By Cocer Peptides 
Watanni 1 da suka gabata
DUKKANIN LABARI DA BAYANIN KYAUTATAWA DA AKE BAYAR A WANNAN SHAFIN KAWAI DOMIN WATSA BAYANI NE DA MANUFOFIN ILIMI.
Kayayyakin da aka bayar akan wannan gidan yanar gizon an yi niyya ne kawai don binciken in vitro. Binciken in vitro (Latin: *a cikin gilashi*, ma'ana a cikin gilashin gilashi) ana gudanar da shi a wajen jikin mutum. Waɗannan samfuran ba magunguna ba ne, Hukumar Abinci da Magunguna ta Amurka (FDA) ba ta amince da su ba, kuma dole ne a yi amfani da su don hanawa, magani, ko warkar da duk wani yanayi na likita, cuta, ko cuta. Doka ta haramta shigar da waɗannan samfuran cikin jikin mutum ko dabba ta kowace hanya.
Dubawa
Wannan labarin ya bincika hanyoyin da ƙwayoyin da ke da hankali ke ba da gudummawa ga farawa da ci gaban cutar Alzheimer (AD). Cutar Alzheimer cuta ce ta gama gari da ta fi shafar tsofaffi, wanda ke da raunin fahimi na ci gaba da nakasu. Yayin da yawan jama'ar duniya ke da shekaru, lamarin AD na ci gaba da karuwa a kowace shekara, yana dora babban nauyi ga al'umma da iyalai. Kodayake an sami ci gaba mai mahimmanci a cikin binciken AD, ainihin ilimin etiology da pathogenesis ya kasance ba a sani ba. A matsayin daya daga cikin abubuwan haɗari na farko ga AD, jin daɗin salula ya sami ƙarin hankali a cikin 'yan shekarun nan don rawar da ya taka a cikin pathogenesis na AD. Tarin kwayoyin halitta a cikin jiki yana da alaƙa da alaƙa da farawa da ci gaban cututtuka daban-daban na shekaru. Kwayoyin halitta suna taka muhimmiyar rawa a cikin tsarin ilimin cututtuka na AD, kuma bayyana hanyoyin aiwatar da su yana da mahimmanci ga haɓaka sabbin jiyya ga AD.
Hoto 1. Sunadaran ƙwayoyin cuta na cutar Alzheimer suna ba da gudummawa ga ƙwayar ƙwayar ƙwayar cuta. (a) Bayyani na hulɗar tsakanin ƙwayoyin ƙwalƙwalwar hankali tare da amyloid plaques da pathogenic tau. (b-e) Cikakken ra'ayi na kowane nau'in tantanin halitta da siffofi masu alaƙa da yanayin da aka ruwaito a cikin wallafe-wallafen: (b) neuron, (c) microglia, (d) oligodendrocyte / oligodendrocyte precursor cell, (e) astrocyte, da (f) shingen kwakwalwa na jini (BBB) wanda ke nuna endostrricthelial cell cell, astrocyte compotes, peatrocytes da peatrocytes. BBB mutunci a cikin AD.
Bayanin Kwayoyin Senescent
(1) Ma'ana da Halayen Kwayoyin Senescent
Senescence yana nufin kamun sel da ba za a iya jurewa ba bayan an sha wasu adadin rarrabuwa ko kuma an fallasa shi ga abubuwan damuwa daban-daban (kamar damuwa na oxidative, lalacewar DNA, raguwar telomere, da sauransu). Kwayoyin ji na jiki suna nuna halaye na musamman na phenotypic, gami da ƙarar ƙarar tantanin halitta, daidaitawa, da haɓaka aikin β-galactosidase (β-gal), wanda alama ce ta ilimin halitta da aka saba amfani da ita don gano ƙwayoyin ji. Bugu da ƙari, sel masu hankali suna nuna haɓakar masu hanawar kinase masu dogaro da cyclin (kamar p16INK4a da p21Cip1), waɗanda ke hana ci gaban sake zagayowar tantanin halitta, yana haifar da sel don kamawa a cikin lokaci na G1 ko G2 / M kuma ta haka ne hana ƙarin rarrabuwa.
Hanyoyi na Samuwar Tantanin Halitta
1. Damuwar Oxidative da Lalacewar DNA: Damuwar iskar Oxidative shine mabuɗin inducer na senescence na salula. Ƙarƙashin yanayin ilimin lissafi na al'ada, samarwa da share nau'in oxygen mai aiki (ROS) a cikin sel suna cikin ma'auni mai ƙarfi. Duk da haka, tare da tsufa ko ƙarƙashin wasu yanayi na cututtuka, ƙara yawan samar da ROS yana haifar da lalacewar DNA. Lokacin da lalacewar DNA ta taru har zuwa wani matsayi kuma ba za a iya gyarawa yadda ya kamata ba, ana kunna jerin hanyoyin sigina, kamar hanyoyin siginar p53-p21 da p16-Rb, suna haifar da sel don shiga yanayin jin dadi. A cikin nama na kwakwalwa daga masu cutar Alzheimer, matakan damuwa na oxidative suna da girma sosai, wanda ke haifar da lalacewar DNA a cikin neurons da glial cell, wanda hakan ke haifar da jin dadi na salula.
2. Taqaitaccen Telomere: Telomeres jerin DNA ne masu maimaitawa a ƙarshen chromosomes waɗanda sannu a hankali suke gajarta tare da rarraba tantanin halitta. Lokacin da telomeres ya gajarta zuwa takamaiman tsayi, suna haifar da siginonin jin daɗi. A cikin ƙwayoyin jijiyoyi na jijiyoyi, raguwa na telomere yana da alaƙa da haɗin kai tare da farawa na jin dadi, wanda zai iya lalata sabuntawar kai da ikon bambance-bambancen ƙwayoyin jijiyoyi, ta haka yana rinjayar ci gaba na al'ada da aiki na tsarin jin tsoro.
Tsarin Ayyukan Ayyukan Jiki a cikin Cutar Alzheimer
(1) Shigar da Neuroinflammation
1. Matsayin Senescence-Associated Secretory Phenotype (SASP): Kwayoyin halitta suna nuna wani nau'i na sirri na musamman wanda aka sani da senescence-associated secretory phenotype (SASP). SASP ya ƙunshi nau'o'in cytokines, chemokines, abubuwan haɓaka, da proteases, irin su interleukin-6 (IL-6), interleukin-8 (IL-8), da ƙari necrosis factor-α (TNF-α). A cikin nama na kwakwalwa na masu cutar Alzheimer, ƙwayoyin glial na glial da neurons suna ɓoye abubuwa masu yawa na SASP, waɗanda zasu iya kunna ƙwayoyin rigakafi da ke kewaye da su kuma suna haifar da amsa mai kumburi. IL-6 da TNF-α suna inganta kunnawa na microglia, suna sa su canzawa daga yanayin da ba a sani ba zuwa yanayin da ke da ƙwayar cuta, suna sakin ƙarin masu shiga tsakani da kuma kara tsananta neuroinflammation. Wannan yanayi mai kumburi na yau da kullun yana lalata ƙwayoyin ƙwayoyin cuta, yana lalata aikin synaptic, kuma yana haifar da tabarbarewar fahimi.
2. Tasiri akan ƙwayoyin glial: tsufa na astrocytes da microglia suna taka muhimmiyar rawa a cikin AD neuroinflammation. Astrocytes masu tsufa suna ɓoye abubuwan SASP waɗanda ke haɓaka haɓakawa da ƙaddamar da β-amyloid (Aβ) yayin da suke hana izinin sa. Tsufa na microglia yana rage ikon su zuwa phagocytose Aβ, yana hana ingantaccen sharewar Aβ plaques a cikin kwakwalwa. Madadin haka, suna sakin ƙarin abubuwan da ke haifar da kumburi, suna haifar da mummunan zagayowar da ke haɓaka neuroinflammation da neurodegeneration.
Hoto na 2 Alamu na senescence na salon salula sun karu a cikin kwakwalwar hTau mice modeling tauopathy na AD.
(2) Inganta Neurodegeneration
1. Lalacewa kai tsaye ga neurons: Wasu cytokines da proteases da ke ɓoye daga ƙwayoyin ji na iya lalata ƙwayoyin jijiyoyin jiki kai tsaye. Matrix metalloproteinases (MMPs) ɗaya ne daga cikin abubuwan da ke tattare da sirrin da ke da alaƙa da senescence (SASP), wanda zai iya lalata matrix na extracellular da sunadarai masu alaƙa da neurotransmitter, rushe tsari da aikin neurons. ROS da sel masu hankali suka samar kuma na iya haifar da lalacewar oxidative ga neurons, wanda ke haifar da apoptosis neuronal da mutuwa. A cikin nama na kwakwalwa na marasa lafiya AD, rashin jin daɗi na neuronal yana da alaƙa da mutuwar kwayar halitta, wanda zai iya zama ɗaya daga cikin mahimman abubuwan da ke ba da gudummawa ga tabarbarewar fahimta.
2. Tsangwama tare da Neurotransmitter Transmission: Kasancewar sel masu hankali kuma na iya rushe kira, saki, da watsawa na neurotransmitters. Abubuwan da ke haifar da kumburi na iya hana haɓakar acetylcholine, neurotransmitter mai mahimmanci don kiyaye aikin fahimi na yau da kullun. Bugu da ƙari, wasu abubuwan da ke ɓoye daga sel masu hankali na iya yin tasiri ga magana da aikin masu karɓa na neurotransmitter, wanda ke haifar da sigina mara kyau na neurotransmitter, yana ƙara lalata sadarwa da sarrafa bayanai tsakanin neurons, kuma ta haka ne ke haifar da rashin fahimta.
(3) Canje-canje a Sadarwar Intercellular
1. Alamar Paracrine mara kyau: Kwayoyin halitta suna sadarwa tare da sel kewaye ta hanyar siginar paracrine ta hanyar ɓoye abubuwan SASP. Wadannan abubuwan zasu iya shafar aiki da makomar sel makwabta, suna haifar da rushewar hanyar sadarwar salula. A cikin kwakwalwar kwakwalwa na marasa lafiya AD, abubuwan SASP da aka ɓoye ta hanyar sel glial na hankali na iya rinjayar ci gaban neuronal, rayuwa, da bambance-bambance, yayin da kuma rinjayar microenvironment na kwayoyin halitta na jijiyoyi, suna hana yaduwar su da bambance-bambancen su, don haka suna shafar farfadowa na jijiyoyi da gyaran gyare-gyare.
2. Rushewar haɗin gwiwar hannu: Kwayoyin masu hankali kuma na iya tarwatsa tsarin haɗin salula, kamar madaidaitan mahaɗai da rata. A cikin shingen kwakwalwar jini, jin daɗin sel na endothelial yana haifar da raguwar maganganun ƙwayoyin sunadaran haɗin gwiwa, haɓaka haɓakar shingen kwakwalwar jini da ƙyale abubuwa masu cutarwa don sauƙin shiga cikin nama na kwakwalwa, yana haɓaka neuroinflammation da neurodegeneration. Matsakaicin rata tsakanin jijiyoyi suna da mahimmanci don watsa siginonin lantarki da daidaitawar rayuwa tsakanin jijiya. Abubuwan da ke ɓoye daga sel masu hankali na iya rushe aikin mahaɗar rata, yana shafar ayyukan aiki tare da watsa bayanai tsakanin ƙwayoyin cuta.
(4) Tasiri akan microenvironment na ƙwanƙwaran ƙwayoyin jijiya
1. Hana haɓakar ƙwayoyin jijiyoyi da bambance-bambance: Kwayoyin jijiyoyi na jijiyoyi suna cikin kwakwalwar manya masu shayarwa kuma suna da ikon sake sabunta kansu da kuma bambanta cikin neurons, astrocytes, da oligodendrocytes. Abubuwan SASP da aka ɓoye ta sel masu hankali na iya canza microenvironment na ƙwayoyin jijiyoyi na jijiyoyi, hana haɓakawa da bambancin su. Wasu cytokines a cikin SASP na iya daidaita maganganun kinase inhibitors na cyclin-dogara, haifar da ƙwayoyin jijiyoyi don kamawa a wasu matakai na sake zagayowar tantanin halitta kuma ba za su iya samun rarrabuwa na al'ada da bambanci ba. Abubuwan da ke haifar da kumburi da sel masu hankali suma na iya yin tasiri akan bambance bambancen sel masu tushe na jijiyoyi, haifar da su don bambanta da yawa cikin sel glial maimakon neurons, wanda hakan ke shafar farfadowa da gyara jijiyoyi.
2. Tasiri kan ƙaurawar ƙwayar jijiyoyi: Ƙaurawar ƙwayar jijiyoyi yana da mahimmanci don daidaitaccen wurin su da aikin aiki a cikin kwakwalwa. Wasu abubuwan da sel masu hankali suka ɓoye suna iya tsoma baki tare da ƙaurawar kwayar halitta ta jijiyoyi, hana su ƙaura zuwa wuraren da ke buƙatar gyara. Magance mara kyau na chemokines na iya canza hanyar ƙaura na ƙwayoyin jijiyoyi na jijiyoyi, hana su isa wurin da aka samu rauni don gyarawa, ta haka yana lalata tsarin tsarin juyayi na kansa.
Dabarun jiyya na cutar Alzheimer da ke niyya ga ƙwayoyin ji
(1) Senolytics
1. Tsarin aiki: Senolytics rukuni ne na mahadi waɗanda za su iya zaɓin kawar da sel masu hankali. Hanyoyin aikinsu da farko sun haɗa da haifar da apoptosis na sel da kuma hana hanyoyin siginar siginar senescent cell. Dasatinib da quercetin a halin yanzu sune mafi yawan nazarin haɗuwa na senolytics. Dasatinib na iya hana hanyoyin siginar kinase da aka yi amfani da su a cikin sel masu hankali, yayin da quercetin ke haɓaka tasirin dasatinib. Lokacin amfani da su a hade, za su iya zaɓin haifar da apoptosis a cikin sel masu hankali kuma su rage tarawarsu a cikin jiki.
2.Ci gaba a cikin gwaje-gwajen dabba da nazarin asibiti: A cikin gwaje-gwajen dabba, jiyya na mice na AD tare da ma'aikatan cirewa na kwayar halitta sun rage yawan adadin kwayoyin halitta a cikin kwakwalwa, saukar da matakan neuroinflammation, da inganta aikin tunani. Nazarin ya gano cewa bayan gudanar da maganin haɗin gwiwar dasatinib da quercetin zuwa mice AD, adadin Aβ plaques a cikin kwakwalwa ya ragu, lalacewar neuronal ya ragu, kuma ilmantarwa na sararin samaniya da ƙwaƙwalwar ajiya sun inganta.
Hoto na 3 Senescence na kwayar halitta azaman bangaren tsufa mai lafiya da AD.
(2) Masu haɓaka abubuwan sirri masu alaƙa da Senescence (Senomorphics)
1. Tsarin aiki: Senomorphics yana nufin daidaita abubuwan da ke haifar da abubuwan SASP ta hanyar sel masu hankali, rage tasirin su akan sel kewaye. Wasu magungunan ƙwayoyin cuta na iya hana magana da ɓoye abubuwan da ke haifar da kumburi a cikin SASP, suna rage neuroinflammation. Wasu ƙananan ƙwayoyin ƙwayoyin ƙwayoyin cuta na iya daidaita hanyoyin rayuwa na sel masu hankali, suna canza tsarin SASP don raunana tasirin sa akan sel kewaye.
2. Yiwuwar Aikace-aikacen Abubuwan Haɓaka: Amfanin masu haɓaka abubuwan da ke da alaƙa da haɓakar phenotype masu haɓakawa ya ta'allaka ne akan ikon su na haɓaka microenvironment na nama ta hanyar daidaita ayyukan sirrin sel masu hankali maimakon kawar da su kai tsaye. Wannan na iya guje wa wasu yuwuwar hatsarori da ke da alaƙa da ma'aikatan kawar da tantanin halitta, kamar lalacewa marasa takamaiman ga sel na al'ada. Don haka, masu daidaita yanayin sirrin phenotype masu daidaitawa suna riƙe da fa'idodin aikace-aikace kuma suna iya fitowa azaman sabuwar dabarar warkewa ga AD.
Kammalawa
Kwayoyin ji na jiki suna taka rawa mai yawa a cikin farawa da ci gaban cutar Alzheimer. Ta hanyar hanyoyin da suka haɗa da haifar da neuroinflammation, inganta neurodegeneration, canza hanyar sadarwa ta intercellular, da kuma rinjayar microenvironment na ƙananan ƙwayoyin jijiyoyi, ƙwayoyin jin dadi suna kara tsananta tsarin pathological na AD. Dabarun warkewa da ke niyya da sel masu hankali, kamar haɓaka wakilai masu kawar da kwayar halitta da kuma masu daidaita abubuwan da ke da alaƙa da haɓakar phenotype, suna ba da sabbin zaɓuɓɓuka don maganin AD.
Sources
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