Kev Ntsuam Xyuas Ntawm Cov Kabmob Neurodegenerative Feem Ntau: Txoj Kev Kho Mob Tam Sim No Thiab Lub Luag Haujlwm Ntawm Nanotherapeutics Part 3
Jun 27, 2024
Ntau cov ntaub ntawv pov thawj lees paub kev coj cwj pwm lossis kev txhim kho hauv vivo thaum kho nrog nanoparticles.
Raws li cov kws tshawb fawb, peb tus cwj pwm sab hauv muaj feem cuam tshuam nrog kev nco. Ntau cov kev tshawb fawb tau pom tias peb lub cev lub cev tuaj yeem cuam tshuam rau peb txoj kev txawj ntse.
Ua ntej tshaj plaws, kev tawm dag zog lub cev ua lub luag haujlwm tseem ceeb hauv kev txhim kho lub hlwb thiab txhim kho kev nco. Kev tawm dag zog tuaj yeem tsis tsuas yog pab peb tso kev ntxhov siab thiab txo kev ntxhov siab, tab sis kuj tseem txhim kho peb cov hlab plawv. Qhov no tuaj yeem ua rau peb cov ntshav ncig thiab cov pa oxygen, yog li txhim kho kev ua haujlwm ntawm lub hlwb. Nyob rau tib lub sijhawm, kev tawm dag zog kuj tuaj yeem txhawb kev sib txuas ntawm cov neurons, thiab txhim kho kev ruaj ntseg thiab kev sib txuas ntawm cov neurons, thiab cov xwm txheej no tseem yuav txhim kho peb lub peev xwm kev txawj ntse thiab kev nco.
Tsis tas li ntawd, kev noj haus kuj muaj txiaj ntsig zoo rau peb lub cim xeeb. Qee cov zaub mov, xws li blueberries, walnuts, cod, nqaij qaib, thiab lwm yam, muaj cov as-ham thiab fatty acids, uas muaj txiaj ntsig zoo rau kev txhim kho lub hlwb thiab tiv thaiv oxidation. Kev noj zaub mov kom zoo tuaj yeem pab peb tswj hwm peb cov ntshav qab zib kom zoo thiab ua kom peb lub hlwb kom tau txais roj txaus thiab lub zog. Cov yam tseem ceeb no yog qhov tseem ceeb los txhim kho peb lub cim xeeb thiab kev txawj ntse.
Feem ntau, peb lub cev lub cev muaj qhov cuam tshuam tseem ceeb rau peb txoj kev paub thiab kev nco. Yog li ntawd, peb yuav tsum tawm dag zog ntau dua thiab ua tib zoo saib xyuas yam xws li kev noj haus thiab kev ua neej nyob kom ua rau peb lub hlwb ua haujlwm thiab nco tau zoo tshaj plaws. Ua ke, peb tuaj yeem ua haujlwm los txhim kho peb lub cev thiab lub hlwb thiab tsim kom muaj lub neej yav tom ntej zoo dua. Nws yog qhov tseeb tias peb yuav tsum txhim kho peb lub cim xeeb, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim tias nws tuaj yeem tswj hwm qhov sib npaug ntawm cov paj hlwb, xws li nce qib ntawm acetylcholine thiab kev loj hlob, uas tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche tseem 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 lub hlwb tseem ceeb thiab kev ua siab ntev.
Nyem paub ntxiv los txhim kho kev nco
Piv txwv li, Wu li al., 2020 tau tshawb nrhiav tias hlau-oxide nanoparticle-tagged MNCs tuaj yeem txav los ntawm qhov chaw tswj hwm mus rau choroidplexus thiab ua rau muaj kev ua haujlwm zoo hauv lub hlwb ischemic-stroke. Tus kws sau ntawv tau hais tias MNCs tuaj yeem muaj txiaj ntsig zoo dua yog tias muab ncaj qha rau hauv lub ventricles sab nraud tsis yog tso rau hauv cov hlab ntshav [119].
5.2. Organic Nanoparticles
Ib txwm tshwm sim molecules, xws li lipids thiab lwm cov organic molecules, tuaj yeem siv los ua cov cuab yeej xa cov nanomedicine vim lawv cov biocompatibility zoo dua piv rau cov khoom siv tsis zoo. Tsis tas li ntawd, lipid nanocarrier muaj txiaj ntsig zoo hauv kev tiv thaiv kev kho mob moiety los ntawm kev degradation, txo toxicity, thiab nce biocompatibility, dua li kev tswj hwm tshuaj dawb [116].
Ntawm cov lipid sib txawv, liposomes tau tshawb pom ntau tshaj plaws rau kev xa cov paj hlwb. Liposomes dual functionalized nrog mApoE thiab phosphatidic acid tau tsim los txhim kho kev xa khoom thoob plaws BBB thiab lub hom phiaj A aggregates nrog siab affinity [120]. Qhov no liposomal formulation tuaj yeem cuam tshuam A fibrils hauv vitro.
Cov tshuaj tsis zoo phosphatidic acid cuam tshuam nrog cov txiaj ntsig zoo ntawm cov amino acid residues ntawm A, thaum lub maple cuam tshuam nrog cov cheeb tsam uas raug them nqi tib yam. Hauv kev tshawb fawb tsis ntev los no, peb lub chaw kuaj mob tau tsim kho qhov chaw liposomes rau lub hlwb-targeted xa ntawm ApoE {{2. }}encoding plasmid DNA [121].
Lub hom phiaj ligand siv yog mannosealong nrog CPP (kev nkag mus thiab tus kab mob rabies glycoprotein peptide, RVG) los txhim kho lub hlwb phiaj thiab cellular internalization, feem.
Ib yam li ntawd, liposomes hloov nrog RVG thiab hloov pauv tau pom muaj txiaj ntsig zoo hauv lub hlwb endothelial hlwb, astrocytes, thiab neuronsas piv rau liposomes [94].
Hauv kev tshawb fawb cais los ntawm Rodriguez li al. [93], surfacefunctionalization ntawm liposomes nrog transferrin thiab CPP yog txaus los txhim kho lub hlwb permeability ntawm liposomes nyob rau hauv nas tom qab ib tug intravenous tswj.
Nyob rau hauv tag nrho cov kev tshawb fawb no, cov tshuaj tsub zuj zuj nyob rau hauv lub hlwb raug ntaus nqi rau saum npoo functionalization.Ib yam li ntawd, optimized lub hlwb tsom liposomes, functionalized nrog mannose thiab ob leeg RVG, nkag mus, rabies-derived peptide (RDP), los yog CGNHPHLAKYNGT (CGN) peptide txaus xa VGF (VGF). paj hlwb kev loj hlob inducible) thoob plaws hauv vitroBBB qauv thiab hauv vivo nas qauv.
Hauv txoj kev tshawb no, cov kws sau ntawv tau pom qhov 1.5–2. Ntxiv mus, cov formulated liposome nanoparticleswere biocompatible ob leeg hauv vivo thiab hauv vitro [122].
Daim duab 3. Nyob rau hauv vivo vgf transfection hauv lub hlwb thiab lwm yam kabmob loj hauv nas. Cov ntaub ntawv yog qhia raws li txhais tau tias ± SD ntawm 6 tsiaj ib pab. ~, |, @, #, *, –, +, thiab " qhia qhov sib txawv tseem ceeb (p < 0.05) los ntawm kev tswj hwm, liab qab DNA, dawb, cwj mem, txiv neej, CGN, RVG9R, thiab RDP liposomes , raws.
Tau qhov twg los: Reprinted los ntawm Arora, S.; Singh, J. Hauv vitro thiab hauv vivo optimization ntawm liposomal nanoparticles basedbrain tsom ntawm kev kho noob. International Journal of Pharmaceutics 2021, 608, 121095 [122]. Kev tso cai los ntawm Elsevier.
Antioxidants tuaj yeem tiv thaiv cov neurons los ntawm amyloid{0}}plaque-mediated oxidative puas. Curcumin tau pom tias muaj peev xwm tiv thaiv antioxidant tiv thaiv ntau yam NDs [123].
Nws khi rau A deposits, cuam tshuam kev sib sau, thiab disaggregates pre-formed fibril, ob leeg hauv vitro thiab hauv vivo [124,125]. Dhau li ntawm liposomes, cov khoom lipid nanoparticles (SLN) kuj tau siv rau lub hlwb-targeted kev kho mob los tswj ntau yam NDs. Rosmarinicacid-loaded SLNs tau muab tshuaj intranasally los kho cov kev coj cwj pwm tsis zoo thiab oxidative kev nyuaj siab cuam tshuam nrog Huntington tus kab mob [126].
Nanomicelle, tshwj xeeb tshaj yog polymeric nano micelle, tau tshwm sim los ua lub tsheb muaj peev xwm xa cov neeg ua haujlwm kho mob sib txawv [127,128]. Nyob ntawm lawv cov yam ntxwv hydrophilic thiab hydrophobic, polymers uas nws tus kheej sib sau ua ke los ua micelles tuaj yeem ua kom muaj kev sib haum xeeb qis dua thaum tuav lub taub me me, txaus thauj khoom [129].
Tsis ntev los no, qee qhov kev tshawb fawb tau pom tias muaj peev xwm ntawm kev ua haujlwm ntawm chitosan nano micelles los hloov cov hlwb hlwb ntawm qhov muaj txiaj ntsig zoo [130].Chitosan nano micelles nthuav qhia qhov zoo ntawm kev ua biodegradable, tsis muaj tshuaj lom ntawm kev siv lub zog, thiab hloov tau yooj yim rau kev hloov kho deg [131].
Cov txiaj ntsig zoo no ua rau chitosan nano micelles yog cov cab kuj zoo heev rau kev xa cov tshuaj, cov proteins, cov noob, thiab cov tshuaj tiv thaiv kab mob rau lub hlwb. Tsis ntev los no, Xue et al. [132], conjugated chitosan nanoparticlessignificantly inhibited los ntawm -syn aggregation nyob rau hauv vitro, raws li zoo raws li nrhiav tau cov teebmeem tseem ceeb neuroprotective hauv Parkinson tus kab mob qauv.
Chitosan tuaj yeem sib npaug siv sib txuas nrog lwm cov polymers los txhim kho kev xa khoom thoob plaws BBB. Hauv ib qho kev kawm cais los ntawm Jaruszewski et al. [133], Chitosan-coated PLGA nanoparticles muaj qhov zoo dua BBB uptake piv rau liab qab PLGA nanoparticles.
Thaum cov txheej txheem sib txawv ntawm cov polymeric tau ua haujlwm hauv kev tsim cov nanoparticles, poly D, L-(lactic-co-glycolic) acid (PLGA) tau siv dav rau kev siv tshuaj tiv thaiv thiab tswj kev xa tshuaj [134].
Qhov no biodegradable, biocompatiblepolymer, nrog adjustable degradation tus nqi, ib tug siab tshuaj loading muaj peev xwm, thiab muaj peev xwm mus hla BBB mus rau lub hom phiaj lub hlwb, ua rau nws ib tug zoo tagnrho cov cab kuj rau kev kho mob NDs. Hauv ib txoj kev tshawb fawb, TET1 peptide-coated PLGA nanoparticles tau siv los encapsulate thiab xa cov tshuaj hydrophilic, nattokinase, mus rau lub hlwb.
TET1 peptide tau pom tias muaj kev sib raug zoo rau cov neurons thiab txhawb nqa kev thauj mus los. Cov qauv no tau ua tiav kev ruaj ntseg ntawm nattokinase protein thiab txo qis amyloid aggregation, ua pov thawj los ua ib qho kev xaiv tseem ceeb rau kev kho AD [135].
Ib qho kev kawm cais los ntawm Carradori thiab al.synthesized Anti A 1-42 conjugated poly (alkyl cyanoacrylate) nanoparticles directedtoward A 1-42. Thaum transgenic AD nas raug kho nrog cov nanoparticles no, muaj qhov txo qis hauv lub hlwb thiab qib plasma ntawm A soluble peptide thiab nws cov oligomer, ua rau kho lub cim xeeb tsis zoo [136].
Hauv kev tshawb nrhiav cais los ntawm Safari li al., phosphatidylserine nanoliposomes kuj tau txhim kho lub cim xeeb ntawm AD-induced nas thaum thauj nrog metformin. Hauv txoj kev tshawb no, IL1- , TNF- , thiab TGF- qib tau pom tias txo qis hauv thaj tsam hippocampal. Neurogenesis tau soj ntsuam nrog rau txo qis necrosis thiab neuroinflamation [137].
Raws li peb tau tham, nanoparticles muaj peev xwm pib neurogenesis hauv vivosystems, tab sis nanoparticles kuj tau tshawb fawb los pab cov qia hlwb sib txawv intoneurons. Piv txwv li, polycaprolactone-lignin nanoparticles ua rau neurogenesis thiab neurite outgrowth hauv PC12 thiab hADSCs hlwb. Tus tsim nano-scaffold yog biocompatible thiab nyab xeeb.
Tus kws sau ntawv tau thov tias kev koom ua ke ntawm 15% lignin nanoparticlesim txhim kho cov txiaj ntsig xav tau: neuro-kev tsim kho thiab rov tsim dua tshiab [138]. Ib yam li ntawd, NGF-loaded chitosan nanoparticles txawv canine mesenchymal qia hlwb intoneuronal hlwb [139].
Ib yam li ntawd, RA-NPs txhim kho neuronal cell sib txawv, muaj sia nyob, thiab muaj peev xwm ntawm cov qia hlwb tom qab cov nyhuv ischemic [113].
6. Nanomedicines nyob rau hauv Clinical Trial
Muaj qhov xav tau tshaj plaws los tsim cov tswv yim kho tshiab tawm tsam cov kab mob neurodegenerative, uas ncua neurodegeneration es tsis muab cov tsos mob nyem.
Ntau qhov kev tshawb fawb ntawm nanoparticles, qhia cov lus cog tseg ntawm txoj kev xa tshuaj zoo, uas tuaj yeem yog lub teeb ci ntawm kev cia siab tiv thaiv cov kab mob neurodegenerative.Kev tshawb fawb tsis ntev los no hauv kev sim tshuaj tsis tu ncua qhia tsawg dua 10 nanoparticle-based formulations nyob rau hauv ntau theem ntawm kev sim tshuaj tiv thaiv NDs (Table 2 ). Tsuas yog ib qho kev kuaj mob ntawm lipid nanoparticle-based formulation rau transthyretin-mediated amyloidosis tau ua tiav thiab pom zoo muag rau pej xeem. Thaum ib (CRISPR)/Cas9-raws li kev tshawb fawb noob nyob rau hauv kev sim tshuaj theem I, lipid nanoparticles tau siv los ua kev xa tshuaj rau txoj kev tshawb no.
Ib txoj hauv kev zoo siab ntawm nanoparticle-mediated xa ntawm APH-1105 tawm tsam me me-rau-nruab nrab AD raug sau npe; Qhov kev sim tshuaj no yuav pib nyob rau xyoo 2023. Txawm li cas los xij, qhov kub nanoparticle-mediated CNM-Au8 tus me nyuam txoj hauv kev yog nyob rau hauv kev sim tshuaj theem 2. Ntawm qhov tod tes, ntau qhov kev tshawb fawb ntawm CNM-Au8-kub nanocrystals-raws li kev tshawb fawb yog nyob rau theem 1 thiab theem 2 ntawm kev sim tshuaj tiv thaiv ALS.
7. Cov kev sib tw, kev cia siab yav tom ntej thiab cov lus xaus
Neuronal tuag yog tus yam ntxwv tseem ceeb ntawm NDs, piv txwv li, AD thiab Parkinson's. Yog li ntawd, neurogenesis yog qhov kev pom zoo tshaj plaws kev kho mob rau cov teeb meem no. Txawm li cas los xij, kev xa tshuaj mus rau lub hlwb tseem yog qhov nyuaj vim muaj ntau yam tseem ceeb, suav nrog BBB, lipophilicity, molecular hnyav ntawm cov tshuaj, thiab lwm yam.
Cov xwm txheej no txwv txoj kev kho mob ntawm cov tshuaj thiab ua rau NDs nyuaj rau kev kho. Yog li, nanoparticle-mediatedtargeted tshuaj xa mus rau lub paj hlwb tau tshawb fawb nyob rau hauv xyoo tas los no rau neurogenesis, thiab nws muab lub platform cog lus rau kev txhim kho cov tswv yim kho mob.
Txawm hais tias muaj peev xwm zoo li no, kev xa tshuaj nanocarrier-mediated muaj qee qhov nyuaj, suav nrog kev nyab xeeb, kev tsim khoom, thiab kev tswj hwm.
Lub toxicity ntawm nanoparticles feem ntau yog nyob ntawm qhov loj me, tus nqi saum npoo, ionic dissolutions, thiab cov duab. Cov yam ntxwv no yuav tsum raug txiav txim siab rau kev tsim kho nanoparticle-baseddrug-xa tshuab raws li cov lus qhia nanotoxicity [140].
Tsis tas li ntawd, kev pom zoo ntawm cov nanocarriers no yuav tsum tau soj ntsuam xyuas, suav nrog cov teebmeem ntawm kev noj qab haus huv thiab ib puag ncig [141]. Ib lub pas dej loj ntawm cov ntaub ntawv qhia txog ntau qhov kev hloov kho kom txo qis qhov toxicity cuam tshuam nrog qhov loj thiab nqi, xws li kev hloov kho saum npoo av nrog biodegradable- lossis bio-molecules ntawm lub hauv paus chiv keeb [142,143].
Raws li qhov kev tsim cov nanocarriers muaj kev txhawj xeeb, lawv yuav tsum tuav cov khoom sib xws ntawm lawv qhov loj thiab cov ntsiab lus. Muaj ntau txoj hauv kev sau tseg rau kev tsim khoom nanoparticle, suav nrog kev kub siab homogenization, microemulsion, extrusion, thiab lwm yam. Tsis tas li ntawd, cov tshuaj pharmacokinetic ntawm nanotherapeutics cuam tshuam rau kev ua tau zoo thiab toxicity.
Yog li ntawd, nws yog ib qho tseem ceeb los soj ntsuam cov tshuaj pharmacokinetic tsis tau ntawm nanotherapeutics nyob rau hauv tus qauv tsiaj. Hauv qhov no, Pharmacokinetic thiab ntau dua physiologically raws li cov qauv tshuaj pharmacokinetic tuaj yeem siv los ua cov cuab yeej muaj peev xwm los kwv yees qhov xwm txheej hauv vivo ntawm nanotherapeutics [144]. Tsis tas li ntawd, kev tswj hwm kev cai rau kev lees txais kev kho mob ntawm nanotherapeutics yuav tsum tau txiav txim siab [145].
Nanomedicine yog lub teeb ci ntawm kev cia siab rau NDs, thiab nws tuaj yeem yog ib qho cuab yeej zoo los tswj cov kev txwv ntawm kev kho tam sim no thiab ib txwm siv [146]. Peb tau hais qhia txog nanoparticle-raws li cov ntaub ntawv tawm tsam ntau yam NDs, uas tuaj yeem qhib qhov kev cia siab ntawm nanomedicine.
Nkag siab, kev txhim kho ntawm kev kho mob tsis yog txheej txheem tam sim ntawd, tab sis kev tshawb fawb ua ntej hauv thaj chaw yuav ua rau lub pob zeb nce qib uas tuaj yeem pab tshem tawm NDs.Txawm li cas los xij, los ua pov thawj qhov ua tau zoo tiv thaiv NDs, tiam sis xav tau ntau dua hauv vitro thiab vivodata. .
Tsis tas li ntawd, kev soj ntsuam zoo hauv vitro thiab hauv vivo thiab lawv cov kev sib raug zoo tsim nyog yuav tsum tau ntsuas qhov ua tau zoo ntawm nanoparticles. Qhov no yuav pab txoj kev tshawb fawb fraternity kom txuas ntxiv lossis txheeb xyuas cov khoom siv nanoparticles zoo rau kev kuaj mob ortherapeutic daim ntawv thov.
Tus Sau Kev Pabcuam: Txhua tus kws sau ntawv (RNLL, BC, RT, AG, BL, thiab JS) tau pab tsim thiab kho cov ntawv sau. Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.
Cov Nyiaj Txiag: Txoj haujlwm no tau txais kev txhawb nqa los ntawm National Institute of Health pab nyiaj RO1 AG051574 thiab RF1 AG068034. BL kuj lees paub txog kev txhawb nqa los ntawm NIGMS COBRE khoom plig 1P20 GM109024 thiab DaCCoTA CTR tus tsav ua tau nyiaj pab U54GM128729.
Institutional Review Board Statement: Tsis siv tau.
Cov Lus Qhia Txog Kev Pom Zoo: Tsis siv tau.
Cov Lus Qhia Muaj Cov Ntaub Ntawv: Tsis siv tau.
Kev tsis sib haum xeeb ntawm kev txaus siab: Cov neeg sau ntawv tshaj tawm tsis muaj teeb meem ntawm kev txaus siab.
Cov ntaub ntawv
1. Merelli, ib.; Czornyj, L.; Lazarowski, A. Erythropoietin: Cov tshuaj tiv thaiv neuroprotective hauv cerebral hypoxia, neurodegeneration, thiab mob vwm. Curr. Pharm. Des. Xyoo 2013, 19, 6791–6801. [CrossRef]
2. Choonara, YEES; Pilai, V.; Du Toit, LC; Modi, G.; Naidoo, D.; Ndesendo, VM; Sibambo, SR Trends in the molecular pathogenesisand therapeutics of common neurodegenerative disorders. Int. J. Mol. Sci. 2009, 10, 2510–2557. [CrossRef]
3. Roob, T.; Chawin, P.; Costa, N.; Molinier, L. Kev noj qab haus huv kev xav txog nyiaj txiag hauv cov kab mob neurodegenerative. Daim duab Neurodegener. Teeb meem. 2015, 42. [CrossRef]
4. Harilal, S.; Jose, J.; Paraambi, DGT; Kumar, R.; Mathew, GE; Uddin, MAS; Kim, H.; Mathew, B. Advancements in nanotherapeutics for Alzheimer's disease: Kev xav tam sim no. J. Pharm. Pharmacol. Xyoo 2019, 71, 1370–1383. [CrossRef]
5. Pob khawm, NS; Kathuria, H.; Pandey, MM Engineering ntawm cov qauv thiab kev ua haujlwm ntawm nanotherapeutics thiab nanodiagnostics rau intranasal hlwb tsom hauv Alzheimer's. Appl. Mater. Hnub no 2022, 26, 101303. [CrossRef]
6. Montazersaheb, S.; Ahmadian, E.; Maleki Dizaj, S.; Jahanbani, Y.; Davara, S.; Huseynov, I.; Zhdanov, R.; Kev, C.; Khalilov, R.; Eftekhari, A. Emerging Nanotherapeutic Strategies in Alzheimer's Disease. Hauv Frontiers hauv Clinical Drug Research-Dementia; Benham Science Publishers Pte. Ltd.: Singapore, 2021; Nqe 2, p. 173.
7. Lub hauv paus hlwb: Lub Neej thiab Kev Tuag ntawm Neuron; Office of Communications and Public Liaison, National Institute of NeurologicalDisorders and Stroke: Bethesda, MD, USA, 2002.
8. Van den Heuvel, MP; Sporns, O. Network hubs nyob rau hauv tib neeg lub hlwb. Trends Cogn. Sci. 2013, 17, 683–696. [CrossRef] [PubMed]
9. Kempermann, G. Cov Neeg Laus Neurogenesis: Stem Cells thiab Neuronal Development nyob rau hauv cov neeg laus lub hlwb; Oxford University Press: New York, NY, USA, 2006.
10. Pino, A.; Fumagalli, G.; Bifari, F.; Decimo, I. New neurons nyob rau hauv cov neeg laus lub hlwb: Distribution, molecular mechanisms, thiab kev kho mob.Biochem. Pharmacol. 2017, 141, 4–22. [CrossRef] [PubMed]
11. Ganat, YM; Silbereis, J.; Qhov tsua, C.; Nug, H.; Anderson, GM; Koj, Y.; Lus, LR; Vaccarino, FM Early postnatal astroglialcells tsim muaj ntau hom kab mob ua ntej thiab neural qia hlwb hauv vivo. J. Neeb. 2006, 26, 8609–{4}}. [CrossRef] [PubMed]
12. Przedborski, S.; Vila, M.; Jackson-Lewis, V. Series Taw Qhia: Neurodegeneration: Nws yog dab tsi thiab peb nyob qhov twg? J. Clin. Investig.2003, 111, 3–10. [CrossRef] [PubMed]
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