Na Cocer Peptides 
ukwezi gushize
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.
Gusaza, nkibikorwa byanze bikunze mubinyabuzima bizima, bimaze igihe kinini byibandwaho mubushakashatsi bwa siyansi. Mugihe ibinyabuzima bigenda bisaza, selile zinjira buhoro buhoro muri senescent, kandi kwirundanya kwingirabuzimafatizo bishobora kugira ingaruka mbi kumikorere isanzwe yimitsi ningingo, biganisha ku ndwara zitandukanye ziterwa nimyaka. FOX04 - DRI ni ingirakamaro mu gukuraho selile.
Incamake ya FOX04 - DRI
FOX04 - DRI ni peptide ikomatanya, hamwe nizina ryuzuye ryumutwe agasanduku O ibintu byandikirwa 4 - D - Retro - Inverso. Ivumburwa ryayo rituruka kubushakashatsi bwimbitse muburyo bwo kugenzura ingirabuzimafatizo. Mugihe cya senescence ya selile, uburyo bwinshi bwa molekuline burimo, kandi ibintu byandikirwa FOX04 bigira uruhare runini muriki gikorwa. FOX04 yerekana uburyo bwihariye bwo kwerekana imiterere nimpinduka zikorwa muri selile. Mugusobanura uburyo bwibikorwa byayo, abahanga bashushanyije kandi bashushanya FOX04-DRI kugirango bagabanye cyane ingirabuzimafatizo za senescent, bagamije gukemura ibibazo bijyanye nimyaka.
Igishushanyo 1 Igishushanyo cyerekana kurandura itabi ryatewe na senescent ibihaha fibroblast ukoresheje FOXO4 siRNA yuzuye ADN nanoparticles.
Mechanism ya FOX04-DRI mugukuraho selile
Kwivanga no gukorana kwa FOX04-p53: Muri selile senescent, FOX04 ikorana na proteine ya p53. Poroteyine ya p53 igira uruhare runini mugukemura ibibazo bya selile, kugenzura ingirabuzimafatizo, na apoptose. Mubihe bisanzwe, p53 itera apoptose mungirangingo zangiritse cyangwa za senescent mukugaragaza imvugo ya genes zijyanye na apoptose, bityo bikomeza ubuzima bwabaturage. Mu ngirabuzimafatizo za senescent, FOX04 ihuza p53, ikabuza gutwara muri nucleus selile, ikabuza p53 gukora imikorere yayo ya apoptotique, bikavamo kubaho no kwirundanya kwingirabuzimafatizo. FOX04-DRI irashobora kubangamira byimazeyo imikoranire hagati ya FOX04 na p53, ikabuza guhuza kwabo, kwemerera p53 kongera kwinjira muri nucleus selile, gukora inzira yerekana ibimenyetso bya apoptose, no gutera apoptose mumasemburo ya senescent, bityo bikagera kumasemburo ya selile.
Amabwiriza yinzira yerekana ibimenyetso: Usibye kubangamira imikoranire ya FOX04-p53, FOX04-DRI irashobora kandi guhindura iherezo ryingirabuzimafatizo za senescent mugutegeka izindi nzira zerekana ibimenyetso. Inzira yerekana PI3K / AKT igira uruhare runini mugutegeka mubice bitandukanye byo gukura kwingirabuzimafatizo, gukwirakwizwa, kubaho, hamwe na metabolism. Ubushakashatsi bwerekanye ko ibikorwa bya PI3K / AKT byerekana inzira akenshi bihindurwa muri selile senescent, bigira ingaruka kumikorere yabo isanzwe. FOX04-DRI irashobora kugenga ibikorwa byinzira ya signal ya PI3K / AKT, igahindura uburinganire bwikwirakwizwa ryibimenyetso mu ngirabuzimafatizo za senescent, bityo bigatuma habaho ibidukikije bitameze neza kugirango bibeho kandi bitera apoptose. Kugenzura iyi nzira yerekana ibimenyetso bishobora no guhindura imiterere ya selile ya metabolike, bikomeza gutwara ingirabuzimafatizo zigana apoptose.
Ingaruka kuri Senescence-Associated Secretory Phenotype (SASP): Utugingo ngengabuzima twa Senescent turekura urukurikirane rwa cytokine, chemokine, na protease, bikora senescence ifitanye isano na senescence yibanga (SASP). SASP ntabwo igira ingaruka mbi gusa ku ngirabuzimafatizo zisanzwe, ihagarika imikorere yabo isanzwe, ahubwo inatera ibisubizo bidakira, bikarushaho kwihuta gusaza kw'imitsi n'ingingo. FOX04-DRI irashobora kugabanya ingaruka mbi zingirabuzimafatizo za senescent ku bidukikije bikikije ibidukikije mu guhagarika imvugo no gusohora ibintu bifitanye isano na SASP mu ngirabuzimafatizo. Mu bushakashatsi, bwagaragaje ko nyuma yo kuvura ingirabuzimafatizo za senescent hamwe na FOX04-DRI, urwego rwo kwerekana ibintu bifitanye isano na SASP nka IL-1α, IL-1β, ikibyimba cya nekrosis α (TNFα), na MMP2 mu ngirabuzimafatizo za senescent cyaragabanutse cyane. Ibi byerekana ko FOX04-DRI ishobora kugenzura neza SASP yingirangingo za senescent, igateza imbere mikorobe ya selile, kandi igateza imbere mu buryo butaziguye ingirabuzimafatizo ya senescent no kugarura ibidukikije bya tissue.
Uruhare rwa FOX04-DRI mu ngingo zitandukanye n'indwara
Uruhare muri sisitemu yimyororokere: Umugabo utinze-gutangira hypogonadism nindwara ijyanye nimyaka, uburyo bwibanze ni imikorere mibi yingirabuzimafatizo zishaje. FOX04 igaragarira cyane mu ngirabuzimafatizo ya muntu, kandi mu bageze mu za bukuru, guhinduranya ingufu za kirimbuzi FOX04 bifitanye isano no kugabanya testosterone. Hifashishijwe hydrogène peroxide iterwa na TM3 ya testicular interstitial selile nka vitro ya vitro, byagaragaye ko FOX04 ishobora gukomeza kubaho kwingirabuzimafatizo zashaje kandi ikabuza apoptose. FOX04-DRI itoranya guhitamo p53 yoherejwe na kirimbuzi hamwe na apoptose yingirabuzimafatizo zishaje zahagaritse guhagarika imikoranire ya FOX04-p53. Muburyo busanzwe bwo gusaza bwimbeba, ubuyobozi bwa FOX04-DRI bwateje imbere mikorobe ya testicular kandi bigabanya ibura rya testosterone. Kubwibyo, FOX04-DRI irashobora kuba ingirakamaro mukuvura hypogonadism yumugabo yatinze.
Igishushanyo 2 Kugaragaza FOXO4 mubizamini byabantu byagaragaye na immunofluorescent yanduye.
Uruhare muri sisitemu y'ubuhumekero
Fibrosis yo mu bihaha: Fibrosis yo mu bihaha (PF) ni indwara y'ibihaha igenda itera imbere. Ubwiyongere bwayo nubwiyongere bwayo uko imyaka igenda ishira, kandi senescence ya selile ifatwa nkimwe mubintu byingenzi bitera indwara. Muri bleomycine (BLM) -yerekana imbeba ya PF yimbeba, FOX04-DRI yerekanye ingaruka zisa niz'ibiyobyabwenge byemewe na pirfenidone. Igabanya umubare w'utugingo ngengabuzima twa senescent, igabanya imvugo ya senescence ifitanye isano na fenotype y'ibanga (SASP), ikanagabanya impinduka ziterwa na BLM iterwa na morphologie hamwe na kolagen yinjira mu ngingo y'ibihaha. Byongeye kandi, FOX04-DRI yongerera igipimo cyubwoko bwa 2 alveolar epithelial selile (AEC2) na fibroblast mugihe igabanya umubare wa myofibroblast. Mu bushakashatsi bwa vitro bwerekanye ko ugereranije n'imbeba na fibroblast ya selile y'ibihaha y'abantu, FOX04-DRI yari ifite ubushake bwo kwica ibintu bikura bikura-β (TGF-β) -yatewe na myofibroblast, kandi mu guhagarika myofibroblast, byatumye habaho kugabanuka kwa matrice idasanzwe yo mu bwoko bwa ECM).
Indwara idakira ifata ibihaha (COPD): Indwara ya COPD niterambere rya COPD bifitanye isano rya bugufi na senescence selile. Mu itabi riterwa na senescent pulmonary fibroblast, imvugo ya FOX04 irashyizwe hejuru. Gukomanga FOX04 muri fibroblast ya senescent, kwishyiriraho ADN nanotubes (siFOXO4-NT) yuzuye FOX04 siRNA imwe imwe yarateguwe kandi irashushanya. Ubushakashatsi bwerekanye ko siFOXO4-NT ishobora kwinjira muri fibroblast yumuntu (HFL-1 selile) muburyo bwo kwibanda hamwe nigihe, bityo bikagabanya urugero rwa FOX04 muri vitro. siFOXO4-NT itoranya ikuraho ingirabuzimafatizo za HFL-1 igabanya imvugo ya BCLXL ihanitse hamwe na BCL2 / BAX mu gipimo cy’umwotsi w’itabi (CSE) -kuyobora ingirabuzimafatizo za HFL-1.
Uruhare mumyanya ya karitsiye: Gutera Autologous chondrocyte (ACI) nuburyo bwo kuvura ibyangiritse hamwe no kwirinda osteoarthritis nyuma yo guhahamuka. Mugihe cyo kwagura vitro ya chondrocytes, intambwe ikenewe muri ACI, selile senescent irabyara, bigira ingaruka mbi kumiterere nubunini bwa karitsiye nshya. Abashakashatsi bavuze ko kuvura FOX04-DRI bishobora kuvana ingirabuzimafatizo za chondrocytes zagutse, bityo bikongerera ubushobozi bwo kubyara karitsiye nziza. Kugereranya uburyo bwo kwagura vitro muri ACI, chondrocytes zitandukanijwe n’abaterankunga bazima zaguwe kugeza ku ncuro ebyiri (PDL) 9, zerekana chondrocytes ziteguye gushyirwaho, mu gihe selile zo muri PDL3 zagize uruhare runini mu kwaguka. Ibisubizo byerekanye ko ubuvuzi bwa FOX04-DRI bwakuyeho kimwe cya kabiri cya selile kuri PDL9 ariko nta ngaruka nini zagize ku mubare wa chondrocytes ya PDL3. Urwego rwa senescence ya PDL9 chondrocytes ivurwa na FOX04-DRI yagabanutse cyane. Hashingiwe ku bisubizo by’umuco bisanzwe bya micro-cluster, kwitegura kwa FOX04-DRI ntabwo byongereye ubushobozi bwa chondrogeneque ya PDL9 ya chondrocytes, ariko ingirangingo ya chondroid ikomoka kuri selile FOX04-DRI-yakozwe na PDL9 yerekanaga imvugo yo hasi yibintu bifitanye isano no gusaza. FOX04-DRI yakuye neza selile ya senescent muri PDL9 chondrocytes.
Uruhare mumirasire iterwa na fibrosis yimpyisi (RIPF): RIPF nikibazo gisanzwe kandi gikomeye nyuma ya thoracic tumor radiotherapi. Imbeba C57BL / 6 zagabanijwe kubice mumirasire no kurasa + FOX04-DRI, hamwe na hemithorax iburyo ya buri tsinda yakira 17 Gy X-ray. Itsinda rya FOX04-DRI hamwe na irrasiyo + Imbeba zo mu matsinda FOX04-DRI zahawe FOX04-DRI hakoreshejwe inshinge za intraperitoneal mu byumweru 16 na 20 nyuma ya irrasiyo. Ibisubizo byerekanye ko FOX04-DRI yagabanije kwibika kwa kolagen mubice by ibihaha byimbeba za RIPF, bigabanya imvugo ya col1α1 na α-SMA, kandi bigabanya umubare wa β-galactosidase (β-gal) selile nziza (ikimenyetso cya selile senescent) mubice byamahaha. FOX04-DRI yashoboye kubuza imvugo ya P21 na P16 ^ (Ink4a) ingirabuzimafatizo hamwe na poroteyine mu ngingo z’ibihaha z’imbeba za RIPF, ndetse no kwerekana ingirabuzimafatizo za SASP IL-1α, IL-1β, ikibyimba cya niyose ya α (TNFα), na MMP2. FOX04-DRI igabanya kandi ubwoko bwa ogisijeni ikora (ROS) mu bice by'ibihaha by'imbeba za RIPF kandi bigatera gukora poroteyine za p-AKT na p-PI3K. Ibi byerekana ko FOX04-DRI igabanya imbaraga za okiside kandi ikabuza senescence ya selile ukoresheje inzira yerekana ibimenyetso bya PI3K / AKT, bityo igahindura RIPF.
Igishushanyo cya 3 FOXO4-DRI igabanya itandukaniro rya myofibroblast mu mbeba za PF zatewe na BLM.
Umwanzuro
Muri make, FOX04-DRI, nkumuti wimpinduramatwara ushobora kurandura byimazeyo ingirabuzimafatizo, ugira uruhare runini mukuvura indwara ziterwa nimyaka no gutabara.
Inkomoko
[1] Han Y, Wu Y, He B, n'abandi. ADN nanoparticles yibasira FOXO4 itoranya ikuraho itabi iterwa na senescent ibihaha fibroblast [J]. Iterambere rya Nanoscale, 2023,5 (21): 5965-5973.DOI: 10.1039 / d3na00547j.
[2] Han X, Yuan T, Zhang J, n'abandi. FOXO4 peptide yibasira myofibroblast ikuraho fibrosis ya bleomycine iterwa na fibrosis yimbeba mu mbeba binyuze munzira ya ECM-reseptor inzira [J]. Ikinyamakuru cyubuvuzi bwa selile na molecular, 2022.26 (11): 3269-3280.DOI: 10.1111 / jcmm.17333.
[3] Huang Y, He Y, Makarcyzk MJ, n'abandi. Senolytike Peptide FOXO4-DRI Yahisemo Gukuraho Utugingo ngengabuzima twa Senescent muri vitro Yaguye Chondrocytes Yabantu [J]. Imipaka muri Bioengineering na Biotechnology, 2021,9: 677576.DOI: 10.3389 / fbioe.2021.677576.
[4] Zhang C, Xie Y, Chen H, n'abandi. FOXO4-DRI igabanya ubukana bwa testosterone iterwa no gusaza yibasira selile ya Leydig ya senescent mu mbeba zashaje [J]. Gusaza (Albany Ny), 2020,12 (2): 1272-1284.DOI: 10.18632 / gusaza.102682.
[5] Baar M P. Ibyangiritse ADN byatewe na selile mugihe cyo gusaza, 2019 [C]. https://api.semanticscholar.org/CorpusID:196682180
Ibicuruzwa biboneka mubushakashatsi bukoreshwa gusa:
