Los ntawm Cocer Peptides 
1 month ago
Tag nrho cov kab lus thiab cov ntaub ntawv ntawm cov khoom lag luam muab rau ntawm lub vev xaib no tsuas yog rau cov ntaub ntawv tshaj tawm kev tshaj tawm thiab cov hom phiaj kev kawm.
Cov khoom muab rau hauv lub vev xaib no yog npaj tshwj xeeb rau kev tshawb fawb hauv vitro. Kev tshawb fawb hauv vitro (Latin: * hauv iav *, lub ntsiab lus hauv iav) yog ua los ntawm tib neeg lub cev. Cov khoom no tsis yog tshuaj, tsis tau txais kev pom zoo los ntawm US Food and Drug Administration (FDA), thiab yuav tsum tsis txhob siv los tiv thaiv, kho, lossis kho txhua yam mob, kab mob, lossis mob. Nws raug txwv nruj raws li txoj cai los qhia cov khoom no rau hauv tib neeg lossis tsiaj lub cev hauv txhua daim ntawv.
Mitochondria-targeted peptide SS-31, tseem hu ua elamipretide, yog ib qho me me-molecule peptide nrog tshwj xeeb mitochondria-targeting functionality. Nyob rau hauv xyoo tas los no, raws li kev tshawb fawb rau hauv cov txheej txheem ntawm kev laus tau tob zuj zus, lub luag haujlwm tseem ceeb ntawm mitochondrial tsis ua haujlwm hauv cov txheej txheem kev laus tau dhau los ua pov thawj. SS-31, nrog nws cov cim mitochondrial lub hom phiaj thiab muaj peev xwm tswj hwm mitochondrial muaj nuj nqi, tuav cov lus cog tseg rau kev tiv thaiv kev laus.
Daim duab 1 Kev ua pa thiab daim nyias nyias muaj peev xwm teb rau ADP stimulation hauv cov leeg leeg mitochondria yuav tsum tau ntxiv cytochrome c thiab hexokinase clamp. ADP/ATP kev thauj mus los thiab kev khi ntawm ELAM rau ATP Synthase thiab ANT.
I. Txheej txheem cej luam ntawm Kev Sib Raug Zoo Ntawm Mitochondria thiab Kev Laus
Mitochondria, raws li lub cell lub zog, yog lub luag hauj lwm rau synthesizing feem ntau ntawm ATP nyob rau hauv lub cell thiab tseem koom nyob rau hauv ntau yam kev cai metabolic thiab teeb liab transduction txheej txheem. Thaum muaj hnub nyoog nce, mitochondrial kev ua haujlwm maj mam poob qis, uas yog ib qho ntawm cov cim tseem ceeb ntawm kev laus. Mitochondrial dysfunction manifests nyob rau hauv ntau txoj kev, nrog rau cov tsub zuj zuj ntawm kev hloov nyob rau hauv mitochondrial DNA (mtDNA), txo cov kev ua ntawm mitochondrial respiratory chain complexes, ua rau tsis txaus lub zog; nce ntau lawm ntawm reactive oxygen hom (ROS) los ntawm mitochondria, ua rau oxidative kev nyuaj siab puas, uas ntxiv cuam tshuam intracellular biomolecules xws li cov proteins, lipids, thiab nucleic acids, accelerating cellular aging thiab tuag. Kev ua haujlwm tsis zoo ntawm mitochondrial kuj cuam tshuam cov calcium homeostasis intracellular, cuam tshuam nrog kev ua haujlwm ntawm cellular physiological. Cov kev hloov pauv no cuam tshuam nrog ib leeg, tsim lub voj voog vicious uas sib sau ua ke ua rau cov txheej txheem kev laus.
II. Mechanism of Action ntawm SS-31
Txhim kho Mitochondrial Zog Metabolism
Txhim khu ADP Sensitivity: Thaum lub sij hawm laus, mitochondrial rhiab heev rau ADP txo, impairing ATP synthesis efficiency. Cov kev tshawb fawb qhia tias SS-31 tuaj yeem khi ncaj qha rau mitochondrial ADP transporter ANT, nce ANT qhov nce ntawm ADP, yog li txhim kho mitochondrial rhiab heev rau ADP. Nyob rau hauv cov laus cov leeg nqaij mitochondria, SS-31 kev kho mob nce ADP uptake ntawm ANT, yog li pab txhawb mitochondrial respiration nyob rau hauv ADP stimulation, nce ATP ntau lawm, thiab txhim kho lub zog metabolism hauv cov laus cov leeg mitochondria.
Kev tswj ntawm mitochondrial respiratory chain complexes: Mitochondrial respiratory chain complexes yog cov khoom tseem ceeb ntawm mitochondrial zog tsim. Thaum lub sij hawm laus, kev ua haujlwm ntawm cov kab mob ua pa nyuaj feem ntau txo qis. SS-31 tuaj yeem tswj lossis txhim kho kev ua haujlwm ntawm cov kab mob ua pa los ntawm kev ruaj khov ntawm lawv cov qauv kev ncaj ncees lossis tswj kev qhia txog cov proteins uas cuam tshuam. Cov kev tshawb fawb yav dhau los tau pom tias hauv cov qauv kev laus uas muaj feem xyuam rau mitochondrial dysfunction, kev ua haujlwm ntawm cov kab mob ua pa nyuaj tau rov qab los tom qab kev kho mob SS-31, qhia txog nws cov txiaj ntsig zoo ntawm cov kab mob mitochondrial.
Daim duab 2 SS-31 kev kho mob thim rov qab mob plawv phenotypes
Txo oxidative kev nyuaj siab puas tsuaj
Txo ROS ntau lawm: Mitochondria yog ib qho tseem ceeb ntawm ROS hauv hlwb, thiab ROS ntau lawm nce hauv mitochondria thaum laus. SS-31 tuaj yeem txo ROS ntau lawm los ntawm ntau txoj hauv kev. Nws txhim kho mitochondrial zog metabolism, ua rau cov mitochondrial electron thauj saw ntau npaum thiab txo electron to, li no txo ROS ntau lawm. SS-31 tuaj yeem ua ncaj qha rau ntawm daim nyias nyias mitochondrial, hloov nws lub cev lub zog, txo cov oxidative puas qhov chaw ntawm daim nyias nyias, thiab inhibiting ROS ntau lawm. Hauv cov kab mob plawv los ntawm cov nas hnub nyoog, kev kho mob nrog SS-31 txo qis mitochondrial ROS qib, qhia nws qhov ua tau zoo hauv kev txo qis ROS ntau lawm.
Kev tswj hwm ntawm cov kab mob antioxidant: Cells muaj cov kab mob antioxidant, suav nrog superoxide dismutase (SOD), catalase (CAT), thiab glutathione peroxidase (GSH-Px), uas yog lub luag haujlwm rau kev tshem tawm ROS. Kev tshawb fawb qhia tias SS-31 tuaj yeem txhim kho cellular antioxidant tiv thaiv lub peev xwm los ntawm kev txhawb nqa kev qhia lossis kev ua haujlwm ntawm cov enzymes antioxidant. Hauv qee cov qauv ntawm tes, kev kho mob nrog SS-31 ua rau muaj kev nce ntxiv hauv kev ua haujlwm ntawm SOD thiab GSH-Px, pab txhawm rau tshem tawm ROS raws sijhawm hauv cov hlwb thiab txo cov oxidative kev ntxhov siab vim kev puas tsuaj.
Txhim kho mitochondrial membrane stability
Kev khi rau mitochondrial membrane phospholipids: SS-31 muaj cov qauv tshwj xeeb uas tso cai rau nws nyiam khi rau thaj tsam ntawm mitochondrial membrane nplua nuj nyob hauv phosphatidylserine. Phosphatidylserine yog ib qho phospholipid tshwj xeeb rau mitochondrial membrane thiab tseem ceeb heev rau kev tswj xyuas cov txheej txheem thiab kev ua haujlwm ntawm mitochondrial membrane. Thaum lub sij hawm kev laus, phosphatidylserine yog qhov cuam tshuam rau oxidative puas tsuaj, ua rau muaj kev txawv txav hauv mitochondrial membrane qauv thiab kev ua haujlwm. Tom qab khi rau phosphatidylserine, SS-31 tuaj yeem tiv thaiv phosphatidylserine los ntawm oxidation thaum stabilizing mitochondrial membrane qauv, tiv thaiv kev txo qis hauv mitochondrial membrane muaj peev xwm thiab qhib mitochondrial permeability hloov pore (mPTP). Kev sim hauv vitro tau pom tias SS-31 muaj txiaj ntsig zoo inhibits oxidative kev ntxhov siab vim qhov txo qis hauv mitochondrial membrane muaj peev xwm thiab mPTP qhib, yog li tswj cov mitochondrial membrane stability.
Kev tswj hwm ntawm daim nyias nyias cov proteins: Lub mitochondrial membrane muaj ntau cov proteins koom nrog hauv kev thauj khoom mitochondrial, lub zog metabolism, thiab cov txheej txheem hloov pauv. SS-31 tuaj yeem cuam tshuam ncaj qha rau mitochondrial membrane stability los ntawm kev tswj cov kev ua ub no los yog kev nthuav qhia ntawm cov membrane-ssociated proteins. Nws tuaj yeem tswj hwm kev ua haujlwm ntawm voltage-dependent anion channels (VDAC), uas yog ib qho tseem ceeb channel proteins nyob rau sab nrauv mitochondrial membrane thiab ua lub luag haujlwm tseem ceeb hauv kev tswj cov khoom sib pauv thiab teeb liab kis ntawm mitochondria thiab cytoplasm. SS-31 txoj cai ntawm VDAC pab tswj kev ua haujlwm ntawm mitochondrial membrane thiab ruaj khov.
III. Cov teebmeem tshwj xeeb ntawm SS-31 hauv kev tiv thaiv kev laus
Cov teebmeem ntawm cov hlab plawv
Txhim kho lub plawv muaj nuj nqi: Lub plawv yog lub cev muaj zog-xav tau lub cev, thiab kev ua haujlwm mitochondrial tseem ceeb heev rau kev ua haujlwm plawv. Hauv cov nas muaj hnub nyoog, lub plawv feem ntau pom cov teeb meem ntsig txog hnub nyoog xws li diastolic dysfunction. Cov kws tshawb fawb tau pom tias tom qab 8 lub lis piam ntawm kev kho SS-31, diastolic kev ua haujlwm ntawm cov nas hnub nyoog lub siab tau txhim kho zoo. Qhov kev txhim kho no tau nrog rau qhov normalization ntawm mitochondrial proton leakage nyob rau hauv myocardial hlwb, txo mitochondrial ROS theem, txo cov hlab plawv protein oxidation theem, thiab ib tug hloov nyob rau hauv lub thiol redox lub xeev ntawm cov proteins mus rau ib tug ntau txo lub xeev. SS-31 kuj tau nce qib phosphorylation ntawm cMyBP-C Ser282 hauv cov hlwb myocardial, uas cuam tshuam nrog kev txhim kho plawv diastolic.
Daim duab 3 Kev kawm tsis zoo ntawm cov nas laus uas tau tshwm sim los ntawm kev pw tsaug zog tau tiv thaiv nrog SS31.
Kev tiv thaiv kab mob: Thaum lub sij hawm laus, endothelial cell muaj nuj nqi yog impaired, vascular elasticity txo, thiab kab mob plawv yuav tshwm sim. Hauv cov qauv ntshav siab-induced microbleeding hauv lub hlwb ntawm cov nas muaj hnub nyoog, kev kho mob nrog SS-31 qhia txog kev tiv thaiv vascular tseem ceeb. Nws txo cov mitochondrial dawb radical ntau lawm induced los ntawm kub siab, alleviates oxidative kev nyuaj siab puas tsuaj rau lub vascular phab ntsa, li no ho ncua qhov pib ntawm microbleeding thiab txo nws cov xwm txheej. Yog li ntawd, SS-31 plays lub luag haujlwm tseem ceeb hauv kev tswj cov qauv thiab kev ua haujlwm ntawm cov hlab ntsha thiab tiv thaiv cov hnub nyoog ntsig txog cov kab mob vascular.
Cov teebmeem ntawm lub paj hlwb
Txhim kho kev paub tsis meej: Raws li hnub nyoog nce, lub paj hlwb ua haujlwm maj mam poob qis, thiab kev paub tsis meej xws li kev nco tsis zoo thiab txo qis kev kawm muaj peev xwm ua tau zoo dua. Mitochondrial dysfunction plays lub luag haujlwm tseem ceeb hauv qhov pib thiab kev loj hlob ntawm cov kab mob neurodegenerative thiab kev paub tsis meej. Hauv cov qauv ntawm kev paub tsis meej vim yog isoflurane hauv cov nas muaj hnub nyoog, SS-31 tuaj yeem thim rov qab mitochondrial dysfunction, cawm isoflurane-induced kev txawj ntse tsis txaus. SS-31 txhawb kev tswj hwm ntawm BDNF signaling, thim rov qab kev tswj hwm ntawm synaptic plasticity-txog cov proteins xws li synaptophysin, PSD-95, thiab p-CREB, thiab upregulates NR2A, NR2B, CaMKIIα, thiab CaMKIIβ, yog li txhim kho synaptic plasticity thiab tiv thaiv.
Txo cov teebmeem tsis zoo ntawm kev pw tsaug zog: Kev pw tsaug zog tsis zoo yog ib qho kev ntxhov siab, thiab nws cov teebmeem tsis zoo ntawm lub paj hlwb ua rau muaj hnub nyoog, ua rau kev paub tsis meej thiab muaj kev pheej hmoo ntawm cov kab mob neurodegenerative. Hauv cov nas muaj hnub nyoog 20 hli, SS-31 (3 mg / kg) tau siv los ntawm kev txhaj tshuaj subcutaneous txhua hnub rau 4 hnub sib law liag, nrog rau 4 teev ntawm kev pw tsaug zog ob hnub dhau los. Cov txiaj ntsig tau pom tias cov nas pw tsaug zog tau kho nrog SS-31 tsis muaj qhov cuam tshuam loj hauv kev kawm, nrog rov qab lub hlwb mitochondrial ATP qib thiab synaptic plasticity-regulating proteins, nrog rau txo qis ntawm cov pa oxygen reactive (ROS) thiab inflammatory cytokines hauv hippocampus. Qhov no qhia tau tias SS-31 tuaj yeem muaj peev xwm kho tau cov txiaj ntsig hauv kev txo qis kev cuam tshuam ntawm lub paj hlwb ntawm kev pw tsaug zog luv luv hauv cov nas hnub nyoog.
Kev cuam tshuam rau lub raum: Hauv ob lub raum ntawm cov nas hnub nyoog, glomerulosclerosis yog txuam nrog kev puas tsuaj mitochondrial hauv glomerular epithelial hlwb. Tom qab 8 lub lis piam ntawm SS-31 kev kho mob hauv cov nas muaj hnub nyoog 26 hli, SS-31 txhim kho lub hnub nyoog ntsig txog mitochondrial morphology thiab alleviated glomerulosclerosis. Tshwj xeeb, nws txo qhov kev qhia ntawm cov cim kev laus (p16, aging-associated β-Gal), nce qhov ceev ntawm apical epithelial hlwb, thiab txo qhov kev qhia ntawm cov cim ntawm parietal epithelial cell activation (collagen IV, pERK1/2, thiab α-smooth leeg actin). Txawm hais tias SS-31 tsis cuam tshuam rau podocyte ntom, nws txo cov cim ntawm kev puas tsuaj ntawm podocyte (desmin), txhim kho cytoskeletal kev ncaj ncees (synaptophysin), thiab tau nrog ntau dua glomerular endothelial cell ceev (CD31). Qhov no qhia tias kev kho mob luv luv SS-31 kuj muaj kev tiv thaiv ntawm glomerular mitochondria thiab txhim kho glomerular qauv.
Cov teebmeem ntawm qib cellular
Kev ncua ntawm cellular aging: Hauv kev sim ntawm tes, H₂O₂ tau siv los ua kom muaj kev ntxhov siab vim kev laus hauv HEK293T hlwb, ua raws li kev cuam tshuam nrog SS-31. Cov txiaj ntsig tau pom tias SA-β-gal tus nqi zoo tau txo qis hauv pawg SS-31, qhia txog kev txo qis hauv cellular aging. Tsis tas li ntawd, qhov intracellular ROS fluorescence siv tau txo qis, mitochondrial membrane muaj peev xwm nce, thiab ATP qib tau nce hauv pawg SS-31. Protein immunoblotting tsom xam tau qhia tias cov qib qhia ntawm P53, P21, thiab Acetyl-p53 cov protein ntau dua nyob rau hauv pawg qauv piv rau pawg tswj hwm, thaum pawg SS-31 pom qhov txo qis piv rau pawg qauv. Hloov pauv, qib kev qhia ntawm Sirt1 protein tau qis dua hauv pawg qauv piv rau pawg tswj hwm, thaum pab pawg SS-31 pom qhov nce ntxiv piv rau pawg qauv. Yog li, nws tuaj yeem xaus lus tias SS-31 tuaj yeem ncua sijhawm HEK293T cell aging los ntawm kev txhim kho mitochondrial muaj nuj nqi thiab tswj kev qhia txog kev laus ntawm cov proteins hauv cov hlwb.
Kev tiv thaiv oxidative kev nyuaj siab vim cellular puas: Nyob rau hauv lub H₂O₂-induced oxidative kev nyuaj siab kev puas tsuaj qauv ntawm ARPE-19 hlwb, kev kho mob nrog SS-31 ho nce cell ciaj sia taus tus nqi, txo intracellular ROS theem, txo cov feem ntawm cov cell nrog txo mitochondrial membrane peev xwm, markedly txo qis PI positten tus nqi ntawm kev tuag, upregulation ntawm RIP3 protein qhia. Cov txiaj ntsig no qhia tau hais tias SS-31 muaj kev tiv thaiv tseem ceeb tiv thaiv H₂O₂-induced oxidative kev nyuaj siab puas tsuaj hauv ARPE-19 hlwb, uas tuaj yeem pab tiv thaiv kev puas tsuaj rau hnub nyoog.
Xaus
Lub mitochondrial-targeted peptide SS-31 pab txhawb kev laus. Los ntawm nws cov txheej txheem kev tswj hwm ntau yam ntawm mitochondrial muaj nuj nqi rau nws qhov tseem ceeb los tiv thaiv kev laus ntawm ntau theem ntawm cov kab mob thiab cov cellular, nws pom muaj peev xwm ua ib qho tseem ceeb los tiv thaiv kev laus.
Qhov chaw
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[2] Pharaoh G, Kamat V, Kannan S, et al. Lub mitochondrially targeted peptide elamipretide (SS-31) txhim kho ADP rhiab heev nyob rau hauv cov laus mitochondria los ntawm kev nce uptake los ntawm 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. Kev kho lub neej lig ntawm mitochondrial muaj nuj nqi thim rov qab lub plawv tsis ua haujlwm hauv cov nas qub [J]. Elife, 2020, 9.DOI: 10.7554/eLife.55513.
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[4] Sweetwyne MT, Pippin JW, Eng DG, et al. Lub mitochondrial-targeted peptide, SS-31, txhim kho glomerular architecture hauv nas ntawm cov hnub nyoog siab heev [J]. Kidney International, 2017,91(5):1126-1145.DOI:10.1016/j.kint.2016.10.036.
[5] Wu J, Zhang M, Li H, et al. BDNF txoj hauv kev yog koom nrog kev tiv thaiv los ntawm SS-31 ntawm isoflurane-induced kev paub tsis meej hauv cov nas laus[J]. Behavioral Brain Research, 2016,305:115-121.DOI:10.1016/j.bbr.2016.02.036.
Cov khoom muaj rau kev tshawb fawb siv nkaus xwb:
