau xyoo 2020, nws tau ntseeg tias caspase-8 ua haujlwm los ntawm qhov ncaj qha cleavage ntawm GSDMD thiab cov haujlwm ntawm caspase-8 ntawm cov complexes sib txawv cuam tshuam rau nws lub peev xwm los ncaj qha GSDMD [53, 54]. Tam sim no, kev tshawb fawb txog kev sib raug zoo ntawm caspase-8 thiabpyroptosistseem tab tom tshwm sim, thiab ntau lub tswv yim txog kev tshawb fawb xav tau kev tshawb nrhiav ntxiv.

Daim duab 1:Canonical caspase-1-dependent and noncanonical caspase-4/5/11-mediated pyroptosis pathways [20, 33, 36, 37, 39, 43, 44, 48, 49]. Lub canonical pyroptosis signaling txoj hauv kev: NLRP3 inflammatory lub cev yog qhib los ntawm cov kab mob sib txuas nrog cov qauv molecular (PAMP) lossis kev puas tsuaj rau cov qauv molecular (DAMP), thiab AIM2 inflammatory lub cev yog qhib los ntawm dsDNA. Lawv induce lub activation ntawm downstream caspase-1. Ntawm ib sab, qhov no txhawb kev tso tawm ntawm cov teeb meem inflammatory IL-1 thiab IL-18; Ntawm qhov tod tes, qhov no tshwj xeeb cleaves GSDMD. GSDMD-N terminal fragment aggregates ntawm lub cell membrane ua rau daim nyias nyias perforation thiab induce pyroptosis. Noncanonical pyroptosis signaling pathway: lipopolysaccharide (LPS) ncaj qha qhib caspase-11 (tib neeg homology caspase-4/5) thiab tom qab ntawd cleaves GSDMD los ua GSDMD-N davhlau ya nyob twg, inducing pyroptosis. Pannexin -1 yog cleaved thiab lysed los ntawm lub tshuab txais caspase-11 (homologous rau tib neeg caspase-4/5), uas ua rau cov channel rau membrane me me molecule tso tawm, ua rau kom nkag mus ntawm intracellular ATP, activates cov ligand-gated channels (P2X7) ntawm purinergic receptor P2X, accelerates K ntxiv rau efflfflfflux, mediates NLRP3/caspase-1 taw qhia txoj kev, thiab indirectly txhawb kev tso tawm ntawm inflammatory yam tseem ceeb IL-1 thiab IL{{ 36}} ib.

Tsis tas li ntawd, activated caspase -3 kuj tseem tuaj yeem lyse GSDME los ntxias pyroptosis [55]. Hauv 2019, Nomenclature Committee on Cell Death (NCCD) tau hloov kho lub ntsiab lus ntawm pyroptosis thiab txhais tias nws yog tus qauv kev tuag ntawm tes nyob ntawm cov gasdermin tsev neeg cov protein koom nrog hauv daim nyias nyias perforation. Txawm li cas los xij, pyroptosis tsis yog ib txwm nyob ntawm qhov induction ntawm inflammatory caspases. Tsis tas li ntawd, hom kev tuag ntawm tes tsis yog txiav txim los ntawm hom caspase, tab sis los ntawm cov substrates cleaved los ntawm caspase [5].

4. Kev sib koom ua ke ntawm Pyroptosis thiab raum kab mob

Cov kab mob hauv lub raum uas tuaj yeem ua rau mob raum kawg (ESRD) muaj xws li mob raum raug mob, mob raum mob ntshav qab zib, mob raum fibrosis, thiab mob raum. Nws tau raug lees paub tias txhua hom kab mob raum raug cuam tshuam los ntawm qee theem ntawm cov tshuaj tiv thaiv kab mob.Pyroptosis, tswj los ntawm ntau yam inflammatory lub cev, plays lub luag haujlwm tseem ceeb hauv kev loj hlob ntawm cov kab mob raum. Tsis tas li ntawd, muaj ntau yam modulatory mechanisms ntawm cov kab mob raum.

4.1. Mob raum mob. Mob raum mob (AKI)yog induced los ntawm ntau yam uas yog yus muaj los ntawm ib tug sai poob rau hauv lub raum ua hauj lwm thiab tsub zuj zuj ntawm metabolic pov tseg thiab toxins; Thaum kawg, muaj teeb meem thiab tsis ua haujlwm ntawm lwm yam kabmob yuav tshwm sim. Cov kab mob tseem ceeb ntawm AKI yog lub raum tubular epithelial cell raug mob, interstitial o, thiab tsis ua haujlwm ntawm cov hlab ntsha. Ischemic reperfusion, endogenous, thiab exogenous nephrotoxins, nrog rau qhov sib piv nruab nrab, yog ib yam ntawm AKI [56]. Ntau cov kev tshawb fawb tau qhia tias cov xwm txheej no tau hais tias ua rau AKI cuam tshuam nrogpyroptosis.

Xyoo 2010, Shigeoka et al. [57] tau tshaj tawm tias NLRP3 tau qhia ntau heev hauv lub raum tubular epithelial hlwb ntawm nas thiab tib neeg tab sis tau txhim kho hauv lub raum IRI, qhia txog lub luag haujlwm tseem ceeb ntawm NLRP3 hauv IRI hauv lub raum. Yang et al. [58] yog thawj pab neeg tshaj tawm tiaspyroptosisyog ib qho xwm txheej tseem ceeb thaum lub sij hawm IRI ntawm lub raum; lub overactivation ntawm endoplasmic reticulum stress-triggered CHOP-caspase- 11 txoj kev taw qhia ua lub luag haujlwm tseem ceeb hauv pyroptosis ntawm lub raum tubular epithelial hlwb tom qab lub raum IRI. Qhov no yuav pab txhawb kev tshawb fawb ntxiv ntawm kev sib raug zoo ntawmpyroptosisthiab mobraumraug mob. AKI yav dhau los lub npe hu ua mob raum tsis ua haujlwm, thiab txoj kev tshawb fawb pom tias rov ua dua LPS tuaj yeem ua rau lub cev ua haujlwm ntawm caspase-1/IL-1 thaum lub raum tsis ua haujlwm, ua rau pyroptosis [59].

Hauv xyoo 2019, qhov kev qhia ntawm caspase-11 tau pom tias tau nce ntxiv hauv tubular cell qauv ntawm cis-platinum-induced AKI. Kev ua kom cov caspase-11 cleaves GSDMD rau hauv GSDMD-NT, uas tau hloov mus rau plasma membrane, ua rau pyroptosis thiab txhawb kev tso tawm ntawm IL-18 [60]. Iodized contrast agents kuj tuaj yeem ua rau mob raum. Nws yog qhov zoo li tias cov neeg ua haujlwm sib txawv ua rau cov membrane ntawm cov hlwb epithelial, nkag mus rau hauv cov hlwb kom qhib tau caspase-4/5/11, cleave GSDMD, thiab pibpyroptosis[61]. Ib txoj kev tshawb fawb tshiab tau pom tias pyroptosis kho los ntawm caspase-11/GSDMD txoj kev qhia tsis tau tsuas yog cuam tshuam rau kev tso tawm cytokines tab sis kuj txiav txim siab qhov hnyav ntawm AKI tom qab septic shock [62]. Cov txiaj ntsig no qhia tias muaj kev sib raug zoo ntawm cov kab mob ntawm AKI thiab cov caspase-4/5/11- txoj kev sib haum xeeb nyob rau hauvpyroptosis. Tsis tas li ntawd, ib txoj kev tshawb fawb tsis ntev los no pom tias caspase-3/GSDME-mediated pyroptosis kuj muaj feem xyuam rau qhov tshwm sim thiab kev loj hlob ntawm AKI. Kev cuam tshuam ntawm caj ces thiab kev tshawb fawb tshuaj nrog GSDME-tsis muaj nas thiab tib neeg lub raum tubular epithelial hlwb pom tias caspase-3 tuaj yeem txo qispyroptosisthiab ncua AKI los ntawm kev thaiv GSDME lysis [63]. Yog li ntawd, tsompyroptosistej zaum yuav yog ib txoj hauv kev tshiab rau kev kho AKI.

4.2. Mob ntshav qab zib raum. Mob ntshav qab zib mellitus (DKD)yog ib qho teeb meem microvascular ntawm ntshav qab zib. Qhov no yog ib hom kab mob tshwm sim los ntawm kev ua haujlwm tsis zoo ntawm cov piam thaj metabolism. DKD yog tus cwj pwm los ntawm glomerular caws pliav, tso zis protein, thiab txo lub raum ua haujlwm. Cov cuab yeej tseem ceeb ntawm DKD yog qhov tuab ntawm glomerular hauv qab daus daim nyias nyias, dilation ntawm glomerular mesangial, poob ntawm Sertoli hlwb, fibrosis ntawm glomeruli, thiab mob fibrosis. Tam sim no, DKD feem ntau yog kho nrog hypoglycemia thiab tswj cov ntshav qabzib zoo dua. Txawm li cas los xij, qhov no tsis ua rau txo qis hauv DKD. Yog li ntawd, nws yog ib qho tseem ceeb los soj ntsuam cov pathogenesis ntawm DKD [63].

Hauv xyoo 2011, NLRP3-ASC-caspase-1 txoj kev taw qhia tau pom los txhawb kev mob ntshav qab zib los ntawm kev tswj hwm kev tso tawm ntawm IL-1 thiab lwm yam inflammatory factor [64]. Nws kuj tau pom tias tsis tu ncua hyperglycemia tuaj yeem ua rau NLRP3 inflammatory lub cev, txhawb kev tso tawm ntawm IL-1 thiab IL-18, thiab thaum kawg ua rau qhov tshwm sim thiab kev loj hlob ntawm DKD [65]. Knockout ntawm NLRP3 noob nyob rau hauv nas ncua DKD thiab alleviated raum raug mob los ntawm inhibition ntawm inflammatory tshuaj [66]. Serum NLRP3 mRNA kuj yog biomarker siv los txheeb xyuas cov neeg mob nrog DN [67]. Qhov no yog qhov qhia txog lub luag haujlwm tseem ceeb ntawm NLRP3 hauv kev tswj hwm qhov tshwm sim thiab kev vam meej ntawm DKD.

NLRP3 inflammatory lub cev yog ib qho ntawm cov hom phiaj tshaj plaws rau kev tswj hwm ntawmpyroptosis. Yog li ntawd, peb txiav txim siab seb pyroptosis puas koom nrog qhov tshwm sim thiab kev loj hlob ntawm DKD. Cov txiaj ntsig ntawm kev tshawb fawb hauv vitro pom tias qhov kev qhia ntawmpyroptosis-related proteins, xws li cleaved caspase-1, GSDMD, thiab N davhlau ya nyob twg ntawm GSDMD (GSDMD-NT), tau txhim kho thaum lub sij hawm kev loj hlob ntawm DKD, thiab hais tias ib tug cim-tso tawm ntawm inflammatory yam tseem ceeb kuj tau pom [68 , 69] ib.

Nyob rau hauv xyoo tas los no, kev sib raug zoo ntawm cov tsis ntev RNAs (lncRNAs),pyroptoss, thiab DN tau txais kev saib xyuas ntau. Nws tau pom tias RNA MALAT1 tuaj yeem cuam tshuam miR-23c qhia thiab txhawb nqa hyperglycemia-inducedpyroptosisntawm lub raum tubular epithelial hlwb los ntawm inhibiting miR-30c ntawm kev ua kom NLRP3 [70]. Kev tshawb fawb tsis ntev los no tau qhia tias NEAT1/miR-34c/NLRP3- hloov khopyroptosisthiab qhov mob tom qab tuaj yeem txhawb nqa kev loj hlob ntawm DKD [71]. Hauv cov ntsiab lus, kev nthuav qhia ntawm lncRNAs muaj kev cuam tshuam zoo nrogpyroptosisthiab yog lub peev xwm biomarker rau DKD. Tam sim no, feem ntau ntawm cov kev tshawb fawb txog DKD yog tsom rau ntawm cov caspase-1-kev kho kom haum xeebpyroptosistxoj hauv kev, uas yuav muab kev nkag siab zoo dua thiab txoj hauv kev zoo dua rau kev tiv thaiv thiab kho DKD.

4.3. Lub raum Fibrosis.Qhov txhab, kab mob, o, ntshav khiav tsis zoo, tiv thaiv kab mob, thiab ntau lwm yam kab mob tuaj yeem txhim kho fibroblasts thiab tsub zuj zuj ntawm collagen nyob rau hauv lub raum interstitium, ua rau lub raum interstitial fibrosis thiab thaum kawg ESRD.

Kev nthuav qhia ntau ntxiv ntawm NLRP3 thiab caspase-1, nrog rau kev txhim kho kev tso tawm ntawm IL-1 thiab IL-18 inflammatory lub cev, tau pom nyob rau hauv ob lub raum biopsy cov qauv ntawm UUO nas thiab tib neeg nrog UUO (unilateral ureteral occlusion), whereas lub raum fibrosis tau markedly alleviated nyob rau hauv NLRP3-/- nas [72, 73]. Hauv kev kawm ntev, Miao et al. [74] pom nyob rau xyoo 2018 tias hauv UUO nas caspase-11 tuaj yeem qhib tau caspases-1, txhim kho qhov tso tawm ntawm cov kab mob inflammatory, thiab txhawb kev loj hlob ntawm lub raum fibrosis; pyroptosis yog ib qho UUO kho los ntawm atypical caspase -11 txoj kev. Necrotic DNA tuaj yeem ua rau UUO ua rau mob raum thiab raug mob los ntawm kev ua kom lub cev inflammatory AIM2 [75]. Kev sib raug zoo ntawmpyroptosisthiab lub raum fibrosis tau kawm zoo. Hauv xyoo 2012,pyroptosistau pom los koom rau hauv lub raum interstitial fibrosis hauv tus qauv nas ntawm UUO; qhov kev koom tes no tej zaum muaj feem cuam tshuam nrog kev mob, tab sis cov txheej txheem tseem tsis paub [76]. Xyoo 2016, Xu et al. [77] pom tias qhov poob ntawm MAP1S ua rau muaj kev sib txuam ntawm nas lub raum fibrosis ntsig txog cov proteins thiab lub raum fibrosis hauv cov nas laus. Tsis tas li ntawd, qhov inhibition ntawm MAP1S nyob ze-kawg lub raum tubular hlwb tuaj yeem ua rau muaj kev loj hlob lossis kev loj hlob ntawm lub raum.pyroptosis, uas yog ntxiv qhia txog kev sib raug zoo ntawm kev sib raug zoopyroptosisthiab lub raum fibrosis. Tsis tas li ntawd, kev tshawb fawb tsis ntev los no tau qhia tias caspase-3/GSDME-mediated UUO muaj feem xyuam rau lub raum tubularpyroptosishauv nas. Qhov no qhia txog lub luag haujlwm rau intraurethral obstruction hauv lub raum tubular raug mob, ua rau lub raum fibrosis [78]. Txawm li cas los xij, tsuas yog qee qhov kev tshawb fawb tau hais txog lawv txoj kev sib raug zoo thiab yuav tsum muaj kev kawm tob ntxiv rau yav tom ntej.

Nug ntxiv:david.deng@wecistanche.com WhatApp:86 13632399501