Na Cocer Peptides 
1 mahina aku nei
ʻO nā ʻatikala a me nā ʻike huahana i hāʻawi ʻia ma kēia pūnaewele pūnaewele wale nō no ka hoʻolaha ʻana i ka ʻike a me nā kumu hoʻonaʻauao.
ʻO nā huahana i hāʻawi ʻia ma kēia pūnaewele i manaʻo wale ʻia no ka noiʻi in vitro. Hana ʻia ka noiʻi in vitro (Latin: *i ke aniani*, ʻo ia hoʻi i ka ipu aniani) ma waho o ke kino kanaka. ʻAʻole kēia mau huahana he lāʻau lapaʻau, ʻaʻole i ʻae ʻia e ka US Food and Drug Administration (FDA), a ʻaʻole pono e hoʻohana ʻia no ka pale ʻana, mālama, a hoʻōla paha i kekahi maʻi olakino, maʻi, a i ʻole maʻi. Ua pāpā loa ʻia e ke kānāwai ke hoʻokomo i kēia mau huahana i loko o ke kino kanaka a holoholona paha ma kekahi ʻano.
Nānā nui
Ke ʻimi nei kēia ʻatikala i nā hana e kōkua ai nā cell senescent i ka hoʻomaka a me ka holomua o ka maʻi Alzheimer (AD). ʻO ka maʻi o Alzheimer kahi maʻi neurodegenerative maʻamau e pili ana i ka poʻe ʻelemakule, i hōʻike ʻia e ka holomua o ka naʻau a me nā hemahema. Ke piʻi aʻe nei ka heluna kanaka o ka honua i kēlā me kēia makahiki, e hoʻokau ana i kahi kaumaha nui i ke kaiāulu a me nā ʻohana. ʻOiai ua holomua ka holomua ma ka noiʻi AD, ʻaʻole maopopo ka etiology a me ka pathogenesis. Ma ke ʻano he kumu pilikia nui no ka AD, ua hoʻonui ʻia ka senescence cellular i nā makahiki i hala iho nei no kāna kuleana i ka pathogenesis o AD. ʻO ka hōʻiliʻili ʻana o nā cell senescent i loko o ke kino e pili kokoke ana i ka hoʻomaka ʻana a me ka holomua o nā maʻi like ʻole e pili ana i ka makahiki. He kuleana koʻikoʻi nā cell Senescent i ke kaʻina hana pathological o AD, a ʻo ka wehewehe ʻana i kā lākou hana o ka hana he mea nui ia no ka hoʻomohala ʻana i nā lāʻau lapaʻau hou no AD.
Kiʻi 1. ʻO nā protein pathogenic maʻi o Alzheimer e kōkua i ka lolo o ka lolo. (a) Ka nānā ʻana o ka pilina ma waena o nā pūnaʻi lolo senescent me nā pā amyloid a me ka tau pathogenic. (b-e) ʻIke kikoʻī o kēlā me kēia ʻano cell a me nā hiʻohiʻona pili i ka senescence i hōʻike ʻia ma ka palapala: (b) neuron, (c) microglia, (d) oligodendrocyte/oligodendrocyte precursor cell, (e) astrocyte, a me (f) blood-brain barrier (BBB) e hōʻike ana i nā pūnaeho endothelial, pericytes, pericytes. AD.
Ka nānā 'ana i nā pūnaewele Senescent
(1) Wehewehe a me nā ʻano o nā Pūnaewele Senescent
ʻO ka Senescence e pili ana i ka hopu ʻia ʻana o ka ulu ʻana o nā cell ma hope o ka loaʻa ʻana o kekahi mau māhele a i ʻole ka ʻike ʻia ʻana i nā kumu koʻikoʻi like ʻole (e like me ke koʻikoʻi oxidative, ka pōʻino DNA, ka pōkole telomere, etc.). Hōʻike nā pūnaewele Senescent i nā hiʻohiʻona phenotypic kū hoʻokahi, me ka hoʻonui ʻana i ka nui o ka cell cell, flattening, a me ka hana β-galactosidase (β-gal) kiʻekiʻe, ʻo ia ka mea i hoʻohana mau ʻia no ka ʻike ʻana i nā cell senescent. Hoʻohui hou, hōʻike nā cell senescent i ka hoʻoponopono ʻana o ka cyclin-dependent kinase inhibitors (e like me p16INK4a a me p21Cip1), ka mea e keʻakeʻa ai i ka holomua o ka pōʻai cell, e hoʻopaʻa ai i nā cell i ka pae G1 a i ʻole ka pae G2/M a ma laila e pale ai i ka mahele hou aʻe.
Mechanisms of Senescent Cell Formation
1. Oxidative Stress a me DNA Poino: Oxidative stress ka mea nui inducer o cellular senescence. Ma lalo o nā kūlana physiological maʻamau, ʻo ka hana ʻana a me ka hoʻomaʻemaʻe ʻana o nā ʻano oxygen reactive (ROS) i loko o nā cell i loko o ka equilibrium dynamic. Eia nō naʻe, me ka ʻelemakule a i ʻole ma lalo o kekahi mau kūlana pathological, hoʻonui ʻia ka hana ROS e alakaʻi i ka pōʻino DNA. Ke hōʻiliʻili ʻia ka pōʻino DNA a hiki ʻole ke hoʻoponopono maikaʻi ʻia, hoʻāla ʻia ke ʻano o nā ala hōʻailona, e like me nā ala hōʻailona p53-p21 a me p16-Rb, e koi ana i nā cell e komo i kahi kūlana kahiko. I loko o ka lolo mai nā maʻi maʻi o Alzheimer, ua hoʻokiʻekiʻe nui ʻia nā pae koʻikoʻi oxidative, e alakaʻi ana i ka hoʻonui ʻana i ka pōʻino DNA i nā neurons a me nā pūnaewele glial, kahi e hoʻoulu ai i ka senescence cellular.
2. Hoʻopōkole Telomere: He mau kaʻina DNA hou nā Telomeres ma nā wēlau o nā chromosomes e hoʻopōkole mālie ana me ka mahele pūlima. Ke hoʻopōkole ʻia nā telomeres i kekahi lōʻihi, hoʻomaka lākou i nā hōʻailona senescence. I loko o nā pūnaewele neural stem, pili pili ka pōkole telomere me ka hoʻomaka ʻana o ke oʻo, hiki ke hōʻino i ka hana hou a me ka hoʻokaʻawale ʻana o nā pūnaʻi neural stem, a laila e hoʻopilikia i ka hoʻomohala maʻamau a me ka hana o ka ʻōnaehana nerve.
ʻO ke ʻano o ka hana a nā Senescent Cells i ka maʻi o Alzheimer
(1) Hoʻokomo i ka Neuroinflammation
1. ʻO ke kuleana o ka Senescence-Associated Secretory Phenotype (SASP): Hōʻike nā pūnaewele Senescent i kahi hiʻohiʻona huna kūikawā i ʻike ʻia ʻo ka senescence-associated secretory phenotype (SASP). Loaʻa i ka SASP nā cytokines like ʻole, chemokines, nā kumu ulu, a me nā proteases, e like me interleukin-6 (IL-6), interleukin-8 (IL-8), a me tumor necrosis factor-α (TNF-α). I loko o ka lolo o ka poʻe maʻi maʻi o Alzheimer, huna nā pūnaewele glial senescent a me nā neurons i ka nui o nā kumu SASP, hiki ke hoʻoikaika i nā cell immune a puni a hoʻoulu i nā pane inflammatory mau. Hoʻoikaika ka IL-6 a me TNF-α i ka hoʻoulu ʻana o ka microglia, e hoʻohuli iā lākou mai kahi noho mālie a i kahi kūlana pro-inflammatory, e hoʻokuʻu ana i nā mea hoʻolaha inflammatory a hoʻonui i ka neuroinflammation. ʻO kēia kaiapuni inflammatory mau e hōʻino i nā neurons, hōʻino i ka hana synaptic, a alakaʻi i ka hana cognitive.
2. Nā hopena ma nā pūnaewele glial: ʻO kaʻelemakule o nā astrocytes a me ka microglia he mea nui i ka AD neuroinflammation. Hoʻopili nā astrocytes kahiko i nā mea SASP e hāpai ana i ka hōʻuluʻulu a me ka waiho ʻana o ka β-amyloid (Aβ) ʻoiai ke keʻakeʻa nei i kāna ʻae ʻana. ʻO ka ʻelemakule o ka microglia e hōʻemi i ko lākou hiki ke phagocytose Aβ, e pale ana i ka hoʻomaʻemaʻe maikaʻi ʻana o nā plaques Aβ i ka lolo. Akā, hoʻokuʻu lākou i nā mea inflammatory hou aʻe, e hana ana i kahi pōʻaiʻino e hoʻonui ai i ka neuroinflammation a me ka neurodegeneration.
Kiʻi 2 Hoʻonui ʻia nā hōʻailona o ka senescence cellular i ka lolo o ka hTau mice modeling tauopathy o AD.
(2) Hoʻolaha i ka Neurodegeneration
1. Poino pololei i nā neurons: Hiki i kekahi mau cytokines a me nā protease huna ʻia e nā pūnaewele kahiko ke hōʻino pololei i nā neurons. ʻO Matrix metalloproteinases (MMPs) kekahi o nā ʻāpana o ka senescence-associated secretome (SASP), hiki ke hoʻohaʻahaʻa i ka matrix extracellular a me nā protein e pili ana i ka neurotransmitter, e hoʻopau i ka hana a me ka hana o nā neurons. Hiki i ka ROS i hana ʻia e nā senescent cell ke hana i ka pōʻino oxidative i nā neurons, e alakaʻi ana i ka apoptosis neuronal a me ka make. I loko o ka lolo o nā maʻi maʻi AD, pili pili loa ka senescence neuronal me ka make cell, ʻo ia paha kekahi o nā kumu nui e hāʻawi i ka cognitive dysfunction.
2. Hoʻopilikia i ka hoʻouna ʻana o Neurotransmitter: ʻO ka hiki ʻana mai o nā cell senescent hiki ke hoʻopau i ka synthesis, hoʻokuʻu, a me ka lawe ʻana o nā neurotransmitters. Hiki i nā mea inflammatory ke kāohi i ka synthesis o acetylcholine, kahi neurotransmitter pono no ka mālama ʻana i ka hana cognitive maʻamau. Hoʻohui ʻia, hiki i kekahi mau mea huna e nā senescent cell ke hoʻopili i ka ʻōlelo a me ka hana o nā mea hoʻokipa neurotransmitter, e alakaʻi ana i ka hōʻailona neurotransmitter abnormal, e hoʻopilikia hou i ka kamaʻilio ʻana a me ka hoʻoili ʻana i ka ʻike ma waena o nā neurons, a ma laila e hoʻoulu ai i nā hemahema cognitive.
(3) Hoʻololi i ka ʻōlelo Intercellular
1. Hōʻailona Paracrine ʻAʻole: Ke kamaʻilio nei nā pūnaewele Senescent me nā keena a puni ma o ka hōʻailona paracrine ma ka huna ʻana i nā mea SASP. Hiki i kēia mau mea ke hoʻopili i ka hana a me ka hopena o nā pūnaewele kokoke, e alakaʻi ana i ka hoʻopau ʻana i ka ʻoihana kamaʻilio intercellular. I loko o ka lolo o nā maʻi maʻi AD, hiki i nā mea SASP i hūnā ʻia e nā senescent glial cell hiki ke hoʻopili i ka ulu ʻana o ka neuronal, ola, a me ka ʻokoʻa, ʻoiai e hoʻopili ana i ka microenvironment o nā pūnaewele neural stem, e kāohi ana i ko lākou hoʻonui a me ka ʻokoʻa, a laila e hoʻopilikia ai i ka neural regeneration a me nā kaʻina hana.
2. Hoʻopilikia i nā pilina pili waena: Hiki ke hoʻopau ʻia nā pūnaewele Senescent i nā hale pili waena, e like me nā junction paʻa a me nā hui āpau. I loko o ka pale koko-lolo, ʻo ka senescence o nā cell endothelial e alakaʻi i ka hōʻemi ʻana i ka hōʻike ʻana o nā protein junction paʻa, e hoʻonui ana i ka permeability o ka pale koko-lolo a me ka ʻae ʻana i nā mea ʻino e komo maʻalahi i ka lolo, e hoʻonui i ka neuroinflammation a me ka neurodegeneration. He mea koʻikoʻi nā hui āpau ma waena o nā neurons no ka hoʻouna ʻana i nā hōʻailona uila a me ka hoʻonohonoho metabolic ma waena o nā neurons. Hiki i nā mea i hūnā ʻia e nā senescent cell ke hoʻopau i ka hana o nā junction gap, e pili ana i ka hana synchronized a me ka hoʻouna ʻana i ka ʻike ma waena o nā neurons.
(4) Nā hopena i ka microenvironment o nā pūnaewele neural stem
1. Ka pale ʻana i ka hoʻonui ʻana a me ka hoʻokaʻawale ʻana o nā neural stem cell: Aia nā pūnaewele neural stem i loko o ka lolo o nā mammals makua a loaʻa iā ia ka hiki ke hoʻololi iā ia iho a hoʻokaʻawale i nā neurons, astrocytes, a me oligodendrocytes. Hiki i nā mea SASP i hūnā ʻia e nā senescent cell ke hoʻololi i ka microenvironment o nā neural stem cell, e kāohi ana i ko lākou hoʻonui a me ka ʻokoʻa. Hiki i kekahi mau cytokines i SASP ke hoʻoponopono i ka hōʻike ʻana o ka cyclin-dependent kinase inhibitors, e hoʻopiʻi i nā pūnaewele neural stem e hopu i nā pae kikoʻī o ka pōʻai cell a hiki ʻole ke hana i ka mahele maʻamau a me ka ʻokoʻa. Hiki ke hoʻopili ʻia nā mea ʻaʻa i huna ʻia e nā senescent cell i ke kuhikuhi ʻokoʻa o nā pūnaewele neural stem, e hoʻokaʻawale iā lākou i loko o nā pūnaewele glial ma mua o nā neurons, a laila e hoʻopilikia ai i ka neural regeneration a me ka hoʻoponopono.
2. Ka hopena ma ka neural stem cell migration: Neural stem cell migration he mea koʻikoʻi no ko lākou localization kūpono a me ka hana hana i loko o ka lolo. Hiki ke hoʻopilikia i kekahi mau mea i huna ʻia e nā cell senescent i ka neural stem cell migration, e pale ana iā lākou mai ka neʻe ʻana i nā wahi e pono ai ka hoʻoponopono. Hiki ke hoʻololi i ka ʻōlelo maʻamau o nā chemokines i ka neʻe ʻana o nā neural stem cell, e pale ana iā lākou mai ka hōʻea ʻana i ke kahua o ka hōʻeha no ka hoʻoponopono ʻana, a laila e hoʻopilikia ai i ka hiki ke hoʻoponopono iā ia iho.
ʻO nā hoʻolālā lapaʻau maʻi o Alzheimer e huli ana i nā cell senescent
(1) Senolytics
1. Mechanism of action: ʻO Senolytics kahi papa o nā pūhui i hiki ke hoʻopau koho i nā cell senescent. ʻO kā lākou hana o ka hana ʻo ia ka hoʻoulu ʻana i ka apoptosis cell senescent a me ka pale ʻana i nā ala hōʻailona anti-apoptotic cell senescent. ʻO Dasatinib a me quercetin i kēia manawa ka hui pū ʻana o nā senolytics. Hiki i ka Dasatinib ke kāohi i nā ala hōʻailona kinase overactivated i nā cell senescent, aʻo ka quercetin e hoʻonui i nā hopena o dasatinib. Ke hoʻohana pū ʻia, hiki iā lākou ke hoʻoulu i ka apoptosis i loko o nā cell senescent a hoʻemi i kā lākou hōʻiliʻili ʻana i ke kino.
2. Ka holomua i nā hoʻokolohua holoholona a me nā noiʻi lāʻau lapaʻau: Ma nā hoʻokolohua holoholona, ʻo ka mālama ʻana i nā mice model AD me nā mea hoʻomaʻemaʻe cell senescent i hoʻemi nui i ka helu o nā senescent cell i loko o ka lolo, hoʻohaʻahaʻa i nā pae neuroinflammation, a hoʻomaikaʻi i ka hana cognitive. Ua ʻike nā haʻawina ma hope o ka lawelawe ʻana i ka dasatinib a me ka quercetin hui ʻana i nā ʻiole AD, ua emi ka nui o nā pā Aβ i loko o ka lolo, ua hoʻemi ʻia ka pōʻino neuronal, a ua hoʻomaikaʻi ʻia ke aʻo ʻana a me ka hoʻomanaʻo.
Kiʻi 3 ʻO ke ola kino o ke kelepona ma ke ʻano he ʻāpana o ka ʻelemakule olakino a me AD.
(2) Nā mea hoʻololi phenotype huna e pili ana i ka Senescence (Senomorphics)
1. Mechanism of action: Ke manaʻo nei ʻo Senomorphics e hoʻoponopono i ka huna ʻana o nā mea SASP e nā senescent cell, e hōʻemi ana i kā lākou hopena ʻino i nā cell a puni. Hiki i kekahi mau lāʻau anti-inflammatory ke kāohi i ka hōʻike a me ka huna ʻana o nā mea inflammatory i SASP, e hoʻēmi ana i ka neuroinflammation. Hiki i kekahi mau pūhui mole liʻiliʻi ke hoʻoponopono i nā ala metabolic o nā cell senescent, e hoʻololi ana i ka haku ʻana o SASP e hoʻonāwaliwali i kāna mau hopena pōʻino i nā cell a puni.
2. Nā Manaʻo Hoʻohana Pono: ʻO ka maikaʻi o nā modulators secretory phenotype modulators pili i ka senescence i ko lākou hiki ke hoʻomaikaʻi i ka microenvironment tissue ma o ka hoʻoponopono ʻana i ka hana huna o nā cell senescent ma mua o ka hoʻopau pololei ʻana iā lākou. Hiki i kēia ke pale aku i kekahi mau pilikia e pili ana i nā mea hoʻomaʻemaʻe cell senescent, e like me ka pōʻino kikoʻī ʻole i nā cell maʻamau. No laila, paʻa nā modulators secretory phenotype modulators e pili ana i ka senescence i nā manaʻo noiʻi ākea a hiki ke kū mai ma ke ʻano he hoʻolālā therapeutic hou no AD.
Ka hopena
ʻO nā pūnaewele Senescent ka hana nui i ka hoʻomaka a me ka holomua o ka maʻi o Alzheimer. Ma o nā hana e like me ka hoʻoulu ʻana i ka neuroinflammation, ka hoʻoulu ʻana i ka neurodegeneration, ka hoʻololi ʻana i ke kamaʻilio intercellular, a me ka hoʻoulu ʻana i ka microenvironment o nā pūnaewele neural stem, nā cell senescent e hoʻonui i ke kaʻina pathological o AD. ʻO nā hoʻolālā lāʻau lapaʻau e kuhikuhi ana i nā cell senescent, e like me ka hoʻomohala ʻana i nā mea hoʻomaʻemaʻe cell senescent a me nā modulators secretory phenotype modulators pili i ka senescence, e hāʻawi i nā koho hou no ka mālama ʻana iā AD.
Nā kumu
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