Highlighting Immune System and Stress in Major Depressive Disorder, Parkinson's, Thiab Alzheimer's Disease, Nrog Kev Sib Txuas Nrog Serotonin Part 2
Sep 01, 2023
2.3. Hauv Parkinson's Disease
Lub tswv yim tias kev ntxhov siab cuam tshuam nrog PD tau raug txiav txim siab ntau dua 100 xyoo. Nws tau pib thaum Gowers txuas kev ntxhov siab thiab kev ntxhov siab raws li kev ua ntej ntawm PD. Tsis tas li ntawd, kev ntxhov siab heev uas tau ntsib hauv Holocaust lossis thaum ua tsov rog tau cuam tshuam nrog tus kab mob no. Kev ntxhov siab cuam tshuam nrog kev loj hlob ntawm PD thiab tuaj yeem ua rau cov tsos mob hnyav dua, xws li nruj thiab tshee. Muaj, muaj tseeb, pov thawj uas qhia tau hais tias lub luag haujlwm no [55,56].
Muaj kev sib raug zoo ntawm kev ntxhov siab thiab kev nco. Thaum peb muaj kev ntxhov siab, theem ntawm cov tshuaj hormones kev ntxhov siab hauv lub hlwb nce, thiab cov tshuaj hormones no cuam tshuam rau peb lub hlwb, yog li cuam tshuam rau peb lub cim xeeb. Kev puas siab puas ntsws tuaj yeem ua rau lub hlwb ua haujlwm, xws li kev ntxhov siab, kev ntxhov siab, thiab kev nyuaj siab, uas tuaj yeem ua rau tus neeg muaj peev xwm kawm thiab nco tau.
Kev ntxhov siab ntev tuaj yeem cuam tshuam tsis zoo rau kev nco, ua rau tib neeg xav tias lub hlwb qeeb qeeb, thiab cuam tshuam rau tus neeg lub peev xwm ua haujlwm thiab kev sib raug zoo hauv lub neej niaj hnub. Kev ntxhov siab tuaj yeem ua rau lub hlwb nqaim, tsis muaj kev ua kom pom tseeb thiab mloog zoo, thiab kev txaus siab ntawm lub hlwb, uas tuaj yeem ua rau tib neeg tsis muaj peev xwm nco qab thiab xav. Ua ntej tshaj plaws, kev ntxhov siab ua rau tib neeg xav tias ntshai thiab nyob tsis tswm, uas cuam tshuam rau lub hlwb kev xav thiab ua rau nws nyuaj rau kev mloog zoo rau kev kawm thiab kev nco. Qhov thib ob, kev ntxhov siab tuaj yeem cuam tshuam rau tib neeg txoj kev pw tsaug zog zoo, uas yog qhov tseem ceeb rau lub hlwb lub peev xwm khaws cia nco. Nrog rau kev pw tsaug zog tsis zoo, lub hlwb tsis tuaj yeem ua haujlwm zoo thiab khaws cov ntaub ntawv, uas tuaj yeem ua rau kev nco tsis zoo hauv tib neeg.
Txawm li cas los xij, qhov ntawd tsis tau txhais hais tias kev ntxhov siab yuav ua rau koj tsis nco qab. Txoj hauv kev zoo tuaj yeem pab koj rov qab los ntawm cov xwm txheej ntxhov siab thiab tuav lub cim xeeb zoo. Ua haujlwm tswj kev ntxhov siab thiab kev ntxhov siab los ntawm txoj hauv kev xws li ua pa tob tob, xav txog, tawm dag zog, thiab kev sib raug zoo. Tsis tas li ntawd, tswj kev pw tsaug zog zoo thiab noj zaub mov zoo txhawb koj kom ua kom zoo dua koj lub hlwb cov qauv kev nco kom txhim kho koj lub cim xeeb. Tsis tas li ntawd, txuas ntxiv nthuav tawm ib qho kev paub thiab kev kawm tshiab tuaj yeem txhawb kev txhim kho kev nco.
Hauv cov ntsiab lus, kev sib raug zoo ntawm kev ntxhov siab thiab kev nco yog qhov nyuaj, tab sis kev tswj hwm tus cwj pwm zoo thiab txoj hauv kev zoo tuaj yeem pab koj kov yeej kev ntxhov siab thiab tswj kev nco zoo. Cia peb ntsib kev ntxhov siab, ua rau peb nco, thiab ua tiav ntau dua hauv peb lub neej txhua hnub. Nws pom tau tias peb yuav tsum txhim kho peb lub cim xeeb. Cistanche tuaj yeem txhim kho kev nco, vim Cistanche tseem tuaj yeem tswj hwm qhov sib npaug ntawm cov tshuaj 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, cov nqaij kuj tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov khoom noj txaus thiab lub zog, yog li txhim kho qhov tseem ceeb thiab kev ua haujlwm ntawm lub hlwb.
Nyem paub txoj hauv kev los txhim kho lub hlwb
Hauv cov tsiaj, kev ua haujlwm ntawm lub cev muaj zog zuj zus thiab muaj qhov poob ntawm nigral neurons thaum nce qib ntawm glucocorticoids thiab corticosterone tau txheeb xyuas [4,57]. Hauv cov neeg mob PD, cortisol nce siab thaum piv rau kev tswj hwm kev noj qab haus huv. Muaj kev sib txuas ntawm HPA axis hyperfunction thiab dopamine, qhia txog qhov tseeb tias kev kho mob nrog levodopa tuaj yeem txo qis cortisol hauv cov neeg mob PD.
Qhov tseeb, glucocorticoids ua kom cov kab mob nce ntxiv. Tsis tas li ntawd, kev ntxhov siab ntawm lub siab tuaj yeem ua rau cov tsos mob ntawm PD. Tom qab raug kev ntxhov siab, cov tib neeg nrog PD muaj cov lus teb hedonic, rau qhov tsawg dua. Tseeb, muaj kev sib raug zoo ntawm kev ntxhov siab, dopaminergic neurodegeneration, thiab dopamine metabolism thiab ntau lawm, uas yog depletion ntawm dopamine nyob rau hauv lub nigrostriatal thiab non-nigrostriatal systems thiab exacerbated qhia ntawm nigrostriatal thiab non-nigrostriatal -synuclein [3,54,56].
Hauv lwm txoj kev tshawb fawb, tom qab MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) tau ua rau muaj kev puas tsuaj rau neuronal thiab kev puas tsuaj hauv kev nrhiav tau cov kev txawj tsav tsheb hauv nas, Cov txiaj ntsig tau qhia txog kev tuag ntawm dopaminergic neurons nyob rau hauv substantia nigra, nrog rau exacerbation ntawm PD cov tsos mob, uas yog lub cev muaj zog thiab kev kawm tsis txaus [58]. Xav txog tag nrho cov no, nws yog ib qho tseem ceeb uas yuav tau xav txog cov kev tshawb fawb no thiab lub luag haujlwm ntawm kev ntxhov siab hauv PD los txhim kho kev tshawb fawb yav tom ntej, nrog rau kev kho mob ntawm cov neeg mob [57].
Cov tsos mob xws li kev nyuaj siab thiab kev ntxhov siab yog nquag pom hauv cov neeg mob PD. Tsis ntev los no, ib txoj kev tshawb fawb tsom los soj ntsuam cov kev ntxhov siab tom qab kev kho mob nrog Fluvoxamine (SSRI) ntawm dopaminergic neurons hauv tus qauv nas nrog PD. Txoj kev tshawb no xaus lus tias cov tsiaj uas raug kev ntxhov siab muaj cov ntshav plasma siab ntawm corticosterone thiab malondialdehyde, ib qho kev cuam tshuam uas tau txo qis nrog kev kho mob nrog Fluvoxamine. Tsis tas li, cov tshuaj no tau tshwm sim los txo qis qhov tsis zoo ntawm dopaminergic neurons rau kev ntxhov siab thiab kev kho mob neurotoxic, xws li 6-hydroxydopamine (6-OHDA) [59]. Yog li, txoj kev tshawb no qhia txog kev sib txuas ntawm serotonin thiab kev ntxhov siab cuam tshuam nrog PD.
Qhov tseeb, los ntawm ntau qhov kev tshawb fawb uas cov tsiaj muaj kev ntxhov siab los ntawm kev sib cais ntawm niam, nws tau pom tias kev ntxhov siab tsis yog rau HPA nkaus xwb tab sis kuj tseem muaj cov kab mob serotonergic tam sim no hauv hippocampus. Tsis tas li ntawd, kev ntxhov siab ua rau lub cev tsis ua haujlwm ntawm lub hauv paus dopaminergic, uas yog qhov tseem ceeb heev hauv cov tsos mob ntawm PD, xws li cov tsos mob ntawm lub cev muaj zog [60]. Tseeb, muaj kev paub ntau ntxiv ntawm serotonergic system hauv PD.
Hauv kev tshawb fawb nrog cov hnub nyoog A53T kev hloov pauv -synuclein-expressing nas, degeneration ntawm axons ntawm serotonergic fibers nyob rau hauv lub prefrontal cortex ntawm cov nas, raws li zoo raws li ib tug hloov fiber ntau network, tau soj ntsuam. Tsis tas li ntawd, nce qib ntawm tryptophan hydroxylase 2 mRNA thiab 5-HT1B kev qhia tau pom nyob rau hauv cov qauv tsiaj hloov pauv rau PD thiab tuaj yeem cuam tshuam nrog cov txheej txheem rov ua haujlwm hauv serotonergic system [61].
Tseem tseem hais txog lub luag haujlwm ntawm serotonin hauv PD, Pimavanserin yog tus antagonist inverse ntawm serotonin 5-HT2A receptor uas nthuav tawm cov txiaj ntsig hauv cov ntsiab lus ntawm levodopa-induced psychosis, nquag pom hauv PD. Muaj kev sib raug zoo rau cov receptor no thiab tsis tshua muaj kev sib raug zoo rau D2 lossis histamine receptors, cov tshuaj no muaj txiaj ntsig ntawm kev txo qis kev ntxhov siab thiab lub cev muaj zog, ua lwm txoj hauv kev rau cov neeg mob uas muaj kev puas siab puas ntsws PD [62]. Lwm qhov kev tshawb nrhiav kev nthuav dav txog kev sib cuam tshuam ntawm serotonin thiab PD tau tshaj tawm tias kev ua haujlwm tsis zoo hauv serotonergic system tuaj yeem ua ntej dopaminergic tsis ua haujlwm thiab cov tsos mob ntawm lub cev muaj zog pom hauv PD cov neeg mob uas muaj A53T hloov pauv hauv -synuclein.
Cov kev tshawb pom no txhawb kev siv cov duab molecular ntawm serotonergic Cheebtsam (xws li cov neeg thauj khoom) raws li kev sib ntxiv ntawm PD kuaj mob [63]. Hauv lwm txoj kev tshawb fawb hauv cov nas, kev hloov pauv ntawm mesenchymal qia hlwb nrog rau cov kab mob intracellular ntawm Notch1 noob (tseem ceeb rau kev tswj hwm) tau pom tias txo qis degeneration ntawm tsis yog dopaminergic nkaus xwb tab sis kuj serotonergic neurons hauv cov neeg mob PD, muab cov txiaj ntsig zoo dua thiab ua lub peev xwm kho cellular. [64].
3. Kev koom tes ntawm lub cev tiv thaiv kab mob
3.1. Nyob rau hauv Major Depressive Disorder
Qee lub cev tiv thaiv kab mob, xws li ncig granulocytes thiab monocytes, chemokines, thiab cytokines, tuaj yeem cuam tshuam rau lub hlwb ncaj qha, cuam tshuam rau cov kev sib txuas neuronal uas koom nrog kev nyuaj siab. Qhov tseeb, qhov mob ua lub luag haujlwm tseem ceeb hauv MDD. Yog li, muaj kev sib raug zoo ntawm kev kho mob antidepressant thiab psychotherapy, thiab txo cov tsos mob ntawm tus mob.
Muaj pov thawj tias ob qho tib si tso tawm cytokines nrog lub cim proinflammatory thiab stimulation ntawm anti-inflammatory cytokines yog inhibited thiab stimulated los ntawm antidepressants, feem [65–67]. Proinflammatory cytokines tuaj yeem ua rau HPA axis, ua rau nce qib ntawm cortisol thiab glucocorticoid receptor tsis kam, cov txheej txheem koom nrog hauv MDD [68].
Tsis tas li ntawd, cov cytokines proinflammatory no ua rau lub pathogenesis ntawm MDD los ntawm kev hloov kho txoj hauv kev tryptophan-kynurenine thiab synthesis ntawm quinolinic acid (NMDA receptor agonist) thiab 3-hydroxykynurenine [69]. Cov neeg mob nyuaj siab uas muaj teeb meem hauv kev teb rau kev kho mob antidepressant muaj TfR, IL-6, sIL-6, CRP, sIL-2R, thiab AGP concentrations siab hauv lawv cov ntshav thiab tej zaum yuav muaj cov alleles txawv txav ntawm IL. -1 thiab TNF noob, nrog rau cov teeb meem hauv kev ua haujlwm ntawm T hlwb [65,67,70,71]. Tsis tas li ntawd, kev tshawb fawb meta-analysis piv MDD cov neeg mob thiab cov neeg noj qab haus huv tau qhia tias hauv MDD cov tib neeg nce qib ntawm cov molecules xws li TNF, IL10, sIL-2 IL-18, IL-12, thiab IL-1RA tau pom, sib piv nrog kev txo qis ntawm cov theem ntawm interferon-g (IFN-g), piv rau cov tswj kev noj qab haus huv [72].
Nyob rau theem genomic, upregulation ntawm kev hais tawm ntawm cov noob caj noob ces code tseem ceeb mediators nyob rau hauv inflammatory pathways (xws li IL-1b, thiab IL-6) kuj tau pom nyob rau hauv peripheral ntshav mononuclear hlwb ntawm cov neeg mob MDD [73]. Ntau cov kev tshawb fawb txhawb nqa lub luag haujlwm ntawm microglia ua kom muaj kev puas siab puas ntsws, xws li MDD [74]. Ib qho piv txwv yog ib qho kev tshawb fawb uas pom tau tias muaj cov qib proinflammatory cytokines nce ntxiv los ntawm kev ua kom microglia thiab qhov kev thauj mus los ntawm monocytes mus rau lub hlwb, ua rau muaj kev ntxhov siab [74,75].
Ntxiv mus, nyob rau hauv cov neeg mob nrog MDD, lub xub ntiag ntawm proinflammatory cytokines keeb kwm los ntawm microglia (xws li TNF-) txo qhov muaj cov neurotransmitters serotonin, dopamine, thiab noradrenaline nyob rau hauv ntau txoj kev, nrog rau txo lawv cov synthesis [76]. Ntxiv mus, neuronal apoptosis thiab qis qis ntawm neurotransmitter synthesis tuaj yeem tshwm sim los ntawm kev ua haujlwm ntev ntawm microglia, ua rau muaj kev nyuaj siab [77]. Kev txhawb nqa lub luag haujlwm ntawm microglia hauv MDD, nws tau tshaj tawm tias qee cov tshuaj tiv thaiv kev ntxhov siab (xws li imipramine) muaj cov tshuaj tiv thaiv kab mob los ntawm kev txo qis microglial activation, yog li txo cov qib ntawm proinflammatory cytokines [78]. Hauv lwm txoj kev tshawb fawb, nws kuj tau pom tias txoj hauv kev ntawm glucocorticoid receptor-NF-κB-NLRP3, thaum ua haujlwm hauv microglia, yog qhov tseem ceeb rau kev kho cov kab mob neuroinflammation vim muaj kev ntxhov siab ntev thiab kev nyuaj siab. Tseeb tiag, dexamethasone (siv los ua cov kab mob glucocorticoid) nce qib NF-κB thiab NLRP3.
Tom qab ntawd, tom qab inhibition ntawm NF-κB thiab knockout ntawm NLRP3, theem ntawm o thiab kev nyuaj siab zoo li tus cwj pwm poob [79]. Lwm qhov kev tshawb fawb tseem ceeb tau qhia tias nce qib ntawm TSPO (translocator protein - tam sim no nyob rau hauv lub tshuab ua kom microglia), muaj nyob rau hauv lub anterior cingulate cortex ntawm cov neeg mob thaum lub sij hawm nruab nrab thiab hnyav kev nyuaj siab, hais txog qhov tseem ceeb ntawm kev kho tshuaj tiv thaiv kab mob rau MDD [80].
Lub upregulation ntawm ionized calcium-binding adapter molecule 1 (IBA1) thiab monocyte chemoattractant protein 1 (MCP-1) noob thiab, yog li ntawd, nce ceev ntawm IBA1-zoo microglia, kuj tau pom nyob rau hauv postmortem hlwb cov ntaub so ntswg. ntawm cov neeg mob kev nyuaj siab heev [81].
Ntau yam kab mob inflammatory, xws li mob caj dab rheumatoid thiab ntau yam sclerosis, yog tus cwj pwm los ntawm kev pheej hmoo rau kev nyuaj siab. Piv txwv li, cov neeg mob uas muaj ntshav qab zib muaj ob zaug kev pheej hmoo ntawm kev nyuaj siab, nrog rau txog li 70% ntawm cov neeg mob rheumatoid mob caj dab lossis kab mob lupus erythematosus [82]. Tsis tas li ntawd, nyob rau hauv cov nas uas muaj kev nyuaj siab tus cwj pwm, qhov nce ntawm cov monocytes hauv cov ntshav tau pom, thiab nws qhov nruab nrab yog txaus kom txo tau tus cwj pwm kev nyuaj siab [83]. Cov kev tshawb fawb ntxiv tau taw qhia tias kev kho cov nas nrog lipopolysaccharide (LPS), uas ua rau muaj kev tiv thaiv kab mob hauv lub cev, ua rau tsis muaj peev xwm ua rau muaj kev txaus siab thiab poob phaus. Qhia txog qhov tseem ceeb ntawm lub cev tiv thaiv kab mob hauv kev nyuaj siab, cov nas tsis muaj peev xwm ntawm cov kab mob inflammatory caspase-1 kuj pom tias muaj kev tiv thaiv rau LPS-induced depressive cwj pwm [84].
Lwm txoj kev tshawb fawb tau qhia tias qhov kev qhia ntawm HMGB1-RAGE (siab mobility box 1 protein-receptor rau qib siab glycation kawg cov khoom) hauv microglia tsis tu ncua ua rau muaj kev pheej hmoo ntawm kev nyuaj siab, feem ntau tom qab muaj kev ntxhov siab [85]. Ntawm qib microbiome, kuj tseem muaj qhov sib txawv ntawm cov neeg noj qab haus huv thiab kev nyuaj siab, ua rau muaj kev tiv thaiv kab mob tsis zoo [86]. Piv txwv li, cov kab mob Coprococcus thiab Dialister muaj tsawg dua nyob rau hauv cov neeg mob MDD piv rau kev noj qab haus huv.
Cov kab mob no yog ib qho tseem ceeb rau kev tswj hwm ntawm ntau lub zog. Coprococcus cuam tshuam nrog txoj hauv kev dopamine, feem ntau cuam tshuam rau cov neeg muaj kev nyuaj siab. Txawm li cas los xij, cov kab mob no tseem tsim cov butyrate, ib qho tshuaj tiv thaiv kab mob [87]. Cov kev tshawb fawb uas tsom mus rau kev sib raug zoo ntawm cov tshuaj uas tsis yog-steroidal anti-inflammatory tshuaj (NSAIDs) raws li cov neeg sib tw rau kev kho mob kev nyuaj siab qhia tau hais tias, tag nrho, cov chav kawm ntawm cov tshuaj no ua rau kom txo tau tus cwj pwm kev nyuaj siab, nrog ib tug tshwj xeeb tsom teeb rau inhibitors ntawm cyclooxygenase{ {5}} (COX-2), xws li celecoxib [88].
Hauv lwm txoj kev tshawb fawb, nce qib ntawm anhedonia kuj tseem cuam tshuam nrog kev txo qis hauv kev sib txuas ntawm prefrontal cortex thiab striatum. Cov kev tshawb pom no kuj tseem cuam tshuam nrog nce qib ntawm proinflammatory cytokines thiab C-reactive protein nyob rau hauv cov neeg mob MDD [89]. Kev tshawb nrhiav hnyav ntawm kev sib txuas ntawm lub cev tiv thaiv kab mob thiab MDD yuav, yeej, txhawb peb txoj kev nkag siab ntawm cov kab mob uas muaj ntau thiab nyuaj, tsim kev kho kom zoo dua qub thiab txhim kho lub neej zoo ntawm cov neeg mob [90]. Nco ntsoov tias lub cev tsis muaj zog thiab yoog raws kev tiv thaiv tsis zoo hauv cov neeg mob MDD, lub tswv yim kho kom zoo yuav tsum tswj cov txheej txheem inflammatory [91].
Ntxiv rau tag nrho nws lub luag haujlwm paub, serotonin kuj tseem muaj lub luag haujlwm tseem ceeb hauv lub cev tiv thaiv kab mob. Ntau qhov kev tshawb fawb tau pom tias, qhov tseeb, ntau hom kev tiv thaiv kab mob, xws li T hlwb, tsim khoom, khw, thiab teb rau serotonin. Qhov kev sib txuas no kuj tau txuas rau kev xav tsis zoo [92]. Cov kev tshawb fawb uas ntsuas lub luag haujlwm ntawm SSRI kev kho mob hauv cov kab mob autoimmune thiab qhov tshwm sim ntawm Th17: Treg piv, tau pom tias qhov kev hloov pauv ntawm qib serotonin nrog SSRI kev kho mob txo qis qhov piv txwv no thiab, yog li ntawd, cov tshuaj no zoo li muaj kev tiv thaiv kab mob [ 92–94] ib. Hauv cov ntsiab lus ntawm MDD, nws tau pom tias cov neeg mob uas muaj cov kab mob no muaj qib siab ntawm Th17:Treg piv, muaj qhov feem pua ntawm Treg tsawg piv rau cov neeg mob uas tsis muaj cov kab mob no [95–97].
Nyob rau hauv cov ntsiab lus no, kev kho mob nrog SSRIs, feem ntau, ua rau muaj kev nce hauv cov hom T hlwb, yog li ua rau muaj qhov normalization ntawm Th17:Treg piv rau qib zoo ib yam rau kev noj qab haus huv tswj [95]. Lwm cov kev tshawb fawb kuj tau qhia txog qhov kev sib raug zoo no, uas yog ib qho kev tshawb fawb uas cov nas tau kho nrog rapamycin, ib qho tshuaj uas nws txoj haujlwm yog txhawm rau nce Treg hlwb. Hauv txoj kev tshawb no, cov tsiaj kho nrog cov tshuaj no tau pom tias muaj kev paub zoo dua qub thiab nce qib ntawm serotonin thiab dopamine piv rau kev tswj hwm [92]. Txawm li cas los xij, txawm tias cov pov thawj no, kev tshawb fawb ntxiv ntawm cov ncauj lus no tseem xav tau. Piv txwv li, SSRIs sib txawv tuaj yeem hloov kho lub cev tiv thaiv kab mob sib txawv ntawm ib leeg, thiab, yog li ntawd, kev tshawb fawb ntxiv txog kev sib raug zoo ntawm serotonin nrog lub cev tiv thaiv kab mob yog qhov tseem ceeb [92,98].
3.2. Hauv Alzheimer's Disease
Ntau qhov kev tiv thaiv kab mob tsis zoo yog suav tias yog qhov muaj feem cuam tshuam rau AD. Feem ntau yog vim muaj cov kab mob inflammatory, nrog rau qhov tshwj xeeb tseem ceeb hauv IgA, lub cev tiv thaiv kab mob tsis zoo hauv cov neeg mob kuaj mob AD. Cov tib neeg uas muaj lossis tsis muaj AD tau qhia ntau theem ntawm IgA. Hauv ib qho kev tshawb fawb tshwj xeeb, qib ntawm IgA hauv cov neeg mob AD thiab cov neeg mob tsis muaj AD yog 103.97 ± 65.62 thiab 23.79 ± 16.1, feem. Cov ntaub ntawv no qhia tias cov neeg mob AD raug kev txom nyem los ntawm kev hloov pauv hauv lub cev [99]. Tseeb tiag, neuroinflamation yog suav tias yog ib qho tseem ceeb ntawm AD. Neuritic plaques tsim los ntawm A thiab neurofibrillary tangles yog, qhov tseeb, ncig los ntawm astrocytes thiab microglia nrog cov yam ntxwv reactive [100].
Qhov no microglia paub tias tso tawm proinflammatory yam. Piv txwv suav nrog cov qog necrosis factor-alpha (TNF) thiab interleukin 1 beta (IL-1) [101,102], qhia txog lub luag haujlwm ntawm neuroinflammation hauv AD. Tsis tas li ntawd, kev sib cuam tshuam ntawm lub cev tiv thaiv kab mob thiab AD tau pom los ntawm kev sib txuas ntawm cov protein ntau ntxiv rau cov ntaub so ntswg puas thiab los ntawm kev ua kom cov hlwb uas cuam tshuam nrog lub cev tsis muaj zog [103,104]. Kev tshawb nrhiav kev tshawb fawb tsom rau kev ntxiv C3, lub cev tiv thaiv kab mob molecule uas pab microglia hauv kev tshem cov plaques thiab tau tswj hwm hauv AD, ua rau cov synapse poob uas ua rau kev txawj ntse poob. Nws tau pom tias kev tshem tawm cov noob ntawm cov molecule no hauv cov qauv nas ntawm AD, txhim kho cov tsiaj txhu kev ua tau zoo hauv ob qho tib si kev kawm thiab kev ntsuam xyuas nco, txawm tias lawv muaj cov plaques ntau hauv lawv lub hlwb thiab tsawg dua thiab tsawg dua microglia [105].
Lwm txoj kev tshawb fawb tsom los tshuaj xyuas amyloid-beta-stimulated T lymphocytes hauv cov neeg mob AD piv rau cov kev paub tsis meej me me hauv cov tib neeg noj qab haus huv. Cov txiaj ntsig tau pom tias A txhawb CD4(+) T hlwb uas tsim IL-21 thiab IL-9, thiab uas qhia txog ROR thiab NFATc1 cov ntsiab lus hloov pauv, nrog rau cov monocytes uas tsim IL-23- thiab IL-6-, tau nce ntxiv. Ntawm qhov tod tes, IL-10- tsim cov monocytes nyob rau hauv tus lej qis hauv AD, piv nrog rau lwm yam xwm txheej [106].
Lwm cov kev tshawb fawb kuj tau taw qhia tias ntau yam proinflammatory cytokines xws li TNF , IL-1 , thiab IL-18 thiab cov tshuaj tiv thaiv cytokines, xws li interleukin -1 receptor antagonists tau nce hauv cerebrospinal kua ntawm cov neeg mob. AD, qhia txog kev tiv thaiv kab mob hauv cov neeg mob uas muaj tus kab mob no [107–109]. Cov kev tshawb fawb genomic kuj tseem cuam tshuam AD nrog rau kev tsis haum tshuaj hauv lub cev tiv thaiv kab mob hauv lub cev thiab cov txheej txheem tsis muaj zog. Txawm li cas los xij, cov txheej txheem tseeb los ntawm kev tiv thaiv kev tiv thaiv innate cuam tshuam AD tseem tsis pom [110]. Th17 hlwb kuj tseem ceeb heev rau lub pathogenesis ntawm AD thiab lawv txoj kev koom tes hauv neuroinflammation pom nyob rau hauv cov neeg mob AD tau kawm. Piv txwv li, qhov kev koom tes no tau pom nyob rau hauv AD nas qauv, inducing neurodegeneration ntawm 1-42.
Los ntawm kev cuam tshuam BBB, cov hlwb no tuaj yeem nkag mus rau hauv lub hlwb, uas ua rau tsim cov proinflammatory cytokines xws li IL-22 thiab IL-17 [111]. Tseeb, hauv lwm txoj kev tshawb fawb hauv nas cov qauv ntawm AD, cov teebmeem ntawm IL-17 neutralizing antibody (IL-17Ab) txo cov neurodegeneration, txhim kho kev nco, thiab txo qis proinflammatory yam, qhia txog qhov tseem ceeb ntawm Th17 hlwb hauv AD. [112]. Lwm txoj kev tshawb fawb txuas qhov kev puas tsuaj ntawm microglial TREM2 (Triggering Receptor Expressed On Myeloid Cells 2) signaling nrog txo qis ntawm neuroinflammation thiab neurodegeneration, tseem ceeb hauv cov ntsiab lus ntawm AD [113]. Yog li, kev nkag siab zoo ntawm cov txheej txheem no tuaj yeem pab txhawb kev kawm txog cov tswv yim kho tshiab.
Raws li twb tau hais lawm, neuroinflamation yog ib qho cim tshwj xeeb hauv AD.
Cov kev tshawb fawb tau pom tias kev kho mob nrog SSRIs txo cov cytokines hauv kev ncig, nrog rau txo qis ntau txoj hauv kev uas feem ntau nce siab hauv cov kab mob no. Yog li, kev sib txuas ntawm serotonin, neuroinflamation, thiab AD yog pom tseeb [114,115]. Cov kev tshawb fawb tau pom tias kev hloov pauv hauv kev ua haujlwm ntawm serotonin transporter yog tshwm sim los ntawm proinflammatory cytokines nce hauv AD, xws li interleukin -1 beta [116]. Tsis tas li ntawd, hauv kev tshawb fawb nrog cov kab mob neuronal thiab hauv vivo kev tshawb fawb, TNF tau pom tias yuav ua rau kom nce siab tshaj plaws ntawm serotonin [117]. Nyob rau hauv lem, kev kho mob nrog IL-6 txo cov theem ntawm SERT mRNA nyob rau hauv nas hippocampus. Yog li, cov ntaub ntawv no qhia tau hais tias, thaum lub sij hawm AD, cov cytokines cuam tshuam nrog serotonergic system nyob rau hauv ib txoj kev tshwj xeeb rau txhua cytokine, nrog rau kev xav tau kev kawm hauv cheeb tsam no [118]. Txawm li cas los xij, nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias kev tshawb fawb ntawm cov ncauj lus no qhia tau hais tias kev loj hlob ntawm cerebellar amyloidosis, tus yam ntxwv ntawm AD, yog txuam nrog neuroinflammation, uas yog mirrored nyob rau hauv cov xwm txheej xws li kev hloov hauv kev ncaj ncees thiab pre-synaptic serotonergic kev ua si [ 116] ib.
Lwm txoj kev tshawb fawb txuas AD, kev nyuaj siab, thiab kev tiv thaiv kab mob. Tseeb, qhov kev tshawb fawb no tau tshaj tawm tias kev sib sau ntawm A oligomers thiab co toxins tam sim no hauv cov neeg mob AD ua rau muaj kev nyuaj siab nyob rau hauv cov nas los ntawm microglial activation, hloov pauv hauv TNF- signaling pathway, thiab txo qhov muaj serotonin hauv lub hlwb. Hauv txoj kev tshawb no, cov kws sau ntawv tau qhia tias serotonin txo qis kev ua haujlwm ntawm microglia, tus tswj tsis zoo ntawm cov hlwb. Tsis tas li ntawd, txoj kev tshawb no pom tau hais tias nyob rau hauv tus xov tooj hu-zoo li receptor 4- cov nas tsis muaj peev xwm, qhov muaj ntawm A oligomers tsis ua rau muaj kev nyuaj siab. Kev txhawb nqa kev sib raug zoo ntawm AD thiab serotonin, nws tau pom tias muaj kev cuam tshuam hauv serotonin signaling txoj hauv kev los ntawm A peptide txhawb kev mob hlwb. Ntawm qhov tod tes, serotonin tuaj yeem tiv thaiv kev ua haujlwm ntawm microglial hlwb uas raug ntxias los ntawm A [119]. Tsis tas li ntawd, SSRI kev tswj hwm rau tsiaj cov qauv ntawm AD, nce qib ntawm serotonin ua rau qis dua A ntau lawm, txhawb lub tswv yim tias serotonin-induced pathways cuam tshuam A deposits hauv txoj kev tsis zoo [120].
3.3. Hauv Parkinson's Disease
Cov pov thawj tseem ceeb qhia txog lub luag haujlwm ntawm ob qho tib si hauv lub cev thiab lub cev tiv thaiv kab mob hauv cov kab mob pathophysiology ntawm PD [121]. Qhov tseeb, kev soj ntsuam tom qab lub hlwb los ntawm cov neeg mob PD qhia tau hais tias kev tiv thaiv kev tiv thaiv kab mob thiab kev ua kom microglia ua rau muaj kev cuam tshuam rau tus kab mob [122,123]. Tam sim no, nws paub tias, nyob rau hauv cov lus teb rau -syn aggregation thiab toxicity, microglia activation tshwm sim nyob rau hauv thawj theem ntawm tus kab mob, yog ib qho tseem ceeb nyob rau hauv clearing aggregates ntawm -syn thiab, yog li, pib ib tug series ntawm inflammatory teb.
Qhov no ua kom microglia los ntawm -syn kuj ua rau infiltration ntawm monocytes thiab macrophages los ntawm CCL2- CCR2 txheej txheem. Tsis tas li ntawd, raws li txoj cai, kev hloov kho lub cev tiv thaiv kab mob los ntawm CD8 lossis CD4 yuav pib los ntawm qhov tseeb tias peptides ntawm -syn yuav nthuav tawm los ntawm cov neurons los ntawm MHCI thiab los ntawm microglia, monocytes, lossis macrophages los ntawm MHCII. Hauv kev teb rau kev ua kom CD4-Th hlwb, cytokines raug tsim tawm uas tuaj yeem ua rau muaj zog ntawm cov xwm txheej proinflammatory, feem ntau yog tias muaj kev sib txawv rau Th1 lossis Th17 hlwb tshwm sim [124].
Cov kev tshawb fawb pom tias CD8+ thiab CD4+ T hlwb muaj nyob rau hauv cov neeg mob PD ntau dua [125]. Hauv lwm txoj kev tshawb fawb, hauv tib neeg cov ntshav kuaj ntawm PD cov neeg mob, qhov txo qis ntawm lymphocytes (tag nrho) tau pom, thaum CD8 + T hlwb nce, nrog rau IFN- / IL-4 piv, piv rau rau kev noj qab haus huv tswj [126] Tsis tas li ntawd, hauv kev tshawb fawb kev tshawb fawb, qhov ntau ntawm IL-1 beta thiab IL-6 nyob rau hauv dopaminergic, striatal cheeb tsam tau ntau dua rau cov neeg mob PD hauv kev sib piv rau kev tswj hwm [127]. Ntawm qhov tod tes, kev tsim cov pa reactive oxygen thiab nitrogen hom thiab cytokines zoo li yuav txhawb nqa apoptotic signals uas cuam tshuam txoj sia nyob ntawm cov neurons. Tsis tas li ntawd, kev tsim cov tshuaj chemokines los ntawm microglia muaj lub luag haujlwm tseem ceeb hauv kev ua rau muaj kev cuam tshuam ntawm lub cev tiv thaiv kab mob mus rau hauv nruab nrab lub paj hlwb, uas tej zaum yuav yog ib qho tseem ceeb hauv kev kis kab mob thiab cuam tshuam rau kev noj qab haus huv neuronal [128,129]. Ntau qhov kev tshawb fawb tau qhia txog lub luag haujlwm tseem ceeb ntawm astrocytes hauv PD neuroinflamation.
Cov hlwb no ua reactive thiab proinflammatory nyob rau hauv teb rau ntau lub teeb liab, xws li TNF- thiab C1q secreted los ntawm microglia [130]. Nyob rau hauv kev pom zoo nrog qhov no, nyob rau hauv cov ntaub so ntswg postmortem ntawm PD cov neeg mob, proinflammatory phenotype ntawm astrocytes tau pom [131]. Cov xwm txheej keeb kwm ntawm PD txuas nrog kev hloov pauv hauv DJ-1 hauv 1% ntawm cov xwm txheej. Cov molecule no tau kawm, thiab cov kev tshawb fawb qhia tau hais tias lub knockdown ntawm no molecule nyob rau hauv microglia ua rau ib tug nce nyob rau hauv microglia lub neurotoxicity, feem ntau yog vim dopaminergic neurons. Tsis tas li ntawd, hauv DJ-1 knockdown microglia, nce hauv kev tsim tawm ntawm IL-6 thiab IL-1 cytokines, txhawb nqa los ntawm -Syn, tau tshaj tawm.
Hauv cov microglia, kev puas tsuaj hauv cov txheej txheem autophagic, cuam tshuam -Syn clearance, kuj tau pom [132].
Neuroinflamation yog tus yam ntxwv uas txhais tau tias PD. Nyob rau hauv cov ntsiab lus ntawm neuroimmunology, dopamine, txawm yog ib tug neurotransmitter, kuj plays lub luag hauj lwm tseem ceeb nyob rau hauv cov kev cai ntawm cov hlwb nyob rau hauv lub cev. Lub dopamine transporter, hu ua DAT, muaj nyob rau hauv lymphocytes thiab lwm lub hlwb ntawm lub cev tiv thaiv kab mob, xws li monocytes thiab macrophages, yog li ua kom pom kev sib raug zoo ntawm lub cev tiv thaiv kab mob thiab cov kab mob dopaminergic uas muaj feem cuam tshuam rau pathophysiology ntawm PD [133]. Dhau li ntawm qhov kev sib raug zoo ntawm dopamine thiab neuroinflammation tam sim no hauv PD, kev sib raug zoo ntawm serotonin thiab neuroinflammation cuam tshuam nrog tus kab mob no kuj raug txiav txim siab, txawm tias tsis tshua muaj kev tshawb fawb hauv daim teb no. Txawm li cas los xij, paub tias muaj kev sib raug zoo ntawm serotonin thiab lub cev tiv thaiv kab mob, raws li tau tham thoob plaws hauv tsab xov xwm no, thiab paub tias serotonin plays lub luag haujlwm tseem ceeb hauv PD, xws li qhov tseeb tias cortical A peptide npaum li cas hauv cov neeg mob nrog PD cov koom haum nyob rau hauv txoj kev sib hloov nrog. serotoninergic innervation [134], nws tau txiav txim siab tias kev sib raug zoo ntawm peb yam no yog qhov tseem ceeb rau kev tshawb fawb yav tom ntej. Kev nkag siab tob txog kev tiv thaiv kab mob thiab yuav ua li cas nws cuam tshuam nrog PD yuav ua rau muaj kev txhim kho tshiab thiab muaj txiaj ntsig zoo dua, txhim kho lub neej zoo ntawm cov neeg mob.
4. Kev Sib Koom Tes ntawm Kev Nyuaj Siab thiab Kev Tiv Thaiv Kab Mob
Ntau lub cev hauv lub cev raug cuam tshuam los ntawm kev ntxhov siab, lub cev tsis muaj qhov tshwj xeeb (Daim duab 3). Cov kab ke no muaj lub luag haujlwm tseem ceeb thaum lub sij hawm teb kev ntxhov siab, txhim kho lossis tshem tawm los ntawm ntau yam kev ntxhov siab. Kev ntxhov siab ua rau muaj ntau yam kev ua ub no tseem ceeb hauv ntau yam pathologies. Ib qho piv txwv yog rooj plaub ntawm kev tiv thaiv kab mob los ntawm kev ntxhov siab thiab kev pheej hmoo ntawm AD hauv cov tib neeg uas tau ntsib kev puas tsuaj, xws li kev ua tsov ua rog lossis kev poob [2,135,136]. Tshwj xeeb tshaj yog, qhov nce hauv IL-1 thiab IL-6 concentrations muaj feem xyuam rau cov lus teb kev ntxhov siab, tseem ceeb rau kev txhim kho lub cev tiv thaiv kab mob thiab ua rau muaj sia nyob. Qhov tseeb, lub hlwb ua haujlwm yog hloov kho los ntawm cytokines, qhov uas lawv tuaj yeem tswj cov txheej txheem zoo li cov lus teb kev ntxhov siab, raws li cov lus teb bidirectional.
Kev ntxhov siab hnyav ua rau muaj kev hloov pauv ntawm lub cev tiv thaiv kab mob hauv lub cev, txhim kho kev ua haujlwm zoo li kev tiv thaiv kab mob. Tsis tas li ntawd, norepinephrine (NE), cortisol, thiab epinephrine (EPI) (cov tshuaj tiv thaiv kev ntxhov siab) cuam tshuam rau lub cev. Raws li ib qho piv txwv, norepinephrine ua rau muaj kev nce hauv cov lej leucocyte thiab kev txav ntawm lub cev tiv thaiv kab mob nkag mus rau cov ntshav. Txawm li cas los xij, cov kev ntxhov siab ntev yog cuam tshuam nrog kev tawm tsam ntawm ob lub cellular thiab humoral tiv thaiv [137]. Qhov tseeb, kev ua kom microglial tom qab kev ntxhov siab ua rau kev tso tawm ntawm norepinephrine, uas ua rau muaj ntau txoj hauv kev hauv lub cev tiv thaiv kab mob, suav nrog microglia nws tus kheej. Cov pov thawj no tau txais kev txhawb nqa los ntawm qhov tseeb tias -adrenergic receptor antagonists tuaj yeem cuam tshuam cov txheej txheem ntawm microglia activation [138]. Los ntawm inducing cytokine ntau lawm, kev ntxhov siab kuj ua rau (IDO-indoleamine 2,3-dioxygenase) / kynurenine txoj hauv kev, yog li cuam tshuam nrog lub cev tiv thaiv kab mob. IDO yog ib qho tseem ceeb hauv cov txheej txheem ntawm catabolism ntawm tryptophan, ua rau txo qis ntawm serotonin uas yog tsim los ntawm tryptophan. Cov kev txo qis ntawm serotonin li no txhawb cov xeev kev nyuaj siab. Los ntawm qhov kev txiav txim ntawm ntau yam proinflammatory cytokines (xws li TNF thiab IL-1b), IDO tau qhib rau hauv cov hlwb xws li glial hlwb thiab macrophages [139].
Hauv cov neeg mob MDD, cov teeb meem hauv kev ua haujlwm ntawm BBB twb tau piav qhia [140]. Tom qab muaj kev ntxhov siab, qhov qhib ntawm BBB tuaj yeem ua rau nkag mus rau hauv lub cev tiv thaiv kab mob. Nws tau raug pom tias tom qab kev ntxhov siab, T hlwb thiab monocytes infiltrate lub hlwb. Hauv cov nas muaj kev nyuaj siab, Th17 hlwb tuaj yeem sib sau ua ke hauv ntau lub hlwb, xws li hippocampus, txhawb kev nyuaj siab [141,142]. Lwm txoj kev tshawb fawb uas txhawb kev sib raug zoo ntawm kev ntxhov siab thiab kev tiv thaiv kab mob yog ib txoj kev tshawb fawb uas cov kws sau ntawv tau tshawb xyuas cov txiaj ntsig ntawm kev poob ntawm Cx3cr1 gene hauv microglia, cov noob tseem ceeb hauv kev tswj hwm ntawm microglia. Cov txiaj ntsig tau pom tau tias cov noob no yog qhov tseem ceeb hauv cov lus teb kev ntxhov siab ua haujlwm los ntawm microglia thiab nws txoj kev knockdown tiv thaiv cov teebmeem ntawm kev ntxhov siab thiab kev nyuaj siab hauv nas [143]. Tsis tas li ntawd, hauv Cx3cr1-GFP tus kws tshaj xov xwm nas, microglia phagocytosed ntau cov khoom siv synaptic thiab neuronal tom qab raug rau cov kev ntxhov siab ntev.
Lwm txoj kev tshawb fawb tau qhia tias, tom qab nthuav tawm cov nas mus rau ntau hom kev ntxhov siab ntev, ntau qhov kev hloov pauv tau tshwm sim, uas yog qhov poob ntawm hippocampal endogenous microglia thiab txo cov txheej txheem ntev thiab ua kom cov cim ntawm cov hlwb. Cov txheej txheem ntawm hippocampal microglia poob yav dhau los tau piav qhia tias yog ib qho tseem ceeb rau kev kho kom haum xeeb ntawm MDD hauv nas [144]. Tsis tas li ntawd, lwm txoj kev tshawb fawb hauv nas tau pom tias qhov nce ntxiv ntawm qhov ntom ntawm Iba1+ microglial hlwb tau pom nyob rau hauv cov menyuam yaus ua ntej yug menyuam tom qab lub sijhawm ntev ntawm niam txiv pw tsaug zog. Cov kev tshawb pom no tau nrog los ntawm kev tsis txaus ntawm neurogenesis thiab kev nco tsis zoo.
Tom qab kev kho mob nrog minocycline, cov kev hloov pauv no tau thim rov qab. Qhov no tau piav qhia los ntawm qhov tseeb tias cov tshuaj no tiv thaiv kev hloov pauv microglial, qhia txog kev sib raug zoo ntawm cov xwm txheej ntxhov siab (xws li kev pw tsaug zog tsis zoo) thiab kev hloov pauv hauv lub cev tsis muaj zog [145]. Tom qab LPS (lipopolysaccharide) kev tswj hwm hauv cov nas cev xeeb tub, kev tshawb fawb pom tau tias kev hloov pauv ntawm kev ntxhov siab ua ntej yug menyuam hauv microglia ntawm cov xeeb ntxwv ua rau muaj kev cuam tshuam rau kev nyuaj siab. Tseeb tiag, cov tsiaj muaj kev ntxhov siab tau nthuav tawm ntau qhov sib npaug ntawm Iba1-immunoreactive hlwb, feem ntau hauv hippocampus [146]. Tom qab muaj kev ntxhov siab ntau, hauv cov nas qus, qhov poob ntawm dopaminergic neurons thiab txo qis ntawm IBA1-zoo microglial tam sim no hauv substantia nigra kuj tau tshaj tawm [147].
Lwm tus neeg nruab nrab tseem ceeb hauv cov lus teb kev ntxhov siab yog ATP / P2X7R-NLRP3 inflammasome txoj hauv kev, pom los ntawm lub cev tsis muaj zog. Tsis ntev los no, nws tau tshaj tawm tias kev tswj hwm ntawm antagonists ntawm P2X7 receptors thaiv qhov kev tso tawm ntawm kev ntxhov siab vim cytokines (xws li TBF-a thiab IL-1B) los ntawm qhov cascade no, txo cov lus teb inflammatory thiab ua qhov kev kho mob zoo rau Tsis tas li ntawd, nyob rau hauv cov noob coding no receptor, ib leeg nucleotide polymorphism (Gln460Arg) tau cuam tshuam nrog kev pheej hmoo siab ntawm kev nyuaj siab [149]. colony-stimulating factor 1 thim rov qab dystrophy hauv microglia hauv thaj chaw hippocampal, qhia lub luag haujlwm ntawm microglial kev ua haujlwm hloov pauv thiab kev coj cwj pwm zoo li kev nyuaj siab (150].
Kev sib txuas ntawm kev ntxhov siab thiab kev tiv thaiv kab mob ua rau qhov no yog ib qho kev nthuav qhia ntawm kev tshawb fawb, tseem ceeb rau cov kev tshawb fawb yav tom ntej kom nkag siab zoo dua thiab, yog li, kev nce qib tshiab hauv cov tshuaj.
5. Cov lus xaus
Cov kab mob neurological, xws li AD, PD, thiab MDD tau hais los saum no, tab tom kawm ntxiv. Qhov kev tshawb xyuas hnyav rau cov kab mob no tau tsim muaj kev paub ntau ntxiv thiab, qhov tseem ceeb tshaj plaws, qhov ua tau zoo dua thiab kev kho mob txog cov xwm txheej no, kev tiv thaiv kab mob thiab kev ntxhov siab, nrog rau lawv cov kev sib cuam tshuam thiab kev sib txuas nrog neurotransmitters xws li serotonin, yog yam tseem ceeb heev. nyob rau hauv cov kab mob. Yog li ntawd, lawv tuaj yeem yog lub hom phiaj tseem ceeb rau kev tsim cov tshuaj tshiab lossis kev txhim kho hauv cov tshuaj uas twb muaj lawm. Rau qhov no, ntau txoj kev tshawb fawb tseem tsis tau ua tiav hauv cheeb tsam no, uas tau txais txiaj ntsig loj heev niaj hnub no. Cov kev tshawb fawb no yuav pab tau kom nkag siab zoo txog cov kab mob no thiab, qhov tseem ceeb tshaj, txhim kho lub neej zoo ntawm cov neeg mob.
Tus sau kev koom tes:
Conceptualization, NV; kev soj ntsuam, ASC, AC, thiab NV; kev sau ntawv- thawj daim ntawv npaj, ASC; sau ntawv- tshuaj xyuas thiab kho, ASC; AC thiab NV; saib xyuas, NV; project tswj, NV; Kev nrhiav nyiaj txiag, NV Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.
Nyiaj txiag:
Qhov kev tshawb fawb no tau txais nyiaj txiag los ntawm FEDER-Fundo Europeu de Desenvolvimento Regional los ntawm COMPETE 2020-Operational Program for Competitiveness and Internationalization (POCI), Portugal 2020, thiab los ntawm Portuguese cov nyiaj los ntawm Fundação para a Ciência ea Tecnologia (FCT) hauv qhov project IB/00092/2014/CP1255/CT0004.
Cov ntaub ntawv
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