Bya Cocer Peptides 
omwezi gumu emabega
EBINTU BYONNNA N’AMAWULIRE GW’EBINTU EBIweereddwa KU MUTINDO GUNO BIKOZESEBWA KU KUSASANYA AMAWULIRE N’EBIKOLWA BY’OKUSOMESA.
Ebintu ebiweereddwa ku mukutu guno bigendereddwamu kunoonyereza mu kisenge (in vitro research) byokka. Okunoonyereza mu vitro (Olulattini: *mu ndabirwamu*, ekitegeeza mu bikozesebwa mu ndabirwamu) kukolebwa ebweru w’omubiri gw’omuntu. Ebintu bino si bya ddagala, tebikkiriziddwa kitongole kya Amerika ekivunaanyizibwa ku by’emmere n’eddagala (FDA), era tebirina kukozesebwa kuziyiza, kujjanjaba oba kuwonya mbeera yonna ya bujjanjabi, bulwadde oba bulwadde. Kikugirwa nnyo mu mateeka okuyingiza ebintu bino mu mubiri gw’omuntu oba ebisolo mu ngeri yonna.
Peptide egenderera mitochondria SS-31, era emanyiddwa nga elamipretide, ye peptide ya molekyu entono ng’erina emirimu egy’enjawulo egy’okutunuulira mitochondria. Mu myaka egiyise, ng’okunoonyereza ku nkola z’okukaddiwa kweyongedde, omulimu omukulu ogw’obutakola bulungi bwa mitochondria mu nkola y’okukaddiwa gweyongedde okweyoleka. SS-31, n’eby’obugagga byayo eby’enjawulo ebigenderera mitochondrial n’obusobozi bw’okulungamya enkola ya mitochondrial, esuubiza okukozesebwa mu kulwanyisa okukaddiwa.
Ekifaananyi 1 Okussa n’okuddamu kw’obusobozi bw’olususu eri okusikirizibwa kwa ADP mu mitochondria z’ebinywa ebyawuddwamu byetaaga supplementary cytochrome c ne hexokinase clamp. Ekkubo ly’entambula ya ADP/ATP n’okusiba kwa ELAM ku ATP Synthase ne ANT.
I. Okulaba enkolagana wakati wa Mitochondria n’okukaddiwa
Mitochondria, nga amaanyi g’obutoffaali, zivunaanyizibwa ku kusengejja ATP ezisinga obungi munda mu katoffaali era era zeenyigira mu nkola ez’enjawulo ez’okulungamya enkyukakyuka mu mubiri n’okukyusa obubonero. Emyaka bwe gyeyongera, emirimu gya mitochondria gikendeera mpolampola, nga kino kye kimu ku bikulu ebiraga okukaddiwa. Obutakola bulungi bwa mitochondrial bweyolekera mu ngeri eziwera, omuli okukuŋŋaanyizibwa kw’enkyukakyuka mu DNA ya mitochondrial (mtDNA), okukendeeza ku mirimu gy’ebizibu by’olujegere lw’okussa mu mitochondria, ekivaako okukola amaanyi agamala; okweyongera kw’okukola ebika bya oxygen ebikola (ROS) ebikolebwa mitochondria, ekivaako okwonooneka kw’okunyigirizibwa okw’okwokya, ekyongera okutaataaganya biomolecules z’omu butoffaali nga puloteyina, lipids, ne nucleic acids, okwanguya okukaddiwa kw’obutoffaali n’okufa. Enkola ya mitochondria etali ya bulijjo nayo etaataaganya enkola ya calcium homeostasis mu butoffaali, ne kitaataaganya emirimu gya bulijjo egy’omubiri gw’obutoffaali. Enkyukakyuka zino zikwatagana, ne zikola enzirukanya embi nga okutwalira awamu evuga enkola y’okukaddiwa.
II. Enkola y’Ekikolwa kya SS-31
Okulongoosa mu nkyukakyuka y’amasoboza ga Mitochondrial
Okwongera ku ADP Sensitivity: Mu kiseera ky’okukaddiwa, mitochondrial sensitivity eri ADP ekendeera, ekikosa obulungi bw’okusengejja ATP. Okunoonyereza kulaga nti SS-31 esobola okwesiba butereevu ku mitochondrial ADP transporter ANT, okwongera ku ANT okutwala ADP, bwe kityo n’eyongera ku mitochondrial sensitivity eri ADP. Mu mitochondria z’ebinywa ezikaddiye, obujjanjabi bwa SS-31 bwayongera okutwala ADP nga buyita mu ANT, bwe kityo ne kyongera okussa kw’emitochondria wansi w’okusikirizibwa kwa ADP, okwongera okukola ATP, n’okulongoosa enkyukakyuka y’amasoboza mu mitochondria z’ebinywa ezikaddiye.
Okulungamya ebizibu by’olujegere lw’okussa mu mitochondrial: Ebizibu by’olujegere lw’okussa mu mitochondrial bye bitundu ebikulu mu kukola amaanyi ga mitochondria. Mu kiseera ky’okukaddiwa, emirimu gy’ebizibu by’enjegere z’okussa gitera okukendeera. SS-31 eyinza okukuuma oba okutumbula emirimu gy’ebizibu by’enjegere z’okussa nga etebenkeza obulungi bw’enzimba yaabyo oba okulungamya okwolesebwa kwa puloteyina ezikwatagana. Okunoonyereza okwakolebwa emabegako kwalaba nti mu bikolwa by’obutakola bulungi bwa mitochondrial ebikwatagana n’okukaddiwa, emirimu gy’ebizibu by’olujegere lw’okussa gikomezebwawo oluvannyuma lw’okujjanjabwa SS-31, ekiraga nti ekikola obulungi mu kulungamya ku lujegere lw’okussa olw’emitochondria.
Ekifaananyi 2 Obujjanjabi bwa SS-31 buzzaawo enkula y’okukaddiwa kw’omutima
Okukendeeza ku kwonooneka kwa oxidative stress
Okukendeeza ku kukola ROS: Mitochondria y’emu ku nsibuko enkulu eya ROS mu butoffaali, era okukola ROS kweyongera mu mitochondria mu kiseera ky’okukaddiwa. SS-31 esobola okukendeeza ku kukola ROS ng’eyita mu makubo agawera. Kilongoosa enkyukakyuka y’amasoboza ga mitochondrial, ne kifuula olujegere lw’okutambuza obusannyalazo mu mitochondrial okukola obulungi era ne kikendeeza ku kukulukuta kw’obusannyalazo, bwe kityo ne kikendeeza ku kukola ROS. SS-31 eyinza okukola butereevu ku luwuzi lwa mitochondrial, okukyusa eby’obutonde byayo, okukendeeza ku bifo eby’okwonoona oxidative ku luwuzi, n’okuziyiza okukola ROS. Mu butoffaali bw’omutima okuva mu mbeba ezikaddiye, obujjanjabi ne SS-31 bwakendeeza nnyo ku mitochondrial ROS levels, ekiraga nti ekola bulungi mu kukendeeza ku kukola ROS.
Okulungamya enkola y’enziyiza y’obuwuka obuziyiza obuwuka obuleeta obulwadde: Obutoffaali bulimu enkola y’enziyiza eziyiza obuwuka obuleeta obulwadde, omuli superoxide dismutase (SOD), catalase (CAT), ne glutathione peroxidase (GSH-Px), ezivunaanyizibwa ku kusenya ROS. Okunoonyereza kulaga nti SS-31 eyinza okutumbula obusobozi bw’obutoffaali obuziyiza obuwuka obuleeta obulwadde nga ekyusakyusa okwolesebwa oba emirimu gy’enziyiza zino eziziyiza obuwuka obuleeta obulwadde. Mu bikolwa ebimu eby’obutoffaali, okujjanjaba ne SS-31 kwavaamu okweyongera okw’amaanyi mu mirimu gya SOD ne GSH-Px, okuyamba mu kugogola mu budde ROS ezisukkiridde munda mu butoffaali n’okukendeeza ku kwonooneka okuva ku situleesi y’okwokya.
Okukuuma obutebenkevu bw’olususu lwa mitochondrial
Okusiba ku phospholipids z’oluwuzi lwa mitochondrial: SS-31 erina ensengekera ey’enjawulo egisobozesa okusinga okwesiba ku bitundu by’oluwuzi lwa mitochondrial ebirimu phosphatidylserine. Phosphatidylserine ye phospholipid eyeetongodde ku luwuzi lwa mitochondrial era nga kikulu nnyo mu kukuuma obulungi ensengekera n’enkola y’oluwuzi lwa mitochondrial. Mu kiseera ky’okukaddiwa, phosphatidylserine etera okwonooneka olw’okwokya, ekivaako obutali bwa bulijjo mu nsengeka n’enkola y’oluwuzi lwa mitochondrial. Oluvannyuma lw’okusiba ku phosphatidylserine, SS-31 eyinza okukuuma phosphatidylserine okuva mu oxidation ate nga etebenkeza ensengekera y’oluwuzi lwa mitochondrial, okuziyiza okukendeera kw’obusobozi bw’oluwuzi lwa mitochondrial n’okugguka kw’obutuli bw’enkyukakyuka y’okuyita mu mitochondrial (mPTP). Okugezesa mu vitro kulaga nti SS-31 eziyiza bulungi okukendeera okuleetebwa oxidative stress mu mitochondrial membrane potential ne mPTP opening, bwe kityo n’ekuuma mitochondrial membrane stability.
Okulungamya obutoffaali obukwatagana n’olususu: Olususu lwa mitochondrial lulimu obutoffaali obw’enjawulo obukwatibwako mu ntambula y’ebintu bya mitochondrial, okukyusakyusa amaanyi, n’enkola z’okukyusa obubonero. SS-31 eyinza okukwata mu ngeri etali butereevu ku nnywevu y’oluwuzi lwa mitochondrial ng’etereeza emirimu oba okwolesebwa kwa puloteyina zino ezikwatagana n’olususu. Kisobola okulung’amya enkola y’emikutu gya aniyoni egyesigama ku vvulovumenti (VDAC), nga zino puloteyini z’emikutu emikulu ku luwuzi lwa mitochondrial olw’ebweru era zikola kinene mu kukuuma okuwanyisiganya ebintu n’okutambuza obubonero wakati wa mitochondria ne cytoplasm. SS-31’s regulation of VDAC eyamba okukuuma enkola ya mitochondrial membrane eya bulijjo n’okutebenkera.
III. Ebikolwa ebitongole ebya SS-31 mu kulwanyisa okukaddiwa
Ebikosa enkola y’emisuwa gy’omutima
Okulongoosa enkola y’omutima: Omutima kitundu ekyetaaga amaanyi mangi, era enkola ya mitochondria nsonga nkulu nnyo mu nkola y’omutima. Mu mbeba ezikaddiye, omutima gutera okulaga ensonga ezeekuusa ku myaka nga diastolic dysfunction. Bannasayansi bakizudde nti oluvannyuma lwa wiiki 8 nga bajjanjabwa SS-31, omulimu gw’okusannyalala kw’emitima gy’ebibe ebikaddiye gwalongooka nnyo. Okulongoosa kuno kwawerekerwako okufuuka okwa bulijjo okw’okukulukuta kwa pulotoni mu mitochondrial mu butoffaali bw’emisuwa gy’omutima, okukendeeza ku miwendo gya ROS mu mitochondrial, okukendeera kw’emiwendo gya puloteyina y’omutima oxidation, n’okukyuka mu mbeera ya thiol redox eya puloteyina okudda mu mbeera ekendedde ennyo. SS-31 era yayongera ku phosphorylation level ya cMyBP-C Ser282 mu myocardial cells, ekikwatagana ennyo n’okulongoosa cardiac diastolic function.
Ekifaananyi 3 Obuzibu mu kuyiga mu mbeba ezikaddiye obuleetebwa obuteebaka bwaziyizibwa ne SS31.
Obukuumi bw’emisuwa: Mu kiseera ky’okukaddiwa, enkola y’obutoffaali bw’omubiri (endothelial cell function) ekendeera, obugumu bw’emisuwa bukendeera, era endwadde z’emisuwa n’emitima zitera okubaawo. Mu nkola y’okufulumya omusaayi omutonotono oguleetebwa puleesa mu bwongo bw’ebibe ebikadde, obujjanjabi ne SS-31 bulaga ebikolwa eby’amaanyi eby’okukuuma emisuwa. Kikendeeza ku kukola kwa mitochondrial free radical okuleetebwa puleesa, kikendeeza ku kwonooneka kw’okunyigirizibwa okw’okwokya (oxidative stress damage) ku bbugwe w’emisuwa, bwe kityo ne kilwawo nnyo okutandika kw’omusaayi omutonotono n’okukendeeza ku bungi bwagwo. N’olwekyo, SS-31 ekola kinene mu kukuuma ensengekera n’enkola ya bulijjo ey’emisuwa n’okuziyiza endwadde z’emisuwa ezeekuusa ku myaka.
Ebikosa enkola y’obusimu
Okukendeeza ku buzibu bw’okutegeera: Emyaka bwe gyeyongera, enkola y’obusimu ekendeera mpolampola, era obutakola bulungi mu kutegeera ng’okulemererwa okujjukira n’okukendeeza ku busobozi bw’okuyiga bweyongera okweyoleka. Obutakola bulungi bwa mitochondrial bukola kinene nnyo mu kutandika n’okukulaakulana kw’endwadde z’obusimu n’obutakola bulungi mu kutegeera. Mu model y’obutakola bulungi mu kutegeera obuleetebwa isoflurane mu mbeba ezikaddiye, SS-31 esobola okuzzaawo obutakola bulungi bwa mitochondrial, okununula obuzibu bw’okutegeera obuleetebwa isoflurane. SS-31 etumbula okulungamya obubonero bwa BDNF, ezzaawo downregulation ya synaptic plasticity-related proteins nga synaptophysin, PSD-95, ne p-CREB, era upregulates NR2A, NR2B, CaMKIIα, ne CaMKIIβ, bwe kityo n’eyongera ku synaptic plasticity n’okukuuma cognitive function.
Okukendeeza ku buzibu obuva mu buteebaka: Obutaba na tulo kintu kya bulijjo ekireetera omuntu situleesi, era ebizibu byakyo ku nkola y’obusimu byeyongera okweyoleka n’emyaka, ekivaako obutakola bulungi mu kutegeera n’okwongera ku bulabe bw’endwadde z’obusimu. Mu mbeba ez’emyezi 20, SS-31 (3 mg/kg) yassibwa ng’eyita mu mpiso wansi w’olususu buli lunaku okumala ennaku 4 ez’omuddiring’anwa, nga ku nnaku ebbiri ezisembayo tebeebaka essaawa 4. Ebivuddemu biraga nti ebibe ebitaliimu tulo ebyajjanjabwa ne SS-31 tebyalaga buzibu bwa maanyi mu busobozi bw’okuyiga, nga bikomyewo emiwendo gya ATP mu mitochondrial mu bwongo ne puloteyina ezitereeza obuveera bw’omubiri (synaptic plasticity-regulating proteins), wamu n’okukendeeza ku miwendo gya reactive oxygen species (ROS) ne inflammatory cytokines mu hippocampus. Kino kiraga nti SS-31 eyinza okuba n’emigaso egisobola okujjanjaba mu kukendeeza ku buzibu obuva mu busimu obuva mu kubulwa otulo okumala akaseera katono mu mbeba ezikaddiye.
Ebikosa enkola y’ekibumba: Mu nsigo z’ebibe ebikadde, glomerulosclerosis ekwatagana n’okwonooneka kwa mitochondria mu butoffaali bw’omubiri obuyitibwa glomerular epithelial cells. Oluvannyuma lwa wiiki 8 nga bajjanjabwa SS-31 mu mbeba ez’emyezi 26, SS-31 yalongoosa enkula y’emisuwa (mitochondrial morphology) eyeekuusa ku myaka era n’ekendeeza ku bulwadde bwa glomerulosclerosis. Okusingira ddala, yakendeeza ku kwolesebwa kw’obubonero bw’okukaddiwa (p16, β-Gal obukwatagana n’okukaddiwa), yayongera ku density y’obutoffaali bw’omubiri obuyitibwa apical epithelial cells, era yakendeeza ku kwolesebwa kw’obubonero bw’okukola kw’obutoffaali bw’omubiri obuyitibwa parietal epithelial cell activation (collagen IV, pERK1/2, ne α-smooth muscle actin). Wadde nga SS-31 teyakosa density ya podocyte, yakendeeza ku bubonero bw’okwonooneka kw’obutoffaali (desmin), yalongoosa obulungi bw’amagumba (synaptophysin), era yawerekerwako density y’obutoffaali bw’omubiri obuyitibwa glomerular endothelial cell density (CD31) esingako. Kino kiraga nti obujjanjabi bwa SS-31 obw’ekiseera ekitono nabwo bulina ekikolwa eky’obukuumi ku mitochondria z’omubiri (glomerular mitochondria) era bulongoosa ensengekera y’ebitundu by’omubiri (glomerular structure).
Ebikosa ku mutendera gw’obutoffaali
Okulwawo okukaddiwa kw’obutoffaali: Mu kugezesa obutoffaali, H2O2 yakozesebwa okuleeta enkola y’okukaddiwa okuva ku situleesi mu butoffaali bwa HEK293T, n’eddirirwa okuyingira mu nsonga ne SS-31. Ebivuddemu biraga nti omuwendo gwa SA-β-gal positive gwakendeera nnyo mu kibinja kya SS-31, ekiraga okukendeera mu miwendo gy’okukaddiwa kw’obutoffaali. Okugatta ku ekyo, amaanyi g’okumasamasa kwa ROS mu butoffaali gakendeera, obusobozi bw’oluwuzi lwa mitochondrial bweyongera, era emiwendo gya ATP ne girinnya mu kibinja kya SS-31. Okwekenenya obutoffaali obuziyiza endwadde (protein immunoblotting analysis) kwalaga nti emitendera gy’okwolesebwa kwa puloteyina za P53, P21, ne Acetyl-p53 gyali waggulu mu kibinja eky’ekyokulabirako bw’ogeraageranya n’ekibinja ekifuga, ate ekibinja kya SS-31 kyalaga okukendeera bw’ogeraageranya n’ekibinja eky’ekyokulabirako. Okwawukana ku ekyo, omutindo gw’okwolesebwa kwa puloteyina ya Sirt1 gwali wansi mu kibinja eky’ekyokulabirako bw’ogeraageranya n’ekibinja ekifuga, ate ekibinja kya SS-31 kyalaga okweyongera bw’ogeraageranya n’ekibinja eky’ekyokulabirako. Bwe kityo, kiyinza okumalirizibwa nti SS-31 esobola okulwawo okukaddiwa kw’obutoffaali bwa HEK293T ng’elongoosa enkola ya mitochondrial n’okulungamya okwolesebwa kwa puloteyina ezikwatagana n’okukaddiwa mu butoffaali.
Obukuumi okuva ku kwonooneka kw’obutoffaali obuleetebwa okunyigirizibwa okw’okwokya: Mu nkola y’okwonooneka kw’obutoffaali obuleetebwa okunyigirizibwa okw’okwokya (oxidative stress-induced oxidative stress model) ey’obutoffaali bwa ARPE-19, obujjanjabi ne SS-31 bwayongera nnyo ku muwendo gw’obutoffaali obuwangaala, bwakendeeza ku miwendo gya ROS mu butoffaali, bwakendeeza ku kitundu ky’obutoffaali obulina obusobozi obukendedde mu mitochondrial membrane, bwakendeeza nnyo omuwendo gw’obulungi bwa PI (nga bulaga obunene wa kufa kw’obutoffaali), era yakendeeza nnyo ku upregulation y’okwolesebwa kwa puloteyina ya RIP3. Ebivudde mu kunoonyereza kuno biraga nti SS-31 erina kinene eky’obukuumi ku kwonooneka kw’okunyigirizibwa okw’okwokya okuleetebwa H2O2 mu butoffaali bwa ARPE-19, ekiyinza okuyamba mu kuziyiza okwonooneka okwekuusa ku myaka.
Mu bufunzi
Peptide SS-31 egendereddwamu mitochondrial eyamba mu kuziyiza okukaddiwa. Okuva ku nkola zaayo ez’okulungamya ez’enjawulo ku nkola ya mitochondria okutuuka ku bikolwa byayo ebikulu eby’okulwanyisa okukaddiwa ku mitendera egy’enjawulo egy’enkola n’obutoffaali, eraga obusobozi ng’enkola enkulu ey’okulwanyisa okukaddiwa.
Ensonda
[1] Patai R, Patel K, Csik B, n’abalala. Okukaddiwa, obutakola bulungi bwa mitochondrial, n’omusaayi omutono mu bwongo: okwekenneenya nga tekunnabaawo kwa SS-31 (elamipretide) n’okukulaakulanya payipu y’okukuba ebifaananyi evugirwa okuyiga kw’ekyuma ekikola ennyo okukebera obujjanjabi bw’okukuuma emisuwa gy’obwongo [J]. Sayansi w’abakadde, 2025.DOI:10.1007/s11357-025-01634-5.
[2] Falaawo G, Kamat V, Kannan S, n’abalala. Peptide elamipretide (SS-31) egendereddwamu mitochondrially etereeza okuwuliziganya kwa ADP mu mitochondria ezikaddiye nga eyongera okutwalibwa okuyita mu adenine nucleotide translocator (ANT)[J]. Sayansi w’abakadde, 2023, 45 (6): 3529-3548.DOI: 10.1007 / s11357-023-00861-y.
[3] Chiao YA, Zhang H, Sweetwyne M, n’abalala. Okuzzaawo emirimu gya mitochondria mu bulamu obusembayo kuzzaawo obuzibu bw’omutima mu mbeba enkadde[J]. Elife, 2020,9.DOI:10.7554/Obulamu bw’oku yintaneeti.55513.
[1] Wu J, Dou Y, Ladiges W C. Ebikosa obubi mu busimu olw’obutaba na tulo mu kiseera ekitono mu mbeba ezikaddiye Biziyizibwa SS31 Peptide[J]. Essaawa & Otulo, 2020,2 (3): 325-333.DOI: 10.3390 / essaawa otulo2030024.
[4] Sweetwyne M. T., Pippin J. W., Eng D. G., n’abalala. Peptide egenderera mitochondrial, SS-31, erongoosa enzimba ya glomerular mu mbeba ez’emyaka egy’obukulu[J]. Ekibumba eky’ensi yonna, 2017, 91 (5): 1126-1145.DOI: 10.1016 / j.kint.2016.10.036.
[5] Wu J, Zhang M, Li H, n’abalala. Ekkubo lya BDNF lyenyigidde mu bikolwa eby’obukuumi ebya SS-31 ku isoflurane-induced cognitive deficits mu mbeba ezikaddiye[J]. Okunoonyereza ku bwongo ku nneeyisa, 2016,305:115-121.DOI:10.1016/j.bbr.2016.02.036.
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