By Cocer Peptides 
Watanni 1 da suka gabata
DUKKANIN LABARI DA BAYANIN KYAUTATAWA DA AKE BAYAR A WANNAN SHAFIN KAWAI DOMIN WATSA BAYANI NE DA MANUFOFIN ILIMI.
Kayayyakin da aka bayar akan wannan gidan yanar gizon an yi niyya ne kawai don binciken in vitro. Binciken in vitro (Latin: *a cikin gilashi*, ma'ana a cikin gilashin gilashi) ana gudanar da shi a wajen jikin mutum. Waɗannan samfuran ba magunguna ba ne, Hukumar Abinci da Magunguna ta Amurka (FDA) ba ta amince da su ba, kuma dole ne a yi amfani da su don hanawa, magani, ko warkar da duk wani yanayi na likita, cuta, ko cuta. Doka ta haramta shigar da waɗannan samfuran cikin jikin mutum ko dabba ta kowace hanya.
Mitochondria-wanda aka yi niyya peptide SS-31, kuma aka sani da elampretide, ƙaramin peptide ne na kwayoyin halitta tare da takamaiman aikin mitochondria-niyya. A cikin 'yan shekarun nan, yayin da bincike game da hanyoyin tsufa ya zurfafa, muhimmiyar rawar da rashin aikin mitochondrial a cikin tsarin tsufa ya kara bayyana. SS-31, tare da ƙayyadaddun ƙayyadaddun niyya na mitochondrial da ikon daidaita aikin mitochondrial, yana riƙe da alƙawari don aikace-aikacen rigakafin tsufa.
Hoto 1 Numfashi da yuwuwar amsawar membrane ga ƙarfafawar ADP a cikin keɓewar tsoka mitochondria na buƙatar ƙarin cytochrome c da matsi na hexokinase. Hanyar jigilar ADP/ATP da ɗaure ELAM zuwa ATP Synthase da ANT.
I. Bayanin Dangantaka Tsakanin Mitochondria da Tsufa
Mitochondria, a matsayin gidan wutar lantarki, sune ke da alhakin haɗa yawancin ATP a cikin tantanin halitta kuma suna da hannu cikin ƙa'idodi daban-daban na rayuwa da tafiyar da sigina. Yayin da shekaru ke ƙaruwa, aikin mitochondrial yana raguwa a hankali, wanda shine ɗayan mahimman alamomin tsufa. Tashin hankali na mitochondrial yana bayyana ta hanyoyi da yawa, ciki har da tarin maye gurbi a cikin DNA mitochondrial (mtDNA), rage yawan ayyukan sarkar numfashi na mitochondrial, wanda ke haifar da ƙarancin samar da makamashi; ƙara yawan samar da nau'in oxygen mai amsawa (ROS) ta hanyar mitochondria, yana haifar da lalacewar danniya na oxidative, wanda ke kara rushe kwayoyin halitta na cikin kwayoyin halitta kamar sunadarai, lipids, da acid nucleic, yana hanzarta tsufa da mutuwa. Ayyukan mitochondrial mara kyau kuma yana rushe intracellular calcium homeostasis, yana tsoma baki tare da ayyukan ilimin halittar jiki na yau da kullun. Waɗannan canje-canjen suna hulɗa da juna, suna haifar da mugun yanayi wanda ke haifar da tsarin tsufa tare.
II. Hanyar Ayyukan SS-31
Inganta Mitochondrial Energy Metabolism
Haɓaka Hankali na ADP: Lokacin tsufa, ƙwarewar mitochondrial zuwa ADP yana raguwa, yana lalata haɓakar haɗin ATP. Nazarin ya nuna cewa SS-31 na iya ɗaure kai tsaye ga mai jigilar ADP na mitochondrial, yana ƙara haɓakar ANT na ADP, ta haka yana haɓaka ƙwarewar mitochondrial ga ADP. A cikin tsofaffin tsoka mitochondria, SS-31 magani ya karu da karɓar ADP ta hanyar ANT, ta haka yana haɓaka numfashi na mitochondrial a ƙarƙashin ƙarfafawar ADP, ƙara yawan samar da ATP, da inganta haɓakar makamashi a cikin tsofaffin tsoka mitochondria.
Ka'idojin sarkar numfashi na mitochondrial: Rukunin sarkar numfashi na Mitochondrial sune mahimman abubuwan samar da makamashi na mitochondrial. A lokacin tsufa, ayyukan sarkar numfashi sau da yawa yana raguwa. SS-31 na iya kiyayewa ko haɓaka ayyukan rukunonin sarkar numfashi ta hanyar daidaita amincin tsarin su ko daidaita maganganun sunadarai masu alaƙa. Nazarin da suka gabata sun lura cewa a cikin nau'ikan dysfunction mitochondrial da suka shafi tsufa, ana dawo da ayyukan sarkar numfashi bayan jiyya na SS-31, yana ba da shawarar ingantaccen tasirin sa akan sarkar numfashi na mitochondrial.
Hoto 2 SS-31 magani yana juyar da yanayin tsufa na zuciya
Rage lalacewar danniya
Rage samar da ROS: Mitochondria ɗaya ne daga cikin tushen tushen ROS a cikin sel, kuma samar da ROS yana ƙaruwa a cikin mitochondria yayin tsufa. SS-31 na iya rage samar da ROS ta hanyoyi da yawa. Yana inganta metabolism na makamashin mitochondrial, yana sa sarkar jigilar lantarki ta mitochondrial ta fi dacewa da rage zubewar lantarki, ta haka rage yawan samar da ROS. SS-31 na iya yin aiki kai tsaye a kan membrane na mitochondrial, yana canza kaddarorinsa na zahiri, rage wuraren lalata oxidative akan membrane, da hana samar da ROS. A cikin sel na zuciya daga tsofaffin beraye, jiyya tare da SS-31 sun rage matakan mitochondrial ROS sosai, yana nuna ingancinsa wajen rage samar da ROS.
Tsarin tsarin enzyme antioxidant: Kwayoyin sun ƙunshi tsarin enzyme antioxidant, ciki har da superoxide dismutase (SOD), catalase (CAT), da glutathione peroxidase (GSH-Px), waɗanda ke da alhakin lalata ROS. Bincike ya nuna cewa SS-31 na iya haɓaka ƙarfin kariyar antioxidant ta salula ta hanyar haɓaka magana ko ayyukan waɗannan enzymes antioxidant. A cikin wasu nau'ikan salon salula, jiyya tare da SS-31 ya haifar da ƙaruwa mai yawa a cikin ayyukan SOD da GSH-Px, suna taimakawa a cikin lokacin share wuce haddi na ROS a cikin sel da rage lalacewa mai haifar da damuwa.
Kula da kwanciyar hankali na mitochondrial
Daure ga mitochondrial membrane phospholipids: SS-31 yana da tsari na musamman wanda ya ba shi damar daure da kyau ga yankuna na membran mitochondrial mai arziki a cikin phosphatidylserine. Phosphatidylserine wani phospholipid ne na musamman ga membrane na mitochondrial kuma yana da mahimmanci don kiyaye tsarin tsari da amincin aikin membrane na mitochondrial. A lokacin tsufa, phosphatidylserine yana da saukin kamuwa da lalacewar oxidative, yana haifar da rashin daidaituwa a cikin tsarin membrane na mitochondrial da aiki. Bayan ɗaure zuwa phosphatidylserine, SS-31 na iya kare phosphatidylserine daga iskar shaka yayin da yake daidaita tsarin membrane na mitochondrial, yana hana raguwa a cikin yuwuwar mitochondrial da kuma buɗewa na mitochondrial permeability canjin pore (mPTP). Gwaje-gwajen in vitro sun nuna cewa SS-31 yadda ya kamata ya hana raguwar damuwa na oxidative a cikin yuwuwar mitochondrial membrane da buɗewar mPTP, don haka yana riƙe da kwanciyar hankali na mitochondrial.
Tsarin sunadaran da ke da alaƙa da membrane: Membran mitochondrial yana ƙunshe da sunadaran sunadarai daban-daban waɗanda ke cikin jigilar kayan mitochondrial, kuzarin kuzari, da tafiyar da sigina. SS-31 na iya yin tasiri a kaikaice na mitochondrial membrane kwanciyar hankali ta hanyar daidaita ayyuka ko maganganun waɗannan sunadarai masu alaƙa da membrane. Yana iya daidaita aikin tashoshin anion masu dogara da wutar lantarki (VDAC), waxanda suke da mahimmancin sunadaran sunadaran tashoshi akan membrane na mitochondrial na waje kuma suna taka muhimmiyar rawa wajen kiyaye musayar abu da watsa siginar tsakanin mitochondria da cytoplasm. Dokokin SS-31 na VDAC na taimakawa wajen kiyaye aikin membrane na mitochondrial na al'ada da kwanciyar hankali.
III. Takamaiman tasirin SS-31 a cikin rigakafin tsufa
Tasiri akan tsarin zuciya da jijiyoyin jini
Inganta aikin zuciya: Zuciya babbar gabo ce mai buƙatar kuzari, kuma aikin mitochondrial yana da mahimmanci ga aikin zuciya. A cikin tsofaffin beraye, zuciya sau da yawa tana nuna al'amurran da suka shafi shekaru kamar tabarbarewar diastolic. Masana kimiyya sun gano cewa bayan makonni 8 na jiyya na SS-31, aikin diastolic na zukatan mice masu tsufa ya inganta sosai. Wannan haɓakawa yana tare da daidaitawa na mitochondrial proton leakage a cikin sel myocardial, rage matakan ROS mitochondrial, rage matakan furotin na zuciya, da kuma canzawa a cikin yanayin thiol redox na sunadaran zuwa yanayin da ya ragu. SS-31 kuma ya haɓaka matakin phosphorylation na cMyBP-C Ser282 a cikin ƙwayoyin myocardial, wanda ke da alaƙa da haɓaka aikin diastolic na zuciya.
Hoto na 3 An hana rashin ilmantarwa a cikin berayen da suka tsufa wanda rashin bacci ya jawo shi tare da SS31.
Kariyar jijiyoyin jini: Lokacin tsufa, aikin sel na endothelial ya lalace, elasticity na jijiyoyin jini yana raguwa, kuma cututtukan zuciya na iya faruwa. A cikin ƙirar hawan jini mai haifar da ƙwayar jini a cikin kwakwalwar tsofaffin beraye, jiyya tare da SS-31 yana nuna mahimman tasirin kariya na jijiyoyin jini. Yana rage samar da radical free mitochondrial wanda hauhawar jini ya haifar, yana rage lalacewar oxidative danniya ga bangon jijiyoyin jini, don haka yana jinkirta farawar microbleeding da rage yawan abin da ya faru. Sabili da haka, SS-31 yana taka muhimmiyar rawa wajen kiyaye tsarin al'ada da aiki na jini da kuma hana cututtuka masu alaka da shekaru.
Tasiri akan tsarin jin tsoro
Rage tabarbarewar fahimi: Yayin da shekaru ke ƙaruwa, aikin jijiyoyi yana raguwa sannu a hankali, kuma tawayar fahimi kamar nakasar ƙwaƙwalwa da rage ikon koyo yana ƙara yin fice. Rashin aikin mitochondrial yana taka muhimmiyar rawa a cikin farawa da ci gaba da cututtukan neurodegenerative da rashin aiki na fahimi. A cikin samfurin rashin aiki na fahimi wanda isoflurane ya haifar a cikin tsofaffin berayen, SS-31 na iya juyar da rashin aiki na mitochondrial, ceton isoflurane-induced fahimi rashi. SS-31 yana haɓaka ƙa'idar siginar BDNF, yana jujjuya ƙa'idodin sunadarai masu alaƙa da synaptic filastik kamar synaptophysin, PSD-95, da p-CREB, kuma yana haɓaka NR2A, NR2B, CaMKIIa, da CaMKIIβ, don haka haɓaka filastik synaptic da kare fahimi.
Rage mummunan tasirin rashin barci: Rashin barci yana da damuwa na yau da kullum, kuma mummunan tasirinsa a kan tsarin jin tsoro ya zama mafi girma tare da shekaru, yana haifar da rashin fahimta da kuma ƙara haɗarin cututtukan neurodegenerative. A cikin berayen watanni 20, an gudanar da SS-31 (3 mg/kg) ta hanyar allurar subcutaneous kowace rana don kwanaki 4 a jere, tare da sa'o'i 4 na rashin barci a cikin kwanaki biyu na ƙarshe. Sakamakon ya nuna cewa berayen da ba su da barci da aka yi wa SS-31 ba su nuna wani lahani mai mahimmanci a cikin ikon ilmantarwa, tare da mayar da matakan ATP na mitochondrial na kwakwalwa da sunadarai masu sarrafa filastik synaptic, da kuma rage matakan nau'in oxygen mai amsawa (ROS) da cytokines masu kumburi a cikin hippocampus. Wannan yana nuna cewa SS-31 na iya samun yuwuwar fa'idodin warkewa a cikin rage mummunan tasirin rashin bacci na ɗan gajeren lokaci a cikin tsofaffin beraye.
Tasiri akan tsarin koda: A cikin kodan tsofaffin beraye, glomerulosclerosis yana da alaƙa da lalacewar mitochondrial a cikin sel epithelial glomerular. Bayan makonni 8 na maganin SS-31 a cikin ƙananan berayen watanni 26, SS-31 ya inganta ilimin halittar mitochondrial mai alaka da shekaru da rage glomerulosclerosis. Musamman, ya rage bayyanar alamun tsufa (p16, β-Gal da ke hade da tsufa), ya karu da yawa na sel epithelial na apical, kuma ya rage alamun alamun kunnawa na epithelial cell (collagen IV, pERK1 / 2, da α-smooth muscle actin). Ko da yake SS-31 bai shafi nauyin podocyte ba, ya rage alamun lalacewa na podocyte (desmin), inganta ingantaccen cytoskeletal (synaptophysin), kuma yana tare da mafi girma glomerular endothelial cell density (CD31). Wannan yana nuna cewa maganin SS-31 na ɗan gajeren lokaci yana da tasirin kariya akan mitochondria na glomerular kuma yana inganta tsarin glomerular.
Tasiri a matakin salula
Jinkirta tsufa na salula: A cikin gwaje-gwajen tantanin halitta, an yi amfani da H₂O₂ don haifar da ƙirar tsufa da ke haifar da damuwa a cikin ƙwayoyin HEK293T, sannan ta hanyar sa baki tare da SS-31. Sakamakon ya nuna cewa ƙimar ƙimar SA-β-gal ta ragu sosai a cikin ƙungiyar SS-31, yana nuna raguwar matakan tsufa na salula. Bugu da ƙari, ƙarfin hasken wuta na ROS na ciki ya ragu, yuwuwar mitochondrial membrane ya karu, kuma matakan ATP sun tashi a cikin ƙungiyar SS-31. Binciken immunoblotting na furotin ya nuna cewa matakan maganganu na P53, P21, da kuma Acetyl-p53 sunadaran sun kasance mafi girma a cikin rukunin samfurin idan aka kwatanta da ƙungiyar kulawa, yayin da ƙungiyar SS-31 ta nuna raguwa idan aka kwatanta da ƙungiyar samfurin. Sabanin haka, matakin bayanin furotin Sirt1 ya kasance ƙasa a cikin ƙungiyar ƙirar idan aka kwatanta da ƙungiyar kulawa, yayin da ƙungiyar SS-31 ta nuna karuwa idan aka kwatanta da ƙungiyar ƙirar. Don haka, ana iya ƙarasa da cewa SS-31 na iya jinkirta tsufa na kwayar halitta na HEK293T ta hanyar inganta aikin mitochondrial da daidaita maganganun sunadarai masu alaƙa da tsufa a cikin sel.
Kariya daga lalatawar salula mai haifar da danniya: A cikin H₂O₂-induced oxidative danniya model na ARPE-19 Kwayoyin, jiyya tare da SS-31 da muhimmanci ya karu cell rayuwa rate, rage intracellular ROS matakan, rage rabo daga cikin sel tare da rage mitochondrial membrane m, da alama saukar da PI positivity da kuma rage girman mutuwa (matsakaicin adadin mutuwa), haɓaka bayyanar furotin RIP3. Wadannan sakamakon sun nuna cewa SS-31 yana da tasiri mai mahimmanci na kariya daga H₂O₂-induced oxidative danniya lalacewa a cikin kwayoyin ARPE-19, wanda zai iya taimakawa wajen magance lalacewar shekaru.
Kammalawa
peptide SS-31 da aka yi niyya na mitochondrial yana ba da gudummawa ga rigakafin tsufa. Daga nau'o'in ka'idoji masu yawa akan aikin mitochondrial zuwa mahimmancin tasirin tsufa a cikin matakan tsarin da salon salula daban-daban, yana nuna yuwuwar azaman muhimmin dabarun rigakafin tsufa.
Sources
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[2] Fir'auna G, Kamat V, Kannan S, et al. The mitochondrially niyya peptide elamipretide (SS-31) inganta ADP ji na ƙwarai a cikin tsofaffi mitochondria ta hanyar karuwa ta hanyar adenine nucleotide translocator (ANT)[J]. Geroscience, 2023,45 (6): 3529-3548.DOI:10.1007/s11357-023-00861-y.
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Samfura akwai don amfani da bincike kawai:
