Human beta-amyloid (1-42) protein, inozivikanwawo seAβ 1-42, chinhu chakakosha pakuvhura zvakavanzika zvechirwere cheAlzheimer.Iyi peptide inoita basa repakati mukuumbwa kweamyloid plaques, enigmatic clusters inokuvadza pfungwa dzevarwere veAlzheimer.Nekukanganisa kunoparadza, kunokanganisa kutaurirana kweuronal, kunokonzera kuzvimba, uye kunokonzeresa neurotoxicity, zvichitungamira mukukanganisa kwekuziva uye kukuvadzwa kwetsinga.Kuongorora kuunganidzwa kwayo uye toxicity nzira hakuna chete kwakakosha;rwendo rwunonakidza rwekugadzirisa dambudziko reAlzheimer uye kugadzira marapirwo emangwana.
Aβ 1-42 ipeptide fragment ye 42 amino acids inotorwa kubva pakutsemuka kweamyloid precursor protein (APP) ne β- uye γ-secretases.Aβ 1-42 chimwe chezvikamu zvikuru zveamyloid plaques inoungana muuropi yevarwere vane chirwere cheAlzheimer, neurodegenerative disorder inoratidzirwa nekusaziva uye kurasikirwa kwendangariro.Aβ 1-42 yakaratidzwa kuve ine mabasa akasiyana siyana uye mashandisiro mubiology uye biomedical research, senge:
1.Neurotoxicity: Aβ 1-42 inogona kuita soluble oligomers inokwanisa kusunga uye kukanganisa basa re neuronal membranes, receptors, uye synapses.Aya maoligomers anogona zvakare kukonzera oxidative kusagadzikana, kuzvimba, uye apoptosis mumaneuroni, zvichitungamira mukurasikirwa nesynaptic uye kufa neuronal.Aβ 1-42 oligomers anoonekwa seane neurotoxic kupfuura mamwe marudzi eAβ, akadai seAβ 1-40, inova iyo yakanyanya kuwanda yeAβ muuropi.Aβ 1-42 oligomers inofungidzirwawo kuti inokwanisa kuparadzira kubva kune sero kuenda kune sero, yakafanana neprions, uye inokonzera kukanganisa uye kuunganidza mamwe mapuroteni, akadai se tau, iyo inoumba neurofibrillary tangles muAlzheimer's disease.
Aβ 1-42 inoonekwa zvakanyanya seAβ isoform ine yakanyanya neurotoxicity.Zvidzidzo zvakati wandei zvakaratidza neurotoxicity yeAβ 1-42 vachishandisa nzira dzakasiyana uye modhi.Somuenzaniso, Lesné et al.(Brain, 2013) yakatsvaga maumbirwo uye chepfu yeAβ oligomers, iyo inonyunguduka yakasanganiswa yeAβ monomers, uye yakaratidza kuti Aβ 1-42 oligomers ine simba rinokuvadza pane neuronal synapses, zvichiita kuti pfungwa dzideredze uye neuronal kurasikirwa.Lambert et al.(Proceedings of the National Academy of Sciences, 1998) yakaratidza neurotoxicity yeAβ 1-42 oligomers uye yakaona kuti yakanga ine simba rakasimba rinotyisa panheyo yepakati, zvichida nekukanganisa synapses uye neurotransmitters.Walsh et al.(Nature, 2002) yakaratidza inhibitory effect yeAβ 1-42 oligomers pane hippocampal yenguva refu potentiation (LTP) mu vivo, iyo inoshandiswa seserura iri pasi pekudzidza nekuyeuka.Iyi inhibition yakabatana nekuyeuka uye kukanganisa kudzidza, kusimbisa kukanganisa kweAβ 1-42 oligomers pa synaptic plasticity.Shankar et al.(Nature Medicine, 2008) yakazviparadzanisa Aβ 1-42 dimers yakananga kubva kuAlzheimer's brain uye yakaratidza maitiro avo pa synaptic plasticity uye ndangariro, ichipa humbowo hune simba hweiyo neurotoxicity yeAβ 1-42 oligomers.
Mukuwedzera, Su et al.(Molecular & Cellular Toxicology, 2019) yakaita transcriptomics uye proteomics kuongororwa kweAβ 1-42-induced neurotoxicity muSH-SY5Y neuroblastoma masero.Vakaziva majini akati wandei uye mapuroteni akabatwa neAβ 1-42 munzira dzine chekuita neapoptotic process, protein translation, cAMP catabolic process uye mhinduro kune endoplasmic reticulum stress.Takeda et al.(Biological Trace Element Research, 2020) yakaongorora basa re extracellular Zn2+ muAβ 1-42-induced neurotoxicity muchirwere cheAlzheimer.Vakaratidza kuti Aβ 1-42-induced intracellular Zn2 + toxicity yakakurumidza nekukwegura nekuda kwekuwedzera kwezera rekuwedzera kweZn2 +.Vakataura kuti Aβ 1-42 yakavanzwa nguva dzose kubva kune neuron terminals inokonzera zera-ane hukama hwekuziva kudzikira uye neurodegeneration kuburikidza ne intracellular Zn2+ dysregulation.Zvidzidzo izvi zvinoratidza kuti Aβ 1-42 chinhu chakakosha mukuyananisa neurotoxicity uye kufambira mberi kwechirwere muchirwere cheAlzheimer nekukanganisa akasiyana mamorekuru nemaserura maitiro muuropi.
2. Antimicrobial chiitiko: Aβ 1-42 inonzi ine antimicrobial chiitiko kurwisa hutachiona hwakasiyana, senge bhakitiriya, fungi, uye mavhairasi.Aβ 1-42 inogona kusunga uye kukanganisa mamembrane emasero ehutachiona, zvichitungamira kune yavo lysis uye kufa.Aβ 1-42 inogona zvakare kumisa immune system yemukati uye kutora maseru ekuzvimba kunzvimbo yehutachiona.Zvimwe zvidzidzo zvakaratidza kuti kuunganidzwa kweAβ muuropi kunogona kuva mhinduro yekudzivirira kune zvirwere zvisingaperi kana kukuvara.Nekudaro, yakawandisa kana kusagadzikana kugadzirwa kweAβ kunogona kukonzera kukuvadzwa kwechibatiso kumasero anotambira uye matishu.
Aβ 1-42 inonzi inoratidzira antimicrobial chiitiko kurwisa huwandu hwehutachiona, hwakadai sebhakitiriya, fungi, uye mavhairasi, akadai seStaphylococcus aureus, Escherichia coli, Candida albicans, uye Herpes simplex virus type 1, kuburikidza nekudyidzana ne membranes uye kukonzera kukanganisa kwavo uye lysis.Kumar et al.(Journal of Alzheimer's Disease, 2016) yakaratidza chiitiko ichi nekuratidza kuti Aβ 1-42 yakashandura membrane permeability uye morphology ye microbial cells, zvichiita kuti vafe.Pamusoro peiyo yakananga antimicrobial chiito, Aβ 1-42 inogona zvakare kugadzirisa iyo innate immune immune mhinduro uye kutora masero ekuzvimba kunzvimbo yehutachiona.Soscia et al.(PLoS One, 2010) yakaratidza basa iri nekutaura kuti Aβ 1-42 yakakurudzira kugadzirwa kwepro-inflammatory cytokines uye chemokines, zvakadai se interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), monocyte. chemoattractant protein-1 (MCP-1), uye macrophage inflammatory protein-1 alpha (MIP-1α), mu microglia uye astrocytes, masero makuru ezvirwere muuropi.
Mufananidzo 2. Aβ peptides ine antimicrobial activity.
(Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, Burton MA, Goldstein LE, Duong S, Tanzi RE, Moir RD. The Alzheimer's disease-associated amyloid beta-protein inonzi antimicrobial peptide. PLoS One 2010 Mar 3;5(3):e9505.)
Kunyange zvazvo zvimwe zvidzidzo zvakaratidza kuti kuunganidzwa kweAβ muuropi kunogona kuva mhinduro yekudzivirira kune zvirwere zvisingaperi kana kukuvara, sezvo Aβ inogona kuita se antimicrobial peptide (AMP) uye kubvisa hutachiona hunogona kuitika, kusangana kwakaoma pakati peAβ uye microbial elements kunoramba kuri musoro wekuongorora.Iyo yakatetepa chiyero inosimbiswa nekutsvagisa kweMoir et al.(Journal of Alzheimer's Disease, 2018), iyo inoratidza kuti kusaenzana kana kuwandisa kugadzirwa kweAβ kunogona kukanganisa maseru nematishu, zvichiratidza kuomesesa kwemaitiro eAβ muhutachiona uye neurodegeneration.Kuwedzeredza kana kusagadzikana kugadzirwa kweAβ kunogona kutungamira mukuunganidzwa kwayo uye kuiswa muuropi, kuumba chepfu oligomers uye fibrils iyo inokanganisa neuronal basa uye inokonzera neuroinflammation.Aya pathological maitiro ane chekuita nekudzikira kwekuziva uye kurasikirwa kwendangariro muAlzheimer's disease, neurodegenerative disorder inoratidzwa nekufambira mberi kwedementia.Naizvozvo, chiyero pakati pezvinobatsira uye zvinokuvadza mhedzisiro yeAβ yakakosha pakuchengetedza hutano hwehuropi uye kudzivirira neurodegeneration.
3.Iron kunze kwenyika: Aβ 1-42 yakaratidzwa kuve nechekuita mukugadzirisa iron homeostasis muuropi.Iron chinhu chakakosha kune akawanda biological process, asi yakawandisa iron inogona kukonzera oxidative kusagadzikana uye neurodegeneration.Aβ 1-42 inogona kusunga kusimbi uye kufambisa kunze kwayo kubva kune neuroni kuburikidza neferroportin, transmembrane iron transporter.Izvi zvinogona kubatsira kudzivirira kuunganidzwa kwesimbi uye chepfu muuropi, sezvo iron yakawandisa inogona kukonzera oxidative kusagadzikana uye neurodegeneration.Duce et al.(Sero, 2010) yakashuma kuti Aβ 1-42 inosungirirwa kune ferroportin uye yakawedzera kutaura kwayo uye basa mumaneuroni, zvichiita kuti kuderedza intracellular iron levels.Vakaratidzawo kuti Aβ 1-42 yakaderedza kutaura kwehepcidin, hormone inodzivisa ferroportin, mune astrocytes, ichiwedzera kusimbisa kunze kwesimbi kubva kune neuroni.Nekudaro, simbi-yakasungwa Aβ inogona zvakare kuve yakajairwa kuunganidzwa uye kuiswa munzvimbo yekunze, ichigadzira amyloid plaques.Ayton et al.(Journal of Biological Chemistry, 2015) yakashuma kuti iron yakakurudzira kuumbwa kweAβ oligomers uye fibrils in vitro uye in vivo.Vakaratidzawo kuti iron chelation yakaderedza Aβ aggregation uye deposition mune transgenic mbeva.Naizvozvo, chiyero pakati pezvinobatsira uye zvinokuvadza mhedzisiro yeAβ 1-42 pane iron homeostasis yakakosha pakuchengetedza hutano hwehuropi nekudzivirira neurodegeneration.
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