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

3.2. Microglia and Tau

Lub senescence ntawm microglia manifests nws tus kheej li morphological alterations, cytokine qhia, phagocytosis, stimulation, thiab ceev [67]. Kev tshawb nrhiav tsis tu ncua qhia tau hais tias microgliamay yog lub luag haujlwm rau synaptic thiab non-synaptic ncig ntawm pathological tau.

Nyob rau hauv xyoo tas los no, ntau thiab ntau txoj kev tshawb fawb tau lees paub qhov kev sib raug zoo ntawm cytokine qhia thiab nco. Cytokines yog cov cim qhia cov molecules uas tuaj yeem txhawb lossis inhibit lub cev tiv thaiv kab mob. Lawv tuaj yeem cuam tshuam rau kev sib kis ntawm cov ntaub ntawv ntawm cov neurons hauv lub hlwb. Cov kev tshawb fawb tau pom tias cov theem qhia ntawm qee cov cytokines muaj feem cuam tshuam nrog kev txhim kho kev nco.

Piv txwv li, ib txoj kev tshawb fawb luam tawm nyob rau hauv phau ntawv journal Nature pom tias muaj protein ntau hauv lub hlwb hu ua BDNF tuaj yeem txhawb kev sib txuas ntawm cov neurons thiab txhim kho kev nco. BDNF qib raug cuam tshuam los ntawm ntau yam, suav nrog kev tawm dag zog, noj zaub mov, pw tsaug zog, thiab kev ua si hauv zej zog. Kev tshawb fawb qhia tau hais tias cov neeg uas koom nrog cov dej num no feem ntau yuav tswj tau cov qib BDNF siab dua, ua kom yooj yim rau kev khaws cia zoo.

Tsis tas li ntawd, cov lus teb inflammatory tuaj yeem cuam tshuam kev nco. Ib txoj kev tshawb fawb luam tawm nyob rau hauv phau ntawv xov xwm Cell qhia tau hais tias cov lus teb inflammatory hauv lub hlwb tuaj yeem ua rau kev sib txuas ntawm cov neurons tsis ruaj khov, cuam tshuam rau kev nco. Yog li ntawd, kev tswj hwm txoj kev noj qab haus huv thiab kev tswj hwm lub cev cov lus teb yog qhov tseem ceeb rau kev khaws cia zoo.

Hauv kev xaus, muaj kev sib raug zoo thiab tseem ceeb ntawm cytokine qhia thiab kev nco. Peb yuav tsum nquag koom nrog hauv kev ua ub no xws li kev tawm dag zog, noj zaub mov, pw tsaug zog, thiab kev sib raug zoo hauv zej zog thaum saib xyuas kev tswj hwm lub cev cov lus teb kom tswj tau cov qib cytokine siab thiab yog li muaj kev nco zoo dua. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco, vim Cistanche deserticola tseem tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob. Cov khoom no tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche deserticola kuj tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov as-ham txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.

Nyem paub ntxiv los txhim kho kev nco

Microglia envelop ob soluble thiab insoluble xeev ntawm tau. Lub hnab ntawv ntawm tau tso cai rau ob leeg tau degradation los yog tso tawm hauv exocytosing microvesicles hu ua exosomes nyob rau hauv cov qib siab yog nyob rau hauv CSF thiab cov ntshav ntawm cov neeg mob AD [68]. Ntxiv postulation ishat dephosphorylated tau contributes rau microglial neurotoxicity [69].
4. Neuroinflammatory Mediators

Kev paub tsis meej vim yog cytokine/chemokine-tswj koom haum ntawm CNS neuronal lub cev tau raug tshawb fawb zoo [70]. AD pathology ua rau theoverexpression ntawm cov neeg kho kom haum xeeb uas ua rau txhim kho cov quav hniav thiab cov neuronalcell deterioration [70].

Inflammatory regulators koom nrog hauv AD yog raws li nram no: (1) tumornecrosis factor-alpha (TNF- ), (2) interleukin (IL) -6, (3) interferon-gamma (IFN)- , (4) inducible protein -10 (CXCL10), (5) monocyte chemoattractant protein 1 (MCP-1), thiab (6)CXC motif ligand (CXCL-8). Interleukin 6 (IL{19}}) tswj ntau lub cev tiv thaiv kab mob cuam tshuam rau CNS cell txoj kev loj hlob thiab kev sib txawv ntawm cov cellular los ntawm kev koom tes nrog cov kua nplaum nplaum nplaum nplaum nplaum nplaum nplaum [30].

IL-6 tau pom tias muaj ntau yam ntawm cov tshuaj tiv thaiv kab mob [71], tab sis nws tseem tuaj yeem txhawb nqa cov qib proteins uas ua rau txhim kho vascular permeability, lymphocyte provocation, thiab tsim tshuaj tiv thaiv. IL-6 activation bynuclear factor kappa B (NF-κB) modulates vascular o [72]. TNF- yog lwm yam proinflammatory cytokine uas tau txuas rau ntau yam kev puas hlwb.

Micestudies tau nthuav tawm kev txhim kho neuronal poob tom qab lesioning vim tsis muaj TNFreceptor piv rau TNF receptor-tsim nas txaus. Cov kev tshawb fawb ntxiv tau pom tias TNF- instigates lub xub ntiag ntawm kev tiv thaiv molecules, xws li manganese superoxidedismutase (MnSOD) [73–75]. Kev tshawb nrhiav tshiab tau pom tias TGF-s tsa APP qhia hauv kab lis kev cai astrocytes thiab microglia thiab apolipoprotein-E (ApoE) tsim hauv lub paj hlwb [30].

Chemokines ntawm CXC los yog alpha () subfamily muaj positionally conservedcysteine ​​residues ntawm cov amino terminus muab faib los ntawm ib tug amino acid tso cai rau chemo-taxis ntawm neutrophils thiab endothelial hlwb (IL-8). Chemokines direct biological teb viaseven-transmembrane G-protein coupled cell surface receptors (GPCRs). CXC Motif ligand12 koom nrog hauv neurogenesis thiab mobilizes neurological lub cev mus rau qhov chaw ntawm qhov txhab hauv CNS [76].

Macrophage migration inhibitory factor (MIF) yog ib qho pleiotropic proinflammatorycytokine uas txhim khu kev tsim ntawm lwm cov inflammatory cytokines thiab yog nyob rau hauv microglia. Kev tshawb fawb tau pom tias MIF txuas rau A hauv AD-kev cuam tshuam thaj chaw [76].

Macrophage inflammatory protein 1 (MIP-1) qhia yog nyob rau hauv ntau lub paj hlwb thiab kev tiv thaiv kab mob xws li astrocytes, microglia, thiab T hlwb. Kev tshawb fawb pom tau tias MIP -1 / CC chemokine receptor type 5 (CCR5) signaling pathway yog lub luag haujlwm rau kev txhawb nqa glial cell aggregation, inflammatory reactions, thiab synaptic/cognitive dysregulation [76].

Vascular o tau cuam tshuam raws li ib tug progenitor ntawm AD nyob rau hauv daim ntawv ntawm rheumatoid mob caj dab (RH), atherosclerosis, thiab kab mob plawv (CVD). Vascularinflammation tuaj yeem yog qhov tseem ceeb hauv kev txhawb nqa ntau yam ntawm proinflammatory mediatorsacting ntawm cerebral microvessels xws li TNF- thiab IL-6 [77].

4.1. Oxidative Stress

Oxidative stress yog ib yam mob uas nce siab hauv lub hlwb nrog kev laus, tsim los ntawm kev tsis sib haum xeeb hauv lub xeev redox, cuam tshuam txog kev tsim ntau dhau ntawm ROS lossis kev ua haujlwm tsis zoo ntawm cov kab mob antioxidant. Vim lub paj hlwb ntau dhau ntawm metabolic tus nqi thiab tsis muaj peev xwm ua rau cov cellular regeneration, nws yog heev raug rau ROS [78].

Lub hlwb kuj muaj ntau phospholipids, uas yog nplua nuj nyob rau hauv polyunsaturated fatty acids (PUFAs), xws li docosahexaenoic acid (DHA) thiab arachidonic acid (AA). Kev tshawb fawb pom tau hais tias raws li kev tsim tawm dawb radical nce, PUFA cov ntsiab lus hauv lub hlwb maj mam txo qis [79]. Cov lipidhydroperoxides yog ib feem tsis ruaj khov thiab tuaj yeem hloov pauv mus rau ntau yam khoom, xws li malondialdehyde (MDA), 4-Hydroxynonenal (4-HNE), ketones, epoxides, thiab hydrocarbons nyob rau hauv muaj hlau. Hauv AD lub hlwb, muaj qib siab ntawm cov proteincarbonyl.

Cov tshuaj tiv thaiv ntawm ntau yam ROS thiab reactive nitrogen hom (RNS) nrog tyrosinelead rau kev tsim khoom ntawm 3-nitrotyrosine thiab tyrosine [79]. DNA oxidation tuaj yeem ua rau muaj kev tsim 8-Oxo-20-deoxyguanosine (8-OHdG), uas tau qhia ntau heev hauv mitochondrialDNA ntawm cov neeg mob AD [79].

Hauv txhua qhov kev hloov pauv ntawm ROS tiam, molecular oxygen yuav tsum tau tshwm sim, thiab lub cellular system tau hloov kho ntau cov metalloenzymes uas txhawb ROS tiam thaum muaj kev cuam tshuam ntawm redox hlau nrog O2 siv ntau yam catalyticpathways [80].

Lub mitochondrial electron thauj saw siv yuav luag 98% ntawm cov pa oxygen molecular ntawm cytochrome oxidase complex, thiab cov pa oxygen ntxiv yog txo rau hydrogenperoxide thiab superoxide radicals. Thaum cov metabolism hauv ib txwm muaj ntau yam haujlwm ntawm cov pa oxygen radical superoxide anion −(O2−•) cov non-radical oxidant hydrogen peroxide (H2O2), thiab hypochlorous acid (HOCl lossis HClO) raug tsim.

Thaum cov khoom tsim tawm (O2−) thiab (H2O2) ua rau tsis muaj zog, lawv tuaj yeem ua rau cov ntaub so ntswg puas tsuaj uas feem ntau cuam tshuam txog kev tsim cov hydroxyl radical (OH·) thiab lwm yam oxidant molecules nyob rau hauv muaj cov hlau catalytic lossis tooj liab ions [81]. Lub hlwb muaj abundantperoxidation-susceptible lipid hlwb thiab yog ib yam kabmob uas muaj siab indulgence rau oxygen.

Ntxiv mus, cov kua cerebrospinal tsis tuaj yeem khi cov hlau ions raug tshem tawm. Yog li ntawd, oxidativestress nyob rau hauv lub paj hlwb tej zaum yuav ua rau lub hlwb puas los ntawm ob peb interconnected mechanisms, xws li nce intracellular dawb Ca2+, tso tawm excitatory amino acids, thiab neurotoxicity [82].

Lwm cov progenitors ntawm oxidative kev nyuaj siab yog RNS, NO, thiab peroxynitrite (ONOO-), uas tuaj yeem ua rau muaj zog nrog cov proteins, lipids, nucleic acid, thiab lwm yam molecules uas ua rau hloov kho cov qauv thiab kev ua haujlwm thiab muaj kev cuam tshuam rau lub hlwb.

Cells nrog tsub zuj zuj ntawm cov khoom oxidized, piv txwv li, aldehydes, protein carbonyls, thiab base adducts los ntawm DNA oxidation, tuaj yeem hloov pauv loj. Lub loj ROS formationelevated los ntawm lub electron thauj system nyob rau hauv lub mitochondria nyob rau hauv kev ntxhov siab vim thiab kev laus muaj kev pheej hmoo rau AD txoj kev loj hlob [81].

TSIS tsis tsuas yog pab txhawb rau oxidative kev nyuaj siab tab sis kuj ua haujlwm hauv o [83] .NO yog ib qho inflammatory mediator nyob rau hauv ntau yam kev sib koom tes, plab, thiab mob ntsws, piv txwv li, rheumatoidarthritis [84].

Tsis muaj kev koom tes nrog lub cev tiv thaiv kab mob thiab glial hlwb tau txais kev txaus siab rau cov kab mob neurodegenerative, xws li AD thiab PD. Kev tshawb fawb tsis ntev los no tau nthuav tawmNO lub luag haujlwm hauv vascular dementia [85], uas zoo sib xws inflammatory molecular mechanisms tuaj yeem siv los tshuaj xyuas AD pathology.

4.2. Nitric Oxide

TSIS yog ib tug multifaceted mediator molecule uas tau nthuav tawm heev nyob rau hauv cov neurons [{{{0}}},87].Lub enzyme nitric oxide synthase (NOS) raug cais nyob rau hauv 1990 nyob rau hauv nas hlwb (neuronalnNOS los yog NOS{{3 }}), nrog rau hauv macrophages (inducible iNOS lossis NOS-2) thiab endothelialcells (eNOS lossis N0S-3) [88].

Cov tshuaj tiv thaiv enzymatic ntawm iNOS raug tswj hwm los ntawm cytokines, qhov kev hloov pauv tom qab kev hloov pauv ntawm Ca2+/calmodulin tswj cov haujlwm ntawm eNOS lossis nNOS [88]. Nquag TSIS yog tsis tu ncua tshem tawm hauv me me thiab ua haujlwm hauv vasodilation. Ntau lub cev tiv thaiv kab mob sib txawv (leukocytes, mast cells, platelets, thiab macrophages) tsim thiab teb NO [83,86].

Tsis muaj haltsplatelet thiab leukocyte khi rau endothelium, uas txo qis cov txheej txheem pro-inflammatory [86]. Kev laus thiab o ua rau cov cim ntawm ROS / RNS superoxide anion (O2−•) uas tuaj yeem hnov ​​​​mob NO los tsim peroxynitrite (ONOO-), uas cuam tshuam nrog mitochondrial ua pa thiab ua rau TSIS MUAJ dyshomeostasis ua rau mitochondrialdysfunction thiab neuronal tuag [88,89] .

Nws tau pom tias kev laus ua rau txo qis NOS-tsim NO ntau lawm, ua rau muaj kev pheej hmoo ntawm cov hlab plawv, uas tuaj yeem txo cov kev ua haujlwm antioxidant, superoxide overproduction, thiab kev hloov kho ntawm NOS enzyme / kev qhia tawm.

AD tuaj yeem cuam tshuam nrog vascular degeneration nyob rau hauv lub hauv nruab nrab lub paj hlwb ua los ntawm NO signaling dysregulation.Cov pov thawj qhia tau hais tias NO-mediated neurotoxicity nyob rau hauv AD yog tshwm sim los ntawm microglial cell stimulation, txhawb INOS- tswj tsis muaj paug [89]. Tsis tas li ntawd, pro-inflammatorycytokine TNF- induces TSIS sib dhos. Immunoreactive Cheebtsam xws li macrophages tuaj yeem tsim superoxide los ntawm NADPH oxidase [87].

Microglia, glia, thiab neurons tso siab ntau ntawm glutamate [89]. TSIS TAU tuaj yeem nres ua pa thiab ua rau glutamate tso tawm los ntawm synaptosomes thiab neurons, cuam tshuam mitochondrial respiration thiab thim rov qab glutamateuptake lossis pib vascular exocytosis [89].NO tau pom tias ua rau muaj kev tuag neuronal ntawm lub zog depletion-induced necrosis, oxidative phosphorylation, los yog exocytosis.

Cov txheej txheem postulated los koom, raws li daim ntawv los ntawm Brown thiab Bal Nqe [87], yog raws li nram no: (1) stimulation ntawm polyADP ribose polymerase (PARP) ua raws li nicotinamide adenosine diphosphate (NAD +) thiab ATP txo, (2) Kev txhawb nqa ntawm apoptosis los ntawm kev tsis to taub tsis zoo, (3) glutamate tso tawm, thiab (4) nres ntawm mitochondrial ua pa.

Research tau pom tias cerebralblood flows ploj zuj zus nrog kev laus, txhawb nqa endothelial cell ua haujlwm tsis zoo txog kev nyuaj siab tsis muaj paug [87]. NF-κB yog postulated los koom nrog vim nws inflammatory regulatory zog; eNOS txwv nws txoj kev ua haujlwm ntawm proinflammatory cytokines [87].

Microvascolopathy tuaj yeem tshwm sim vim qhov txo qis NO tso tawm thiab NF-κB stimulation [87] .NO ntawm kev txo qis suppresses cytochrome oxidase hauv kev sib cav nrog oxygen thiab tuaj yeem ua tus neeg nruab nrab ntawm cellular zog metabolism [88].

4.3. Autophagy

Autophagy yog ib qho evolutionarily khaws cia mechanism los txhawb nqa neuronal homeostasis thaum lub sij hawm cellular txoj kev loj hlob thiab maturation. Nws yog tswj hwm los ntawm kev ua lysosomal, uas tswj cov khoom noj khoom haus rov qab rau hauv kev tshaib plab, kev tso tawm neurotransmitter, synaptic restructuring, thiab pruning thaum lub sij hawm loj hlob ntawm axons thiab dendrites [90].

Txog niaj hnub no, muaj peb hom autophagy loj hauv cov tsiaj txhu: (1) Macroautophagy, uas yog hais txog kev cais tawm ntawm cov ntaub ntawv cytoplasmic rau hauv ob lossis ntau lub membrane vesicles hu ua autophagosomes.

Cov txheej txheem yuav tsim autophagosomal thauj siv microtubulesin uas cellular byproducts xa mus rau degradative compartments; lub sijhawm no, thaum lub sijhawm ua haujlwm no, lysosomes tsim autolysosomes. (2) Microautophagy cuam tshuam qhov sib txawv ntawm cov tshuaj cytosolic los ntawm invagination ntawm lysosomal daim nyias nyias. heatshock cognate protein ntawm 70 kDa (hsc70) thiab nws cov co-chaperones faib lawv mus rau cellurface ntawm lysosomes [91].

Autophagy ua lub luag haujlwm tseem ceeb hauv kev muaj sia nyob ntawm tes los ntawm kev tiv thaiv cov xwm txheej ntxhov siab, piv txwv li, ER thiab kev ntxhov siab metabolic. Kev xaiv autophagy tso cai rau kev tswj hwm lub cev zoo dua qub, txwv tsis pub ua haujlwm tsis zoo, thiab cov kab mob pov tseg los ntawm kev sib koom ua ke ntawm ubiquitin-proteasome system (UPS) thiab autophagic apparatus. Raws li cov txheej txheem zoo li no yuav ua tau, cov xwm txheej tshwm sim los ntawm overabundance thiab destabilization tuaj yeem ua rau cell tuag [92–94].

Kev laus thiab o ua raws li cov precursors rau autophagic dysregulation thiab bolstercell tuag los ntawm exacerbating cellular lub nra ntawm misfolded thiab puas cellular deposits thiab diminishing cellular degradative muaj peev xwm hlwb thiab lwm yam kev hloov kho ntawm intracellularproteolytic systems [95]. Nws tau raug pom tias autophagy modulates cov ntsiab lus tseem ceeb ntawm lub cev tiv thaiv kab mob, uas yog, macrophages, lymphocytes, thiab neutrophils [96].

Autophagic proteins (Beclin1 los yog ATG16L1) tuaj yeem kho cov proinflammatory cytokine ntau lawm hauv macrophages thiab lwm yam inflammatory regulators. Nws tuaj yeem, dhau los, tswjcytokine ntau lawm nws tus kheej, ua los ntawm Il-1 . Kev tshawb fawb suav tsis txheeb hauv ntau hom tsiaj txhu (cov nas thiab tib neeg) tau pom tias kev laus ua rau muaj kev ntxhov siab oxidative, DNA puas, thiab telomere shortening uas ua rau muaj kev cuam tshuam autophagy, thiab txhawb ADgenesis [97,98].

Kev tshawb fawb tsis ntev los no tau pom tias hauv AD, mitophagy (ib hom kev xaiv autophagythat koom nrog mitochondria) dysregulation ua rau kev sib sau ntawm mitochondrialdebris thiab destabilization ntawm mitochondrial kev ncaj ncees ua rau kev tuag ntawm tes [93,97].

Kev tshawb fawb ua tiav ntawm cov txheej txheem phosphatase thiab tensin homolog (PTEN)-inducedthe kinase 1 (PINK1)-Parkin txoj kev qhia txog qhov poob ntawm mitochondrial membranepotential, uas nce PINK1 ntawm daim nyias nyias ntawm mitochondria (OMM) toenlist thiab hloov rau Parkinquity. ligase, los ntawm phosphorylation ntawm ubiquitin.

Parkinubiquitinates ntau OMM cov proteins, uas txhawb UPS kom degenerate cov ubiquitinated OMM cov proteins, uas ua rau lub zog ntawm lub tshuab autophagy toinstigate engulfment ntawm impaired mitochondria los ntawm phagophore los yog secluded membranesand yog li tsim mitophagosoms tshwj tseg ntawm 9 qhov system.

Cov pov thawj ntawm oxidative kev nyuaj siab nyob rau hauv lub hlwb AD muaj xws li (1) lipid peroxidation, nyob rau hauv uas lipid byproducts, piv txwv li, 4-hydroxy-2, 3-nonenal (HNE); (2) protein oxidation nyob rau hauv daim ntawv ntawm 3-nitrotyrosine thiab protein carbonyls tau pom nyob rau hauv lub hippocampus ntawm AD cov neeg mob; thiab 3) DNA / RNA puas ua rau cuam tshuam DNA kho mechanisms thiab elevated DNAmutations tshwm sim nyob rau hauv lub hippocampus thiab cerebral cortex [100].

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