Bya Cocer Peptides 
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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.
Okutwalira awamu
Obutabeera bulungi mu nkyukakyuka y’amasavu obuva ku bulwadde bwa siriimu n’obujjanjabi obuziyiza akawuka ka siriimu (ART) buleeta okusoomoozebwa okw’amaanyi eri obulamu n’omutindo gw’obulamu bw’abalwadde ba siriimu. Obutabeera bulungi buno bweyolekera mu ngeri ez’enjawulo, gamba nga lipoatrophy ne lipohypertrophy, nga okukuŋŋaanyizibwa okuyitiridde kw’ebitundu by’amasavu mu bitundu by’omubiri (VAT) kwe kusinga okweyoleka. Okweyongera kw’omusolo gwa VAT tekukoma ku kukosa ndabika ya balwadde yokka wabula kukwatagana nnyo n’ebizibu eby’amaanyi ebiva mu nkyukakyuka y’emmere, omuli endwadde z’emisuwa, okuziyiza insulini, n’obulwadde bw’ekibumba obutali bwa masavu (NAFLD), ekiteeka akabi ak’amaanyi eri obulamu bw’abalwadde obw’ekiseera ekiwanvu n’embeera y’obulamu.
Tesamoreli, eddagala eriyitibwa synthetic growth hormone-releasing hormone (GHRH) analog, liwa essuubi eppya mu kujjanjaba obuzibu mu nkyukakyuka y’amasavu mu balwadde ba siriimu. Kikwatagana mu ngeri ey’enjawulo ku bikwata GHRH mu nseke y’omu maaso (anterior pituitary gland), ne kisitula bulungi okusengejja n’okufulumya obusimu bw’okukula obw’omunda (GH). GH ekola kinene nnyo mu kulungamya enkyukakyuka y’amasavu mu mubiri gw’omuntu, okutumbula lipolysis, okutumbula oxidation ya asidi w’amasavu, n’okulungamya okwolesebwa kw’obuzaale obukwatagana n’okukyusakyusa amasavu, bwe kityo n’ekola akakwate akalungi ku nkyukakyuka y’amasavu. Enkola eno ey’enjawulo ey’okukola esobozesa Tesamoreli okuyamba okulongoosa obuzibu mu nkyukakyuka y’amasavu mu balwadde ba siriimu.
Ekifaananyi 1 Enteekateeka y’okwekenneenya. Omugatte gwa puloteyina za plasma 9 zaakeberebwa, ezikwatagana n’obuzaale obukulembedde waggulu mu makubo g’obuzaale bw’ekibumba agakyusibwakyusibwa mu ngeri ey’enjawulo tesamorelin.
Enkola y’Ekikolwa kya Tesamoreli ku nkyukakyuka y’amasavu mu siriimu
Abalwadde
Okulungamya ensengekera y’ensonga y’okukula eringa obusimu bw’okukula-Insulin-Like Growth Factor
Tesamoreli yeekwata ku GHRH receptor ku cell membrane ya anterior pituitary gland, okukola amakubo g’obubonero agakwatagana n’ekikwata nga JAK-STAT signaling pathway. Enkola eno ey’okukola etumbula okusengejja n’okufulumya obusimu bw’okukula (GH) okuva mu nseke y’omu maaso (anterior pituitary gland). Oluvannyuma lw’okuyingira mu musaayi, atuuka ku bitundu ebigendereddwamu ng’ekibumba, n’esitula ekibumba okukola n’okufulumya insulin-like growth factor-1 (IGF-1). IGF-1 ekola nga omutabaganya omukulu mu bikolwa bya GH mu nkyukakyuka y’emmere era ekola kinene mu nkyukakyuka y’amasavu. IGF-1 esobola okukola ekkubo ly’obubonero bwa PI3K-AKT, okuziyiza adipocyte apoptosis, n’okukuuma enkola ya adipocyte eya bulijjo. Era kitumbula okutwalibwa n’okufuula asidi z’amasavu okufuuka oxidation (oxidation) kwa asidi z’amasavu (adipocytes), ekikendeeza okukuŋŋaanyizibwa kw’amasavu mu butoffaali. Mu balwadde ba siriimu, omulimu gw’ekirungo ky’okukula ekiringa obusimu bw’okukula obulinga insulini gutera okukosebwa olw’obulwadde bwennyini n’ebiva mu bujjanjabi obuziyiza akawuka ka siriimu (ART). Tesamoreli esobola okukola ekisiki kino okuzzaawo omulimu gwayo ogwa bulijjo ogw’okulungamya enkyukakyuka y’amasavu.
Ebikosa obutereevu ku nkyukakyuka y’obutoffaali bw’amasavu
Okutumbula lipolysis: Tesamoreli esobola okutumbula okwolesebwa n’emirimu gya hormone-sensitive lipase (HSL) mu adipocytes. HSL ye enzyme enkulu mu lipolysis, catalyzing hydrolysis ya triglycerides mu glycerol ne fatty acids, bwe kityo ne kitumbula catabolic metabolism y’amasavu. Mu vitro, okugatta Tesamoreli ku adipocytes ezikuziddwa kyongera nnyo ku mirimu gya HSL era kyongera nnyo ku kufulumya asidi w’amasavu. Tesamoreli era esobola okukola HSL mu ngeri etali butereevu nga etereeza ekkubo ly’obubonero erya cyclic AMP (cAMP)-protein kinase A (PKA), okwongera okutumbula lipolysis. Mu balwadde ba siriimu, kino ekiyamba okuzimba amasavu kiyamba okukendeeza ku masavu agasukkiridde naddala okukendeeza amasavu mu bitundu by’omubiri, bwe kityo ne kitereeza ensaasaanya y’amasavu etali ya bulijjo mu balwadde.
Okulungamya okuwunyiriza kwa asidi w’amasavu: Tesamoreli ayongera ku mirimu gy’enziyiza enkulu ezenyigira mu kuziyiza asidi w’amasavu mu busimu obuyitibwa adipocytes, nga carnitine palmitoyltransferase 1 (CPT1). CPT1 ye enzyme ekoma ku sipiidi ya asidi w’amasavu okuyingira mu mitochondria okusobola okukola β-oxidation, era omulimu gwayo ogwongezeddwayo gutumbula okumenya kwa asidi z’amasavu mu oxidative mu mitochondria, okuwa amaanyi eri obutoffaali. Tesamoreli era esobola okutumbula okwolesebwa kw’enziyiza endala n’ebitambuza ebikwatibwako mu kukyusa asidi w’amasavu β-oxidation, nga acetyl-CoA carboxylase 2 (ACC2) ne fatty acid transporter 1 (FATP1), okwongera okulongoosa enkola y’okukyusakyusa asidi w’amasavu. Nga atumbula okuziyiza asidi w’amasavu, Tesamoreli asobola okukendeeza ku kutereka amasavu mu butoffaali n’okulongoosa obuzibu mu nkyukakyuka y’amasavu mu balwadde ba siriimu.
Okulungamya okulaga kw’obuzaale obukwatagana n’enkyukakyuka y’amasavu
Okufuga obuzaale obukwatagana n’okuzaala kw’amasavu: Tesamoreli esobola okuziyiza okwolesebwa kw’obuzaale obukwatagana n’okuzaala kw’amasavu, nga peroxisome proliferator-activated receptor γ (PPARγ) ne CCAAT/enhancer-binding protein α (C/EBPα). PPARγ nsonga nkulu mu kuwandiika mu kwawukana kw’obutoffaali bw’amasavu n’okutondebwa kw’amasavu, etumbula okwawukana kwa fibroblasts mu masavu amakulu, era ereeta okwolesebwa kw’obuzaale obukwatagana n’okutondebwa kw’amasavu, nga fatty acid-binding protein 4 (FABP4) ne fatty acid synthase (FAS). C/EBPα era ekola kinene nnyo mu kwawula obutoffaali bw’amasavu n’okutondebwa kw’amasavu. Nga aziyiza okwolesebwa kwa PPARγ ne C/EBPα, Tesamoreli akendeeza ku njawulo y’obutoffaali bw’amasavu n’okutondebwa kw’amasavu, bwe kityo n’akendeeza ku kukuŋŋaanyizibwa kw’amasavu mu mubiri. Mu balwadde ba siriimu, enkola eno ey’okulungamya ku buzaale obukwatagana n’okutondebwa kw’amasavu eyamba okutereeza amasavu agasukkiridde agava ku nkyukakyuka y’amasavu mu ngeri etaali ya bulijjo.
Ekifaananyi 2 Enkolagana y’enkyukakyuka mu Plasma VEGFA ne CSF1 n’enkyukakyuka mu NAS Score mu Beetabyemu abajjanjabiddwa Tesamoreli.
Okulungamya entambula y’amasavu n’obuzaale bw’okukyusakyusa mu mubiri: Tesamoreli esobola okulungamya okwolesebwa kw’obuzaale obukwatagana n’entambula y’amasavu n’enkyukakyuka y’amasavu, gamba ng’aba famire ya apolipoprotein (Apo). ApoB ye apolipoprotein enkulu eya lipoprotein eya low-density ennyo (VLDL) ne low-density lipoprotein (LDL), era emitendera gyayo egy’okwolesebwa gikwatagana nnyo n’emiwendo gya VLDL ne LDL mu plasma. Tesamoreli esobola okukendeeza ku ApoB expression, okukendeeza ku kusengejja n’okufulumya VLDL ne LDL, bwe kityo ne kikendeeza ku miwendo gya plasma egya atherogenic lipoproteins. Okugatta ku ekyo, Tesamoreli asobola okutumbula okwolesebwa kwa ApoA-I, apolipoprotein enkulu eya high-density lipoprotein (HDL). Okwongera mu kwolesebwa kwa ApoA-I kiyamba okulinnyisa emiwendo gya HDL, okutumbula entambula ya kolesterol okudda emabega, n’okukendeeza ku bulabe bw’endwadde z’emisuwa. Mu balwadde ba siriimu, ng’obuzibu mu nkyukakyuka y’amasavu butera okuwerekera obutali bwa bulijjo mu nkyukakyuka y’amasavu, ebikolwa bya Tesamoreli ebifuga ku ntambula y’amasavu n’obuzaale bw’okukyusakyusa amasavu bisobola okuyamba okulongoosa ebifaananyi by’amasavu g’abalwadde.
Ebikolwa ebitongole ebya Tesamoreli ku nkyukakyuka y’amasavu mu balwadde ba siriimu
Okukendeeza ku bitundu by’omubiri ebiyitibwa Visceral Adipose Tissue (VAT) .
Tesamoreli ekendeeza nnyo VAT mu balwadde ba siriimu. Mu kugezesebwa okw’omutendera III okwali kuzingiramu abalwadde ba siriimu, abeetabye mu kugezesebwa baalondebwa mu ngeri ey’ekifuulannenge okufuna oba 2 mg za Tesamoreli buli lunaku oba placebo okumala wiiki 26. Mu kibinja ky’obujjanjabi bwa Tesamoreli, abalwadde baayoleka okukendeera okw’amaanyi mu VAT, era okukendeera kuno kwalabibwa mu balwadde bonna abalina engeri ez’enjawulo ez’omusingi (okugeza, okubeerawo oba obutabaawo masavu mu bulago). Ku ba Tesamoreli responders (abategeezebwa ng’abalwadde abalina okukendeera waakiri 8% mu VAT era abanywerera ku bujjanjabi), VAT yakendeera nnyo awatali kulowooza ku kubeerawo kw’amasavu mu bulago n’omugongo, era tewaaliwo njawulo ya muwendo wakati w’ebibinja byombi (P = 0.657). Kino kiraga nti Tesamoreli alina obusobozi bugazi mu kukendeeza VAT mu balwadde ba siriimu, nga tekyesigamye ku kubeerawo kw’amasavu mu bulago. Okukendeeza ku VAT tekukoma ku kulongoosa ndabika ya balwadde wabula ekisinga obukulu kikendeeza ku bulabe bw’ebizibu ebiva ku VAT, gamba ng’endwadde z’emisuwa n’obuziyiza insulini.
Okulongoosa enkola y’amasavu mu kibumba
Okukendeeza ku masavu mu kibumba: Mu balwadde ba siriimu, obulwadde bw’ekibumba obutali bwa masavu (NAFLD) buba bungi era bukwatagana nnyo n’enkyukakyuka y’amasavu mu ngeri etaali ya bulijjo. Tesamoreli alina akakwate akalungi mu bujjanjabi ku NAFLD eyeekuusa ku siriimu. Mu kunoonyereza okwakolebwa mu ngeri ey’ekifuulannenge, okwakolebwa mu bifo bibiri, okwakolebwa mu bifo bingi, abalwadde abalina akawuka ka siriimu nga balina ekitundu ky’amasavu mu kibumba (HFF) ≥5% baagabibwa mu ngeri ey’ekifuulannenge mu kibinja kya tesamorelin oba ekibinja kya placebo ne bajjanjabwa okumala emyezi 12. Ebivuddemu biraga nti abalwadde mu kibinja kya Tesamoreli baalina okukendeera okw’amaanyi mu HFF, nga balina obunene bw’ekikolwa ekituufu obwa -4.1% (95% CI -7.6 okutuuka ku -0.7, P = 0.018) n’okukendeera okw’enjawulo okwa 37% okuva ku ntandikwa (95% CI -67 okutuuka ku -7, P = 0.016). Oluvannyuma lw’emyezi 12 nga bajjanjabwa, abalwadde 35% mu kibinja kya Tesamoreli baalina emiwendo gya HFF wansi wa 5%, bw’ogeraageranya n’abalwadde 4% bokka mu kibinja kya placebo (P = 0.0069). Kino kiraga nti Tesamoreli akendeeza bulungi amasavu mu kibumba n’okulongoosa enkola y’amasavu mu kibumba mu balwadde ba siriimu.
Ebiyinza okuva ku bitundu by’ekibumba: Okwekenenya ebifaananyi by’obuzaale bw’ekibumba mu balwadde ba siriimu-NAFLD kwalaga nti Tesamoreli yakendeeza ku buzaale obukwatagana n’okuzimba, okuddaabiriza ebitundu, n’okugabanya obutoffaali mu kibumba. Okunoonyereza okulala ku proteomics kwalaga nti Tesamoreli yaleeta okukendeera okw’amaanyi mu miwendo gya puloteyina mu plasma eya vascular endothelial growth factor A (VEGFA), transforming growth factor β1 (TGFB1), ne macrophage colony-stimulating factor 1 (CSF1), ezikwatagana ennyo n’okuzimba ekibumba n’okuzimba. Mu balwadde abajjanjabwa ne Tesamoreli, okukendeera mu plasma VEGFA ne CSF1 kwakwatagana n’okukendeera mu bubonero bw’emirimu gya NAFLD, ate okukendeera mu TGFB1 ne CSF1 kwakwatagana n’okukendeera mu bubonero bwa fibrosis ku ddaala ly’obuzaale. Kino kiraga nti Tesamoreli eyinza okukola ebirungi ku histology y’ekibumba ng’etereeza amakubo agakwatagana n’okuzimba n’obusimu obuyitibwa fibrosis mu kibumba.
Ekifaananyi 3 Enkolagana y’enkyukakyuka mu Plasma TGFB1 ne CSF1 n’enkyukakyuka mu Gene-Level Fibrosis Score mu beetabye mu kujjanjabwa Tesamoreli.
Okulungamya Engabanya y’amasavu mu mubiri gwonna n’obutonde bw’omubiri
Okukendeeza amasavu g’omu kifuba: Ng’oggyeeko okukendeeza ku VAT, Tesamoreli era alina kinene ky’akola ku masavu g’omu kifuba mu balwadde ba siriimu. Mu kunoonyereza okwakolebwa mu malwaliro, abalwadde abajjanjabwa ne Tesamoreli baalaga nti amasavu mu kikolo gakendeera mpolampola, ekiyamba okulongoosa enkula y’omubiri n’okukendeeza ku nsonga ng’okufuluma mu lubuto okuva ku kusaasaana kw’amasavu mu ngeri etaali ya bulijjo. Okukendeera kw’amasavu g’omu kifuba kukwatagana n’okukendeeza ku musolo gwa VAT, nga byonna awamu bitereeza obutonde bw’omubiri.
Okulongoosa okwetooloola ekiwato: Okwetoloola ekiwato kikulu ekiraga nti amasavu gakuŋŋaanyiziddwa mu lubuto. Obujjanjabi bwa Tesamoreli bulongoosa nnyo okwetooloola ekiwato mu balwadde ba siriimu. Mu kugezesebwa okukwatagana, bombi aba Tesamoreli responders nga balina n’abataliiko masavu mu bulago mu mugongo baalaga okukendeera okw’amaanyi mu kwetooloola ekiwato oluvannyuma lwa wiiki 26 nga bajjanjabwa. Okulongoosa mu kiwato tekikoma ku kwoleka masavu mu lubuto okukendeera wabula kikwatagana nnyo n’okukendeeza ku bulabe bw’okukyusakyusa emmere ng’endwadde z’emisuwa.
Ebikosa ku bipimo ebirala eby’obutonde bw’omubiri: Tesamoreli era erina ekikolwa eky’okulungamya ku bipimo ebirala eby’obutonde bw’omubiri mu balwadde ba siriimu. Okugeza, mu kunoonyereza okumu, wadde nga body mass index (BMI) tekyalaze nkyukakyuka nnene, amasavu mu mubiri galongooka. Tesamoreli esobola okulongoosa ensaasaanya y’amasavu mu mubiri awatali kukosa buzito okutwalira awamu, okukendeeza ku masavu agasukkiridde okukuŋŋaanyizibwa, okwongera ku bitundu by’omubiri ebigonvu ng’ebinywa, n’okutumbula omutindo gw’omubiri gw’abalwadde.
Okukozesa Tesamoreli mu Fat Metabolism mu balwadde ba siriimu
Omuwendo gw’abantu ogugendereddwamu
Abalwadde ba siriimu abalina amasavu agatali ga bulijjo: Tesamoreli okusinga eragiddwa eri abalwadde ba siriimu abalina amasavu agatali ga bulijjo naddala abo abalina amasavu agasukkiridde mu bitundu by’omubiri (okugeza, nga bwe kizuulibwa mu CT oba MRI scans z’omu lubuto nga ziraga ebitundu by’amasavu eby’omunda [VAT] nga bisukka mu bitundu ebya bulijjo). Abalwadde bano batera okwoleka omugejjo mu lubuto, okwetooloola ekiwato okweyongera, era bayinza n’okwolesebwa n’obubonero obulala obw’obulwadde bw’okukyusakyusa emmere, gamba ng’okuziyiza insulini n’okukendeeza ku masavu mu musaayi.
Mu bufunzi
Nga eddagala eddungi erijjanjaba enkyukakyuka y’amasavu mu ngeri etaali ya bulijjo mu balwadde ba siriimu, Tesamoreli etereeza enkyukakyuka y’amasavu ng’ayita mu nkola eziwera, ng’akola kinene mu kukendeeza VAT, okulongoosa enkyukakyuka y’amasavu mu kibumba, okulungamya ensaasaanya y’amasavu mu mubiri gwonna, n’okulongoosa ebitonde by’omubiri.
Ensonda
[1] Rahman F, de Chantal M, Mesquita P, n’abalala. . Open Forum Endwadde ezisiigibwa, 2020,7(Supplement_1):S500-S501.DOI:10.1093/ofid/ofaa439.1121.
[2] Alipoota y’okuddamu okwetegereza obujjanjabi: Tesamoreli (Egrifta)[M]. Ottawa (ON): Ekitongole kya Canada ekikola ku ddagala ne tekinologiya mu by’obulamu, 2016.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Ggyayo&db=pubmed&dopt=Ebikwata ku biwandiiko&olukalala_uids=30920787&okubuuza_hl=1.
Ekintu ekiriwo okukozesebwa mu kunoonyereza kwokka:
