By Cocer Peptides 
1 ọnwa gara aga
Edemede na ozi ngwaahịa niile enyere na webụsaịtị a bụ naanị maka mgbasa ozi na ebumnuche mmụta.
Ngwaahịa ndị enyere na webụsaịtị a bụ naanị maka nyocha in vitro. A na-eme nyocha in vitro (Latin: * na iko *, nke pụtara na ihe eji enyo) na mpụga ahụ mmadụ. Ngwaahịa ndị a abụghị ọgwụ, ndị US Food and Drug Administration (FDA) akwadoghị ya, ha agaghịkwa eji ya gbochie, gwọọ, ma ọ bụ gwọọ ọnọdụ ahụike ọ bụla, ọrịa, ma ọ bụ ọrịa. Iwu amachibidoro nke ọma iwebata ngwaahịa ndị a n'ime ahụ mmadụ ma ọ bụ anụmanụ n'ụdị ọ bụla.
Ịka nká, dị ka usoro okike a na-apụghị izere ezere n'ime ihe ndị dị ndụ, abụwo ogologo oge isi ihe nyocha sayensị. Ka ihe ndị dị ndụ na-akawanye nká, mkpụrụ ndụ na-eji nwayọọ nwayọọ na-abanye n'ọnọdụ mmetụta uche, na nchịkọta nke mkpụrụ ndụ ndị a nwere ike imetụta ọrụ nkịtị nke anụ ahụ na akụkụ ahụ, na-ebute ọrịa dị iche iche metụtara afọ. FOX04 - DRI bara uru maka ikpochapụ mkpụrụ ndụ senescent.
Nchịkọta nke FOX04 - DRI
FOX04 - DRI bụ peptide sịntetik, nke nwere igbe isi ndụdụ zuru oke O ihe odide ederede 4 - D - Retro - Inverso. Nchọpụta ya sitere na nyocha miri emi n'ime usoro nhazi nke mkpụrụ ndụ senescent. N'oge senescence cellular, ọtụtụ usoro molekụla na-etinye aka, na ihe odide ederede FOX04 na-arụ ọrụ dị mkpa na usoro a. FOX04 na-egosipụta usoro okwu akọwapụtara yana mgbanwe arụ ọrụ na sel senescent. Site n'ịkọwapụta usoro omume ya, ndị ọkà mmụta sayensị haziri ma mejupụta FOX04-DRI ka ha wee lekwasị anya kpọmkwem n'ime mkpụrụ ndụ senescent, na-achọ ilebara nsogbu ndị metụtara afọ.
Ọgụgụ 1 Ntụle atụmatụ nke mkpochapụ nke anwụrụ ọkụ sịga na-ebute senescent nku ume fibroblasts na-eji FOXO4 siRNA bujuru DNA nanoparticles.
Usoro nke FOX04-DRI na-ekpochapụ mkpụrụ ndụ senescent
Ntinye aka na mmekorita FOX04-p53: N'ime sel senescent, FOX04 na-emekọrịta ihe na protein p53. Protein p53 na-arụ ọrụ dị mkpa na nzaghachi nrụgide cellular, usoro okirikiri cell, na apoptosis. N'okpuru ọnọdụ nkịtị, p53 na-akwalite apoptosis na mkpụrụ ndụ mebiri emebi ma ọ bụ nke na-ahụ anya site n'ime ka ngosipụta nke usoro mkpụrụ ndụ ihe nketa metụtara apoptosis, si otú a na-edobe ahụike nke ọnụ ọgụgụ sel. Na mkpụrụ ndụ senescent, FOX04 na-ejikọta na p53, na-egbochi ibufe ya na cell cell, na-egbochi p53 ịrụ ọrụ ya pro-apoptotic, na-ebute ndụ na nchịkọta nke mkpụrụ ndụ senescent. FOX04-DRI nwere ike igbochi mmekọrịta a n'etiti FOX04 na p53, na-egbochi njikọ ha, na-ekwe ka p53 banyeghachi na cell cell, mee ka ụzọ mgbaàmà apoptosis dị, ma mee ka apoptosis dị na mkpụrụ ndụ senescent, si otú ahụ nweta nkwụsị nke mkpụrụ ndụ senescent.
Iwu nke ụzọ mgbaàmà intracellular: Na mgbakwunye na itinye aka na mmekọrịta FOX04-p53, FOX04-DRI nwekwara ike imetụta akara nke mkpụrụ ndụ senescent site n'ịhazi ụzọ mgbaàmà intracellular ndị ọzọ. Ụzọ mgbama PI3K/AKT na-arụ ọrụ nchịkwa dị iche iche n'akụkụ dị iche iche nke uto cell, mmụba, nlanarị, na metabolism. Nnyocha egosiwo na ọrụ nke ụzọ akara PI3K/AKT na-agbanwekarị na sel senescent, na-emetụta ọrụ nkịtị ha. FOX04-DRI nwere ike ịhazi ọrụ nke ụzọ akara ngosi PI3K/AKT, na-agbanwe nguzozi nke ntụgharị mgbaàmà n'ime mkpụrụ ndụ senescent, si otú a na-emepụta gburugburu intracellular na-adịghị mma maka nlanarị ha na ịkpata apoptosis. Iwu nke ụzọ mgbaàmà a nwekwara ike imetụta steeti metabolic cellular, na-ebuga mkpụrụ ndụ senescent na-aga n'ihu apoptosis.
Mmetụta na Senescence-Associated Secretory Phenotype (SASP): Mkpụrụ ndụ Senescent na-ezobe usoro cytokines, chemokines, na proteases, na-eme ka senescence-metụtara secretory phenotype (SASP). Ọ bụghị nanị na SASP na-emetụta mkpụrụ ndụ nkịtị gbara ya gburugburu, na-akpaghasị ọrụ nkịtị, ma na-akpalite nzaghachi mkpali na-adịghị ala ala, na-eme ka usoro ịka nká nke anụ ahụ na akụkụ ahụ dịkwuo ngwa ngwa. FOX04-DRI nwere ike ibelata mmetụta ọjọọ nke mkpụrụ ndụ senescent na microenvironment gbara ya gburugburu site na igbochi nkwupụta na nzuzo nke ihe ndị metụtara SASP na sel senescent. N'ime ọmụmụ ihe ahụ, achọpụtara na mgbe a gwọchara mkpụrụ ndụ senescent na FOX04-DRI, ọkwa nkwupụta nke ihe ndị metụtara SASP dị ka IL-1a, IL-1β, tumor necrosis factor α (TNFα), na MMP2 na mkpụrụ ndụ senescent belatara nke ukwuu. Nke a na-egosi na FOX04-DRI nwere ike ịhazi SASP nke ọma nke mkpụrụ ndụ senescent, melite microenvironment cellular, ma na-akwalite nkwụsị nke mkpụrụ ndụ senescent na mgbake nke microenvironment anụ ahụ.
Ọrụ FOX04-DRI na anụ ahụ na ọrịa dị iche iche
Ọrụ dị n'ime usoro ọmụmụ: hypogonadism mmalite mmalite nke nwoke bụ ọrịa metụtara afọ nke isi usoro ya na-arụ ọrụ nke mkpụrụ ndụ interstitial testicular merela agadi. A na-egosipụta FOX04 kpọmkwem na mkpụrụ ndụ interstitial testicular mmadụ, na ndị agadi, nsụgharị nuklia nke FOX04 jikọtara ya na njikọ testosterone belata. N'iji hydrogen peroxide mere agadi TM3 testicular interstitial cell dị ka ihe nlereanya in vitro, a chọpụtara na FOX04 nwere ike ịnọgide na-enwe ike nke mkpụrụ ndụ interstitial testicular agadi ma gbochie apoptosis ha. FOX04-DRI na-ahọrọ p53 mbupụ nuklia na apoptosis nke sel interstitial testicular agadi site na imebi mmekọrịta FOX04-p53. N'ụdị òké ịka nká nke okike, nchịkwa nke FOX04-DRI kwalitere microenvironment testicular na belata ụkọ nzuzo testosterone metụtara afọ. Ya mere, FOX04-DRI nwere ike ịba uru maka ọgwụgwọ nke hypogonadism mmalite mmalite nke nwoke.
Ọgụgụ 2 Nkwuwapụta FOXO4 n'ime ule ụmụ mmadụ chọpụtara site na ntụpọ immunofluorescent.
Ọrụ na usoro iku ume
Fibrosis pulmonary: Fibrosis pulmonary (PF) bụ ọrịa ngụgụ na-aga n'ihu na-aga n'ihu. Ọganihu ya na mgbasawanye ya na-abawanye na afọ, yana senescence cellular ka a na-ahụta dị ka otu n'ime isi ihe na-ebute ụzọ na pathogenesis ya. Na bleomycin (BLM) na-ebute ụdị òké PF, FOX04-DRI gosipụtara mmetụta yiri nke pirfenidone ọgwụ akwadoro. Ọ na-ebelata ọnụ ọgụgụ nke mkpụrụ ndụ senescent, na-ebelata nkwupụta nke senescence-metụtara secretory phenotype (SASP), ma na-eme ka BLM na-eme mgbanwe mgbanwe morphological na ntinye collagen na anụ ahụ ngụgụ. Na mgbakwunye, FOX04-DRI na-abawanye nha nke ụdị 2 alveolar epithelial cell (AEC2) na fibroblasts ebe mbelata ọnụ ọgụgụ myofibroblasts. Nnwale in vitro gosiri na e jiri ya tụnyere òké na ngụgụ mmadụ fibroblast cell, FOX04-DRI nwere mmasị karịa igbu ihe na-agbanwe agbanwe-β (TGF-β) -induced myofibroblasts, na site n'igbochi myofibroblasts, ọ na-eduga na nkwụsịtụ nke extracellular matrix (ECM) na-emekọrịta ihe na-anabata BLM.
Ọrịa akpa ume na-adịghị ala ala (COPD): pathogenesis na ọganihu nke COPD na-ejikọta ya na senescence cellular. N'ime anwụrụ ọkụ sịga kpatara senescent pulmonary fibroblasts, okwu FOX04 na-ebuli elu. Iji kụtuo FOX04 na senescent fibroblasts, DNA nanotubes (siFOXO4-NT) na-agbakọta onwe ya nke nwere FOX04 siRNA nwere otu eriri ka emebere ma hazie ya. Nnyocha egosiwo na siFOXO4-NT nwere ike ịbanye fibroblasts ngụgụ mmadụ (sel HFL-1) na ntinye uche na oge dabere, si otú ahụ belata ọkwa FOX04 na vitro. siFOXO4-NT na-ahọrọ nke ọma na-ewepụ mkpụrụ ndụ HFL-1 merela agadi site na ibelata okwu BCLXL dị elu na BCL2 / BAX ratio na anwụrụ sịga sịga (CSE) na-ebute sel HFL-1 merela agadi.
Ọrụ na anụ ahụ cartilage: Autologous chondrocyte implantation (ACI) bụ usoro maka ịgwọ mmebi nkwonkwo cartilage na igbochi osteoarthritis post-traumatic. N'oge mgbasawanye in vitro nke chondrocytes, nzọụkwụ dị mkpa na ACI, a na-emepụta mkpụrụ ndụ senescent, nke na-emetụta àgwà na ọnụ ọgụgụ nke cartilage ọhụrụ emepụtara na-adịghị mma. Ndị na-eme nchọpụta chere na ọgwụgwọ FOX04-DRI nwere ike wepụ mkpụrụ ndụ senescent na chondrocytes gbasaa, si otú a na-eme ka ikike ha nwee ike ịmepụta cartilage dị elu. Iji mee ka usoro mgbasawanye in vitro dị na ACI, chondrocytes dịpụrụ adịpụ site na ndị na-enye onyinye ahụike gbasaa ruo ọkwa ọnụọgụ abụọ (PDL) 9, na-anọchite anya chondrocytes dị njikere maka ịkụnye, ebe sel ndị dị na PDL3 jere ozi dị ka njikwa mgbasawanye ntakịrị. Nsonaazụ gosiri na ọgwụgwọ FOX04-DRI wepụrụ ihe karịrị ọkara nke sel na PDL9 mana enweghị mmetụta dị ukwuu na ọnụọgụ PDL3 chondrocytes. Ọkwa senescence nke PDL9 chondrocytes ejiri FOX04-DRI belatara nke ukwuu. Dabere na nsonaazụ ọdịnala micro-ụyọkọ ọkọlọtọ, FOX04-DRI pretreatment emeghị ka ike chondrogenic nke PDL9 chondrocytes pụta, mana anụ ahụ chondroid sitere na FOX04-DRI-pretreated sel PDL9 gosipụtara ngosipụta dị ala nke ihe nzuzo metụtara ịka nká. FOX04-DRI wepụrụ mkpụrụ ndụ senescent nke ọma na PDL9 chondrocytes.
Ọrụ na radieshon-induced pulmonary fibrosis (RIPF): RIPF bụ ihe mgbagwoju anya na nke siri ike na-eso ọgwụgwọ redio thoracic tumor. A na-ekewa ụmụ oke C57BL/6 na-enweghị usoro n'ime irradiation na irradiation + FOX04-DRI, na hemithorax ziri ezi nke otu ọ bụla na-anata 17 Gy X-ray irradiation. FOX04-DRI otu na irradiation + FOX04-DRI otu ụmụ oke na-elekọta FOX04-DRI site na intraperitoneal injection na izu 16 na 20 post-irradiation. Nsonaazụ gosiri na FOX04-DRI belatara ntinye collagen na anụ ahụ ngụgụ nke ụmụ oke RIPF, mbelata okwu col1α1 na α-SMA, wee belata ọnụ ọgụgụ β-galactosidase (β-gal) mkpụrụ ndụ dị mma (akara nke mkpụrụ ndụ senescent) na anụ ahụ ngụgụ. FOX04-DRI nwere ike igbochi okwu nke P21 na P16 ^ (Ink4a) mkpụrụ ndụ ihe nketa na protein na anụ ahụ anụ ahụ nke ụmụ oke RIPF, yana nkwupụta nke SASP genes IL-1a, IL-1β, tumor necrosis factor α (TNFα), na MMP2. FOX04-DRI na-ebelatakwa ụdị oxygen na-arụ ọrụ (ROS) na anụ ahụ anụ ahụ nke ụmụ oke RIPF ma na-akwalite nkwalite nke p-AKT na p-PI3K protein. Nke a na-egosi na FOX04-DRI na-ebelata nrụgide oxidative ma na-egbochi senescence cellular site na ịgbalite ụzọ akara PI3K/AKT, si otú ahụ na-atụgharị RIPF.
Ọgụgụ 3 FOXO4-DRI na-ebelata myofibroblast dị iche iche na ụmụ oke PF BLM kpatara.
Mmechi
Na nchịkọta, FOX04-DRI, dị ka ọgwụ na-agbanwe agbanwe nke nwere ike ikpochapụ mkpụrụ ndụ senescent kpọmkwem, na-arụ ọrụ dị mkpa n'ịgwọ ọrịa ndị metụtara afọ na ịka nká.
Isi mmalite
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[2] Han X, Yuan T, Zhang J, et al. FOXO4 peptide lekwasịrị anya myofibroblast ameliorates bleomycin na-ebute fibrosis pulmonary na ụmụ oke site na ụzọ mmekọrịta ECM-receptor[J]. Akwụkwọ akụkọ nke Cellular and Molecular Medicine, 2022,26 (11): 3269-3280.DOI: 10.1111 / jcmm.17333.
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[4] Zhang C, Xie Y, Chen H, et al. FOXO4-DRI na-ebelata ụkọ ihe nzuzo testosterone metụtara afọ site n'ịkwado mkpụrụ ndụ Leydig n'ime ụmụ oke [J]. Ịka nká (Albany Ny), 2020,12 (2): 1272-1284.DOI: 10.18632 / ịka nká.102682.
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