Targeting S100B Protein Ua Ib Tus Neeg Sawv Cev Biomarker Thiab Nws Lub Luag Haujlwm hauv Ntau Yam Kev Nyuaj Siab Part 2

2. Structure ntawm S100B protein

S100B yog zinc (Zn2+) thiab calcium (Ca2+) khi acidicprotein nyob rau hauv lub nucleus thiab cytoplasm ntawm ntau lub hlwb. S100 protein genes muaj 13 tus tswv cuab tam sim no ua ib pawg ntawm chromosome 1q21 [45, 46].

Acidic proteins yog ib qho tseem ceeb ntawm chromatin nyob rau hauv lub nucleus ntawm paj hlwb. Nws cov ntsiab lus thiab kev faib tawm yog ze ze rau kev nco.

Kev tshawb fawb tshawb fawb pom tau tias muaj ob hom kev nco hauv tib neeg lub hlwb: kev nco luv luv thiab kev nco mus ntev. Lub cim xeeb ntev ntev tuaj yeem nyob ntev hnub, hli, lossis ntev dua, thiab yog txoj kev nco uas xav tau hauv tib neeg lub neej.

Hauv lub hlwb, kev nco mus ntev yog ua tiav los ntawm kev sib txuas ntawm cov neurons. Thaum lub cim xeeb khaws cia, acidic proteins nyob rau hauv neurons tau nthuav tawm, uas tuaj yeem ua rau kom muaj zog ntawm synapses thiab tuav lub cim xeeb mus ntev.

Nyob rau tib lub sijhawm, overexpression ntawm acidic proteins tuaj yeem ua rau synaptic abnormalities, nco poob, thiab txawm mob hlwb. Yog li ntawd, nws tseem ceeb heev kom khaws cov kua qaub acidic nyob rau theem tsim nyog.

Txhawm rau tiv thaiv thiab txhim kho kev nco, cov kev ntsuas hauv qab no tuaj yeem ua:

1. Kev tawm dag zog. Kev tawm dag zog tsim nyog tuaj yeem txhawb kev sib txuas ntawm cov neurons, nce cov kua qaub protein ntau, thiab ua kom lub cim xeeb zoo.

2. Txhim kho kev ua neej nyob. Ua tib zoo so, thiab tsis txhob nyob twj ywm lig thiab siv cov khoom siv hluav taws xob ntau dhau, uas yuav pab tswj kev ua haujlwm zoo ntawm lub paj hlwb.

3. Noj zaub mov nco ntxiv. Piv txwv li, ntses, walnuts, tsaus qhob noom xim kasfes, qe, thiab lwm yam. Cov khoom noj no yog nplua nuj nyob rau hauv Omega-3 fatty acids, zinc, tooj liab, folic acid, thiab lwm yam khoom xyaw, uas pab txhim kho kev nco.

Hauv ntej, kev sib raug zoo ntawm acidic protein thiab kev nco yog qhov tseem ceeb heev. Los ntawm txoj kev tshawb fawb, peb tuaj yeem ua kom muaj qhov tsim nyog faib cov kua qaub protein, yog li txhim kho kev nco. Nyob rau tib lub sijhawm, peb yuav tsum tau ua tib zoo saib xyuas tus cwj pwm zoo thiab tswj lub cev thiab lub hlwb kom zoo kom muaj kev nco zoo. Nws tuaj yeem pom tau tias peb yuav tsum txhim kho kev nco, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim Cistanche yog cov tshuaj suav tshuaj suav nrog ntau yam tshwj xeeb, ib qho ntawm kev txhim kho kev nco. Kev ua tau zoo ntawm Cistanche los ntawm ntau yam khoom xyaw uas nws muaj, suav nrog tannic acid, polysaccharides, flavonoid glycosides, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv ntau txoj hauv kev.

Nyem Paub Txoj Kev Txhim Kho Kev Nco

Raws li kev tsim qauv, nws muaj ob thaj tsam ntawm EF-tes hom, lub npe hu ua ahelix-loop-helix motif koom nrog hauv cheeb tsam pob khawm [27].

Cov protein yog tsim los ntawm 2 zoo tib yam chains ntawm 91-amino acid polypeptide, uas muaj ob lub tswv yimEF-tes helix-loop-helix calcium-binding regions.Txhua subunit ntawm S100B suav nrog plaub helixes (helix 1,E{{8 }}R20; helix 2, K29-N38; helix 3, Q50-D61; {21}}K28; thiab strand 2, E67-D69). Cov helices thiab cov ntawv sau ua qauv thiab pseudo-EF ob txhais tes ua ke [47, 48].

C-terminal domain muaj canonical 12 amino acid-binding loopswith classical EF-tes thiab N-terminal domain muaj 14 S100B tshwj xeeb amino acid-binding loops [49,50].

Cov amino acid ib ntus tau pom tias muaj thaj tsam ntawm kev sib koom ua ke ntawm lipophilic, yooj yim, thiab acidic aminoacids thiab thaj tsam calcium-binding hauv cov kua qaub [51].

S100b nrog kev sib raug zoo nruab nrab (2-20M) khi nrog ob lub calcium ions rau ib lub subunit [27] (Daim duab 1). Tsis tas li ntawd, calcium-binding rau EF-tes pib cov kev hloov pauv uas tso cai rau lub hom phiaj ntawm cov protein sib cuam tshuam.S100B proteins yog sib txawv los ntawm lwm cov helix-loop-helix EF-tes proteins los ntawm lawv cov peev xwm los khi Ca{10}}ions hauv lawv cov amino-terminal binding qhov chaw uas yog peculiardiametric tsev tsim.

Ntxiv mus, muaj peev xwm hloov pauv hlau khi xws li tooj liab, zinc, thiab manganeseat dimer interface ntawm histidine-nplua nuj binding qhov chaw [27]. Hauv kev muaj magnesium thiab poov tshuaj, affinity ntawm cov protein rau Ca2+ ions yog txo.

Cov calcium-binding tuaj yeem tshwm sim ntawm ob qhov chaw uas yog alpha thiab beta, uas muaj zog tiv thaiv los ntawm potassium [52].

Cov protein no cuam tshuam nrog lub hom phiaj cov protein uas pom tias coj cov cysteine ​​residues (ib qho ntawm S100A1 thiab ob hauv S100B); Tsis tas li ntawd ntawm astretch ntawm 13 amino acids, ib cheeb tsam txuas hauv nruab nrab koom nrog EF-tes calcium-binding domains [53].

3. LUB RECEPTOR ntawm S100B PROTEIN

S100 proteins ua rau RAGE thiab TLR-4 receptors.RAGE yog lub cell nto receptor ntawm immunoglobulin tam sim no hauv ntau hom cell xws li mononuclear phagocytes, cov ntaub so ntswg macrophages, plawv myocytes, ntsws, fibroblasts, epithelialcells, endothelial hlwb, neurons, thiab cov leeg nqaij. [54].

Lawv kuj tau piav raws li tus qauv lees paub receptor. Kev ua kom muaj zog ntawm cov hlwb RAGE los ntawm S100proteins pib ua ntau yam intracellular signaling pathways thiab ntau yam kev hloov pauv xws li NF-kB, AP-1, thiab STAT3 (Signal transducer thiab activator of transcription 3), uas ua rau muaj kev nthuav qhia ntawm proinflammatory cytokines thiab cellular. adhesion molecules.

S100 proteins cuam tshuam nrog ntau yam RAGE domains xws li V domain, C1 domain, thiab C2 domain [55]. Lub V domain yog nyob ntawm N- lub davhlau ya nyob twg ntawm feem ntau lateral txoj hauj lwm ntawm lub plasma membrane, whereas lub C2 domain yog nyob ze ntawm daim nyias nyias. Ob tug uas nyob ib sab V thiab C1 koom ua ke thiab builda me ntsis bent elongated qauv [56, 57] (Daim duab 2).

S100B protein cuam tshuam nrog V domain whereasother proteins like S100A12 and S100A6 is know to interact with the V and C domains. S100A12 cuam tshuam ntawm V thiab C1domain thiab S100A6 cuam tshuam ntawm V thiab C2 sau. Qhov tseeb khi qhov chaw ntawm S100A8 / A9 hauv RAGE domain tseem tsis tau lees paub.

RAGE domain feem ntau yog qhib los ntawm S100 proteins sib txawv xws li S100B, S100A12, S100A8/A9, thiab lwm yam, thiab ntxiv rau lawv tuaj yeem ua rau MAPKpathway ua kom thiab NF-Kb hloov pauv los ntawm cytosol mus rau lub nucleus, uas ua rau lub cell ciaj sia thiab Kev loj hlob zoo li cov noob caj noob ces [55]

4. S100B hauv ALZHEIMER'S SAIB

AD yog ib qho kev hloov pauv tsis tau, kev loj hlob ntawm cov kab mob neurodegenerative uas maj mam ua rau kev xav, lub peev xwm nco, thiab lub peev xwm los ua cov haujlwm yooj yim [58]. Thawj cov cim histopathological ntawm AD yog cov neurofibrillary tangles pom intracellularly thiab amyloid plaques pom extracellularly uas paub zoo tias degenerate hippocampal neurons [59].

Hauv cov neeg mob AD, qib ntawm S100B protein nyob rau hauv frontotemporal lobepromotes inflammatory cascade, thiab oxidative kev nyuaj siab thiab altersCa2+homeostasis [60]. Oxidative kev nyuaj siab pib mitochondrial DNA puas, ua rau kev nthuav tawm thiab / lossis kev puas tsuaj ntawm cov neurons, uas tau ua rau muaj kev txhawj xeeb hauv cov kab mob ntawm cov kab mob neurological.

Ntau cov ntawv ceeb toom tau xav tias qhov tsis txaus ntseeg ntawm cytotoxicONOO- thiab kev tiv thaiv NO tuaj yeem yog qhov tseem ceeb rau ntau yam kab mob vascular thiab neuronal nrog rau AD [5].

Kev tsim tawm NO tshwm sim vim qhov nce hauv kev tsim cov A los ntawm kev cuam tshuam ntawm Ca + homeostasis thiab tom qab nce hauv intracellular Ca + (eNOS thiab nNOS mediated NOrelease) lossis los ntawm kev cuam tshuam nrog glial hlwb (iNOS-mediated NO tso tawm) [61]. TSIS yog ib qho dawb radical nrog lub peev xwm tsim peroxynitrite.

Cov ROS no ua rau muaj ntau yam kev cuam tshuam ntawm neurotoxicity, suav nrog kev hloov pauv ntawm cov protein / DNA, mitochondria tsis ua haujlwm, lipid peroxidation, neuro-o, thiab apoptosis, inducing kev ncaj ncees ntawm cellularmembrane, uas ua rau ntxiv Ca + influx thiab tsis tso tawm [62].

Cov txheej txheem no tau paub tias muaj feem cuam tshuam rau kev tuag ntawm tes thiab pom qhov kev paub tsis zoo hauv AD [63].Muaj kev sib cuam tshuam ntawm extracellular beta-amyloid thiab S100B protein qhia uas tau nce siab hauv AD thiab cuam tshuam nrog cov plaques senile.

Cov biomarker no tuaj yeem ua lub luag haujlwm hauv amyloid aggregation thiab pab txiav txim siab txog kev mob hlwb [64]. Activated astrocytes yog qhov pom zoo ntawm cov plaques hauv AD.

Cov activated astrocytes pom nyob rau hauv AD neeg mob lub hlwb markedlyover-express S100B uas yog reflected los ntawm nws nce hlwb hlwb. Feem ntau ntawm cov activated astrocytes thiab S100Boverexpression nyob rau hauv lub hlwb ntawm cov neeg mob AD yog ze ze nrog ib tug diffuse los yog neuritic A plaques. Kev faib tawm ntawm cov astrocytes no thoob plaws hauv lub paj hlwb tau lees paub cov qauv faib rau A plaques.

Cov koom haum topographical no ntawm S100B overexpression-activated astrocytesand A plaques hauv AD ua ke nrog cov paub txog neurotrophiceffects ntawm S100B qhia tias S100B overexpression yuav yog ib qho tseem ceeb ntawm cov kab mob ua lub luag haujlwm rau lub hauv paus chiv keeb thiab kev hloov pauv ntawm neurotic plaques hauv AD.

Astrocytes activation thiab overexpression ntawm S100B yog qhov tseem ceeb thiab zoo ib yam ntawm AD tej yam kev mob uas muaj kev pheej hmoo siab rau AD.S100B muaj ob qho tib si trophic thiab muaj feem cuam tshuam rau cov neurons thiab neurites uas qhia tias S100B overexpression plays lub luag haujlwm tseem ceeb hauv lub hauv paus ntawm kev hloov pauv hauv cov plaques.

Nyob rau hauv lub lig AD theem, qhov kev loj hlob ntawm non-fibrillary amyloid deposits li neurite cov ntaub ntawv thiaj li ua rau kev loj hlob ntawm tus kab mob nws tus kheej [65].Nws tau raug pov thawj tias cov synthesis ntawm S100Bprotein mRNA thiab S100B protein nyob rau hauv kab lis kev cai ntawm astrocytes yog stimulated. los ntawm beta-amyloid [14]. Kev sib txuam thiab kev nkag mus ntawm alpha-beta (-) hauv lub hlwb yog kho los ntawmRAGE.

Ncaj nraim los yog tsis ncaj - pib calcium homeostasis dysregulation uas ua rau kom ua rau S100B protein.Glial cell activation los ntawm RAGE ua rau NF-kB beta activation uas ua rau gene transcription thiab inflammatory cytokines tso tawm [66].

Hauv cov neeg mob AD, lub hlwb yog qhov chaw mob hnyav thiab oxidative kev nyuaj siab uas ua rau AGEformation. S100B protein, alpha-beta, AGEs, thiab lwm yam RAGE ligands xws li HMGB1, TTR, S100A6, S100A8 / A9, thiab S100A12 mloog zoo nyob rau hauv lub hlwb thaum lub sij hawm tus kab mob.

Kev tso tawm ntau dhau ntawm S100B thiab RAGE tseem pib hloov pauv neuropathological hauv lub hlwb los ntawm kev ua kom microglia, neurite degeneration, neuronal apoptosis, thiab tsim NFT uas thaum kawg ua rau kev puas tsuaj ntawm kev nco [27].

Tshaj AGE tsim los ntawm kev hloov pauv protein kuj tseem ua rau RAGE-dependent oxidative stress thiab NF-k . Theactivated NF-kB ua rau qhov kev nthuav qhia siab ntawm RAGEvim hais tias NF-kB cov ntsiab lus teb tam sim no nyob rau hauv cheeb tsam RAGE txhawb nqa [65].

Kev ua kom muaj zog ntawm RAGE thiab NF-kB ua rau muaj kev hloov pauv hauv neuronal redox muaj peev xwm thiab neuroinflammation. Ntawm qhov chaw ntawm qhov mob, cov qib siab ntawm AGEs, NFT, thiab senile plaques nyob hauv lub hlwb ntawm cov neeg mob AD [67].

Amyloid-forming proteins xws li amyloid--beta peptides thiab TTR pib tsim cov pab pawg thib ob ntawm RAGE ligands. APP ua los ntawm beta andgamma-secretase ua rau amyloid beta-peptide ntau lawm.

Accumulated amyloid beta proteins nyob rau hauv AD tus neeg mob lub hlwb yog ib qho tseem ceeb nyob rau hauv cov kab mob pathogenesis. Kev thauj amyloid beta los ntawm cov cell membrane ntawm cov neurons thiab BBB kuj yog pov thawj los ntawm RAGE. Tsis tas li ntawd, hauv cov neeg mob AD, TTR tau pom tias muaj kev tiv thaiv los ntawm kev khi rau amyloid beta hauv kev zoo li chaperone [55].

5. S100B IN PARKINSON'S DISEASE

Parkinson's disease (PD) yog ib qho kev mob tshwm sim ntawm cov kab mob neurodegenerative uas tau piav qhia los ntawm kev sib sau ntawm -synuclein hauv cheeb tsam cortical lossis paj hlwb [68].

Qhov kev tsis taus ntawm lub cev thawj zaug thiab tseem ceeb tshaj plaws vim qhov kev hloov pauv no suav nrog kev sib koom ua ke ntawm lub cev muaj zog uas yog hu ua Parkinsonism. Cov no suav nrog kev tsis txaus thiab qeeb zog uas yog akinesia, bradykinesia, rigidity, thiab tshee ua rau so [69].

Pathogenesis ntawm PD tsom rau ROS, qhov pib ntawm oxidative kev nyuaj siab uas ua rau oxidative puas tsuaj rau substantia nigra pars compacta. Cov tsiaj dawb radical yog qhov ua rau tuag ntawm dopaminergic cell hauv PD tsis paub meej, tab sis qee cov ntaub ntawv tau qhia tias hydroxyl radical (OH'), NO, thiab peroxynitrite koom nrog [70].

Nitric oxidesynthase (NOS) ua kom tsis muaj, uas reacts withsuperoxide los ua peroxynitrite. Cov molecule no hloov cov nucleic acid, protein, thiab lipids, ua rau oxidative kev puas tsuaj, proteasome inhibition, mitochondrialdamage, thiab endoplasmic reticulum stress (ER).

Kev ntxhov siab ntau dhau ntawm nitrosative ua rau hyperactivation ntawm glutamate receptor pawg N-methyl-D-aspartate (NMDA), mitochondrial dysfunction, thiab cell aging. Ntau dhau dawb radicalsand TSIS muaj hom kab mob tau tshaj tawm los ua kom cov txheej txheem pathological suav nrog mitochondrial dynamics, misfolded proteins, thiab apoptotic txoj hauv kev hauv dopaminergiccells [71].

Qee cov kev tshawb fawb tau qhia tias ntau dhau ntawm NO tuaj yeem ua rau cov txheej txheem pathological no, feem ntau yog los ntawm S-nitrosylation ntawm cov hom phiaj tshwj xeeb, xws li ubiquitin-protein ligase, parkin, protein disulfideisomerases (PDI), thiab mitochondrial degradation los ntawm ß-amyloid-txog S. -nitrosylation ntawm dynamin-related protein-1.

PDI yog lub luag haujlwm rau qhov qub folding ntawm cov proteins hauv theER, ntawm cov proteins no [72]. Tsis tas li ntawd, Tsis muaj kev cuam tshuam los ntawm dopaminergic neuron hlwb tuaj yeem suav nrog inhibition ntawm mitochondria complexes I, II, thiab IV, cytochromeoxidase, ribonucleotide reductase, glyceraldehyde-3-phosphate dehydrogenase, superoxide dismutase, lipid peroxidation, activation lossis DNA. breakage, protein oxidation thiab nce zus tau tej cov tshuaj dawb radicals xws li hydroxyl radicals thiab peroxynitrite.

Cov ntaub ntawv pov thawj tau qhia tias ntau dhau RNS / ROS tuaj yeem ua rau UPS kev puas tsuaj thiab ua rau lub cev tsis zoo ntawm cov protein molecules, ua rau kev sib sau ntawm cov protein thiab dopaminergic neuronal tuag [73].

Qhov kev qhia qis S100B protein ua rau muaj kev tiv thaiv neuroprotection vim txo qis microgliosis, AGEs, thiab TNF-alpha qhia. Muaj ntau qhov qhia tau tias S100B tsis yog koom nrog kev mob o tab sis kuj neurodegenerativedisease activates proinflammatory cytokine tso tawm thiab ua rau kev puas tsuaj rau dopaminergic neurons.

Qhov nce qib ntawm S100B proteins hauv post-mortem substantia nigra ntawm PDpatients tau raug tshaj tawm raws li piv nrog cov ntaub so ntswg ib txwm nyob hauv CSF [74].

Tsis tas li ntawd, S100B qhia tau hais tias ob qho kev ua haujlwm ntawm qhov tsis tshua muaj siab (nanomolar), ua rau muaj qhov cuam tshuam rau neurotrophic, thiab txhawb kev muaj sia nyob ntawm neuronal nrog rau kev loj hlob ntawm neurites thaum lub sij hawm kev loj hlob [75]. Nws kuj tseem pib neuronal apoptosis ntawm micromolar concentrations ob qho tib si los ntawm kev ua ncaj qha rau cov neurons thiab microglia activation [76].

Rau qee qhov, cov teebmeem no tuaj yeem kho los ntawm iNOS enzyme uas ua rau kom muaj nitric oxide ntau lawm, cov calcium hauv cov cell, thiab ua kom cov caspase-3 [24].

Tsis tas li ntawd, nws tau raug tshaj tawm tias kev kho mob astrocyte kab lis kev cai nrog S100B protein ua rau iNOS ua kom thiab tsim nitricoxide. Nitric oxide tsim nyob rau hauv cov lus teb rau S100B tuaj yeem ua rau astrocytes mus rau apoptotic cell tuag.

Nitric oxide-mediated excitotoxicity, o, oxidative kev nyuaj siab, mitochondrial function impairment, DNA puas, thiab S-nitrosylation ntawm ntau yam proteins ua rau thaum kawg toneuronal tuag [47] (Fig. 3).

Qhov no qhia tau hais tias S100B tuaj yeem yog qhov cim qhia tau zoo rau qib ntawm cov kab mob hnyav thaum pib tus kab mob. Cov neeg mob PD muaj qis dua ntawm S100B thiab cov tib neeg uas txo qis S100B tuaj yeem ua rau muaj kev cuam tshuam ntau dua rau cov teeb meem neurological.

Cov kev tshawb pom no qhia tias S100B tuaj yeem muaj lub luag haujlwm ua tau nyob rau hauv lub hauv paus ntawm PD txoj kev loj hlob mechanism los yog hauv kev ntsuam xyuas ntawm tus kab mob [14] Tsis tas li ntawd, astroglial C6 thiab oligodendroglial OLN-93 hlwb kho nrog haloperidol andclozapine ntawm ib qho concentration sib xws rau kev kho mob ntau yam. ntawm cov tshuaj no txo ​​qis S100B tso tawm invitro [77].

6. S100B hauv MULTIPLE SCLEROSIS

Ntau tus kab mob sclerosis (MS) yog ib qho kab mob autoimmune ntawm CNS tshwm sim los ntawm kev mob ntev demyelination ntawm neurons, cuam tshuam rau cov tub ntxhais hluas [78]. Nyob rau hauv cov kab mob thaum ntxov, cov tsos mob tshwm sim los ntawm T-cell activation, infiltration, thiab tsub zuj zuj ntawm monocyte macrophages uas txhawb kev puas tsuaj rau myelin sheath uas ntxiv ua rau tsim ntawm focal demyelinated lesions [79].

Ntxiv mus, qib siab dua S100B ua rau muaj kev ua haujlwm ntawm astrocytes thiab microglial txhawb qhov TSIS tso tawm [80]. TSIS yog ib qho dawb radical uas pom muaj nyob rau ntawm qhov siab tshaj qhov qub hauv cov kab mob MS. Qhov kev nce ntxiv no tshwm sim vim qhov pom ntawm iNOS hauv astrocytes thiab macrophages.

Cov cim ntawm TSIS MUAJ ntau lawm xws li nitrite thiab nitrate ntau ntxiv hauv cov ntshav, CSF, thiab zis ntawm MS cov neeg mob. Tsis tas li, cov pov thawj qhia txog kev ua haujlwm ntawm NO hauv ntau yam kab mob xws li BBB kev puas tsuaj, kev raug mob ntawm oligodendrocyte, demyelination, thiab degeneration ntawm axon thiab nws ntxiv rau kev ua haujlwm tsis zoo vim axonal conduction impairment [81].

Kev nce qib S100B tau pom thawj zaug hauv cov kua cerebrospinal ntawm cov neeg mob MS mob hnyav [82]. Hauv kev kuaj mob ntawm cov neeg mob rov qab-remitting MS, nce qib ntawm S100B hauv CSF lossis ntshav ntshav tau kuaj pom, uas txo qis tom qab kho nrog kev tiv thaiv kab mob lossis natalizumab [83].

Thaum raug mob, nce qib ntawm S100B tuaj yeem ua rau muaj kev cuam tshuam tsis zoo, ua rau cov ntaub so ntswg puas lossis ncua remyelination. Kev nce qib S100B tau kuaj pom hauv CSF ntawm cov neeg mob rov qab-remitting MS tom qab kuaj pom [84].

Active demyelinating MS lesions pom qhov nce qib ntawm S100B thiab nws cov receptor, RAGE nyob rau hauv qhov chaw mob thaum cov kab mob ua haujlwm ntev pom tau nce S100B qib hauv cov cheeb tsam demyelinated nrog qis qhia ntawm RAGE receptors hauv therim [85].

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