Na Cocer Peptides 
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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.
Mitochondria yibasiwe na peptide SS-31, izwi kandi nka elamipretide, ni peptide ntoya ya molekile ifite imikorere yihariye ya mitochondriya. Mu myaka yashize, uko ubushakashatsi bwerekeye uburyo bwo gusaza bwarushijeho kwiyongera, uruhare rukomeye rw’imikorere mibi ya mito-iyambere mu gusaza rwarushijeho kugaragara. SS-31, hamwe nimiterere yihariye ya mitochondrial yibikoresho hamwe nubushobozi bwo kugenzura imikorere ya mito-iyambere, itanga amasezerano yo kurwanya gusaza.
Igicapo 1 Guhumeka hamwe nibishobora guterwa no gukurura ADP mumitsi yihariye mitochondriya bisaba cytochrome c hamwe na clamp ya hexokinase. ADP / ATP inzira yo gutwara no guhuza ELAM kuri ATP Synthase na ANT.
I. Incamake yumubano uri hagati ya Mitochondria nubusaza
Mitochondria, nk'imbaraga z'akagari, ishinzwe guhuza igice kinini cya ATP mu kagari kandi ikagira uruhare mu kugenzura ibintu bitandukanye no guhinduranya ibimenyetso. Uko imyaka igenda yiyongera, imikorere ya mitochondial igenda igabanuka buhoro buhoro, kikaba ari kimwe mu bimenyetso byingenzi byo gusaza. Imikorere mibi ya Mitochondrial igaragarira mu buryo bwinshi, harimo no gukusanya ihinduka ry’imiterere muri ADN ya mitochondial (mtDNA), kugabanya ibikorwa by’urunigi rw’ubuhumekero rwa mitochondial, bigatuma ingufu zidahagije; kongera umusaruro w’ubwoko bwa ogisijeni (ROS) na mitochondriya, bigatera kwangirika kwa okiside, ibyo bikaba bikomeza guhungabanya ibinyabuzima byo mu nda nka poroteyine, lipide, na acide nucleique, byihuta gusaza n’urupfu. Imikorere idasanzwe ya mitochondrial nayo ihagarika calcium yo mu nda ya calcium homeostasis, ikabangamira imikorere isanzwe yimikorere ya selile. Izi mpinduka zikorana, zikora uruziga rukomeye rutera hamwe gusaza.
II. Uburyo bwibikorwa bya SS-31
Kunoza ingufu za Mitochondrial Metabolism
Kongera ibyiyumvo bya ADP: Mugihe cyo gusaza, mitochondrial sensitivite kuri ADP iragabanuka, bikabangamira imikorere ya ATP. Ubushakashatsi bwerekana ko SS-31 ishobora guhuza byimazeyo na ADT itwara mitochondrial ADP, bigatuma ANT ifata ADP, bityo bikongerera imbaraga za mitochondial kuri ADP. Muri mitochondriya yimitsi ishaje, kuvura SS-31 byongereye ADP binyuze muri ANT, bityo byongera ubuhumekero bwa mitochondial biterwa na ADP, kongera umusaruro wa ATP, no kuzamura imbaraga za metabolism mumitsi ya mitochondriya ishaje.
Kugena imiyoboro yubuhumekero ya mitochondrial: Urwego rwubuhumekero rwa Mitochondrial ningingo zingenzi zibyara ingufu za mito-iyambere. Mugihe cyo gusaza, ibikorwa byurwego rwubuhumekero akenshi bigabanuka. SS-31 irashobora gukomeza cyangwa kuzamura ibikorwa byuruhererekane rwubuhumekero muguhindura ubusugire bwimiterere cyangwa kugenzura imvugo za poroteyine zifitanye isano. Ubushakashatsi bwibanze bwerekanye ko muburyo bwo gusaza bujyanye no gusaza biterwa na mitochondrial imikorere idahwitse, ibikorwa byurwego rwubuhumekero bigarurwa nyuma yo kuvurwa kwa SS-31, bikaba byerekana ingaruka nziza zabyo mumikorere yubuhumekero bwa mitochondial.
Igishushanyo 2 SS-31 ivura ihindura imitekerereze yumutima
Kugabanya kwangirika kwa okiside
Kugabanya umusaruro wa ROS: Mitochondriya ni imwe mu nkomoko y'ibanze ya ROS mu ngirabuzimafatizo, kandi umusaruro wa ROS wiyongera muri mitochondriya mu gihe cyo gusaza. SS-31 irashobora kugabanya umusaruro wa ROS binyuze munzira nyinshi. Itezimbere imbaraga za mitochondial metabolism, bigatuma urwego rwa transport ya mitochondrial transport itwara neza kandi ikagabanya imyuka ya electron, bityo bikagabanya umusaruro wa ROS. SS-31 irashobora gukora muburyo butaziguye kuri mitochondrial membrane, guhindura imiterere yumubiri, kugabanya ibibanza byangiza okiside kuri membrane, no kubuza umusaruro wa ROS. Mu ngirangingo z'umutima ziva ku mbeba zishaje, kuvura hamwe na SS-31 byagabanije cyane urwego rwa mitochondrial ROS, byerekana akamaro kayo mu kugabanya umusaruro wa ROS.
Amabwiriza ya sisitemu ya antioxydeant: Utugingo ngengabuzima turimo sisitemu ya antioxyde de antioxyde, harimo na superoxide dismutase (SOD), catalase (CAT), na glutathione peroxidase (GSH-Px), ishinzwe gusiba ROS. Ubushakashatsi bwerekana ko SS-31 ishobora kongera ubushobozi bwo kwirwanaho bwa antioxydeant selile muguhuza imvugo cyangwa ibikorwa byiyi misemburo ya antioxydeant. Muri moderi zimwe na zimwe za selile, kuvura hamwe na SS-31 byatumye ubwiyongere bugaragara bwibikorwa bya SOD na GSH-Px, bifasha mugukuraho mugihe gikwiye ROS irenze ingirabuzimafatizo no kugabanya ibyangiritse biterwa na okiside.
Kubungabunga mitochondrial membrane ituje
Guhambira mitochondrial membrane fosifolipide: SS-31 ifite imiterere yihariye ituma ishobora guhuza cyane cyane n'uturere twa mitochondrial membrane ikungahaye kuri fosifatidylserine. Phosphatidylserine ni fosifolipide yihariye ya mito-iyambere kandi ni ingenzi cyane mu gukomeza ubusugire bwimiterere n'imikorere ya mito-iyambere. Mugihe cyo gusaza, phosphatidylserine irashobora kwangirika kwa okiside, biganisha kubintu bidasanzwe mumiterere ya mitochondrial membrane n'imikorere. Nyuma yo guhambira kuri fosifatiqueylserine, SS-31 irashobora kurinda fosifatiidylserine kwirinda okiside mu gihe ihindura imiterere ya mitochondrial membrane, ikarinda kugabanuka kwa mikorobe ya mitochondial no gufungura pore (mPTP). Mu bushakashatsi bwa vitro bwerekanye ko SS-31 ibuza neza kugabanuka kwa okiside iterwa no kugabanuka kwa mitochondrial membrane ishobora no gufungura mPTP, bityo bikagumya gukomera kwa mitochondial.
Kugena poroteyine zifitanye isano na membrane: Indwara ya mitochondial irimo poroteyine zitandukanye zigira uruhare mu gutwara ibintu bya mitochondial, metabolisme yingufu, hamwe nuburyo bwo kohereza ibimenyetso. SS-31 irashobora guhindura mu buryo butaziguye mitochondrial membrane ituje muguhuza ibikorwa cyangwa imvugo ya poroteyine zifitanye isano na membrane. Irashobora kugenga imikorere yimiyoboro ya anion iterwa na voltage (VDAC), zikaba proteine zingenzi zumuyoboro wa membrane yo hanze ya mitochondrial kandi ikagira uruhare runini mugukomeza guhanahana amakuru no kwanduza ibimenyetso hagati ya mitochondriya na cytoplazme. Amabwiriza ya SS-31 ya VDAC afasha kugumana imikorere isanzwe ya mito-iyambere.
III. Ingaruka zihariye za SS-31 mukurwanya gusaza
Ingaruka kuri sisitemu yumutima
Kunoza imikorere yumutima: Umutima ningingo ikenera imbaraga nyinshi, kandi imikorere ya mito-iyambere ningirakamaro kumikorere yumutima. Imbeba zishaje, umutima akenshi ugaragaza ibibazo bijyanye nimyaka nko kudakora neza kwa diastolique. Abahanga basanze nyuma yibyumweru 8 bivura SS-31, imikorere ya diastolique yimitima yimbeba zashaje zateye imbere cyane. Iri terambere ryaherekejwe n’ibisanzwe bya mitochondial proton isohoka mu ngirabuzimafatizo ya myocardial, igabanya urugero rwa ROS ya mitochondrial ROS, igabanuka rya poroteyine y’umutima, hamwe n’imihindagurikire y’imiterere ya poroteyine ya thiol redox yerekeza kuri leta igabanuka. SS-31 yongereye kandi urwego rwa fosifora ya cMyBP-C Ser282 muri selile myocardial, ifitanye isano rya bugufi no kunoza imikorere ya diastolique yumutima.
Igicapo 3 Kubangamira imyigire yimbeba zishaje zatewe no kubura ibitotsi byakumiriwe hamwe na SS31.
Kurinda imitsi: Mugihe cyo gusaza, imikorere ya selile ya endoteliyale irabangamiwe, imitsi yimitsi iragabanuka, kandi indwara zifata umutima nimiyoboro. Muri moderi iterwa na hypertension iterwa n'ubwonko bwimbeba zishaje, kuvura hamwe na SS-31 byerekana ingaruka zikomeye zo gukingira imitsi. Igabanya umusaruro wa mitochondial yubusa iterwa na hypertension, igabanya kwangirika kwa okiside kwangirika kurukuta rwimitsi, bityo bikadindiza cyane gutangira mikorobe no kugabanya indwara zayo. Kubwibyo, SS-31 igira uruhare runini mukubungabunga imiterere n'imikorere isanzwe yimiyoboro yamaraso no kwirinda indwara zifata imitsi.
Ingaruka kuri sisitemu y'imitsi
Kugabanya imikorere mibi yubwenge: Uko imyaka igenda yiyongera, imikorere ya sisitemu yimitsi igenda igabanuka buhoro buhoro, kandi imikorere mibi yubwenge nko kutibuka neza no kugabanya ubushobozi bwo kwiga bigenda bigaragara cyane. Imikorere mibi ya Mitochondrial igira uruhare runini mugutangira no gutera imbere kwindwara zifata ubwonko no kudakora neza. Muburyo bwimikorere idahwitse iterwa na isoflurane mumbeba zishaje, SS-31 irashobora guhindura imikorere mibi ya mitochondrial, gutabara isoflurane-iterwa na cognitive deficits. SS-31 iteza imbere amabwiriza ya BDNF yerekana ibimenyetso, ihindura igabanuka rya poroteyine zijyanye na plastike nka synaptophysine, PSD-95, na p-CREB, ikanagenga NR2A, NR2B, CaMKIIα, na CaMKIIβ, bityo bikazamura plastike ya synaptic no kurinda imikorere yubwenge.
Kugabanya ingaruka mbi zo kubura ibitotsi: Kubura ibitotsi ni ibintu bikunze guhangayika, kandi ingaruka mbi zayo kuri sisitemu y'imitsi igaragara cyane uko imyaka igenda ishira, biganisha ku mikorere idahwitse kandi byongera ibyago byo kwandura indwara zifata ubwonko. Imbeba zimaze amezi 20, SS-31 (3 mg / kg) yatanzwe hakoreshejwe inshinge zo munsi munsi yiminsi 4 ikurikiranye, hamwe namasaha 4 yo kubura ibitotsi muminsi ibiri ishize. Ibisubizo byerekanye ko imbeba zabuze ibitotsi zavuwe na SS-31 zerekanye ko nta mbogamizi zigaragara zifite mu bumenyi bwo kwiga, hamwe n’ubwonko bwa mitochondrial ATP bwagaruwe hamwe na poroteyine zigenga synaptic plastique, ndetse no kugabanya urugero rw’ubwoko bwa ogisijeni ikora (ROS) na cytokine ikongora muri hippocampus. Ibi birerekana ko SS-31 ishobora kugira inyungu zo kuvura mukugabanya ingaruka mbi zubwonko ziterwa no kubura ibitotsi mugihe gito imbeba zashaje.
Ingaruka kuri sisitemu yimpyiko: Mu mpyiko zimbeba zishaje, glomerulosclerose ifitanye isano no kwangirika kwa mitochondial selile glitular epithelial selile. Nyuma yibyumweru 8 bivura SS-31 mumbeba zifite amezi 26, SS-31 yateje imbere imitekerereze ya mitochondrial morphologie kandi igabanya glomerulosclerose. By'umwihariko, yagabanije imvugo yerekana ibimenyetso byo gusaza (p16, gusaza bifitanye isano no gusaza β-Gal), byongera ubwinshi bwimikorere ya selitile epithelial selile, kandi bigabanya imvugo yibimenyetso bya parietal epithelial selile (kolagen IV, pERK1 / 2, na α-yoroshye imitsi actin). Nubwo SS-31 itagize ingaruka ku bucucike bwa podocyte, yagabanije ibimenyetso byangiza podocyte (desmin), iteza imbere ubunyangamugayo bwa cytoskeletal (synaptophysine), kandi iherekezwa n’ubucucike bukabije bw’imitsi (CD31). Ibi byerekana ko kuvura SS-31 mugihe gito nabyo bigira ingaruka zo gukingira mitochondriya yisi kandi bigahindura imiterere yisi.
Ingaruka kurwego rwa selire
Gutinda gusaza kwa selile: Mubushakashatsi bwakagari, H₂O₂ yakoreshejwe mugutera imbaraga zo gusaza zatewe no guhagarika umutima muri selile HEK293T, hanyuma hakurikiraho gutabarana na SS-31. Ibisubizo byerekanye ko igipimo cyiza cya SA-gal cyagabanutse cyane mu itsinda rya SS-31, byerekana ko igabanuka ry’urwego rwo gusaza. Byongeye kandi, ubukana bwa ROS fluorescence ubukana bwaragabanutse, mitochondrial membrane ishobora kwiyongera, kandi urwego rwa ATP rwazamutse mumatsinda ya SS-31. Isesengura rya poroteyine immunoblotting ryerekanye ko imvugo ya poroteyine ya P53, P21, na Acetyl-p53 yari hejuru mu itsinda ry’icyitegererezo ugereranije n'itsinda rishinzwe kugenzura, mu gihe itsinda rya SS-31 ryagabanutse ugereranije n'itsinda ry'icyitegererezo. Ku rundi ruhande, imvugo ya poroteyine ya Sirt1 yari hasi mu itsinda ry'icyitegererezo ugereranije n'itsinda rishinzwe kugenzura, mu gihe itsinda rya SS-31 ryerekanye kwiyongera ugereranije n'itsinda ry'icyitegererezo. Rero, dushobora kwanzura ko SS-31 ishobora gutinza gusaza selile HEK293T mugutezimbere imikorere ya mito-iyambere no kugenzura imvugo ya poroteyine ziterwa no gusaza muri selile.
Kurinda okiside itera kwangirika kwingirabuzimafatizo: Muri moderi ya H₂O₂ iterwa na okiside yangiza ya selile ya ARPE-19, kuvura hamwe na SS-31 byongereye cyane umuvuduko wokubaho kwingirabuzimafatizo, bigabanya urugero rwa ROS, bigabanya igipimo cyingirabuzimafatizo zigabanya ubushobozi bwa mitochondrial membrane, byagabanije cyane igipimo cyiza cya PI (kigaragaza urugero rwurupfu rwa selile). Ibisubizo byerekana ko SS-31 ifite ingaruka zikomeye zo gukingira indwara ya H₂O₂ iterwa na okiside itera imbaraga mu ngirabuzimafatizo za ARPE-19, zishobora gufasha mu kurwanya ibyangijwe n’imyaka.
Umwanzuro
Indwara ya mitochondrial peptide SS-31 igira uruhare mu kurwanya gusaza. Kuva muburyo butandukanye bwo kugenzura imikorere ya mito-iyambere kugeza ku ngaruka zikomeye zo kurwanya gusaza mu nzego zitandukanye za sisitemu na selile, byerekana ubushobozi nkingamba zingenzi zo kurwanya gusaza.
Inkomoko
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[2] Farawo G, Kamat V, Kannan S, n'abandi. Mitochondrially yibasiwe na peptide elamipretide (SS-31) iteza imbere ADP ibyiyumvo bya mitochondriya ishaje byongera ubwiyongere binyuze muri adenine nucleotide translocator (ANT) [J]. Geroscience, 2023,45 (6): 3529-3548.DOI: 10.1007 / s11357-023-00861-y.
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Ibicuruzwa biboneka mubushakashatsi bukoreshwa gusa:
