Bya Cocer Peptides 
omwezi gumu emabega
EBINTU BYONNNA N’AMAWULIRE GW’EBINTU EBIweereddwa KU MUTINDO GUNO BIKOZESEBWA KU KUSASANYA AMAWULIRE N’EBIKOLWA BY’OKUSOMESA.
Ebintu ebiweereddwa ku mukutu guno bigendereddwamu kunoonyereza mu kisenge (in vitro research) byokka. Okunoonyereza mu vitro (Olulattini: *mu ndabirwamu*, ekitegeeza mu bikozesebwa mu ndabirwamu) kukolebwa ebweru w’omubiri gw’omuntu. Ebintu bino si bya ddagala, tebikkiriziddwa kitongole kya Amerika ekivunaanyizibwa ku by’emmere n’eddagala (FDA), era tebirina kukozesebwa kuziyiza, kujjanjaba oba kuwonya mbeera yonna ya bujjanjabi, bulwadde oba bulwadde. Kikugirwa nnyo mu mateeka okuyingiza ebintu bino mu mubiri gw’omuntu oba ebisolo mu ngeri yonna.
Okukaddiwa, ng’enkola ey’obutonde eteewalika mu biramu, okuva edda ng’ekintu ekikulu mu kunoonyereza kwa ssaayansi. Ebiramu bwe bikaddiwa, obutoffaali buyingira mpolampola mu mbeera y’okukaddiwa, era okukuŋŋaanyizibwa kw’obutoffaali buno obukaddiye kuyinza okukosa obubi enkola eya bulijjo ey’ebitundu n’ebitundu by’omubiri, ekivaako endwadde ez’enjawulo ezeekuusa ku myaka. FOX04 – DRI ya mugaso mu kugogola obutoffaali obukaddiye.
Okulaba ebikwata ku FOX04 - DRI
FOX04 - DRI ye peptide ey’obutonde, ng’erina erinnya mu bujjuvu bbokisi y’omutwe gwa fooro O ensonga y’okuwandiika 4 - D - Retro - Inverso. Okuzuula kwayo kusibuka mu kunoonyereza okw’obwegendereza ku nkola y’okulungamya obutoffaali obukaddiye. Mu kiseera ky’okukaddiwa kw’obutoffaali, enkola za molekyu eziwera zeenyigiddemu, era ensonga y’okuwandiika eya FOX04 ekola kinene mu nkola eno. FOX04 eraga enkola ezenjawulo ez’okwolesebwa n’enkyukakyuka mu nkola mu butoffaali obukaddiye. Nga bannyonnyola enkola yaayo ey’okukola, bannassaayansi baakola ne bakola FOX04-DRI okusobola okutunuulira mu ngeri ey’enjawulo obutoffaali obukaddiye, nga baluubirira okukola ku nsonga ezikwata ku myaka.
Ekifaananyi 1 Ekifaananyi eky’ensengeka y’okumalawo ebiwuziwuzi by’amawuggwe ebikaddiye ebiva ku mukka gwa sigala nga tukozesa obutundutundu bwa DNA obutikkiddwa FOXO4 siRNA.
Enkola ya FOX04-DRI mu kugogola obutoffaali obukaddiye
Okutaataaganyizibwa mu nkolagana ya FOX04-p53: Mu butoffaali obukaddiye, FOX04 ekwatagana ne puloteyina ya p53. Puloteeni ya p53 ekola kinene mu kuddamu kw’obutoffaali ku situleesi, okulungamya enzirukanya y’obutoffaali, n’okufa kw’obutoffaali. Mu mbeera eya bulijjo, p53 etumbula apoptosis mu butoffaali obwonooneddwa oba obukaddiye nga ekola okulaga omuddirirwa gw’obuzaale obukwatagana n’okufa, bwe kityo n’ekuuma obulamu bw’omuwendo gw’obutoffaali. Mu butoffaali obukaddiye, FOX04 yeekwata ku p53, n’eziyiza entambula yaayo okutuuka mu nucleus y’obutoffaali, n’eremesa p53 okukola omulimu gwayo ogwa pro-apoptotic, ekivaamu okuwangaala n’okukuŋŋaanyizibwa kw’obutoffaali obukaddiye. FOX04-DRI esobola okutaataaganya mu ngeri ey’enjawulo enkolagana eno wakati wa FOX04 ne p53, okuziyiza okusiba kwazo, okusobozesa p53 okuddamu okuyingira mu nyukiliya y’obutoffaali, okukola ekkubo ly’obubonero bwa apoptosis, n’okuleeta apoptosis mu butoffaali obukaddiye, bwe kityo ne kituuka ku kulongoosebwa kw’obutoffaali obukaddiye.
Okulungamya amakubo g’obubonero mu butoffaali: Ng’oggyeeko okutaataaganya enkolagana ya FOX04-p53, FOX04-DRI era eyinza okukwata ku nkomerero y’obutoffaali obukaddiye ng’etereeza amakubo amalala ag’obubonero mu butoffaali. Ekkubo ly’obubonero bwa PI3K/AKT likola omulimu omukulu ogw’okulungamya mu bintu eby’enjawulo eby’okukula kw’obutoffaali, okukula, okuwangaala, n’okukyusakyusa mu mubiri. Okunoonyereza kulaga nti emirimu gy’ekkubo ly’obubonero bwa PI3K/AKT gitera okukyusibwa mu butoffaali obukaddiye, ne kikosa emirimu gyabwo egya bulijjo. FOX04-DRI eyinza okulungamya emirimu gy’ekkubo ly’obubonero erya PI3K/AKT, okukyusa bbalansi y’okukyusa obubonero mu butoffaali obukaddiye, bwe kityo n’ekola embeera etali nnungi mu butoffaali eri obulamu bwazo n’okuleeta okufa. Okulungamya ekkubo lino ery’obubonero nakyo kiyinza okukwata ku mbeera z’obutoffaali bw’enkyukakyuka mu mubiri, okwongera okuvuga obutoffaali obukaddiye okutuuka ku apoptosis.
Enkola ku Senescence-Associated Secretory Phenotype (SASP): Obutoffaali obukaddiye bufulumya omuddirirwa gwa cytokines, chemokines, ne proteases, ne bukola senescence-associated secretory phenotype (SASP). SASP tekoma ku kukosa bubi butoffaali bwa bulijjo obwetoolodde, okutaataaganya emirimu gyabwo egya bulijjo, naye era ereeta okuddamu kw’okuzimba okutambula obutasalako, okwongera okwanguya enkola y’okukaddiwa kw’ebitundu n’ebitundu by’omubiri. FOX04-DRI eyinza okukendeeza ku buzibu obuva mu butoffaali obukaddiye ku microenvironment egyetoolodde nga eziyiza okwolesebwa n’okufulumya ensonga ezikwatagana ne SASP mu butoffaali obukaddiye. Mu kunoonyereza kuno, kyazuulibwa nti oluvannyuma lw’okujjanjaba obutoffaali obukaddiye ne FOX04-DRI, emitendera gy’okwolesebwa kw’ensonga ezikwatagana ne SASP nga IL-1α, IL-1β, tumor necrosis factor α (TNFα), ne MMP2 mu butoffaali obukaddiye gyakendeera nnyo. Kino kiraga nti FOX04-DRI esobola bulungi okulung’amya SASP y’obutoffaali obukaddiye, okulongoosa obutonde obutono obw’obutoffaali, n’okutumbula obutatereevu okugogola obutoffaali obukaddiye n’okuddamu okukola obutonde obutono obw’ebitundu.
Omulimu gwa FOX04-DRI mu bitundu by’omubiri n’endwadde ez’enjawulo
Omulimu mu nkola y’okuzaala: Obulwadde bw’ekisajja obutandika ekikeerezi bulwadde obukwatagana n’emyaka nga enkola yaago enkulu kwe kukola obubi mu butoffaali bw’ensigo obukaddiye. FOX04 yeeyoleka mu ngeri ey’enjawulo mu butoffaali bw’ensigo obw’omuntu, era mu bakadde, okukyusakyusa kwa nukiriya kwa FOX04 kukwatagana n’okukendeeza ku kusengejja obusimu obuyitibwa testosterone. Nga tukozesa obutoffaali bw’ensigo obwa TM3 obukaddiye obuleetebwa haidrojeni perokisayidi ng’ekyokulabirako mu vitro, kyazuulibwa nti FOX04 esobola okukuuma obulamu bw’obutoffaali bw’ensigo obukaddiye n’okuziyiza okufa kwabwo. FOX04-DRI elondamu okuleeta p53 nuclear export ne apoptosis y’obutoffaali obukaddiye obw’ensigo nga etaataaganya enkolagana ya FOX04-p53. Mu nkola y’ebibe eby’obutonde ebikaddiye, okugaba FOX04-DRI kyalongoosa embeera y’ensigo entonotono era ne kikendeeza ku bbula ly’okufulumya eddagala lya testosterone eryekuusa ku myaka. N’olwekyo, FOX04-DRI eyinza okuba ey’omugaso mu kujjanjaba obulwadde bw’ekisajja obutandika ekikeerezi.
Ekifaananyi 2 Okwolesebwa kwa FOXO4 mu nsigo z’omuntu okuzuuliddwa nga bakozesa immunofluorescent staining.
Omulimu mu nkola y’okussa
Obulwadde bw’amawuggwe: Obulwadde bw’amawuggwe (PF) bulwadde bw’amawuggwe obugenda mu maaso. Obulwadde bwayo n’obungi bwayo byeyongera n’emyaka, era okukaddiwa kw’obutoffaali kutwalibwa ng’ekimu ku bintu ebikulu ebigivuga mu ntandikwa y’obulwadde bwayo. Mu nkola ya PF mouse model eya bleomycin (BLM), FOX04-DRI yalaga ebikolwa ebifaananako n’eby’eddagala eryakkirizibwa erya pirfenidone. Kikendeeza ku muwendo gw’obutoffaali obukaddiye, kikendeeza ku kwolesebwa kw’ekikula ky’ekyama ekikwatagana n’okukaddiwa (SASP), era kikendeeza ku nkyukakyuka mu nkula ezireetebwa BLM n’okuteekebwa kwa kolagini mu bitundu by’amawuggwe. Okugatta ku ekyo, FOX04-DRI eyongera ku kitundu ky’obutoffaali bw’ekika kya 2 alveolar epithelial cells (AEC2) ne fibroblasts ate nga ekendeeza ku muwendo gwa myofibroblasts. Okugezesa mu vitro kwalaga nti bw’ogeraageranya ne layini z’obutoffaali bw’amawuggwe g’amawuggwe g’ebibe n’abantu, FOX04-DRI yali esinga kwagala kutta myofibroblasts ezireetebwa transforming growth factor-β (TGF-β), era nga eziyiza myofibroblasts, kyavaako okukka wansi w’amakubo g’enkolagana y’ebikwata eby’ebweru w’obutoffaali (ECM) mu BLM-induced PF.
Obulwadde bw’amawuggwe obutawona (COPD): Entandikwa y’obulwadde n’okukulaakulana kwa COPD bikwatagana nnyo n’okukaddiwa kw’obutoffaali. Mu fibroblasts z’amawuggwe ezikaddiye ezireetebwa omukka gwa sigala, okwolesebwa kwa FOX04 kuli waggulu. Okukoona FOX04 mu fibroblasts ezikaddiye, DNA nanotubes ezeekuŋŋaanya (siFOXO4-NT) ezitikkiddwa FOX04 siRNA ey’omuguwa gumu zakolebwa era ne zisengekebwa. Okunoonyereza kulaga nti siFOXO4-NT esobola okuyingira mu fibroblasts z’amawuggwe g’omuntu (HFL-1 cells) mu ngeri eyeesigama ku bungi n’obudde, bwe kityo n’ekendeeza ku miwendo gya FOX04 mu vitro. siFOXO4-NT elonda okumalawo obutoffaali bwa HFL-1 obukaddiye nga ekendeeza ku kwolesebwa kwa BCLXL okulinnya n’omugerageranyo gwa BCL2/BAX mu butoffaali bwa HFL-1 obukaddiye obuleetebwa omukka gwa sigala (CSE).
Omulimu mu bitundu by’amagumba: Autologous chondrocyte implantation (ACI) nkola ya kujjanjaba okwonooneka kw’amagumba g’ennyondo n’okuziyiza obulwadde bw’amagumba oluvannyuma lw’okukosebwa. Mu kiseera ky’okugaziwa mu vitro (in vitro expansion of chondrocytes), omutendera ogwetaagisa mu ACI, obutoffaali obukaddiye butondebwawo, ekikosa obubi omutindo n’obungi bw’amagumba amapya agatondeddwa. Abanoonyereza baateebereza nti obujjanjabi bwa FOX04-DRI busobola okuggya obutoffaali obukaddiye okuva mu chondrocytes ezigaziyiziddwa, bwe kityo ne kyongera ku busobozi bwabwo okukola amagumba ag’omutindo ogwa waggulu. Okukoppa enkola y’okugaziwa mu kisenge (in vitro expansion process) mu ACI, obutoffaali obuyitibwa chondrocytes obwawuddwa okuva mu bagabi abalamu bwagaziyizibwa okutuuka ku ddaala ly’okukubisaamu emirundi ebiri (PDL) 9, nga bukiikirira chondrocytes ezeetegefu okuteekebwamu, ate obutoffaali ku PDL3 bwakola ng’ekifuga okugaziwa ekitono ennyo. Ebivuddemu biraga nti obujjanjabi bwa FOX04-DRI bwaggyawo obutoffaali obusukka mu kitundu ku PDL9 naye nga tebulina kinene kye bukola ku muwendo gwa PDL3 chondrocytes. Omutindo gw’okukaddiwa kwa PDL9 chondrocytes ezajjanjabwa ne FOX04-DRI gwakendeera nnyo. Okusinziira ku bivudde mu kulonda kwa micro-cluster okwa bulijjo, FOX04-DRI pretreatment teyayongera ku busobozi bwa chondrogenic bwa PDL9 chondrocytes, naye chondroid tissue eziggiddwa mu FOX04-DRI-pretreated PDL9 cells zaayoleka wansi okwolesebwa okukaddiwa-associated secretory factors. FOX04-DRI yaggya bulungi obutoffaali obukaddiye okuva mu PDL9 chondrocytes.
Omulimu mu bulwadde bw’amawuggwe obuva ku masanyalaze (RIPF): RIPF kizibu kya bulijjo era eky’amaanyi oluvannyuma lw’okujjanjaba amasannyalaze g’ekizimba ky’omu kifuba. Ebibe bya C57BL/6 byagabanyizibwamu mu ngeri ey’ekifuulannenge mu bibinja eby’obusannyalazo n’obusannyalazo + FOX04-DRI, nga hemithorax eya ddyo eya buli kibinja yafuna obusannyalazo bwa X-ray obwa 17 Gy. Ebibe ekibinja kya FOX04-DRI n’ekibinja kya FOX04-DRI byaweebwa FOX04-DRI nga bayita mu mpiso mu lubuto mu wiiki 16 ne 20 oluvannyuma lw’okubunyisa obusannyalazo. Ebivuddemu biraga nti FOX04-DRI yakendeeza ku kuteekebwa kwa kolagini mu bitundu by’amawuggwe g’ebibe bya RIPF, yakendeeza ku kwolesebwa kwa col1α1 ne α-SMA, era yakendeeza ku muwendo gw’obutoffaali obulungi β-galactosidase (β-gal) (akabonero k’obutoffaali obukaddiye) mu bitundu by’amawuggwe. FOX04-DRI yasobola okuziyiza okwolesebwa kw’obuzaale bwa P21 ne P16^(Ink4a) ne puloteyina mu bitundu by’amawuggwe eby’ebibe bya RIPF, wamu n’okwolesebwa kw’obuzaale bwa SASP IL-1α, IL-1β, tumor necrosis factor α (TNFα), ne MMP2. FOX04-DRI era ekendeeza ku miwendo gy’ebika bya oxygen ebikola (ROS) mu bitundu by’amawuggwe eby’ebibe bya RIPF era etumbula okukola kwa puloteyina za p-AKT ne p-PI3K. Kino kiraga nti FOX04-DRI ekendeeza ku situleesi y’okwokya (oxidative stress) era eziyiza okukaddiwa kw’obutoffaali ng’ekola ekkubo ly’obubonero bwa PI3K/AKT, bwe kityo n’ezzaawo RIPF.
Ekifaananyi 3 FOXO4-DRI ekendeeza ku njawulo ya myofibroblast mu mbeba za PF ezireetebwa BLM.
Mu bufunzi
Mu bufunze, FOX04-DRI, ng’eddagala ery’enkyukakyuka erisobola okumalawo mu ngeri ey’enjawulo obutoffaali obukaddiye, likola kinene mu kujjanjaba endwadde ezeekuusa ku myaka n’okuyingira mu nsonga z’okukaddiwa.
Ensonda
[1] Han Y, Wu Y, Ye B, n’abalala. DNA nanoparticles targeting FOXO4 selectively okumalawo omukka gwa sigala-induced senescent amawuggwe fibroblasts[J]. Enkulaakulana mu Nanoscale, 2023, 5 (21): 5965-5973.DOI: 10.1039 / d3na00547j.
[2] Han X, Yuan T, Zhang J, n’abalala. FOXO4 peptide etunuulira myofibroblast etereeza bleomycin-induced pulmonary fibrosis mu mbeba okuyita mu ECM-receptor interaction pathway[J]. Journal of Eddagala ly'obutoffaali ne molekyu, 2022, 26 (11): 3269-3280.DOI: 10.1111 / jcmm.17333.
[3] Huang Y, Ye Y, Makarcyzk M. J., n’abalala. Senolytic Peptide FOXO4-DRI Elonda Okuggya Obutoffaali Obukaddiye Okuva mu In vitro Expanded Human Chondrocytes[J]. Ensalo mu yinginiya w’ebiramu ne tekinologiya w’ebiramu, 2021,9:677576.DOI:10.3389/fbioe.2021.677576.
[4] Zhang C, Xie Y, Chen H, n’abalala. FOXO4-DRI ekendeeza ku myaka egy’obutafulumya testosterone nga etunuulira obutoffaali bwa Leydig obukaddiye mu mbeba ezikaddiye[J]. Okukaddiwa (Albany Ny), 2020,12 (2): 1272-1284.DOI: 10.18632 / okukaddiwa.102682.
[5] Baar M P. Enkomerero z’obutoffaali obuleetebwa okwonooneka kwa DNA mu kiseera ky’okukaddiwa, 2019[C]. 196682180. Enkola y’okukuuma obutonde bw’ensi mu bitundu by’eggwanga eby’enjawulo
Ekintu ekiriwo okukozesebwa mu kunoonyereza kwokka:
