Epigallocatechin-3-Gallate (EGCG): Txoj Kev Kho Tshiab Rau Neuroprotection, Kev Laus, Thiab Neuroinflammation Rau Hnub Nyoog Niaj Hnub No Part 2

Raws li qhov tseeb ntawm cov lus tseeb no, cov tswv yim kho mob feem ntau yog cov kev kho mob uas tsis yog-steroidal anti-inflammatory tshuaj (NSAIDs) pom tias yuav txo qis kev pheej hmoo ntawm AD thiab ncua kev loj hlob, tab sis tsuas yog hauv kev soj ntsuam yav tom ntej los ntawm kev tso tseg cyclooxygenase2 (COX-2) los yog prostaglandin E2 receptor, activating phagocytosis los ntawm microglia, ua rau peroxisome proliferator-activated receptor gamma (PPAR-), thiab xaiv qhov txo qis ntawm A 42 [19].

Nyob rau hauv xyoo tas los no, tib neeg tau them nyiaj ntau dua los tiv thaiv lawv lub cim xeeb. Ntau tus neeg ntseeg hais tias kev siv cov tshuaj nonsteroidal anti-inflammatory (NSAIDs) mus ntev yuav ua rau kev nco. Txawm li cas los xij, kev tshawb fawb uas twb muaj lawm qhia tias qhov kev txhawj xeeb no yuav tsis muaj tseeb.

NSAIDs yog cov tshuaj siv dav siv los txo qhov mob, ua npaws, thiab mob, xws li tshuaj aspirin, ibuprofen, thiab naproxen. Lawv ua haujlwm los ntawm kev thaiv cov enzyme hauv lub cev, uas ua rau txo qis cov lus teb. Qee qhov kev tshawb fawb thaum ntxov tau qhia tias cov tshuaj no yuav muaj qee qhov tsis zoo rau kev nco, tab sis cov kev sim loj loj uas twb muaj lawm tsis tau pom qhov txiaj ntsig no.

Hauv kev tshawb fawb thoob ntiaj teb, cov kws tshawb fawb tau tshuaj xyuas kev sib raug zoo ntawm qhov ncauj NSAIDs thiab kev pheej hmoo ntawm kev paub tsis meej. Lawv tau kawm 2,721 tus neeg muaj hnub nyoog 65 txog 96 xyoo, uas tau xeem cov kev txawj ntse rau tsib xyoos sib law liag. Cov txiaj ntsig tau pom tias qhov ncauj NSAIDs, tshwj xeeb tshaj yog cov tshuaj kho mob, tau cuam tshuam nrog kev pheej hmoo qis dua. Nyob rau hauv sib piv, thaum cov kws tshawb fawb soj ntsuam kev kawm inhibitors thiab lwm yam analgesics cais, tsis muaj kev sib raug zoo tseem ceeb.

Cov kws tshawb fawb tau taw qhia tias vim yog kev kho mob ntawm NSAIDs, kev siv cov tshuaj no mus ntev yuav txo tau qhov kev pheej hmoo ntawm cov neeg mob uas muaj kab mob inflammatory. Kev mob tshwm sim yog txuam nrog kev ua haujlwm ntawm lub hlwb tsis zoo, yog li NSAIDs tuaj yeem pab tiv thaiv kev nco los ntawm kev txo qhov mob. Tsis tas li ntawd, hauv txoj kev tshawb no, cov kws tshawb fawb tsis pom muaj kev koom tes ntawm NSAIDs thiab kev pheej hmoo ntawm Alzheimer's kab mob lossis lwm yam dementias.

Zuag qhia tag nrho, kev tshawb fawb tshawb fawb tsis tau lees paub tag nrho cov kev sib raug zoo ntawm NSAIDs thiab nco. Yog tias koj noj NSAIDs qhov ncauj mus sij hawm ntev los daws qhov tsis xis nyob hauv lub cev, koj tsis tas yuav txhawj xeeb txog qhov tsis zoo ntawm koj lub cim xeeb. Txawm li cas los xij, peb tseem xav kom koj hu rau koj tus kws kho mob thiab ua raws li koj tus kws kho mob cov lus qhia thaum siv hom tshuaj no. Thaum nws los tiv thaiv peb lub cim xeeb, nws yog ib qho tseem ceeb uas yuav tsum ua raws li kev noj qab haus huv thiab tsim kom muaj tus cwj pwm zoo, xws li kev tswj hwm kev tawm dag zog txhua hnub, noj zaub mov kom tsim nyog thiab kev ua ub ua no, txhim kho kev paub txog tus kheej, thiab kawm txuj ci tshiab, thiab lwm yam. . Cia peb tiv thaiv thiab txhim kho peb lub cim xeeb ua ke. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco, vim Cistanche deserticola muaj antioxidant, tiv thaiv kev mob, thiab tiv thaiv kev laus, uas tuaj yeem pab txo qis oxidation thiab inflammatory tshwm sim hauv lub hlwb, yog li tiv thaiv cov kab mob. kev noj qab haus huv ntawm lub paj hlwb. Tsis tas li ntawd, Cistanche deserticola kuj tseem tuaj yeem txhawb kev loj hlob thiab kho cov paj hlwb, yog li txhim kho kev sib txuas thiab kev ua haujlwm ntawm neural networks. Cov teebmeem no tuaj yeem pab txhim kho kev nco, kev kawm, thiab kev xav nrawm, thiab tseem tuaj yeem tiv thaiv kev loj hlob ntawm kev paub tsis meej thiab kab mob neurodegenerative.

Nyem Paub txhawm rau txhim kho lub cim xeeb luv luv

Lub Chaw Tswj Xyuas Khoom Noj thiab Tshuaj (FDA) tau pom zoo acetylcholinesteraseinhibitors (AChEI) (rivastigmine thiab donepezil) thiab NMDA receptor antagonist (Memantine) cov tshuaj tau siv los txo cov cholinergic thiab glutamatergic disintegration / excitotoxicity, ntsig txog, kev cuam tshuam los ntawm AD. 32–34] ib. Cov kev kho tam sim no yog cov kab mob-hloov kho cov neeg ua haujlwm feem ntau tsom rau kev nthuav tawm A, tab sis lawv tau ua tsis tiav hauv kev sim tshuaj [35].

Lwm cov phiaj xwm phiaj xwm yog sirtuins (SIRT), uas tsis ntev los no tau cuam tshuam nrog cov kab mob muaj hnub nyoog, thiab caspases, uas cuam tshuam nrog apoptosis thiab autophagy [36]. Tsis ntev los no, ntau cov kev tshawb fawb tau tsom mus rau kev tiv thaiv cov kev pheej hmoo thiab kev sib koom ua ke, tshwj xeeb, kev noj haus thiab kev rog [37], cerebrovascular (lub hlwb renin-angiotensin system (RAS) [38]), thiab kev tswj hwm zog [39].

2.3. Protein Aggregation hauv AD: Lub luag haujlwm ntawm Amyloid Beta (A)

Kev tshawb fawb dav dav tau txuas APP nrog AD pathogenesis [40]. Qhov adhesion rau APPoccurs nyob rau hauv ob txoj kev tshwj xeeb: -secretase, ib tug proteolytic enzyme uas ua rau txoj kev nonamyloidogenic, uas ua rau APP koom nrog hauv cheeb tsam A, ua rau A tiam. Adherence ntawm APP los ntawm -secretase generates -secreted APP (sAPP) thiab cov seem seem C davhlau ya nyob twg (-CTF).

Lwm txoj hauv kev suav nrog BACE-catalyzed - txuas ntawm APP txhawb nqa A tsim thiab txoj hauv kev amyloidogenic. BACEcleavage tsim -secreted APP (sAPP) thiab c-terminal fragment -CTF ntawm APP.Cov c-terminal remnants (thiab CTF) yog substrates rau -secretase, universal multimeric protease. Kev khi ntawm -CTF rau -secretase yields luv luv nonamyloidogenicpeptide (p3).

Txawm li cas los xij, -CTF adherence txhawb kev nthuav tawm. A yog pov thawj ntawm cov tseem ceeb proteinous seem ntawm amyloid plaques nyob rau hauv lub hlwb AD [41] .Lub APP intracellular domain (AICD) yog generated nyob rau hauv ob qho tib si amyloidogenic thiab nonamyloidogenic txoj kev los ntawm kev koom ntawm -secretase. Feem ntau amyloid-beta remnantsare A 40 nyob rau hauv ntev; Txawm li cas los xij, qhov elongated A 42 variant yog cov kab mob feem ntau.

Ib qho kev xav tau yog tias kev sib dhos tas li ntawm A oligomers ua rau muaj kev puas tsuaj rau hauv cov neurodegeneration [3]. Cov kev tshawb fawb tshiab tshaj plaws tau pom tias A tuaj yeem ua rau microglia thiab txhawb lub xeev mob ntev uas ua rau tsis muaj kev tiv thaiv proinflammatory cytokine tso tawm, ua rau neurodegeneration [42,43].

Alasmari et al. [40] pom tau tias proinflammatory cytokines tuaj yeem kho A neurotoxicity ntawm APPprotein homeostasis / metabolism. A kuj tau txuas rau ua rau cov hlau dysomeostasis, stimulating oxidative kev nyuaj siab nyob rau hauv microglia ua rau neurodegeneration [44,45].

2.4. Tau Protein: Neurofibrillary Tangles thiab Aggregation hauv AD

Tau muaj feem cuam tshuam rau tsev neeg ntawm microtubule-associated proteins (MAPs) uas nyob hauv cov neurons, ua haujlwm txhawb nqa microtubules, thiab pab hauv kev lag luam cellular thiab cytoskeleton scaffolds rau cov hlwb. Tau protein pab tsim cov neurofibrillarytangles vim tsis muaj oxidative phosphorylation lossis apoptotic muaj nuj nqi [46].

Tau dhau los ua pathological vim hyperphosphorylation uas tshwm sim vim tsis ruaj khov kinase thiab phosphatase ua haujlwm ntawm tau protein [47]. Lub phosphorylation ntawm tau tau txuam nrog N methyl D aspartate receptor (NMDAR) ntawm qhov chaw postsynaptic, uas tej zaum yuav cuam tshuam rau cov synaptic instability uas tshwm sim hauv PD [48].

Lub mechanism ntawm filament aggregation uas tshwm sim nyob rau hauv tau tseem raug soj ntsuam. Cov txheej txheem ntawm fibrillogenesis (zoo ib yam li A fibrillogenesis) tau raug postulated ua ib qho ntawm cov txheej txheem.

Ua ntej, proteindimerization tshwm sim los ntawm kev npaj ntawm disulfide txuas hniav los yog ionic bonds; ces, ib tug nucleation theem ua raws li, nyob rau hauv uas lub dimers nws tus kheej-tsim los tsim oligomers; kawg, lub elongation theem tshwm sim nyob rau hauv uas cov oligomers thicken.

Tau autosomal dominantmutations nyob rau hauv microtubule-associated protein (MAPT), cov noob encoding rau tau, tau pom ua rau frontotemporal dementia nrog parkinsonism (FTPD-17 mutation) [49].

3. Lub luag hauj lwm ntawm qhov mob

Cov kev tshawb fawb tam sim no tau coj mus rau neuroinflamation ua ib qho tseem ceeb hauv kev tsim ntawm neurodegeneration. Lub cev tsis muaj zog tiv thaiv kab mob los yog kev raug mob ntawm lub hlwb ua rau glial cell activation, piv txwv li, microglia thiab astrocytes, qhov tseem ceeb rau immunoregulative central nervous system (CNS) homeostasis [50].

Cov kev cai no yog ua nyob rau hauv ib tug series ntawm cov txheej txheem conjunctionally ntawm lub microglia thiab astrocytes, ua toneurodegeneration ntawm ntau yam molecular intervals uas muaj cell tuag kev sib kho, synapticremodeling, raws li zoo raws li kev tiv thaiv kab mob, xws li, (a) apoptosis, (b) necroptosis, ( c) autophagy, (d) retrograde degeneration, (e) Wallerian degeneration, (f) demyelination, thiab (g) astrogliopathy [51].

Cov txheej txheem ntxiv ua haujlwm ua ib txoj hauv kev tseem ceeb rau kev tswj hwm kev sib cuam tshuam ntawm kev mob hnyav vs. mob neuroinflammation hauv CNS microenvironment thiab txuas rau kev nkag siab CNS immunoregulation [52–54].

Neuroinflamation yog ib txwm muaj txiaj ntsig zoo rau kev tswj hwm kev ntxhov siab sab nraud. Txawm li cas los xij, nws tuaj yeem ua rau muaj kev puas tsuaj thaum lub cev tiv thaiv kab mob ntev (lossis ntev) vim qhov kev laus ntawm kev tiv thaiv kab mob, uas ua rau lub cev tsis muaj zog tiv thaiv kab mob culminating hauv neurodegenerative pathogenesis [55,56].

De Oliveira et al. [57] tham txog kev cuam tshuam ntawm lub zog ntuj (mitochondrial) homeostasis los ntawm mitochondrial kev puas tsuaj-txuas nrog cov qauv molecular (mDAMPs), uas tuaj yeem ua rau receptor-mediated (NOD-zoo li receptor (NLR) thiab TLR) cascade ntawm inflammatory immunological teb. Kev tshawb fawb txuas ntxiv yog tsom rau kev sib raug zoo ntawm kev mob ntev thiab AD.

3.1. Microglia thiab Debilitating teebmeem tshwm sim los ntawm kev laus

Microglia yog cov macrophages tshwj xeeb ntawm CNS. Microglia muaj nuj nqi hauv kev soj ntsuam ntawm CNS microenvironment los ntawm 6 qhov kev faib tawm: (1) kev loj hlob, (2) morphological hloov pauv, (3) kev txav mus los thiab kev tsiv teb tsaws, (4) Kev sib txuas lus ntawm tes, (5) phagocytosis, thiab (6) proteostasis. Microglia txawv ntawm lwm cov glial hlwb, xws li astrocytes, los ntawm lawv cov keeb kwm hematopoietic thiab cov lus teb tseem ceeb rau cov kab mob thiab kev raug mob [58].

Microgliacontains ntau cov cim qhia txog macrophage, piv txwv li, CD11b thiab CD14. Cov hlwb no tau qhib los ntawm ob qho tib si classical lossis lwm txoj kev ntxiv ntxiv; classically, microglia tau ua haujlwm vim muaj kab mob ntxeem tau thiab pib qhov loj histocompatibility complex II (MHC-II), uas recruits T hlwb thiab lwm yam proinflammatory mediators.

Lawv kuj muaj ntau cov receptors uas ua haujlwm hauv kev soj ntsuam, xws li cov qauv lees paub receptors (Tolllike receptors (TLRs)), retinoic acid-inducible gene-I-zoo li receptors (RIG-1 zoo li receptors), thiab nucleotide-binding oligomerization domain. -zoo li receptors (NOD-zoo li receptors).

Protein recognition receptors (PPRs) paub cov kab mob paub txog cov qauv molecular (PAMPs), thaum TLRs pom kev puas tsuaj cuam tshuam nrog cov qauv molecular (dAMPs) [59,60].Nyob rau hauv AD, kev loj hlob zoo li ua rau cov hlwb microglial tsis tshua muaj txiaj ntsig hauv kev degrading cov dense aggregates [61] .

Microglia kuj muaj ntau lwm yam receptors, xws li ion channels, uas pab nyob rau hauv microglial paub txog cov kab mob-koom nrog cov qauv molecular (DAMPs) raug tshem tawm los ntawm cov hlwb puas los yog necrotic thiab ua lub luag haujlwm hauv kev tshem tawm cov khib nyiab thiab txhawb kev kho cov ntaub so ntswg tom qab CNS raug mob, xws li raws li purinergic receptor thiab receptor rau qib siab glycation kawg khoom (RAGE).

Cov purinergic P2 purinoreceptors yog categorized rau ob pawg: ionotropic receptors (P2X receptors), uas tsim cov ion channel uas qhib los ntawm adenosine triphosphate (ATP), thiab metabotropic receptors (P2Y receptors), uas khi purines lossis pyrimidines cov xwm txheej hauv qab no. Coupled receptors (GPCRs) [62].

Nucleoside triphosphates (NTPs) raug tshem tawm los ntawm cov hlwb raug mob tuaj yeem xa mus rau P2X lossis Y receptors thiab txhawb nqa cov neeg sib koom ua ke ntawm kev sib txuas lus ntawm cov khoom siv, cov khoom siv nuclear kappa B (NF-κB), thiab activator protein I (AP1). Microglia kuj tau pom tias sib tham nrog astrocytes thiab ua kom lub cev tiv thaiv kab mob. Microglia yog ib qho tseem ceeb hauv kev loj hlob ntawm neurovascular thiab koom nrog hauv angiogenesis [63].

Lub luag haujlwm no tau tso cai rau kev tshawb fawb dav hauv nws txoj kev koom tes nrog ntau yam kab mob ntsig txog lub hlwb, xws li ischemic stroke, hlwb qog, thiab neurodegenerative disorders.

Kev laus ua rau maj mam txo qis hauv kev ua haujlwm ntawm lub cev thiab kev coj tus cwj pwm, uas tau tshwm sim nyob rau ntau theem ntawm lub cev, tshwj xeeb tshaj yog nyob rau hauv CNS [64] .Microglia muaj ntau yam kev hloov pauv uas muaj hnub nyoog uas nce mus rau kev txhawb nqa ib puag ncig inflammatory, piv txwv li, nce ntau lawm. ntawm inflammatory cytokines andROS. Kev tshawb fawb tau pom tias lub hlwb ib txwm atrophies 2-3% ib xyoo caum tom qab 50 [64].

Siv tshuab magnetic resonance (MRT) thiab voxel-based morphometry, atrophies tau tshwm sim feem ntau nyob rau hauv cov teeb meem grey thiab dawb qhov hloov pauv hauv thaj chaw prefrontal, parietal, thiab sab cev nqaij daim tawv. Tsis tas li ntawd, kev kawm nyuaj ua haujlwm tau ploj zuj zus nrog hnub nyoog. Nyob rau theem cellular, kev laus ua rau shrinking telomeres thiab pib ntawm cov qog nqaij hlav qog, suav nrog DNA puas, oxidative kev nyuaj siab, thiab tsis txaus ntseeg ntawm pro- thiab inhibitory inflammatory cytokine kev ua.

Mosher thiab Coray [65] tau hais cov lus tseem ceeb, "Cov cim ntawm kev laus ntawm microglial tej zaum kuj yuav ua rau muaj qhov tsis zoo thiab txawm tias cov lus teb tsis zoo." Nws tau raug postulated tias cumulativestimulation nyob rau hauv cov lus teb rau cov kab mob kab mob thoob plaws hauv lub neej ua rau systemicinflammation, ua rau cov hlwb ua hyperactivated, thiab pab nyob rau hauv neurodegeneration.

Tsis tas li ntawd, kev nce hauv engineering ntawm ROS los ntawm permeability ntawm cov ntshav-hlwb barrier (BBB) ​​ua rau lub deterioration ntawm neurons thiab lwm lub hlwb hlwb thiab siab systemicinflammation [65].

Kev tshawb fawb tau pom tias microglia proliferation thiab nws tus kheej rov ua dua tshiab nrog lub hnub nyoog.

Txawm li cas los xij, nws ntseeg tau tias qhov kev sib sau ua ke ntawm microglia no yog ib qho txiaj ntsig los txhawb nqa qib tsim nyog ntawm kev tiv thaiv los ntawm tag nrho cov neeg microglial vim lawv cov hlwb tsis muaj peev xwm nrog hnub nyoog [65]. Morphological hloov hauv AD qhia tias microglia muaj cov txheej txheem luv luv, tuab, thiab tsis zoo ramified [65]. Microglial motility txo qis nrog lub hnub nyoog thiab qhia txog kev txo qis rau exogenous ATP thiab laser-inducedfocal cov ntaub so ntswg raug mob.

Cov hnub nyoog microglia tso tawm ntau dhau ntawm cov cim pro-inflammatory, xws li MHCII, antigens, CD11b / CR3, thiab CD14. Nws kuj tau pom tias cov neeg nruab nrab ntawm microglial activation thiab cov lus teb inflammatory yog curtailed vim kev laus [66].

Microglia feem ntau hloov kho cov txheej txheem phagocytotic koom nrog hauv kev tiv thaiv kab mob. Txawm li cas los xij, kev laus txo qis cov txheej txheem no raws li muaj pov thawj hauv dysregulatedproteostasis txoj hauv kev uas cuam tshuam nrog kev cuam tshuam ntawm chaperone-mediated protein folding thiab ruaj khov, kev lag luam protein, kev puas tsuaj ntawm cov protein, autophagy, thiab suav nrog cov proteinsin AD [65].

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