Connexin 43: Lub Hom Phiaj Rau Kev Kho Mob Ntawm Cov Kab Mob Ntshav Qab Zib hauv Cov Mob Thib Ob ntawm Lub raum Thiab Qhov Muag

Ntsiab lus:ntshav qab zib; teeb meem; mob ntshav qab zib nephropathy; ntshav qab zib retinopathy; sib 43; hemichannels; hemichannel blockers; mob; purinergic; adenosine triphosphate

1. Taw qhia

Kev cuam tshuam yuav luag 10% ntawm cov neeg laus, ntshav qab zib yog kev txhawj xeeb txog kev noj qab haus huv thoob ntiaj teb uas cuam tshuam txog kwv yees li 463 lab tus tib neeg thoob ntiaj teb. Nrog rau qhov tshwm sim ntawm cov ntshav qab zib xav tias yuav nce mus rau 700 lab tus tib neeg los ntawm 2045 [1], nws tsis yog kev kho tus kab mob nws tus kheej, tab sis kev tswj hwm cov teeb meem thib ob uas ua rau muaj kev hem thawj loj tshaj plaws rau peb txoj kev noj qab haus huv [2].Kab mob nyuajhauvntshav qab zibtuaj yeem categorized li ib qhomacrovascularlos yogmicrovascular, nrog rau yav dhau los txuam nrogkab mob coronary artery[3], peripheral arterial disease [4], thiab stroke [5], whilstcov teeb meem microvascularsuav nrognephropathy[6–8], retinopathy [9,10] thiabkho qhov txhab tsis zoo[11,12]. Nyob rau theem pib ntawm kev kis kab mob, kev tswj hwm tsom mus rau kev tswj cov ntshav siab thiab kev tswj hwm glycemic zoo [13]. Txawm li cas los xij, rau ntau tus, kev tsis zoo ntawm kev noj qab haus huv yog qhov yuav tsum tsis txhob muaj, nrog rau lub raum tsis ua haujlwm, tsis pom kev lossis teeb meem ntawm cov hlab ntshav, ua rau muaj kev cuam tshuam los ntawm comorbidities (xws li, kub siab, rog rog, kab mob plawv) thiab kev noj qab haus huv tsis sib xws [14]. Thaum tsis muaj kev kho mob meej rau cov mob no, cov kev kho tshiab yuav tsum tau ceev.

NEW HERBS RAUCHRONIC INFLAMMATION DIABATES

Hauvntshav qab zibCov teeb meem tshwm sim nyob rau hauv cov lus teb rau sustained hyperglycemia thiab qis-qib systemic o, tom kawg ntawm uas yog siab nyob rau hauv hom 2 mob ntshav qab zib mellitus (T2DM), qhov twg ua ke nrog rog rog, nce adipose cov ntaub so ntswg secretes inflammatory mediators uas exacerbate lub xeev ntawm pre-muaj o. [15–18]. Muaj kev sib koom ua ke ntawm cov teeb meem microvascular hauv cov neeg mob T2DM, thiab cov tib neeg uas muaj ntshav qab zib nephropathy feem ntau muaj qhov tshwm sim ntau dua ntawm retinopathy piv rau cov neeg mob uas tsis muaj teeb meem ntshav qab zib raum [19-22]. Ib yam li ntawd, nyob rau hauv cov neeg uas muaj ntshav qab zib retinopathy tshwm sim ntau dua rau qhov pib ntawm lub raum teeb meem [23]. Cov kev tshawb pom no qhia txog 'txoj kev zoo' tus neeg sawv cev ntawm cov kab mob microvascular puas thiab mob ntev uas, thib ob rau ntshav qab zib, ua rau muaj kev ua haujlwm tsis zoo ntawm cov ntaub so ntswg. Tsis ntev los no retinopathy thiab nephropathy cov kev tshawb fawb pom zoo hais tias thaiv kev nthuav qhia thiab / lossis kev ua haujlwm ntawm cov qog nqaij hlav me me hu ua connexins nyob rau hauv cov kab mob pathophysiological, tuaj yeem ua rau cov kab mob matory ua rau cov kab mob loj hlob thoob plaws cov hnub nyoog no thiab lwm cov hnub nyoog cuam tshuam nrog pathologies, piv txwv li, rog [24,25. ], Alzheimer's disease [26,27] thiab osteoarthritis [28].

Connexins yog ib tsev neeg ntawm daim nyias nyias bound proteins koom nrog rau kev hloov ntawm cov me me molecules thiab ions ntawm ob lub hlwb (nruab nrab junctions) thiab nruab nrab ntawm cov hlwb thiab lawv imme diate ib puag ncig (hemichannels), highlighted nyob rau hauv daim duab 1. Nomenclature yog dictated los ntawm molecular hnyav [29] , nrog connexin 43 (Cx43) ntau tshaj hauv tib neeg [30]. Tsim los ntawm ib qho intracellular thiab ob lub voj voog ntxiv, thiab ib qho N- thiab C-terminus [31], lawv oligomerise rau hauv cov qauv hexameric hu ua connexons thiab raug xa mus rau plasma membrane hauv vesicles uas hla txoj hauv kev secretory [32,33]. Thaum cov neeg nyob sib ze ntawm cov hlwb sib raug zoo, connexons dock los tsim ib qho kev sib txuas tsis tu ncua, tsim txoj hauv kev ncaj qha rau kev sib txuas lus ntawm tes uas tso cai rau cov hlwb los synchronize lawv cov haujlwm [34–36]. Txawm hais tias qhov sib txawv ntawm kev sib txuas ua haujlwm tswj cov cellular muaj nuj nqi nyob rau hauv physiological tej yam kev mob undocked connexons, hu ua hemichannels, feem ntau txuas nrog pathophysi ological stimuli, xws li oxidative kev nyuaj siab [37] thiab o [35,38]. Dysregulation ntawm hemichannel muaj nuj nqi yog txuam nrog cov kab mob ntev, xws li lag ntseg [39], hlwb ischaemia [40] thiab mob ntev [41,42]. Lub luag haujlwm ntawm hyperglycemia hauv kev tswj hwm connexin qhia [43,44], qhov sib txawv ntawm kev sib txuas lus [45] thiab kev ua haujlwm hemichannel [46-48] tau sau tseg zoo [49], thiab ntawm 21 isoforms paub tias tau hais tawm hauv tib neeg lub cev, Cx43 tau txuas nrog rau cov kab mob pathogenesis ntawm ntau yam mob ntshav qab zib mellitus [43,50-52]. Hauv tsab xov xwm no, peb tshuaj xyuas lub luag haujlwm rau Cx43 hemichannels hauv cov mob ntev thiab cov teeb meem microvascular ntawm ntshav qab zib nephropathy thiab retinopathy, ua ntej tshawb nrhiav cov peev xwm kho mob ntawm hemichannel blockers hauv kev tiv thaiv kab mob Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW progression.

Daim duab 1. Daim duab qhia txog kev hloov pauv hauv hemichannel kev ua haujlwm hauv kev noj qab haus huv thiab ntshav qab zib. Thaum raug mob, qhov sib txawv junctions sib nrug. Cov kab tawg no tau dhau los ua endocytosis, sib sau ua ke rau hauv cov qauv ntawm ob sab hu ua connexosome thiab tom qab ntawd muaj kev txheeb xyuas endosome ua ntej thauj mus rau lysosomes rau degradation [53]. Cov xwm txheej no yog sib npaug los ntawm kev tswj hwm ntawm hemichannel kev ua si thiab tus lej, ua rau muaj kev tso tawm ntawm cov molecules, suav nrog ATP ua rau cov dej ntws qis thiab fibrosis ntawm purinergic signaling.

2. Kev Tiv Thaiv Kab Mob hauv Microvascular Complications of Diabetes

Instrumental rau lub pathogenesis ntawm cov ntshav qab zib thiab nws cov teeb meem, lub hom phiaj los tiv thaiv inflammatory kev kho mob tau pom zoo rau ob qho tib si kev tiv thaiv thiab kev kho mob ntawm cov ntshav qab zib thiab tau raug tshuaj xyuas ntau [54–56]. Paub txog kev cuam tshuam cov kab mob kis thoob plaws ntau lub hnub nyoog cuam tshuam xws li ntshav qab zib [55], rog rog [25] thiab hnub nyoog ntsig txog macular degeneration [57], tsis ntev los no tau tsom mus rau kev tsim cov tshuaj pharmacological uas thaiv cov neeg sib tw tseem ceeb, xws li nod-zoo li receptor protein 3 (NLRP3) inflammasome (piv txwv li, MCC950) [58], kev hloov hauv cell phenotype (xws li, senolytics) [59] los yog cell function (piv txwv li, sodium-glucose co-transporter-2 inhibitors: SGLT2i) [60–62].

NLRP3 inflammasome tau raug xa mus rau "tus txiv neej laus laus ntawm mob khaub thuas" [63] thiab txuas rau ntau yam mob xws li atherosclerosis [64], Alzheimer's disease [27], inflammatory plob tsis so tswj [65], thiab tsis. -alcoholic steatohepati tis [66]. Nws yog upregulated nyob rau hauv lub cev tsis muaj zog thiab epithelial hlwb nyob rau hauv ntau hom ntaub so ntswg, qhov ua kom culminates nyob rau hauv secretion ntawm pro-inflammatory mediators, interleukin -1 (IL1) thiab interleukin -18 (IL18). Nyob rau hauv tas li ntawd, cov no activates qog necrosis factor-alpha (TNF ) thiab interleukin -6 (IL6), ob qho tib si uas qhia tau hais tias nce qib ntshav nrog lub hnub nyoog thiab kab mob thiab kho mob o / fibrosis nyob rau hauv ntau yam mob thib ob mob ntshav qab zib [67-71. ]. Txij li cov mob mob ntev tau nthuav dav thiab nthuav dav los ntawm txoj kev ua rau mob, nws tsis yog qhov xav tsis thoob tias kev thaiv NLRP3 inflammasome ncaj qha (xws li, MCC950) alleviates o nyob rau hauv ntau lub hnub nyoog morbidities [60,68,72].

Txawm hais tias muaj kev txhawb nqa kev soj ntsuam no, daim pam thaiv ntawm ib feem tseem ceeb ntawm kev tiv thaiv kab mob hauv lub cev tau ntsib nrog kev txhawj xeeb. Ua kom muaj kev puas tsuaj los ntawm ob qho tib si cuam tshuam nrog cov qauv molecular (DAMPs) thiab cov kab mob txuam nrog cov qauv molecular (PAMPs), NLRP3 inflammasome mediates ob leeg sterile thiab non-sterile o [73]. Yog li ntawd, thaum inhibition ntawm NLRP3 inflammasome tuaj yeem tiv thaiv cov kab mob tsis zoo uas tshwm sim los ntawm endogenous noxious stimuli, qhov no tuaj yeem ua rau cov tib neeg raug mob qhov twg PAMP-koom nrog cov kab mob microbial tsis ua rau cov lus teb [74,75]. Nev ertheless, nrog rau NLRP3 tau raug txheeb xyuas tias yog tus neeg kho mob tseem ceeb ntawm kev mob hauv ntau dua 80 tus qauv sib txawv ntawm kev raug mob [76–80], nws tsis yog qhov xav tsis thoob tias ntau lub tebchaw tau nkag mus rau kev sim tshuaj, xws li Inzomelid (NCT04015076), IFM{{ 12}} (DFV890) (NCT04382053) and Dapansutrile (OLT1177) (NCT04540120) [81]. Txawm hais tias qhov no, cov tshuaj uas ua tiav lub hom phiaj NLRP3 tseem tsis tau mus txog nws qhov kawg qhov kawg, qhov kev soj ntsuam ua ke los ntawm peb tsis muaj kev paub txog nws cov qauv thiab cov chaw muaj peev xwm khi [82]. Yog li ntawd, cov kev cuam tshuam rau lub hom phiaj cov neeg nruab nrab hauv qab xws li IL1 thiab TNF, tau txais txiaj ntsig zoo heev. Canakinumab (ACZ885, Ilaris) yog ib tug neeg recombinant monoclonal antibody uas xaiv inhibits IL1 receptor binding thiab pom tau hais tias zoo thawj tshwm sim nyob rau hauv Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) [83]. Tom qab ntawd nws tau raug tso cai rau kev kho mob ntawm cov mob uas tsis tshua muaj mob, suav nrog kev mob caj dab hauv menyuam yaus [84]. Txawm li cas los xij, nws qhov kev ua tau zoo tau ua pov thawj tias kev poob siab hauv kev kho mob ntawm cov mob ntshav qab zib retinopathy (NCT01589029), Hom I Diabetes Mellitus (T1DM) (NCT00947427, [85]) thiab atherosclerosis (NCT00900146, [86]), muaj peev xwm txuas tau. kom nce tus kab mob thiab sepsis [87]. Cov kev siv zog zoo sib xws rau lub hom phiaj TNF suav nrog cov tebchaw uas muaj receptor fusion proteins (etanercept) [88], uas txwv tsis pub lub cev muaj zog teb rau TNF, lossis monoclonal antibodies (golimumab, infliximab, adalimumab thiab certolizumab pegol), tag nrho cov uas tau ntsib kev vam meej. [89].

Txawm hais tias pom tseeb tias muaj ntau yam uas yuav tsum tau kawm hauv peb qhov kev tshawb nrhiav los tsim cov kev cuam tshuam tshiab uas ua tiav (a) lub hom phiaj tsis muaj menyuam thiab (b) ua li ntawd thaum tsis muaj kev phiv loj, tsis ntev los no FDA pom zoo ntawm SGLT2 inhibitors tej zaum yog cov kauj ruam tseem ceeb tshaj plaws. pem hauv ntej hauv kev tswj hwm thiab txhim kho cov txiaj ntsig hauv cov neeg mob nephropathy [90] thiab kab mob plawv [91]. Los ntawm kev thaiv cov sodium glucose co-transport thiab txo cov ntshav qabzib, SGLT2i ua kom pom kev txhim kho lub raum thiab cov hlab plawv hauv cov neeg mob T2DM thiab ntshav qab zib nephropathy [92–94]. Txawm hais tias kev tiv thaiv thawj zaug tau xav tias yog los ntawm kev txo qis hauv glomerular hyperfiltration, ntau qhov kev tshawb fawb pom tau tias SGLT2i muab kev tiv thaiv los ntawm kev tawm tsam ntawm qhov mob thiab fibrosis, txawm hais tias cov txheej txheem dav dav tseem yuav tsum tau ua kom tiav [95-97]. Txawm li cas los xij, nrog cov tshuaj kho mob rau cov tib neeg uas muaj T2DM tsis yog T1DM thiab cov kev mob tshwm sim uas muaj nyob rau hauv clude ketoacidosis [98], nce kev pheej hmoo ntawm amputation [99], thiab nce kab mob genitourinary [100], SGLT2i tsis yog ib qho me me haum rau txhua tus. . Raws li lwm txoj hauv kev, Cx43 hemichan nel blockers yog ib chav kawm ntawm cov tshuaj uas suav nrog Gap19 [101] thiab Tonabersat [102,103]. Lawv khi rau, thiab kaw hemichannels los tiv thaiv kev tso tawm ntau DAMPs, suav nrog ATP (rau kev tshuaj xyuas ntau ntxiv txog seb cov peptides ua haujlwm li cas peb xa tus nyeem ntawv mus rau King li al. raws li luam tawm hauv qhov tshwj xeeb no) [104]. Nyob rau hauv lub xub ntiag ntawm DAMPs, NLRP3 complex yog qhib thiab elicits ib tug tsis tsim nyog inflammatory teb, stimulating thiab activat ing ntawm lub zos paracrine mediated signalling, ob qho tib si infiltrating lub cev tiv thaiv kab mob thiab cov neeg nyob hauv fibroblasts [50,78,105,106]. Raws li qhov no ib leeg, nws tsis yooj yim to taub yog vim li cas connexin hemichannel blockers tau nce qib raws li kev kho mob zoo hauv kev tiv thaiv kab mob tsis muaj menyuam hauv cov kab mob.