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.
Mitochondria-ezubere iche peptide SS-31, nke a makwaara dị ka elamipretide, bụ peptide pere mpe nwere ọrụ mtochondria-ezubere iche. N'ime afọ ndị na-adịbeghị anya, ka nchọpụta n'ime usoro nke ịka nká na-esiwanyewanye ike, ọrụ dị oke egwu nke mitochondrial dysfunction na usoro ịka nká aghọwo ihe na-apụtawanye ìhè. SS-31, nwere ihe nleba anya mitochondrial pụrụ iche yana ikike ịhazi ọrụ mitochondrial, na-ekwe nkwa maka ngwa mgbochi ịka nká.
Ọgụgụ 1 iku ume na akpụkpọ ahụ nwere ike nzaghachi nye mkpali ADP na mitochondria muscle dịpụrụ adịpụ chọrọ mgbakwunye cytochrome c na hexokinase. Ụzọ njem ADP/ATP na njikọ nke ELAM na ATP Synthase na ANT.
I. Nchịkọta nke Mmekọrịta dị n'etiti Mitochondria na ịka nká
Mitochondria, dị ka ụlọ ọrụ ike nke cell, na-ahụ maka ịmepụta ọtụtụ ATP n'ime cell ma na-etinyekwa aka na nhazi usoro metabolic dị iche iche na usoro ntụgharị mgbaàmà. Ka afọ na-abawanye, ọrụ mitochondrial ji nwayọọ nwayọọ na-agbada, nke bụ otu n'ime akara akara nke ịka nká. Ọrịa mitochondrial na-egosipụta n'ọtụtụ ụzọ, gụnyere mmụkọ nke mmụgharị na mitochondrial DNA (mtDNA), mbelata ọrụ nke mitochondrial respiratory chain complexes, na-eduga na-ezughị ezu ike mmepụta; ụbara mmepụta nke ụdị oxygen na-emeghachi omume (ROS) site na mitochondria, na-ebute mmebi nrụgide oxidative, nke na-akpaghasịkwa biomolecules intracellular dị ka protein, lipids, na nucleic acid, na-eme ka ịka nká na ọnwụ dịkwuo elu. Ọrụ mitochondrial na-adịghị mma na-akpaghasịkwa intracellular calcium homeostasis, na-egbochi ọrụ physiological cellular nkịtị. Mgbanwe ndị a na-emekọrịta ihe n'etiti ibe ha, na-etolite usoro ọjọọ nke na-ejikọta usoro ịka nká.
II. Usoro nke Action nke SS-31
Na-emeziwanye Mitochondrial Energy Metabolism
Ịkwalite Mmetụta ADP: N'oge ịka nká, mitochondrial sensitivity na ADP na-ebelata, na-emebi arụmọrụ ATP. Nnyocha na-egosi na SS-31 nwere ike ijikọ ozugbo na mitochondrial ADP transporter ANT, na-abawanye nnabata ANT nke ADP, si otú ahụ na-eme ka mmetụta mitochondrial na ADP dịkwuo elu. Na mitochondria muscle merela agadi, ọgwụgwọ SS-31 mụbara nnabata ADP site na ANT, si otú ahụ na-eme ka iku ume mitochondrial dị n'okpuru mkpali ADP, na-amụba mmepụta ATP, na imeziwanye ike metabolism na muscle mitochondria agadi.
Iwu nke ogige iku ume mitochondrial: ogige mitochondrial iku ume bụ akụkụ dị mkpa nke mmepụta ike mitochondrial. N'oge ịka nká, ọrụ nke mgbagwoju anya nke iku ume na-ebelatakarị. SS-31 nwere ike idowe ma ọ bụ welie ọrụ nke ogige ndị na-eku ume iku ume site n'ịkwado iguzosi ike n'ezi ihe nhazi ha ma ọ bụ na-achịkwa okwu nke protein ndị metụtara ya. Nnyocha ndị gara aga achọpụtala na n'ụdị mitochondrial dysfunction nke ịka nká, a na-eweghachi ọrụ nke mgbagwoju anya iku ume mgbe ọgwụgwọ SS-31 gasịrị, na-atụ aro mmetụta ya dị mma na usoro iku ume mitochondrial.
Ọgụgụ 2 SS-31 ọgwụgwọ na-atụgharị phenotypes ịka nká obi
Na-ebelata mmebi nrụgide oxidative
Mbelata mmepụta ROS: Mitochondria bụ otu n'ime isi mmalite nke ROS n'ime sel, na mmepụta ROS na-abawanye na mitochondria n'oge ịka nká. SS-31 nwere ike ibelata mmepụta ROS site n'ọtụtụ ụzọ. Ọ na-eme ka metabolism ike mitochondrial dịkwuo mma, na-eme ka agbụ njem ụgbọ njem mitochondrial dị mma na ibelata ntapu elektrọn, si otú a na-ebelata mmepụta ROS. SS-31 nwere ike na-eme ihe ozugbo na akpụkpọ ahụ mitochondrial, na-agbanwe ihe onwunwe ya, na-ebelata saịtị mmebi oxidative na akpụkpọ ahụ, na igbochi mmepụta ROS. N'ime mkpụrụ ndụ obi sitere na ụmụ oke merela agadi, ọgwụgwọ na SS-31 belatara ọkwa mitochondrial ROS nke ukwuu, na-egosi ịdị irè ya n'ibelata mmepụta ROS.
Iwu nke sistemu enzyme antioxidant: Selụ nwere sistemu enzyme antioxidant, gụnyere superoxide dismutase (SOD), catalase (CAT), na glutathione peroxidase (GSH-Px), bụ ndị na-ahụ maka ịchụpụ ROS. Nnyocha na-egosi na SS-31 nwere ike ịkwalite ikike nchekwa nchekwa cellular site na ịkwalite okwu ma ọ bụ ọrụ nke enzymes antioxidant ndị a. N'ụdị cellular ụfọdụ, ọgwụgwọ na SS-31 butere mmụba dị ukwuu na ọrụ SOD na GSH-Px, na-enyere aka na mkpochapụ ROS n'oge n'ime sel na ibelata mmebi nke nrụgide oxidative.
Na-edobe nkwụsi ike nke akpụkpọ ahụ mitochondrial
Na-ejikọta na mitochondrial membrane phospholipids: SS-31 nwere nhazi pụrụ iche nke na-enye ya ohere ijikọta ya na mpaghara nke mitochondrial membrane bara ụba na phosphatidylserine. Phosphatidylserine bụ phospholipid kpọmkwem na akpụkpọ ahụ mitochondrial ma dị oké mkpa maka ịnọgide na-enwe nguzozi na nhazi nke akpụkpọ ahụ mitochondrial. N'oge ịka nká, phosphatidylserine na-enwe ike imebi mmebi nke oxidative, na-eduga n'ọdịdị na nhazi na ọrụ nke mitochondrial membrane. Mgbe ejikọtara ya na phosphatidylserine, SS-31 nwere ike ichebe phosphatidylserine site na oxidation ka ọ na-eme ka usoro akpụkpọ anụ mitochondrial guzosie ike, na-egbochi mbelata nke akpụkpọ ahụ mitochondrial na oghere nke mitochondrial permeability Transition pore (mPTP). Nnwale in vitro egosila na SS-31 na-egbochi mbelata nrụgide oxidative nke ọma na ike mitochondrial membran na oghere mPTP, si otú a na-edobe nkwụsi ike nke akpụkpọ anụ mitochondrial.
Iwu nke protein ndị metụtara akpụkpọ ahụ: akpụkpọ ahụ mitochondrial nwere protein dị iche iche na-etinye aka na njem ihe onwunwe mitochondrial, metabolism ume, na usoro ntụgharị mgbaàmà. SS-31 nwere ike imetụta nkwụsi ike nke akpụkpọ ahụ mitochondrial n'ụzọ na-edoghị anya site na ịhazi ọrụ ma ọ bụ nkwupụta nke protein ndị metụtara akpụkpọ ahụ. Ọ nwere ike na-ahazi ọrụ nke voltaji-based anion channels (VDAC), nke bụ protein ọwa dị mkpa na mpụta mitochondrial membrane ma na-arụ ọrụ dị mkpa n'ịdokwa mgbanwe ihe onwunwe na nnyefe mgbaàmà n'etiti mitochondria na cytoplasm. Usoro SS-31 nke VDAC na-enyere aka ịnọgide na-arụ ọrụ akpụkpọ ahụ mitochondrial nkịtị na nkwụsi ike.
III. Mmetụta kpọmkwem nke SS-31 na mgbochi ịka nká
Mmetụta na usoro obi
Ịkwalite ọrụ obi: Obi bụ akụkụ na-achọ ike dị elu, na ọrụ mitochondrial dị oké mkpa maka ịrụ ọrụ obi. N'ime ụmụ oke ndị merela agadi, obi na-egosipụtakarị okwu metụtara afọ dịka arụrụ ọrụ diastolic. Ndị ọkà mmụta sayensị achọpụtala na mgbe izu asatọ nke ọgwụgwọ SS-31 gasịrị, ọrụ diastolic nke obi ụmụ oke merela agadi na-akawanye mma. Ọganihu a so na nhazigharị nke mitochondrial proton leakage na mkpụrụ ndụ myocardial, belata ọkwa mitochondrial ROS, mbelata ogo protein oxidation nke obi, yana ngbanwe na steeti thiol redox nke protein na ọnọdụ mbelata karịa. SS-31 mekwara ka ọkwa phosphorylation nke cMyBP-C Ser282 dị na mkpụrụ ndụ myocardial, nke jikọtara ya na ọrụ diastolic obi ka mma.
Ọgụgụ 3 SS31 gbochiri mmebi mmụta na ụmụ oke ịka nká nke enweghị ihi ụra kpatara.
Nchedo akwara: N'oge ịka nká, ọrụ sel endothelial na-emebi emebi, elasticity vaskụla na-ebelata, ọrịa obi na-enwekwa ike ime. N'ụdị microbleeding na-akpata ọbara mgbali elu na ụbụrụ ụmụ oke agadi, ọgwụgwọ na SS-31 na-egosipụta mmetụta nchebe vaskụla dị ịrịba ama. Ọ na-ebelata mmepụta radical free mitochondrial nke ọbara mgbali elu na-ebute, na-ebelata nrụgide oxidative na mgbidi vaskụla, si otú ahụ na-egbu oge mmalite nke microbleeding nke ukwuu na ibelata ya. Ya mere, SS-31 na-arụ ọrụ dị mkpa n'ịnọgide na-enwe usoro nkịtị na ọrụ nke arịa ọbara na igbochi ọrịa vaskụla metụtara afọ.
Mmetụta na usoro ụjọ ahụ
Na-ebelata ikike ọgụgụ isi: Ka afọ na-abawanye, usoro ụjọ ahụ na-eji nwayọọ nwayọọ na-ebelata, na arụrụ ọrụ nke ọgụgụ isi dị ka nsogbu ebe nchekwa na mbelata ikike mmụta na-aghọwanye nke ọma. Ngwọta Mitochondrial na-arụ ọrụ dị oke mkpa na mmalite na ọganihu nke ọrịa neurodegenerative na arụ ọrụ ụbụrụ. N'ihe atụ nke dysfunction uche nke isoflurane na-ebute na ụmụ oke agadi, SS-31 nwere ike gbanwee arụ ọrụ mitochondrial, napụta adịghị ike nke isoflurane kpatara. SS-31 na-akwalite ụkpụrụ nke BDNF nrịbama, na-atụgharị nbibi nke protein ndị metụtara synaptic plasticity dị ka synaptophysin, PSD-95, na p-CREB, ma na-emezi NR2A, NR2B, CaMKIIa, na CaMKIIβ, si otú ahụ na-eme ka synaptic plasticity na-echebe ọrụ cognitive.
Ibelata mmetụta na-adịghị mma nke ụra ihi ụra: Ụra ụra bụ ihe na-akpatakarị nchekasị, na mmetụta ọjọọ ya na usoro ụjọ ahụ na-apụtawanye mgbe ọ dị afọ, na-eduga n'ịgwọ ọrịa uche na ịba ụba nke ọrịa neurodegenerative. N'ime ụmụ oke dị ọnwa 20, a na-enye SS-31 (3 mg/kg) site na injection subcutaneous kwa ụbọchị maka ụbọchị 4 n'usoro, yana ụra 4 awa n'ime ụbọchị abụọ gara aga. Nsonaazụ gosiri na ụmụ oke ndị na-adịghị ehi ụra nke ejiri SS-31 egosipụtaghị enweghị mmerụ dị ịrịba ama na ikike mmụta, yana mweghachi ụbụrụ mitochondrial ATP na protein synaptic na-achịkwa protein, yana mbelata ọkwa nke ụdị oxygen reactive (ROS) na cytokines mkpali na hippocampus. Nke a na-egosi na SS-31 nwere ike nweta uru ọgwụgwọ nwere ike ibelata mmetụta akwara ozi nke ụra nwa oge na ụmụ oke merela agadi.
Mmetụta na sistemu akụrụ: N'ime akụrụ nke oke oke, glomerulosclerosis na-ejikọta ya na mmebi mitochondrial na sel epithelial glomerular. Mgbe izu asatọ nke ọgwụgwọ SS-31 na ụmụ oke dị ọnwa 26 gasịrị, SS-31 kwalitere morphology mitochondrial metụtara afọ yana belata glomerulosclerosis. Kpọmkwem, ọ belatara ngosipụta nke nrịbama ịka nká (p16, β-Gal na-eme agadi), mụbara njupụta nke mkpụrụ ndụ epithelial apical, ma belata ngosipụta nke nrịbama nke cell epithelial cell activation (collagen IV, pERK1/2, na α-smooth muscle actin). Ọ bụ ezie na SS-31 emetụtaghị njupụta podocyte, ọ na-ebelata ihe nrịbama nke mmebi podocyte (desmin), mezie iguzosi ike n'ezi ihe nke cytoskeletal (synaptophysin), yana njupụta cell endothelial glomerular dị elu (CD31). Nke a na-egosi na ọgwụgwọ SS-31 dị mkpirikpi nwekwara mmetụta nchebe na mitochondria glomerular ma na-eme ka nhazi glomerular dịkwuo mma.
Mmetụta na ọkwa cellular
Na-egbu oge ịka nká cellular: N'ime nyocha cell, a na-eji H₂O₂ mee ihe iji mee ka ụdị ịka nká na-akpata nchekasị na sel HEK293T, na-esote ntinye aka na SS-31. Nsonaazụ gosiri na ọnụọgụ SA-β-gal dị mma belatara nke ukwuu n'ime otu SS-31, na-egosi mbelata ọkwa ịka nká cellular. Na mgbakwunye, ike intracellular ROS fluorescence ike belatara, mitochondrial akpụkpọ ahụ nwere ike mụbara, na ọkwa ATP bilitere na otu SS-31. Nyocha nke immunoblotting Protein gosipụtara na ọkwa ngosipụta nke protein P53, P21 na Acetyl-p53 dị elu n'ime otu ụdị atụnyere otu njikwa, ebe otu SS-31 gosipụtara mbelata ma e jiri ya tụnyere otu ụdị. N'aka nke ọzọ, ọkwa ọkwa nke protein Sirt1 dị ala na ụdị ihe nlereanya ma e jiri ya tụnyere otu njikwa, ebe otu SS-31 gosipụtara mmụba ma e jiri ya tụnyere ndị nlereanya. Ya mere, enwere ike ikwubi na SS-31 nwere ike igbu oge HEK293T cell ịka nká site na imeziwanye ọrụ mitochondrial na ịhazi okwu nke protein ndị metụtara ịka nká n'ime sel.
Nchedo megide nrụgide oxidative na-akpata mmebi cellular: N'ime ụdị mmebi nrụgide oxidative na-akpata H₂O₂ nke mkpụrụ ndụ ARPE-19, ọgwụgwọ na SS-31 mụbara ọnụ ọgụgụ ndụ ndụ cell, belata ọkwa ROS intracellular, belata ọnụ ọgụgụ nke sel na mbelata akpụkpọ anụ mitochondrial, na-ebelata PI nke ọma ma na-ebelata ọnụ ọgụgụ sel nke ukwuu. Mmebi nke okwu protein RIP3. Nsonaazụ ndị a na-egosi na SS-31 nwere mmetụta nchebe dị ịrịba ama megide mmebi nrụgide oxidative na-akpata H₂O₂ na sel ARPE-19, nke nwere ike inye aka n'ịkwụsị mmebi metụtara afọ.
Mmechi
Mitochondrial-ezubere iche peptide SS-31 na-enye aka na mgbochi ịka nká. Site na usoro nhazi ya dị iche iche na ọrụ mitochondrial na mmetụta mgbochi ịka nká ya dị iche iche na ọkwa dị iche iche nke sistemu na cellular, ọ na-egosipụta ike dị ka atụmatụ dị mkpa mgbochi ịka nká.
Isi mmalite
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[2] Fero G, Kamat V, Kannan S, et al. peptide elamipretide (SS-31) ezubere iche nke mitochondrially na-eme ka uche ADP dị na mitochondria megoro agadi site n'ịbawanye nnabata site na adenine nucleotide translocator (ANT)[J]. Geroscience, 2023,45 (6): 3529-3548.DOI:10.1007/s11357-023-00861-y.
[3] Chiao YA, Zhang H, Sweetwyne M, et al. Mweghachi nke ọrụ mitochondrial n'oge ndụ na-atụgharị arụrụ ọrụ obi na ụmụ oke ochie[J]. Elife, 2020,9.DOI:10.7554/eLife.55513.
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[5] Wu J, Zhang M, Li H, et al. Ụzọ BDNF na-etinye aka na mmetụta nchebe nke SS-31 na adịghị ike nke isoflurane na-ebute na oke oke [J]. Nyocha ụbụrụ omume, 2016,305:115-121.DOI:10.1016/j.bbr.2016.02.036.
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