Na Cocer Peptides 
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INGINGO ZOSE N'AMAKURU Y’IBICURUZWA BITANZWE KURI URU RUBUGA BISANZWE KUBONA AMAKURU N'INTEGO Z'UBUREZI.
Ibicuruzwa byatanzwe kururu rubuga bigenewe gusa mubushakashatsi bwa vitro. Mu bushakashatsi bwa vitro (Ikilatini: * mu kirahure *, bisobanura mu bikoresho by'ibirahure) bikorwa hanze y'umubiri w'umuntu. Ibicuruzwa ntabwo ari imiti, ntabwo byemejwe n’ikigo cy’Amerika gishinzwe ibiryo n’ibiyobyabwenge (FDA), kandi ntigomba gukoreshwa mu gukumira, kuvura, cyangwa gukiza indwara iyo ari yo yose y’ubuvuzi, indwara, cyangwa indwara. Birabujijwe rwose n'amategeko kwinjiza ibyo bicuruzwa mumubiri wabantu cyangwa inyamaswa muburyo ubwo aribwo bwose.
Incamake
Iyi ngingo iragaragaza uburyo ingirabuzimafatizo zigira uruhare mu gutangira no gutera imbere indwara ya Alzheimer (AD). Indwara ya Alzheimer ni indwara ikunze kwibasira cyane abasaza, irangwa no kutamenya neza ubwenge no kubura imyitwarire. Uko abatuye isi bagenda basaza, umubare wa AD ukomeje kwiyongera buri mwaka, bigatera umutwaro ukomeye umuryango ndetse nimiryango. Nubwo hari intambwe igaragara imaze guterwa mubushakashatsi bwa AD, etiologiya nyayo na patogenezi ntisobanutse neza. Nka kimwe mu bintu byambere bishobora guteza AD, senescence ya selile yakunze kwitabwaho mumyaka yashize kubera uruhare rwayo mu gutera AD. Ikwirakwizwa ry'uturemangingo twa senescent mu mubiri rifitanye isano rya bugufi no gutangira no gutera imbere kwindwara zitandukanye ziterwa n'imyaka. Ingirabuzimafatizo zifite uruhare runini mugikorwa cy’indwara ya AD, kandi gusobanura uburyo bwibikorwa bifite akamaro kanini mugutezimbere imiti mishya ya AD.
Igicapo 1. Indwara ya Alzheimer itera poroteyine igira uruhare mu bwonko bwakuze. (a) Incamake yimikoranire hagati yubwonko bwubwonko bwa senescent hamwe na plaque amyloide na tau itera indwara. .
Incamake y'utugari twa Senescent
(1) Ibisobanuro n'ibiranga Utugingo ngengabuzima
Senescence bivuga ifatwa ryikura ridasubirwaho ryingirabuzimafatizo nyuma yo gutandukana numubare runaka cyangwa guhura nibintu bitandukanye (nka stress ya okiside, kwangirika kwa ADN, kugabanuka kwa telomere, nibindi). Ingirabuzimafatizo zerekana imiterere yihariye ya fenotipiki, harimo kwiyongera kwingirabuzimafatizo, gusibanganya, no kuzamura ibikorwa β-galactosidase (β-gal), kikaba ari ikimenyetso cyibinyabuzima gikunze gukoreshwa mu kumenya ingirabuzimafatizo. Byongeye kandi, selile senescent yerekana igenzurwa rya cyclin iterwa na kinase inhibitor (nka p16INK4a na p21Cip1), ibuza iterambere ryingirabuzimafatizo, bigatuma selile zifatwa mugice cya G1 cyangwa G2 / M bityo bikarinda amacakubiri.
Uburyo bwo Gushinga Akagari ka Senescent
1. Stress ya Oxidative na ADN yangiritse: Guhangayikishwa na Oxidative ni ikintu cyingenzi gitera senescence. Mubihe bisanzwe byimiterere yumubiri, kubyara no gukuraho ubwoko bwa ogisijeni ikora (ROS) muri selile biri muburinganire buringaniye. Ariko, hamwe no gusaza cyangwa mubihe bimwe na bimwe by’indwara, kongera umusaruro wa ROS biganisha kuri ADN. Iyo ADN yangiritse ku rugero runaka kandi ntishobora gusanwa neza, urukurikirane rw'inzira zerekana ibimenyetso, nka p53-p21 na p16-Rb byerekana inzira, bigatuma selile zinjira muri reta ya senescent. Mu bwonko bw’abarwayi b’indwara ya Alzheimer, urugero rwa oxydeide rwiyongera cyane, bigatuma ADN yangirika muri neuron na glial selile, ari nako itera umusemburo wa selile.
2. Kugabanya itumanaho rya Telomere: Telomeres isubiramo ADN ikurikiranye kumpera ya chromosomes igenda igabanuka buhoro buhoro hamwe no kugabana. Iyo telomereri igufi kugeza muburebure runaka, itera ibimenyetso bya senescence. Mu ngirabuzimafatizo ngengabuzima, kugabanuka kwa telomere bifitanye isano rya bugufi no gutangira kwa senescence, bishobora kubangamira ubushobozi bwo kwiyubaka no gutandukanya ingirabuzimafatizo ngengabuzima, bityo bikagira ingaruka ku mikurire isanzwe n'imikorere ya sisitemu y'imitsi.
Uburyo bwibikorwa byingirabuzimafatizo za Senescent mu ndwara ya Alzheimer
(1) Kwinjiza Neuroinflammation
1. Uruhare rwa Senescence-Associated Secretory Phenotype (SASP): Utugingo ngengabuzima twa Senescent twerekana phenotype yihariye y'ibanga izwi nka senescence ifitanye isano na senescence ifitanye isano (SASP). SASP igizwe na cytokine zitandukanye, chemokine, ibintu bikura, hamwe na protease, nka interleukin-6 (IL-6), interleukin-8 (IL-8), hamwe na kanseri yibibyimba-α (TNF-α). Mu bwonko bw'abarwayi ba Alzheimer, abarwayi ba senescent glial selile na neurone basohora ibintu byinshi bya SASP, bishobora gukora ingirabuzimafatizo zikikije umubiri kandi bigatera ibisubizo bidakira. IL-6 na TNF-α biteza imbere imikorere ya microglia, bigatuma bahinduka bava muri leta ituje bakajya muri reta itera umuriro, bakarekura abunzi benshi kandi bikarushaho kwiyongera kwa neuroinflammation. Ibidukikije bidakira byangiza neuron, byangiza imikorere ya synaptic, kandi biganisha kumikorere mibi.
2. Ingaruka kuri selile glial: Gusaza kwa astrocytes na microglia bigira uruhare runini muri AD neuroinflammation. Gusaza astrocytes isohora ibintu bya SASP biteza imbere gukusanya no gushira β-amyloide (Aβ) mugihe bibuza kwemerwa kwayo. Gusaza kwa microglia bigabanya ubushobozi bwabo kuri fagocytose Aβ, bikarinda gukuraho neza ibyapa bya Aβ mubwonko. Ahubwo, barekura ibintu byinshi bitera umuriro, bigatera uruziga rukabije rwongera neuroinflammation na neurodegeneration.
Igishushanyo 2 Ibimenyetso bya senescence ya selile byiyongera mubwonko bwimbeba ya HTau yerekana tauopathie ya AD.
(2) Guteza imbere Neurodegeneration
. Matrix metalloproteinase (MMPs) ni kimwe mu bigize ibanga rya senescence rifitanye isano n’ibanga (SASP), rishobora gutesha agaciro matrise idasanzwe ndetse na poroteyine zijyanye na neurotransmitter, bikabangamira imiterere n'imikorere ya neuron. ROS ikorwa na selile senescent irashobora kandi kwangiza okiside kuri neuron, biganisha kuri neuronal apoptose nurupfu. Mu bwonko bw'abarwayi ba AD, senescence ya neuronal ifitanye isano rya bugufi n'urupfu rw'utugingo ngengabuzima, ibyo bikaba bishobora kuba bimwe mu bintu by'ingenzi bigira uruhare mu gukora nabi.
2. Kwivanga no kwanduza Neurotransmitter: Kubaho kwa selile senescent birashobora kandi guhungabanya synthesis, kurekura, no kwanduza neurotransmitter. Ibintu bitera umuriro birashobora kubuza synthesis ya acetylcholine, neurotransmitter ya ngombwa kugirango ikomeze imikorere isanzwe yubwenge. Byongeye kandi, ibintu bimwe na bimwe byasohowe na selile ya senescent birashobora kugira ingaruka kumvugo n'imikorere yabakira reseptor ya neurotransmitter, biganisha ku bimenyetso bidasanzwe bya neurotransmitter, bikabangamira itumanaho no gutunganya amakuru hagati ya neuron, bityo bigatera ubumuga bwo kutamenya.
(3) Impinduka mu Itumanaho hagati
1 . Izi ngingo zirashobora kugira ingaruka kumikorere no kugenwa kwingirabuzimafatizo zegeranye, biganisha ku guhagarika imiyoboro y'itumanaho hagati. Mu bwonko bw’abarwayi ba AD, ibintu bya SASP byasohowe ningirabuzimafatizo ya senescent glial selile bishobora kugira ingaruka kumikurire ya neuronal, kubaho, no gutandukana, mugihe bigira ingaruka no kuri microen ibidukikije byingirabuzimafatizo, bikabuza ikwirakwizwa ryabyo no gutandukana, bityo bikagira ingaruka kumyuka mishya no gusana.
2.Guhagarika imiyoboro ihuza ingirabuzimafatizo: Utugingo ngengabuzima twa Senescent turashobora kandi guhungabanya imiterere ihuza imiyoboro, nk'imikoranire ifatanye hamwe n’ikinyuranyo. Muri bariyeri yubwonko bwamaraso, senescence ya selile endothelia itera kugabanya imvugo ya poroteyine zifatika zifatika, bikongerera ubushobozi bwinzitizi yubwonko bwamaraso no kwemerera ibintu byangiza kwinjira mubwonko bworoshye, bikongera neuroinflammation na neurodegeneration. Guhuza icyuho hagati ya neuron ningirakamaro mugukwirakwiza ibimenyetso byamashanyarazi no guhuza metabolike hagati ya neuron. Ibintu byasohowe na selile ya senescent birashobora guhagarika imikorere yimikorere ihuza icyuho, bigira ingaruka kumikorere no guhererekanya amakuru hagati ya neuron.
(4) Ingaruka kuri microen ibidukikije ya selile stem selile
. Ibintu bya SASP byasohowe ningirabuzimafatizo za senescent birashobora guhindura microen ibidukikije yingirabuzimafatizo ngengabuzima, bikabuza ikwirakwizwa ryabyo no gutandukana. Cytokine zimwe na zimwe muri SASP zirashobora kugenzura imvugo ya cyclin iterwa na kinase inhibitor, bigatuma ingirangingo zifata imitsi zifata mugice cyihariye cyizunguruka kandi ntizishobora gutandukana no gutandukana bisanzwe. Ibintu bitwika byasohowe na selile senescent birashobora kandi guhindura icyerekezo cyo gutandukanya ingirangingo ngengabuzima, bigatuma batandukanya byinshi mu ngirabuzimafatizo aho kuba neuron, bityo bikagira ingaruka ku kuvugurura imitsi no gusana.
2 . Ibintu bimwe na bimwe byihishwa ningirabuzimafatizo zishobora kubangamira kwimuka kwimitsi yimitsi, bikababuza kwimukira mubice bisaba gusanwa. Imvugo idasanzwe ya chemokine irashobora guhindura icyerekezo cyo kwimuka kwingirangingo ngengabuzima, ikabuza kugera aho yakomeretse kugirango isanwe, bityo bikabangamira ubushobozi bwimitsi yo kwikosora.
Ingamba zo kuvura indwara ya Alzheimer yibasira selile
(1) Senolitike
1. Uburyo bwibikorwa: Senolytike nicyiciro cyibintu bishobora guhitamo gukuraho selile. Uburyo bwabo bwibikorwa burimo cyane cyane gutera ingirabuzimafatizo ya senescent apoptose no guhagarika ingirabuzimafatizo ya anti-apoptotique yerekana inzira. Dasatinib na quercetin kuri ubu nibyo byizwe cyane hamwe na senolytike. Dasatinib irashobora kubuza kinase ikora cyane yerekana inzira mumasemburo ya senescent, mugihe quercetin yongera ingaruka za dasatinib. Iyo ikoreshejwe hamwe, irashobora guhitamo gutera apoptose mumasemburo ya senescent no kugabanya kwirundanya kwayo mumubiri.
2.Iterambere mubushakashatsi bwinyamaswa nubushakashatsi bwubuvuzi: Mubushakashatsi bwinyamanswa, kuvura imbeba ntangarugero ya AD hamwe na selile zo mu bwoko bwa senescent byagabanije cyane umubare wingirabuzimafatizo mu bwonko, bigabanya urwego rwa neuroinflammation, kandi binonosora imikorere yubwenge. Ubushakashatsi bwerekanye ko nyuma yo gutanga imiti ya dasatinib na quercetin ivura imbeba z'icyitegererezo cya AD, umubare wa plaque Aβ mu bwonko wagabanutse, kwangirika kw'imitsi byagabanutse, ndetse n'ubushobozi bwo kwiga ahantu hamwe n'ubushobozi bwo kwibuka.
Igishushanyo cya 3 Senescence ya selile nkigice cyo gusaza neza na AD.
(2) Senescence ifitanye isano na banga ya phenotype modulator (Senomorphics)
1. Uburyo bwibikorwa: Senomorphics igamije kugenzura ururenda rwibintu bya SASP na selile senescent, bikagabanya ingaruka mbi zabyo kuri selile. Imiti imwe n'imwe irwanya inflammatory irashobora kubuza imvugo no gusohora ibintu bitera umuriro muri SASP, bikagabanya neuroinflammation. Ibice bimwe na bimwe bya molekile bishobora kugenga inzira ya metabolike ya selile ya senescent, bigahindura imiterere ya SASP kugirango bigabanye ingaruka zangiza kuri selile zikikije.
2.Ibisabwa Byifuzo Byiza: Ibyiza bya senescence bifitanye isano na senescence yibanga ya modotype modulators iri mubushobozi bwabo bwo kuzamura mikorobe ya tissue muguhuza imikorere yibanga ya selile aho kubirandura burundu. Ibi birashobora kwirinda ingaruka zimwe zishobora kuba ziterwa na senescent selile zohanagura, nkibyangiritse bidasanzwe kuri selile zisanzwe. Kubwibyo, senescence ifitanye isano nububiko bwa phenotype modulator ifite ibyifuzo byinshi kandi birashobora kugaragara nkuburyo bushya bwo kuvura AD.
Umwanzuro
Ingirabuzimafatizo za Senescent zigira uruhare runini mugutangira no gutera imbere kwindwara ya Alzheimer. Binyuze mu buryo nko gutera neuroinflammation, guteza imbere neurodegeneration, guhindura itumanaho hagati y’imitsi, no kugira ingaruka ku bidukikije byangiza ingirabuzimafatizo ngengabuzima, selile senescent byongera inzira y’indwara ya AD. Ingamba zo kuvura zigamije ingirabuzimafatizo za senescente, nk'iterambere ry'imikorere ya selile ya senescent hamwe na moderi ya senescence ifitanye isano na senescence, itanga uburyo bushya bwo kuvura AD.
Inkomoko
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