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.
Ebikulu ebikwata ku KPV
KPV ye tripeptide erimu obusobozi obw’amaanyi obuziyiza okuzimba, ekigisobozesa okukola omulimu mu bintu bingi.
Ekifaananyi 1 Ebikolwa by’obujjanjabi ebya HA-KPV-NPs ku UC Okugaba HA-KPV-NPs mu kamwa eziteekeddwa mu hydrogel (chitosan/alginate) kiwa obujjanjabi obw’omugatte ku UC nga kwanguyiza okuwona kw’omubiri gw’omubiri n’okukendeeza ku kuzimba.
Enkola y’okulwanyisa okuzimba eya KPV
1. Okulungamya Amakubo g’Obubonero bw’Obutoffaali
NF-κB Signaling Pathway: NF-κB ye nsonga enkulu ey’okuwandiika ekola kinene mu kuddamu kw’okuzimba. Obutoffaali bwe buba bufunye ebizimba, NF-κB ekyukakyuka okuva mu cytoplasm okudda mu nucleus, n’etandika okuwandiika obuzaale bwa pro-inflammatory cytokine. KPV esobola okuziyiza okukola kwa NF-κB. Mu butoffaali bw’ekyenda ky’omuntu n’obutoffaali bwa T obw’omuntu, obutoffaali bwasikirizibwa ne pro-inflammatory cytokines, era KPV n’eyongerwako mu kiseera kye kimu. Nga tukozesa enkola nga NF-κB luciferase gene reporter assays, protein immunoblotting, real-time reverse transcription polymerase chain reaction, ne enzyme-linked immunosorbent assay (ELISA), kyazuulibwa nti KPV ku nanomolar concentrations esobola okuziyiza NF-κB activation, bwe kityo ne kikendeeza ku kufulumya pro-inflammatory cytokines. Enkola eno nkulu nnyo mu kulungamya okuzimba kw’ekyenda, kubanga okukola ennyo kwa NF-κB mu butoffaali bw’ekyenda n’obutoffaali bw’abaserikale b’omubiri kye kintu ekikulu mu bulwadde bw’ekyenda ekizimba (IBD) n’embeera endala ez’okuzimba ekyenda.
Ekkubo ly’obubonero bwa MAP kinase: Ekkubo ly’obubonero erya mitogen-activated protein kinase (MAPK) lye kkubo eddala ery’okulungamya mu kuddamu kw’okuzimba, omuli extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), ne p38 MAPK. Kinase zino zikola nga obutoffaali bufunye ebizimba, ekivaako okukola phosphorylation y’ensonga z’okuwandiika wansi n’okutumbula okwolesebwa kw’obuzaale obukwatagana n’okuzimba. KPV era esobola okuziyiza ekkubo ly’obubonero bw’okuzimba erya MAP kinase. Obutoffaali bwe bukwatibwa ebizimba, KPV esobola okuziyiza okukola kwa MAPK, okukendeeza ku phosphorylation yaayo ey’ensonga z’okuwandiika wansi, bwe kityo ne kikendeeza ku kukola kwa pro-inflammatory cytokines. Mu mbeera y’okuzimba, okukola kwa p38 MAPK kuleeta okweyongera kw’okwolesebwa kwa cytokines eziyamba okuzimba nga TNF-α ne IL-6, ate KPV esobola okuziyiza emirimu gya p38 MAPK, okukendeeza ku kufuluma kwa cytokines zino era bwe kityo n’ekendeeza ku kuddamu kw’okuzimba.
2. Ebikolwa ebitambulizibwa omutambuza w’obutoffaali
PepT1 transporter: PepT1 ye di/tripeptide transporter etera okulagibwa mu kyenda ekitono naye nga ereetebwa mu kyenda ekinene mu kiseera kya IBD. Ebikolwa bya KPV ebiziyiza okuzimba ekitundu bitabaganyizibwa PepT1. Mu kugezesa okutwala, KPV ennyogovu yakozesebwa ng’ekiziyiza eky’okuvuganya ku hPepT1 nga substrate eriko akabonero ka radioactive, oba [⊃3;H]KPV yakozesebwa okuzuula engeri z’entambula y’okutwala KPV. KPV eyingira mu butoffaali bw’abaserikale b’omubiri n’obutoffaali bw’ekyenda obuyitibwa epithelial cells ng’eyita mu hPepT1. Kino kiraga nti PepT1, ng’ekitambuza, kyanguyiza KPV okuyingira mu butoffaali okukola ebikolwa byayo eby’okulwanyisa okuzimba. Omulimu gwa PepT1 bwe guziyizibwa, obungi bwa KPV obuyingira mu butoffaali bukendeera, era ebikolwa byayo eby’okulwanyisa okuzimba binafuwa mu ngeri y’emu. Mu bikolwa by’obutoffaali ebirina okukoona okwolesebwa kwa PepT1, ne bwe biweebwa ku kigero kye kimu, KPV eraga okukendeeza ennyo ku bikolwa ebiziyiza ku kukola kwa NF-κB n’okukendeeza ku kufulumya kwa cytokines eziyamba okuzimba bw’ogeraageranya n’obutoffaali obulina okwolesebwa kwa PepT1 okwa bulijjo, okwongera okukakasa omulimu omukulu ogw’okutabaganya ogwa PepT1 mu nkola y’okuziyiza okuzimba eya KPV.
3. Okulungamya obutoffaali obuzimba (inflammatory cytokines).
Okuziyiza cytokines eziyamba okuzimba: KPV esobola okuziyiza ennyo okukola n’okufulumya cytokines eziwera eziyamba okuzimba. TNF-α ye cytokine enkulu mu kuddamu kw’okuzimba, esobola okukola obutoffaali bw’abaserikale b’omubiri, okuleeta okukola cytokines endala eziyamba okuzimba, n’okuleeta okwonooneka kw’ebitundu. Mu bikolwa eby’enjawulo eby’okuzimba, emiwendo gy’okwolesebwa kwa TNF-α gyakendeera nnyo oluvannyuma lw’okujjanjabwa KPV. Okugeza, mu nkola ya sodium sulfate-induced mouse colitis model, obujjanjabi ne KPV bwavaamu okukendeera okw’amaanyi mu mRNA expression ya TNF-α mu colon tissue, nga bwe kyazuulibwa mu kiseera ekituufu RT-PCR, n’okukendeera okw’amaanyi mu protein content ya TNF-α mu serum, nga bwe kyazuulibwa mu ELISA. IL-1β, IL-6, ne cytokines endala eziyamba okuzimba nazo zaziyizibwa KPV. IL-1β esobola okuleeta enkola ya inflammatory cascade reaction, okutumbula okufulumya ebirungo ebirala ebizimba. KPV esobola okukendeeza ku kwolesebwa kwayo n’okufulumya kwayo mu bitundu ebizimba, bwe kityo n’ekendeeza ku maanyi g’okuddamu kw’okuzimba.
Okutumbula obutoffaali obuziyiza okuzimba: Ng’oggyeeko okuziyiza obusimu obuziyiza okuzimba, KPV esobola n’okutumbula okwolesebwa kw’obusimu obuziyiza okuzimba. Interleukin-10 (IL-10) ye cytokine enkulu eziyiza okuzimba esobola okuziyiza okukola kw’obutoffaali bw’abaserikale b’omubiri n’okukendeeza ku kukola cytokines eziyamba okuzimba.
4. Okulungamya obutoffaali bw’abaserikale b’omubiri
Okulungamya enkola y’obutoffaali bwa T: Obutoffaali bwa T bukola kinene nnyo mu kuddamu kw’abaserikale b’omubiri n’okulungamya okuzimba. Mu mbeera z’okuzimba, obutoffaali bwa T bukola ne bufulumya obusimu obuyamba okuzimba. Okunoonyereza kulaga nti KPV esobola okulungamya enkola y’obutoffaali bwa T. Mu kugezesa ku layini y’obutoffaali bwa T obw’omuntu Jurkat, obutoffaali bwa Jurkat bwe bwasikirizibwa n’obutoffaali obuyamba okuzimba, okugattako KPV kyaziyiza okukola kw’obutoffaali bwa T era ne kikendeeza ku kufulumya obutoffaali obuyamba okuzimba nga IFN-γ. Kino kiyinza okutuukibwako nga tuziyiza amakubo g’obubonero bwa NF-κB ne MAPK munda mu butoffaali bwa T. Okugatta ku ekyo, mu bikolwa by’ebisolo ebimu, nga CD45RB(hi) colonic inflammation model, obujjanjabi bwa KPV busobola okulungamya okuyingira kw’obutoffaali bwa T n’okukola mu kyenda, okukendeeza ku bitundu by’obutoffaali bwa T obukwatagana n’okuzimba nga Th1 ne Th17 cells, n’okwongera ku kitundu ky’obutoffaali bwa T obulung’amya, bwe kityo ne kikendeeza ku kuzimba kw’ekyenda.
Okukyusa enkola ya macrophage: Macrophages butoffaali bukulu mu kuddamu kw’okuzimba era busobola okugabanyizibwa mu classically activated M1 macrophages ne alternatively activated M2 macrophages okusinziira ku mbeera yaabwe ey’okukola. M1 macrophages zifulumya obungi bwa pro-inflammatory cytokines, ate M2 macrophages zirina emirimu egy’okulwanyisa okuzimba n’okuddaabiriza ebitundu by’omubiri. KPV esobola okulung’amya polarization ya macrophage. Okugezesa mu vitro kwalaga nti macrophages bwe zasikirizibwa ne lipopolysaccharide (LPS) okukola polarize okutuuka ku kika kya M1, co-administration ya KPV yaziyiza macrophage polarization eri ekika kya M1, kyakendeeza ku kwolesebwa kw’obubonero bwa M1 macrophage, ate nga kitumbula polarization yaabwe eri ekika kya M2, okwongera okwolesebwa kw’obubonero bwa M2 macrophage (nga arginase-1 Arg-1) nga bwe. Mu bikolwa eby’okuzimba mu mubiri, nga DSS-induced colitis mu mbeba, okujjanjaba ne KPV kwavaamu macrophages nnyingi mu bitundu by’ekyenda ekinene polarizing okutuuka ku kika kya M2, bwe kityo ne kikendeeza ku kuddamu kw’okuzimba n’okutumbula okuddaabiriza ebitundu.
5. Ebikolwa eby’obukuumi ku butoffaali bw’ekyenda obuyitibwa epithelial cells
Okwongera ku nkola y’ekiziyiza eky’omubiri: Ekiziyiza eky’omubiri ekikolebwa obutoffaali bw’ekyenda kikola ng’olunyiriri olusooka olw’okuziyiza obuwuka obuleeta endwadde n’okulumba kw’ebintu eby’obulabe. Mu mbeera z’okuzimba, okukosebwa kw’emirimu gy’ekiziyiza ky’ekyenda kivaako okukyusakyusa kwa bakitiriya n’okukulukuta kw’obutwa mu mubiri, ekyongera okusajjula okuddamu kw’okuzimba. KPV esobola okutumbula omulimu gw’okuziyiza ogw’obutoffaali bw’ekyenda obuyitibwa epithelial cells. Okugezesa obutoffaali mu vitro, nga layini z’obutoffaali bw’omubiri obuyitibwa intestinal epithelial cell lines zajjanjabwa ne pro-inflammatory cytokines okukoppa embeera y’okuzimba, kyavaamu okukendeeza ku kwolesebwa kwa tight junction proteins (nga ZO-1 ne occludin) n’okukosa enkola y’ekiziyiza. Naye, okugattako KPV kukuuma okwolesebwa kwa puloteyina ezikwatagana ennyo, kyongera ku kuyungibwa wakati w’obutoffaali, era kuzzaawo omulimu gw’okuziyiza ogw’obutoffaali bw’ekyenda. Mu mbeba z’obulwadde bw’olubuto obuleetebwa DSS ezajjanjabwa ne KPV, immunohistochemistry ne Western blot analysis zalaga okweyongera kw’okwolesebwa kwa puloteyina ezikwatagana ennyo mu bitundu by’ekyenda ekinene n’okukendeeza ku kuyita kw’ekyenda, ekiraga nti KPV ekuuma ekiziyiza ky’ekyenda eky’omubiri mu vivo, ekendeeza okulumba ebintu eby’obulabe, n’okukendeeza ku kuddamu kw’okuzimba.
Okutumbula okukula n’okuddaabiriza obutoffaali bw’ekyenda: Okuzimba kuyinza okuleeta okwonooneka n’okufa kw’obutoffaali bw’ekyenda, ne kikosa enkola y’ekyenda eya bulijjo. KPV erina obusobozi okutumbula okukula n’okuddaabiriza obutoffaali bw’ekyenda obuyitibwa epithelial cells. Okugezesa okukuza obutoffaali mu vitro kwalaga nti okujjanjaba obutoffaali bw’ekyenda obwonooneddwa ne KPV kyayongera okukula kw’obutoffaali, nga bwe kyazuulibwa mu Cell Counting Kit (CCK-8). Okugatta ku ekyo, okwekenneenya immunofluorescence kwalaga okweyongera kw’okwolesebwa kwa proliferating cell nuclear antigen (PCNA), ekiraga nti obutoffaali bwali mu mbeera ya proliferative ekola. Mu nkola ya TNBS-induced ulcerative colitis rat model, oluvannyuma lw’okujjanjabwa ne KPV/SH-PGA hydrogel, histological observations kwalaga nti okwonooneka kw’obutoffaali bw’omubiri obuyitibwa colonic epithelial cells kwaddaabirizibwa, era crypt structures zadda mpolampola mu mbeera eya bulijjo. Kino kiyinza okuba nga kyekuusa ku KPV okutumbula okukula n’okuddaabiriza obutoffaali bw’omubiri (epithelial cell proliferation and repair), ekiyamba okukendeeza ku kuzimba n’okutumbula okuddamu kw’ebitundu by’ekyenda.
Ekifaananyi 2 KPV ejjanjaba mu bulwadde bw’olubuto bwa DSS.
6. Ebikolwa ebiziyiza obuwuka obuleeta obulwadde
Okulungamya obubonero obukwatagana n’okunyigirizibwa kw’okwokya: Okuzimba kutera okuwerekerwako enkola z’okunyigirizibwa okw’okwokya, nga kweyongera okukola ebika bya oxygen ebikola (ROS) n’ebika bya nayitrojeni ebikola (RNS), ekivaako okwonooneka kw’obutoffaali n’ebitundu by’omubiri. KPV eraga ebikolwa eby’okuziyiza obuwuka obuleeta obulwadde era esobola okulung’amya obubonero obukwata ku situleesi y’okwokya. Mu bikolwa ebimu ebizimba, gamba nga ppamba-induced mouse granuloma model ne egg white-induced rat dorsal air sac synovitis model, emiwendo gya malondialdehyde (MDA) egy’okulinnya n’okukendeeza ku mirimu gya superoxide dismutase (SOD) gyazuulibwa mu bitundu ebizimba. Oluvannyuma lw’okujjanjabwa KPV, emiwendo gya MDA gyakendeera nnyo, era emirimu gya SOD gyeyongera. MDA kiva mu lipid peroxidation, era emiwendo gyayo egyakendedde giraga okukendeera kw’okwonooneka kw’obutoffaali obuyitibwa lipid peroxidation; SOD ye enzyme enkulu eyamba okuziyiza obuwuka obuleeta obulwadde, era okweyongera kw’emirimu gyayo kitegeeza obusobozi obweyongedde okuyoola obuwuka obuyitibwa free radicals. KPV esobola okukendeeza ku kwonooneka kw’okwokya mu bitundu ebizimba nga etereeza emitendera gy’okunyigirizibwa okw’okwokya, bwe kityo n’ekola ebikolwa eby’okulwanyisa okuzimba.
7. Enkola Endala Eziyinza Okukolebwa
Enkolagana n’ekirungo kya melanocortin: KPV ye tripeptide eggibwa mu α-MSH. Wadde ng’ebikolwa byayo eby’okulwanyisa okuzimba tebirina kitundu ku bubonero bwa MC1R, biyinza okuba nga bikwatagana ne MC1R mu mbeera ezimu. Mu bisolo ebiraga MC1Re/e, obujjanjabi bwa KPV oluvannyuma lw’obulwadde bw’olubuto obuleetebwa DSS bwakyakola ebikolwa eby’amaanyi eby’okulwanyisa okuzimba, okununula ebisolo byonna mu kibinja ky’obujjanjabi okuva mu kufa mu kiseera ky’obulwadde bw’olubuto obuleetebwa DSS, ekiraga nti ebikolwa bya KPV eby’okulwanyisa okuzimba waakiri tebyetongodde ku bubonero bwa MC1R. Mu bisolo ebirina MC1R expression eya bulijjo, KPV eyinza okwongera ku anti-inflammatory effects nga ekwatagana ne MC1R oba okulungamya amakubo gaayo ag’obubonero wansi.
Ebikolwa bya KPV ebiziyiza okuzimba
1. Omulimu mu bikolwa by’okuzimba ebyenda
DSS-induced colitis model: Mu DSS-induced mouse colitis model, KPV yalaga ebikolwa ebinene eby’okulwanyisa okuzimba. Mu nkyukakyuka mu buzito, ebibe ebyajjanjabwa ne KPV byaddamu okuzitowa nga bukyali era ku kigero ekinene bw’ogeraageranya n’ebibe ebitajjanjabiddwa. Okwetegereza ebitundu by’omubiri (histological observations) kwalaga okukendeera okw’amaanyi mu kuyingira kw’okuzimba mu bitundu by’ekyenda ekinene eby’ebibe ebijjanjabiddwa KPV, ekyayongera okukakasibwa okukendeera okw’amaanyi mu mirimu gya myeloperoxidase (MPO). MPO ye enzyme eri mu neutrophils, era emitendera gyayo egy’emirimu giraga ekigero ky’okuyingira kw’obutoffaali obuzimba mu bitundu by’omubiri. Okukendeera mu mirimu gya MPO oluvannyuma lw’okujjanjabwa KPV kiraga okukendeera kw’okuyingira kwa neutrophil mu bitundu by’ekyenda ekinene n’okukendeeza ku kuddamu kw’okuzimba. Mu kuzuula mRNA expression ya pro-inflammatory cytokines mu colonic tissue, nga TNF-α ne IL-1β, kyazuulibwa nti obujjanjabi bwa KPV bwakendeeza nnyo ku mitendera gy’okwolesebwa kwa pro-inflammatory cytokines zino. KPV yakendeeza ku bubonero bw’obulwadde bw’olubuto obuleetebwa DSS okuva mu bintu ebingi, omuli okukendeeza ku kuyingira kw’obutoffaali obuzimba, okukendeeza ku kwolesebwa kw’ensonga ezizimba, n’okutumbula okuddamu okugejja.
CD45RB(hi) colonic inflammation model: Mu CD45RB(hi) colonic inflammation model, KPV nayo yalaga ebikolwa ebirungi eby’okulwanyisa okuzimba. Omuze guno gwaleetebwa nga gukyusa obutoffaali bwa T obulaga ennyo CD45RB mu mbeba ezirina obusimu obuziyiza endwadde. Oluvannyuma lw’okujjanjabwa KPV, ebibe byalaga obubonero bw’okuzimba obulongooseddwa, okugejja mpolampola, era okukeberebwa mu bitundu by’omubiri kwalaga enkyukakyuka mu kuzimba mu byenda nga zikendedde. Ekibinja ekyajjanjabwa KPV kyalaga okukendeera kw’okuyingira kw’obutoffaali obuzimba n’okukendeeza ku kwonooneka kw’ensengekera ya crypt mu bitundu by’ekyenda, ekiraga nti KPV ekendeeza bulungi okuzimba kw’ekyenda okuleetebwa CD45RB(hi) n’okuzzaawo ensengeka n’enkola y’ebitundu by’ekyenda ebya bulijjo.
TNBS-induced ulcerative colitis model: Mu TNBS-induced ulcerative colitis rat model, KPV nayo yalaga ebikolwa ebinene mu bujjanjabi. Oluvannyuma lw’okugabira envunza KPV/SH-PGA hydrogel mu nseke, obubonero bw’obulwadde bw’olubuto bwatereera nnyo. Diguli y’okugejja mu nvunza yakendeezebwa, era obubonero bw’ebikolwa by’obulwadde (DAI) bwakendeera. Obukodyo bwa DAI butunuulira mu bujjuvu ebiraga ng’enkyukakyuka mu buzito bw’omubiri gw’envunza, engeri y’omusulo, n’okuzimba omusaayi. Okukendeera kwayo kulaga nti KPV/SH-PGA hydrogel esobola bulungi okukendeeza ku buzibu bw’obulwadde bw’amabwa obuleetebwa TNBS. Obujjanjabi bwa KPV/SH-PGA hydrogel era buziyiza okukendeera kw’ekyenda ekinene mu nvunza, okukendeeza ku miwendo gya myeloperoxidase mu kyenda, n’okuzzaawo ensengekera y’enkula y’olubuto, omuli ekiziyiza eky’omubiri ekiyitibwa epithelial barrier, crypts, n’obutoffaali bwa goblet obutakyuse. Okwolesebwa kwa pro-inflammatory cytokines, TNF-α ne IL-6, mu bitundu by’ekyenda ekinene nakyo kyakendeera nnyo, ne kyongera okulaga enkola y’okulwanyisa okuzimba eya KPV mu TNBS-induced ulcerative colitis model.
Mu bufunzi
KPV, nga tripeptide erimu obusobozi obuziyiza okuzimba, eraga ebisuubiza mu kuziyiza n’okujjanjaba okuzimba ekyenda n’endwadde endala ez’enjawulo ezikwatagana n’okuzimba. Enkola zaayo ez’okulwanyisa okuzimba zirimu ebintu ebingi, omuli okulungamya amakubo g’obubonero bw’obutoffaali, okunyigirizibwa kw’ebiziyiza obuwuka obuleeta obulwadde, n’okukyusakyusa apoptosis ne autophagy.
Ensonda
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Ekintu ekiriwo okukozesebwa mu kunoonyereza kwokka:
