By Cocer Peptides 
1 ọnwa gara aga
Edemede na ozi ngwaahịa niile enyere na webụsaịtị a bụ naanị maka mgbasa ozi na ebumnuche mmụta.
Ngwaahịa ndị enyere na webụsaịtị a bụ naanị maka nyocha in vitro. A na-eme nyocha in vitro (Latin: * na iko *, nke pụtara na ihe eji enyo) na mpụga ahụ mmadụ. Ngwaahịa ndị a abụghị ọgwụ, ndị US Food and Drug Administration (FDA) akwadoghị ya, ha agaghịkwa eji ya gbochie, gwọọ, ma ọ bụ gwọọ ọnọdụ ahụike ọ bụla, ọrịa, ma ọ bụ ọrịa. Iwu amachibidoro nke ọma iwebata ngwaahịa ndị a n'ime ahụ mmadụ ma ọ bụ anụmanụ n'ụdị ọ bụla.
Nchịkọta
Edemede a na-enyocha usoro nke mkpụrụ ndụ senescent na-enye aka na mmalite na ọganihu nke ọrịa Alzheimer (AD). Ọrịa Alzheimer bụ ọrịa neurodegenerative a na-ahụkarị na-emetụta ndị agadi, nke a na-eji nhụsianya na-aga n'ihu na adịghị ike omume. Ka ọnụ ọgụgụ ndị mmadụ n'ụwa niile na-eto, ihe omume AD na-aga n'ihu na-arị elu kwa afọ, na-etinye nnukwu ibu n'ahụ ọha mmadụ na ezinụlọ. Ọ bụ ezie na enweela ọganihu dị ukwuu na nyocha AD, kpọmkwem etiology na pathogenesis ka edoghị anya. Dị ka otu n'ime ihe ndị bụ isi ihe ize ndụ maka AD, cellular senescence enwetawo nlebara anya na-arịwanye elu n'afọ ndị na-adịbeghị anya maka ọrụ ya na pathogenesis nke AD. Mkpokọta nke mkpụrụ ndụ senescent n'ime ahụ nwere njikọ chiri anya na mmalite na ọganihu nke ọrịa dị iche iche metụtara afọ. Sel sesent na-ekere òkè dị mkpa na usoro pathological nke AD, na ịkọwapụta usoro ha si eme dị oke mkpa maka ịmepụta ọgwụgwọ ọhụrụ maka AD.
Ọgụgụ 1. Ọrịa Alzheimer na-akpata protein na-enye aka na ụbụrụ ụbụrụ ụbụrụ. (a) Nleba anya nke mmekọrịta dị n'etiti mkpụrụ ndụ ụbụrụ nke nwere amyloid plaques na pathogenic tau. (b-e) Echiche zuru ezu nke ụdị cell ọ bụla na njirimara ndị metụtara senescence nke a kọrọ na akwụkwọ ndị a: (b) neuron, (c) microglia, (d) oligodendrocyte / oligodendrocyte precursor cell, (e) astrocyte, na (f) mgbochi ụbụrụ ọbara (BBB) nke na-egosi endostrricthelial sel, na-eme ka mkpụrụ ndụ na-eme ihe na-eme ka ọkpụkpụ na-eme ka ọkpụkpụ, na-eme ka sel ndị na-eme ihe na-eme ka ọkpụkpụ na-eme ka ọkpụkpụ, na-eme ka ọkpụkpụ na-eme ka ọkpụkpụ na-egbuke egbuke, na-egosi endostrocytes. BBB iguzosi ike n'ezi ihe na AD.
Nchịkọta nke Selụ Senescent
(1) Nkọwa na njirimara nke mkpụrụ ndụ Senescent
Senescence na-ezo aka na njide uto na-enweghị ike ịgbanwe nke mkpụrụ ndụ mgbe ọ nwesịrị ọnụ ọgụgụ nke nkewa ma ọ bụ kpughee ya n'ọnọdụ dị iche iche na-akpata nchekasị (dị ka nrụgide oxidative, mmebi DNA, telomere shortening, wdg). Mkpụrụ ndụ Senescent na-egosipụta njirimara phenotypic pụrụ iche, gụnyere ụbara ụda cell, ịgbasa, na ọrụ β-galactosidase (β-gal), nke bụ ihe nrịbama ndu nke a na-ejikarị eme ihe maka ịchọpụta mkpụrụ ndụ senescent. Tụkwasị na nke ahụ, mkpụrụ ndụ senescent na-egosipụta ngbanwe nke ndị na-emechi kinase na-adabere na cyclin (dị ka p16INK4a na p21Cip1), nke na-egbochi ọganihu cell cell, na-eme ka sel jide n'aka na usoro G1 ma ọ bụ G2 / M ma si otú ahụ gbochie nkewa ọzọ.
Usoro nke nhazi cell Senescent
1. Nchegbu Oxidative na DNA Mmebi: Nchegbu Oxidative bụ isi ihe na-ebute senescence cellular. N'okpuru ọnọdụ physiological nkịtị, mmepụta na mkpochapụ nke ụdị oxygen na-emeghachi omume (ROS) n'ime sel dị n'ogo siri ike. Otú ọ dị, na ịka nká ma ọ bụ n'okpuru ọnọdụ ụfọdụ, mmụba ROS na-eduga ná mmebi DNA. Mgbe mmebi DNA na-agbakọba ruo n'ókè ụfọdụ na enweghị ike ịrụzi ya nke ọma, a na-eme ka usoro ụzọ mgbaàmà rụọ ọrụ, dị ka ụzọ p53-p21 na p16-Rb, na-eme ka mkpụrụ ndụ banye n'ọnọdụ dị nro. N'ime anụ ahụ ụbụrụ sitere na ndị ọrịa ọrịa Alzheimer, ọkwa nrụgide oxidative na-ebuli elu nke ukwuu, na-eduga n'ịbawanye mmebi DNA na neurons na sel glial, nke na-ebute senescence cellular.
2. Telomere dị mkpụmkpụ: Telomeres bụ usoro DNA ugboro ugboro na njedebe nke chromosomes nke ji nwayọọ nwayọọ na-eji nkewa sel dị mkpụmkpụ. Mgbe telomeres na-adị mkpụmkpụ ruo ogologo oge, ha na-ebute akara senescence. N'ime mkpụrụ ndụ akwara neural, mkpirisi telomere nwere njikọ chiri anya na mmalite nke ịdị ndụ, nke nwere ike imebi mmeghari ohuru nke onwe na ikike iche nke mkpụrụ ndụ akwara, si otú ahụ na-emetụta mmepe nkịtị na ọrụ nke usoro ụjọ ahụ.
Usoro nke Omume nke Senescent Cells na Ọrịa Alzheimer
(1) Mmalite nke Neuroinflammation
1. Ọrụ nke Senescence-Associated Secretory Phenotype (SASP): Senescent cell na-egosipụta phenotype nzuzo pụrụ iche nke a maara dị ka senescence-Associated secretory phenotype (SASP). SASP nwere cytokines dị iche iche, chemokines, ihe na-eto eto, na proteases, dị ka interleukin-6 (IL-6), interleukin-8 (IL-8), na tumor necrosis factor-α (TNF-α). N'ime ụbụrụ anụ ahụ nke ndị ọrịa ọrịa Alzheimer, mkpụrụ ndụ glial senescent na neurons na-ezobe nnukwu ihe SASP, nke nwere ike mee ka mkpụrụ ndụ na-alụso ọrịa ọgụ dị gburugburu ma kpalite nzaghachi mkpali na-adịghị ala ala. IL-6 na TNF-α na-akwalite ntinye nke microglia, na-eme ka ha gbanwee site na ọnọdụ na-adịghị mma na ọnọdụ pro-inflammatory, na-ahapụ ndị mgbasa ozi na-egbuke egbuke ma na-eme ka neuroinflammation dịkwuo njọ. Ebe a na-egbu egbu na-adịghị ala ala na-emebi neurons, na-emebi ọrụ synapti, ma na-eduga n'ịrụ ọrụ ọgụgụ isi.
2. Mmetụta na mkpụrụ ndụ glial: Ịka nká nke astrocytes na microglia na-arụ ọrụ dị mkpa na AD neuroinflammation. Astrocytes merela agadi na-ezobe ihe SASP na-akwalite nchịkọta na ntinye nke β-amyloid (Aβ) ma na-egbochi nkwụsị ya. Ịka nká nke microglia na-ebelata ikike ha nwere phagocytose Aβ, na-egbochi nkwụsị nke ọma nke Aβ plaques na ụbụrụ. Kama nke ahụ, ha na-ahapụ ihe ndị na-akpasu iwe, na-emepụta usoro ọjọọ nke na-eme ka neuroinflammation na neurodegeneration dịkwuo njọ.
Ọgụgụ 2 A na-abawanye ihe nrịbama nke senescence cell n'ụbụrụ hTau ụmụ oke ụdị tauopathy nke AD.
(2) Nkwalite nke Neurodegeneration
1. Mmebi nke akwara ozi ozugbo: Ụfọdụ cytokines na proteases nke mkpụrụ ndụ senescent zoro ezo nwere ike imebi akwara ozi ozugbo. Matrix metalloproteinases (MMPs) bụ otu n'ime akụkụ nke senescence-Associated secretome (SASP), nke nwere ike imebi matrix extracellular na protein ndị metụtara neurotransmitter, na-akpaghasị nhazi na ọrụ nke neurons. ROS nke mkpụrụ ndụ senescent mepụtara nwekwara ike ime ka oxidative mebie neurons, na-eduga na apoptosis neuronal na ọnwụ. N'ime ụbụrụ ụbụrụ nke ndị ọrịa AD, neuronal senescence na-ejikọta ya na ọnwụ cell, nke nwere ike ịbụ otu n'ime isi ihe na-enye aka n'ịrụ ọrụ ụbụrụ.
2. Ntinye aka na Neurotransmitter Nyefee: Ọnụnọ nke mkpụrụ ndụ senescent nwekwara ike imebi njikọ, ntọhapụ, na nnyefe nke neurotransmitters. Ihe na-egbuke egbuke nwere ike igbochi njikọ nke acetylcholine, neurotransmitter dị mkpa maka ịnọgide na-arụ ọrụ ọgụgụ isi nkịtị. Na mgbakwunye, ụfọdụ ihe zoro ezo site na mkpụrụ ndụ senescent nwere ike imetụta nkwupụta na ọrụ nke ndị na-anabata neurotransmitter, na-eduga na nrịbama neurotransmitter na-adịghị mma, na-emebikwu nzikọrịta ozi na nhazi ozi n'etiti neurons, wee si otú a na-ebute adịghị ike nghọta.
(3) Mgbanwe na nkwurịta okwu intercellular
1. Nrịbama Paracrine na-adịghị mma: Senescent cell na-ekwurịta okwu na sel ndị gbara ya gburugburu site na akara paracrine site na nzuzo ihe SASP. Ihe ndị a nwere ike imetụta ọrụ na akara aka nke mkpụrụ ndụ agbata obi, na-eduga na nkwụsị nke netwọk nkwurịta okwu intercellular. N'ime ụbụrụ ụbụrụ nke ndị ọrịa AD, ihe SASP zoro ezo site na mkpụrụ ndụ glial senescent nwere ike imetụta uto nke neuronal, nlanarị, na ọdịiche dị iche iche, ebe ọ na-emetụtakwa microenvironment nke mkpụrụ ndụ stem neural, na-egbochi mgbasa ha na ọdịiche ha, si otú ahụ na-emetụta usoro mmeghari na nrụzi.
2.Disruption nke intercellular njikọ: Senescent cell nwekwara ike na-akpaghasị intercellular njikọ owuwu, dị ka tights junctions na oghere junction. N'ime ihe mgbochi ụbụrụ nke ọbara, mkpụrụ ndụ endothelial na-eduga n'ịbelata nkwupụta nke protein njikọ siri ike, na-abawanye ikike nke mgbochi ụbụrụ ọbara na ikwe ka ihe ndị na-emerụ ahụ banye n'ime ụbụrụ ụbụrụ ngwa ngwa, na-eme ka neuroinflammation na neurodegeneration dịkwuo njọ. Njikọ dị n'etiti neurons dị oke mkpa maka nnyefe nke akara eletrik na nhazi nke metabolic n'etiti neurons. Ihe ndị zoro ezo site na mkpụrụ ndụ senescent nwere ike imebi ọrụ nke oghere oghere, na-emetụta ọrụ mmekọrịta yana nnyefe ozi n'etiti neurons.
(4) Mmetụta na microenvironment nke mkpụrụ ndụ stem neural
1. Mgbochi nke mmụba nke cell stem neural na ọdịiche: Neural stem cell dị na ụbụrụ nke ndị okenye mammals ma nwee ike ime ka onwe ya dị ọhụrụ ma dị iche na neurons, astrocytes, na oligodendrocytes. Ihe ndị SASP zoro ezo site na mkpụrụ ndụ senescent nwere ike ịgbanwe microenvironment nke mkpụrụ ndụ stem neural, na-egbochi mmụba na ọdịiche ha. Ụfọdụ cytokines dị na SASP nwere ike imeziwanye okwu nke ndị na-emechi kinase na-adabere na cyclin, na-eme ka mkpụrụ ndụ akwara na-ejide n'oge ụfọdụ nke usoro cell na enweghị ike ịnweta nkewa na ọdịiche nkịtị. Ihe na-egbuke egbuke nke mkpụrụ ndụ senescent zoro ezo nwekwara ike imetụta ntụziaka dị iche iche nke mkpụrụ ndụ stem neural, na-eme ka ha dị iche n'ime sel glial karịa neurons, si otú ahụ na-emetụta mmeghari na nrụzi akwara.
2. Mmetụta na mbugharị cell stem neural: Mbugharị mkpụrụ ndụ akwara dị oke mkpa maka nhazi ha kwesịrị ekwesị na arụ ọrụ n'ime ụbụrụ. Ụfọdụ ihe ndị sel sesescent zoro ezo nwere ike igbochi mkpagharị sel stem neural, na-egbochi ha ịkwaga na mpaghara chọrọ nrụzi. Ngosipụta na-adịghị mma nke chemokines nwere ike gbanwee ntụzịaka mbugharị nke mkpụrụ ndụ stem neural, na-egbochi ha iru ebe mmerụ ahụ maka nrụzi, si otú ahụ na-emebi usoro ụjọ ahụ nke imezi onwe ya.
Usoro ọgwụgwọ ọrịa Alzheimer na-elekwasị anya na mkpụrụ ndụ senescent
(1) Senolytics
1. Usoro nke ime ihe: Senolytics bụ klas nke ogige nwere ike ịhọrọ kpochapụ mkpụrụ ndụ senescent. Usoro ha na-eme ihe bụ isi gụnyere ịkpata apoptosis cell senescent na igbochi ụzọ mgbama mgbochi apoptotic cell senescent. Dasatinib na quercetin bụ ugbu a kacha amụ ihe gbasara senolytics. Dasatinib nwere ike igbochi ụzọ nrịbama kinase mechiri emechi na sel senescent, ebe quercetin na-eme ka mmetụta nke dasatinib dịkwuo elu. Mgbe ejiri ya mee ihe, ha nwere ike ịhọrọ ime apoptosis n'ime mkpụrụ ndụ sesenescent ma belata mkpokọta ha n'ime ahụ.
2.Ọganihu na nnwale anụmanụ na ọmụmụ ụlọ ọgwụ: N'ime nnwale anụmanụ, ọgwụgwọ nke ụmụ oke ụdị AD na ndị na-ahụ maka mkpochapụ cell na-ebelata nke ukwuu na-ebelata ọnụ ọgụgụ nke mkpụrụ ndụ senescent na ụbụrụ, na-ebelata ọkwa neuroinflammation, ma kwalite ọrụ ọgụgụ isi. Nnyocha achọpụtara na mgbe inyechara dasatinib na quercetin ọgwụgwọ nchikota nke ụmụ oke AD, ọnụ ọgụgụ nke plaques Aβ dị na ụbụrụ belatara, mmebi nke neuronal belatara, yana mmụta ohere na ikike nchekwa dị mma.
Ọgụgụ 3 Senescence cellular dị ka akụkụ nke ịka nká na AD.
(2) Ndị modulators nzuzo phenotype na-ejikọta Senescence (Senomorphics)
1. Usoro nke ime ihe: Senomorphics bu n'obi ịhazi ihe nzuzo nke SASP site na mkpụrụ ndụ senescent, na-ebelata mmetụta ha na-emerụ ahụ na sel ndị gbara ya gburugburu. Ụfọdụ ọgwụ ndị na-egbu egbu nwere ike igbochi nkwupụta na nzuzo nke ihe ndị na-egbuke egbuke na SASP, na-ebelata neuroinflammation. Ụfọdụ ogige molekul dị nta nwere ike ịhazi ụzọ metabolic nke mkpụrụ ndụ senescent, na-agbanwe nhazi nke SASP iji mee ka mmetụta ya dị njọ na sel ndị gbara ya gburugburu.
2.Potential Application Prospects: Uru nke senescence-metụtara secretory phenotype modulators dabeere na ha nwere ike imeziwanye microenvironment anụ ahụ site n'ịhazi ọrụ nzuzo nke mkpụrụ ndụ senescent kama ikpochapụ ha ozugbo. Nke a nwere ike ịzenarị ụfọdụ ihe egwu nwere ike jikọta ya na ihe ndị na-ewepụ mkpụrụ ndụ sesenescent, dị ka mmebi nke akpaghị aka nke sel nkịtị. Ya mere, senescence-metụtara secretory phenotype modulators na-enwe atụmanya ngwa sara mbara ma nwee ike pụta dị ka usoro ọgwụgwọ ọhụrụ maka AD.
Mmechi
Mkpụrụ ndụ senescent na-ekere òkè dị iche iche na mmalite na ọganihu nke ọrịa Alzheimer. Site na usoro ndị dị ka ịkpata neuroinflammation, ịkwalite neurodegeneration, na-agbanwe nkwurịta okwu intercellular, na-emetụta microenvironment nke mkpụrụ ndụ stem neural, mkpụrụ ndụ senescent na-eme ka usoro pathological AD dịkwuo njọ. Usoro ọgwụgwọ na-elekwasị anya na mkpụrụ ndụ senescent, dị ka mmepe nke ndị na-ewepụ ihe na-eme ka cell senescence na senescence metụtara secretory phenotype modulators, na-enye nhọrọ ọhụrụ maka ọgwụgwọ AD.
Isi mmalite
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