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.
ʻO kaʻelemakule, ma keʻano he kaʻina hana kūlohelohe i nā mea ola, ua lōʻihi ke kumu o ka noiʻiʻepekema. Ma ke ʻano o ka makahiki o nā mea ola, komo mālie nā cell i kahi kūlana oʻo, a hiki i ka hōʻiliʻili ʻana o kēia mau senescent cell ke hoʻopilikia maikaʻi ʻole i ka hana maʻamau o nā ʻiʻo a me nā kino, e alakaʻi ana i nā maʻi like ʻole. FOX04 - Pono ka DRI no ka hoʻomaʻemaʻeʻana i nā pūnaewele senescent.
Nānā o FOX04 - DRI
ʻO FOX04 - DRI kahi peptide synthetic, me ka pahu poʻo fork piha piha O transcription factor 4 - D - Retro - Inverso. Loaʻa kona ʻike ʻia mai ka noiʻi hohonu ʻana i nā hana hoʻoponopono o nā cell senescent. I ka wā o ka cellular senescence, nui nā mīkini molecular i komo, a ʻo ka FOX04 transcription factor ke kuleana nui i kēia kaʻina hana. Hōʻike ʻo FOX04 i nā hiʻohiʻona hōʻike kikoʻī a me nā loli hana i nā cell senescent. Ma ka wehewehe ʻana i kāna ʻano hana, ua hoʻolālā a hoʻohui nā ʻepekema i ka FOX04-DRI e kuhikuhi pono i nā cell senescent, me ka manaʻo e hoʻoponopono i nā pilikia pili makahiki.
Kiʻi 1 Hōʻike kiʻi kiʻi o ka hoʻopau ʻana i nā fibroblasts senescent lung senescent i ka uahi paka me ka hoʻohana ʻana i nā nanoparticles DNA i hoʻokomo ʻia ʻo FOXO4 siRNA.
Mechanism o FOX04-DRI i ka hoʻomaʻemaʻe ʻana i nā cell senescent
Hoʻopilikia me ka launa pū ʻana o FOX04-p53: I loko o nā cell senescent, pili ʻo FOX04 me ka protein p53. He koʻikoʻi ka p53 protein i ka pane ʻana i ke koʻikoʻi o ka cellular, ka hoʻoponopono ʻana i ka pōʻai cell, a me ka apoptosis. Ma lalo o nā kūlana maʻamau, hoʻolaha ka p53 i ka apoptosis i loko o nā pūnaewele i hōʻino ʻia a i ʻole nā senescent ma o ka hoʻoulu ʻana i ka hōʻike ʻana o ke ʻano o nā genes pili i ka apoptosis, a laila e mālama ai i ke olakino o ka heluna cell. I loko o nā cell senescent, hoʻopaʻa ʻo FOX04 i ka p53, e kāohi ana i kāna lawe ʻana i ka nucleus cell, e pale ana i ka p53 mai ka hana ʻana i kāna hana pro-apoptotic, e hopena i ke ola a me ka hōʻiliʻili ʻana o nā cell senescent. Hiki i ka FOX04-DRI ke hoʻopili pono i kēia pilina ma waena o FOX04 a me p53, e ālai ana i kā lākou hoʻopaʻa ʻana, e ʻae ana i ka p53 e hoʻokomo hou i ka nucleus cell, hoʻāla i ke ala hōʻailona apoptosis, a hoʻoulu i ka apoptosis i loko o nā cell senescent, a laila e loaʻa ai ka hoʻomaʻemaʻe o nā cell senescent.
Hoʻoponopono i nā ala hōʻailona intracellular: Ma waho aʻe o ka hoʻopili ʻana i ka pilina FOX04-p53, hiki i ka FOX04-DRI ke hoʻololi i ka hopena o nā cell senescent ma o ka hoʻoponopono ʻana i nā ala hōʻailona intracellular ʻē aʻe. ʻO ke ala hōʻailona PI3K/AKT he kuleana koʻikoʻi koʻikoʻi i nā ʻano like ʻole o ka ulu ʻana o ka cell, proliferation, ola, a me ka metabolism. Ua hōʻike ʻia nā haʻawina e hoʻololi pinepine ʻia ka hana o ke ala hōʻailona PI3K/AKT i nā cell senescent, e pili ana i kā lākou mau hana maʻamau. Hiki i ka FOX04-DRI ke hoʻoponopono i ka hana o ke ala hōʻailona PI3K / AKT, e hoʻololi i ke koena o ka transduction hōʻailona i loko o nā cell senescent, a laila e hana i kahi ʻano intracellular maikaʻi ʻole no ko lākou ola ʻana a me ka hoʻoulu ʻana i ka apoptosis. Hiki i ka hoʻoponopono ʻana i kēia ala hōʻailona ke hoʻoikaika i nā mokuʻāina metabolic cellular, e hoʻohuli hou i nā cell senescent i ka apoptosis.
ʻO ka hopena ma ka Senescence-Associated Secretory Phenotype (SASP): Hoʻopili nā pūnaewele Senescent i ke ʻano o nā cytokines, chemokines, a me nā proteases, e hana ana i ka senescence-associated secretory phenotype (SASP). ʻAʻole hoʻopilikia wale ʻo SASP i nā mea maʻamau a puni, e hoʻopau i kā lākou mau hana maʻamau, akā hoʻoulu pū kekahi i nā pane inflammatory mau, e hoʻolōʻihi i ke kaʻina hana o nā ʻiʻo a me nā kino. Hiki i ka FOX04-DRI ke hoʻēmi i nā hopena ʻino o nā cell senescent ma ka microenvironment a puni ma ke kāohi ʻana i ka hōʻike a me ka huna ʻana o nā mea pili i ka SASP i nā cell senescent. I loko o ke aʻo ʻana, ua ʻike ʻia ma hope o ka mālama ʻana i nā cell senescent me FOX04-DRI, ua hoʻemi nui ʻia nā pae hōʻike o nā mea pili i ka SASP e like me IL-1α, IL-1β, tumor necrosis factor α (TNFα), a me MMP2 i nā cell senescent. Hōʻike kēia e hiki i ka FOX04-DRI ke hoʻoponopono pono i ka SASP o nā cell senescent, hoʻomaikaʻi i ka microenvironment cellular, a hoʻoikaika ʻole i ka hoʻomaʻemaʻe ʻana o nā cell senescent a me ka hoʻihoʻi ʻana o ka microenvironment tissue.
ʻO ke kuleana o FOX04-DRI i nā ʻāpana like ʻole a me nā maʻi
Hana i loko o ka Pūnaehana Reproductive: ʻO ka hypogonadism hoʻomaka ʻana o ke kāne he maʻi e pili ana i ka makahiki nona ka hana koʻikoʻi o ka hana ʻole o nā pūnaewele interstitial testicular kahiko. Hōʻike ʻia ʻo FOX04 i loko o nā cell testicular interstitial kanaka, a i ka poʻe ʻelemakule, pili ka translocation nuklea o FOX04 me ka hoʻohaʻahaʻa testosterone synthesis. Ke hoʻohana nei i ka hydrogen peroxide-induced kahiko TM3 testicular interstitial cell ma ke ʻano he in vitro model, ua ʻike ʻia e hiki i ka FOX04 ke mālama i ka hiki ʻana o nā cell testicular interstitial kahiko a kāohi i kā lākou apoptosis. FOX04-DRI koho i ka p53 nuclear export a me ka apoptosis o na kahiko testicular interstitial cell ma ka hoopau ana i ka pilina FOX04-p53. I loko o kahi ʻano ʻiole kahiko kahiko, hoʻomaikaʻi ka hoʻokele ʻana o FOX04-DRI i ka microenvironment testicular a hoʻopau i ka hemahema o ka testosterone huna i ka makahiki. No laila, pono paha ka FOX04-DRI no ka mālama ʻana i ka hypogonadism male hope loa.
Kiʻi 2 Hōʻike o FOXO4 i nā hōʻike kanaka i ʻike ʻia e ka immunofluorescent staining.
Ke kuleana ma ka ʻōnaehana hanu
Pulmonary fibrosis: ʻO ka pulmonary fibrosis (PF) kahi maʻi maʻi maʻi interstitial holomua. Hoʻonui ʻia kona maʻi a me ka hoʻonui ʻana i ka makahiki, a ua manaʻo ʻia ka senescence cellular ʻo ia kekahi o nā kumu alakaʻi nui i kāna pathogenesis. I loko o ka bleomycin (BLM) -induced PF kiʻiʻiole, FOX04-DRI hōʻike i nā hopena like me ka pirfenidone lāʻau lapaʻau i ʻāpono ʻia. Hoʻemi ia i ka helu o nā senescent cell, hoʻohaʻahaʻa i ka hōʻike o ka senescence-associated secretory phenotype (SASP), a hoʻohaʻahaʻa i nā loli morphological i hoʻokomo ʻia e BLM a me ka waiho ʻana o ka collagen i loko o ka ʻiʻo māmā. Hoʻohui ʻia, hoʻonui ʻo FOX04-DRI i ka hapa o ke ʻano 2 alveolar epithelial cell (AEC2) a me nā fibroblasts ʻoiai e hoʻemi ana i ka nui o nā myofibroblasts. Ua hōʻike ʻia nā hoʻokolohua in vitro i ka hoʻohālikelike ʻia me nā laina kelepona fibroblast ʻiole a me ka māmā o ke kanaka, ua ʻoi aku ka makemake o FOX04-DRI e pepehi i ka hoʻololi ʻana o ka ulu ʻana o ka myofibroblasts (TGF-β) -induced myofibroblasts, a ma ke kāohi ʻana i nā myofibroblasts, ua alakaʻi ia i ka downregulation o extracellular matrix (ECM) nā ala pili i ka PF i hoʻokomo ʻia i BLM-induced.
ʻO ka maʻi pulmonary obstructive Chronic obstructive pulmonary (COPD): ʻO ka pathogenesis a me ka piʻi ʻana o COPD pili pili loa me ka cellular senescence. I loko o nā fibroblast pulmonary senescent i ka uahi paka, ua hoʻokiʻekiʻe ʻia ka ʻōlelo FOX04. No ka hoʻohaʻahaʻa ʻana i ka FOX04 i loko o nā fibroblasts senescent, ua hoʻolālā ʻia a hoʻohui ʻia ʻo DNA nanotubes (siFOXO4-NT) i hoʻopiha ʻia me ka FOX04 siRNA. Ua hōʻike ʻia nā haʻawina e hiki i ka siFOXO4-NT ke komo i nā fibroblasts lung kanaka (HFL-1 cell) ma ke ʻano o ka hoʻopaʻa ʻana a me ka hilinaʻi o ka manawa, a laila e hōʻemi ana i nā pae FOX04 in vitro. Hoʻopau koho ʻo siFOXO4-NT i nā pūnaewele HFL-1 kahiko ma o ka hōʻemi ʻana i ka hōʻike BCLXL kiʻekiʻe a me ka ratio BCL2/BAX i loko o nā pūnaewele HFL-1 kahiko.
Ke kuleana i loko o ka ʻiʻo cartilage: Autologous chondrocyte implantation (ACI) kahi ala no ka mālama ʻana i ka pōʻino o ka cartilage a me ka pale ʻana i ka osteoarthritis post-traumatic. I ka wā o ka hoʻonui in vitro o nā chondrocytes, kahi hana e pono ai i ka ACI, hana ʻia nā cell senescent, kahi hopena maikaʻi ʻole i ka maikaʻi a me ka nui o ka cartilage i hana hou ʻia. Ua manaʻo ka poʻe noiʻi e hiki i ka lāʻau FOX04-DRI ke wehe i nā cell senescent mai nā chondrocytes i hoʻonui ʻia, a laila e hoʻonui ai i ko lākou hiki ke hana i ka cartilage kiʻekiʻe. No ka hoʻohālikelike ʻana i ke kaʻina hana hoʻonui in vitro ma ACI, ua hoʻonui ʻia nā chondrocytes i hoʻokaʻawale ʻia mai nā mea hāʻawi olakino i ka helu pālua pālua (PDL) 9, e hōʻike ana i nā chondrocytes mākaukau no ka hoʻokomo ʻana, aʻo nā cell ma PDL3 i lawelawe ma ke ʻano he mana hoʻonui liʻiliʻi. Hōʻike nā hualoaʻa ua wehe ʻia ka lāʻau lapaʻau FOX04-DRI ma luna o ka hapalua o nā cell ma PDL9 akā ʻaʻohe hopena koʻikoʻi i ka helu o nā chondrocytes PDL3. ʻO ka pae senescence o PDL9 chondrocytes i mālama ʻia me FOX04-DRI ua hoʻemi nui ʻia. Ma muli o nā hopena moʻomeheu micro-cluster maʻamau, FOX04-DRI pretreatment ʻaʻole i hoʻonui i ka chondrogenic hiki o PDL9 chondrocytes, akā chondroid kiko i loaʻa mai FOX04-DRI-pretreatment PDL9 mau hōʻike hōʻike haʻahaʻa o nā mea huna e pili ana i ka wā kahiko. Ua wehe pono ʻo FOX04-DRI i nā cell senescent mai nā chondrocytes PDL9.
Ke kuleana i loko o ka radiation-induced pulmonary fibrosis (RIPF): ʻO ka RIPF kahi pilikia maʻamau a paʻakikī hoʻi ma hope o ka radiotherapy tumor thoracic. Ua hoʻokaʻawale ʻia nā ʻiole C57BL/6 i ka irradiation a me ka irradiation + FOX04-DRI pūʻulu, me ka hemithorax kūpono o kēlā me kēia hui e loaʻa ana i ka 17 Gy X-ray irradiation. ʻO ka hui FOX04-DRI a me ka irradiation + FOX04-DRI hui pūʻulu i lawelawe ʻia ʻo FOX04-DRI ma o intraperitoneal injection i nā wiki 16 a me 20 post-irradiation. Ua hōʻike nā hualoaʻa ua hoʻemi ʻo FOX04-DRI i ka waiho ʻana o ka collagen i loko o ka ʻiʻo māmā o nā ʻiole RIPF, hoʻemi i ka hōʻike ʻana o col1α1 a me α-SMA, a ua hoʻemi i ka helu o nā β-galactosidase (β-gal) mau mea maikaʻi (he hōʻailona o nā pūnaewele senescent) i loko o ka ʻiʻo māmā. Ua hiki iā FOX04-DRI ke kāohi i ka hōʻike ʻana o nā genes P21 a me P16 ^ (Ink4a) a me nā protein i loko o ka ʻiʻo māmā o nā ʻiole RIPF, a me ka hōʻike ʻana o nā genes SASP IL-1α, IL-1β, tumor necrosis factor α (TNFα), a me MMP2. Hoʻemi pū ʻo FOX04-DRI i nā kiʻekiʻe o nā ʻano oxygen reactive (ROS) i loko o ka ʻiʻo māmā o nā ʻiole RIPF a paipai i ka hoʻoulu ʻana o nā protein p-AKT a me p-PI3K. Hōʻike kēia e hōʻemi ʻo FOX04-DRI i ke koʻikoʻi oxidative a keʻakeʻa i ka senescence cellular ma o ka hoʻāla ʻana i ke ala hōʻailona PI3K/AKT, a laila hoʻohuli i ka RIPF.
Kiʻi 3 FOXO4-DRI hoʻohaʻahaʻa i ka ʻokoʻa myofibroblast i nā ʻiole PF i hoʻokomo ʻia e BLM.
Ka hopena
I ka hōʻuluʻulu ʻana, ʻo FOX04-DRI, ma ke ʻano he lāʻau hoʻololi i hiki ke hoʻopau pono i nā cell senescent, he hana koʻikoʻi i ka mālama ʻana i nā maʻi pili makahiki a me ka hana ʻelemakule.
Nā kumu
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[2] Han X, Yuan T, Zhang J, a me al. ʻO ka FOXO4 peptide e hoʻopaʻa i ka myofibroblast e hoʻomaikaʻi i ka bleomycin-induced pulmonary fibrosis i nā ʻiole ma o ka ECM-receptor interaction pathway [J]. Nūpepa o ka Cellular and Molecular Medicine, 2022,26(11):3269-3280.DOI:10.1111/jcmm.17333.
[3] Huang Y, He Y, Makarcyzk MJ, et al. Hoʻopau koho ʻo Senolytic Peptide FOXO4-DRI i nā Selescent Senescent mai ka in vitro Hoʻonui ʻia nā Chondrocytes kanaka [J]. Frontiers in Bioengineering and Biotechnology, 2021,9:677576.DOI:10.3389/fbioe.2021.677576.
[4] Zhang C, Xie Y, Chen H, et al. Hoʻopau ʻo FOXO4-DRI i ka lawa ʻole o ka testosterone huna e pili ana i ka makahiki ma o ka huli ʻana i nā cell senescent Leydig i nā ʻiole kahiko [J]. ʻO ka ʻelemakule (Albany Ny), 2020,12(2):1272-1284.DOI:10.18632/ʻelemakule.102682.
[5] Baar M P. DNA Damage Induced Cell Fates during Aging, 2019[C]. https://api.semanticscholar.org/CorpusID:196682180
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