Ubururu bwa metilene n'ihererekanya ry'ibimenyetso by'ububyimbirwe: inflammasome, IL-6 na STAT3

Tekereza laboratwari eshatu zitangaje ko ikinyabutabire kimwe cy'ubururu kigabanya ububyimbirwe. Imwe igaragaza ko makorofaje zirekura IL-1beta nke. Indi igaragaza ko anzime ya iNOS yagabanutse muri ubwo bwoko bw'uturemangingo. Indi igaragaza ko IL-6 yagabanutse mu maraso kandi ko imikorere ya STAT3 yagabanutse mu bwonko. Biroroshye gushaka guhuriza ibyo bitatu mu mwanzuro umwe. Ariko uko kubihuza guhisha ibyagaragajwe n'ubushakashatsi.

Buri gisubizo ni icy'uburyo butandukanye bw'ihererekanya ry'ibimenyetso, bufite ikibutangiza, intambwe yo guteranya ibibugize, n'igipimo cyabwo. Ubururu bwa metilene bugira icyo bukora kuri buri buryo ahantu hatandukanye. Kumenya niba ibyo hari icyo biteza imbere ku buzima ni ikindi kibazo, kivugwa mu ncamake yacu ku bururu bwa metilene n'ububyimbirwe. Uru rupapuro rwibanda gusa ku nzira z'ibimenyetso.

Inzira 1: iteranywa rya inflammasome na caspase-1

Inflammasome ni urufatiro rwa poroteyine rwubakwa igihe rukenewe imbere mu karemangingo ko mu muryango wa myeloid. Ibiyigize ni poroteyine yumva ikimenyetso, poroteyine ihuza izindi yitwa ASC, n'anzime ishyira igikorwa mu bikorwa yitwa caspase-1. Iyo bimaze guteranywa, caspase-1 icamo pro-IL-1beta na pro-IL-18 ikabihindura mu buryo bushobora gusohorwa n'akaremangingo, kandi ishobora gutangiza pyroptosis, uburyo bwo gupfa kw'akaremangingo bujyana n'ububyimbirwe. Poroteyine yumva ikimenyetso ni yo igena ubwoko: NLRP3 yitabira kirisitali n'uburozi butobora utwenge, nka nigericin na ATP; NLRC4 yitabira flagellin ya bagiteri; AIM2 yitabira DNA ifite imirongo ibiri iri mu gice cy'amazi cy'akaremangingo; naho inzira itari isanzwe ikitabira lipopolysaccharide iri imbere mu karemangingo.

Gutangiza imikorere bisaba ibimenyetso bibiri. Ikimenyetso cya mbere ni ugutegura: ikinyabutabire gifata ku cyakira cyo mu bwoko bwa Toll gitera iyandukurwa rya NLRP3 na pro-IL-1beta rishingiye kuri NF-kB, bityo ibice bikenewe bikaboneka. Ikimenyetso cya kabiri ni uguteranya: ikindi gitangiza gituma molekile za ASC zishyira hamwe zikaba utudomo, caspase-1 igacibwamo igice cyayo cya p20, na IL-1beta p17 imaze gutunganywa igasohorwa. Ubwoko bwa ogisijeni bwitabira imikoranire y'imiti buturuka muri mitokondiriya, no kwinjiza kirisitali mu karemangingo, bizwi ko bigira uruhare mu kimenyetso cya kabiri cya NLRP3.

Ubushakashatsi bwo mu 2017 kuri makorofaje ku kubuza imikorere y'ubwoko bwinshi bwa inflammasome bwagerageje ubururu bwa metilene kuri ibyo bimenyetso byombi. Muri makorofaje zo mu musokoro w'amagufwa y'imbeba zari zateguwe hakoreshejwe lipopolysaccharide, nigericin, ATP na kirisitali za monosodium urate buri kimwe cyateye isohorwa rya IL-1beta na caspase-1, hamwe no kwirema kw'utudomo twa ASC. Ubururu bwa metilene kuri 20 kugeza kuri 200 micromolar bwagabanyije ibyo bitatu, igabanuka rikiyongera uko ingano yakoreshejwe yiyongeraga, butishe uturemangingo. Flagellin na Salmonella kuri NLRC4, DNA ifite imirongo ibiri na Listeria kuri AIM2, na lipopolysaccharide yinjijwe mu turemangingo cyangwa E. coli nzima ku nzira itari isanzwe, byagaragaje uburyo bumwe. Icyo kinyabutabire cyonyine nticyateye isohorwa, kandi amasahani y'igereranya ntiyagaragaje ingaruka zo kurwanya bagiteri; bityo igisubizo kijyanye n'uburyo umubiri wakiriye ibiwukangura.

Ku ntambwe zibanziriza ibyo, hapimwe ingaruka ku bintu bitatu. Superoxide yo muri mitokondiriya yatewe na rotenone yagabanutse hakoreshejwe ubururu bwa metilene, n'isohorwa rya IL-1beta ryatewe na rotenone na ryo riragabanuka. Kwinjiza udu粒 duto tubengerana mu karemangingo byaragabanutse, bihuye n'igabanuka ry'imikorere yo kumira uduce mbere yo kumva kirisitali. Igipimo cy'ikimenyetso cyagenzurwaga n'akarere gatangiza iyandukurwa rya NLRP3, gafite ahantu habiri NF-kB ifata, cyagaragaje imikorere yagabanutse hakoreshejwe ubururu bwa metilene; ariko akarere kagabanyijwe kadashizemo aho hantu ntikagize impinduka. Mu muyoboro w'igerageza utarimo uturemangingo, ubururu bwa metilene bwanagabanyije mu buryo butaziguye imikorere ya caspase-1 y'umuntu yakozwe hakoreshejwe ikoranabuhanga ryo guhuza DNA. Kongeramo icyo kinyabutabire mu gihe cyo gutegura gusa cyangwa mu gihe cyo gutangiza gusa na byo byagabanyije isohorwa rya IL-1beta, IL-18 na caspase-1; bityo intambwe zombi zirarebwa.

Ibizamini ku mbeba byahuje n'uku kugabanya ibintu bimwe gusa. Ingano yica ya lipopolysaccharide yishe imbeba zo mu itsinda ry'igereranya mu masaha make, mu gihe ubururu bwa metilene bwongereye izarokotse; IL-1beta yo mu mwanya wa peritoneum yagabanutse, ariko IL-6 yo muri ayo mazi ntiyagabanuka. Mu rugero rw'ububyimbirwe bwa peritoneum bwatewe na Listeria, IL-1beta yo muri uwo mwanya yagabanutse, mu gihe umubare rusange w'uturemangingo utahindutse. Monosite za THP-1 z'umuntu zitwaye nka makorofaje z'imbeba mu bwoko bune bwose bwa inflammasome. Igisubizo cya inflammasome gisobanura gutunganywa kwa IL-1beta na IL-18, si kwa buri sitokine. Ibyo ni na byo bituma imiterere y'uturemangingo tw'ubudahangarwa bwo mu bwonko mu magerageza kuri mikorogiliya n'astorosite isubiza ikindi kibazo gitandukanye n'iteranywa ry'urufatiro rwa poroteyine.

Inzira 2: iyandukurwa rya jene ya iNOS binyuze ku gufata kwa NF-kB na STAT1

Anzime ikora nitric oxide igihe itangijwe, cyangwa iNOS, iba ari nke cyane igihe akaremangingo karuhutse, kandi jene yayo yandikwa igihe bikenewe. Lipopolysaccharide ibitera cyane cyane binyuze mu gusenyuka kwa IkB-alpha, gukurikirwa no kongerwa kw'itsinda rya fosifate kuri NF-kB no kwinjira kwayo mu ntima y'akaremangingo. Interferon-gamma ibitera cyane cyane binyuze kuri Janus kinase yongeraho itsinda rya fosifate kuri STAT1, bigakurikirwa no kwinjira kwa STAT1 mu ntima y'akaremangingo. Buri poroteyine igenzura iyandukurwa ihita ifata ahantu hayo ku karere gatangiza iyandukurwa rya iNOS. Imikorere ya anzime no gutangiza iyandukurwa rya jene ni ahantu habiri hatandukanye ho kugenzura, kandi umuti ushobora gukora kuri hamwe cyangwa kuri hombi.

Ubushakashatsi bwo mu 2015 ku gutangizwa kwa iNOS muri makorofaje no mu mbeba zifite endotoksine mu maraso bwagaragaje ko ingaruka zari ku butumwa bwa jene. Mu turemangingo twa RAW 264.7 na makorofaje zakuwe mu mbeba, ubururu bwa metilene bwa 1 micromolar bwatanzwe iminota 30 mbere ya lipopolysaccharide, interferon-gamma cyangwa byombi, bwagabanyije poroteyine ya iNOS na mRNA yayo mu gihe cy'amasaha 8 kugeza kuri 24, hamwe na nitrite nke mu ruvange rwo gukuriramo uturemangingo kandi nta kugabanuka k'ubushobozi bw'uturemangingo bwo gukomeza kubaho. Mu mbeba zahawe lipopolysaccharide ya 25 mg per kg, ingano imwe y'ubururu bwa metilene ya 5 mg per kg yatanzwe isaha imwe mbere yagabanyije poroteyine ya iNOS na mRNA yayo mu bihaha, mu mwijima no mu mutima.

Icy'ingenzi gitandukanya ibi ni ibyagumye uko byari biri. Gusenyuka kwa IkB-alpha, kongerwa kw'itsinda rya fosifate kuri NF-kB, kongerwa kw'itsinda rya fosifate kuri STAT1, no kwiyongera kwa buri poroteyine mu ntima y'akaremangingo ntibyahindutse. Ihagarikwa ryabaye ku ntambwe yakurikiyeho: ibyakuwe mu ntima z'uturemangingo byagaragaje ko NF-kB yafashe ku gice cyayo cya DNA ku rugero ruto nyuma ya lipopolysaccharide, na STAT1 igafata ku rugero ruto nyuma ya interferon-gamma. Uburyo bwo gutandukanya kromatine hakoreshejwe poroteyine z'ubudahangarwa bwemeje ko buri poroteyine yari nke ku karere gatangiza iyandukurwa rya iNOS imbere mu turemangingo. Tumor necrosis factor alpha, na yo ifite akarere gatangiza iyandukurwa gakoresha NF-kB, yaragabanutse. Izo poroteyine zari zatangijwe kandi zageze aho zagombaga kugera, ariko zifata ku rugero ruto kuri DNA zigenewe.

Zirikana itandukaniro n'inzira 1. Ibi bireba gufata kwa poroteyine igenzura iyandukurwa kuri DNA, bikoresha STAT1 aho kuba STAT3, kandi bipima mRNA, poroteyine na nitrite aho gupima utudomo twa ASC n'ibice bya caspase-1. Ikarita yacu y'aho ubururu bwa metilene bugira icyo bukora mu ngero z'uturemangingo itandukanya uru rwego rw'iyandukurwa rya jene n'ibipimo by'imikorere ya anzime mu buryo butaziguye n'ibya mitokondiriya.

Inzira 3: IL-6 yo muri serumu no gutangizwa kwa STAT3 mu nyama z'umubiri

IL-6 yohereza ibimenyetso binyuze ku muryango w'ibyakira bya gp130, bikagera ku ruhererekane rwa Janus kinase rugana kuri STAT3. STAT3 yongereweho itsinda rya fosifate ihuza molekile ebyiri, ikinjira mu ntima y'akaremangingo, kandi igatangiza gahunda z'ububyimbirwe. Na IL-6 ubwayo ni kimwe mu bigenzurwa na NF-kB; bityo byombi bigakora uruziga rwo gusubizanya ibimenyetso, akenshi rwitwa umurongo uva kuri IL-6 ugana kuri STAT3. Ibipimo bisanzwe ni IL-6 yo muri serumu ku ntambwe zibanza, ikigereranyo cya STAT3 yongereweho itsinda rya fosifate kuri STAT3 yose, n'anzime zishyira ibikorwa mu bikorwa nka iNOS na COX2 ku ntambwe zikurikira.

Ubushakashatsi bwo mu 2023 ku mbeba, kuri IL-6 na STAT3 nyuma ya lipopolysaccharide bwapimye uwo murongo mu bice bitandukanye by'umubiri. Imbeba z'ingabo zo mu bwoko bwa C57BL/6 zahawe lipopolysaccharide ya 1 mg per kg buri munsi mu minsi itatu, hamwe n'ubururu bwa metilene bwa 5 cyangwa 10 mg per kg iminota 30 nyuma ya buri ngano yatanzwe. Ku munsi wa gatatu, IL-6 yo muri serumu yari nke mu matsinda yombi yahawe ubururu bwa metilene ugereranyije n'iryahawe lipopolysaccharide gusa, mu gihe izindi sitokine nyinshi zapimwe zitahindutse kubera icyo cyatanzwe. Ibigereranyo bya STAT3 yongereweho itsinda rya fosifate kuri STAT3 yose byari bito mu gice cy'inyuma cy'ubwonko, muri hippocampus no mu ruhu rw'ugutwi, hamwe no kugaragara guke kwa Iba-1 muri mikorogiliya hakoreshejwe uburyo bwo gusiga ibara, iNOS na COX2 nke, n'igabanuka ry'ibiro ryagabanyijwe igice.

Hari ibintu bibiri byo kwitondera hano. IL-6 nke yo muri serumu hamwe no kongerwa guke kw'itsinda rya fosifate kuri STAT3 yo mu nyama z'umubiri bihuye no guhindura imikorere y'uwo murongo, ariko ntibigaragaza neza aho impinduka ibanza yabereye. Sitokine nke ku ntambwe zibanza, ibimenyetso bike binyura mu cyakira, cyangwa imikorere ya phosphatase yahindutse, buri kimwe gishobora gutanga icyo kigereranyo kimwe. Ikindi kandi, ibiro mu minsi itatu y'ikangura rikaze ni igipimo cy'inyamaswa yose, si igipimo cy'ikimenyetso cy'indwara cyangwa cy'igabanuka ryayo. Byongeraho amakuru arenze ay'ikizamini kigaragaza poroteyine, bitahinduye igisubizo cy'ihererekanya ry'ibimenyetso mo umwanzuro wo kuvura. Uburyo butandukanye bw'imikoranire y'imiti mu kugenzura okisidasiyo n'igabanyamugabane muri mitokondiriya bukorwa bujyanye n'iyi nkuru ya sitokine, ariko ntibukwiye guhuzwa na yo.

Kugereranya inzira: aho ubururu bwa metilene bugira icyo bukora n'ibipimo byahindutse

Imbonerahamwe ibuza kwimurira imyanzuro ahatari ho mu buryo butatu. Igisubizo ku kadomo ka ASC nticyemeza igisubizo kuri STAT3. Igisubizo ku gufata kwa STAT1 ku karere gatangiza iyandukurwa rya iNOS nticyemeza igisubizo kuri STAT3, nubwo izo poroteyine zombi ziri mu muryango wa STAT. Igisubizo kuri IL-6 yo muri serumu nticyemeza igabanuka ry'iteranywa rya inflammasome: mu igerageza ryo muri peritoneum, IL-1beta yagabanutse mu gihe IL-6 itagabanutse. Buri murongo ukeneye igitangiza n'igipimo byawo. Ni yo mpamvu gusoma ubushakashatsi ku bururu bwa metilene mu turemangingo, mu nyamaswa no ku bantu bisaba guhuza buri mwanzuro n'urwego rwapimwe.

Nta na kimwe muri ibi cyemeza ingano yo gukoresha, umutekano cyangwa inyungu ku bantu. Ingero zikoresha lipopolysaccharide ni ibitangiza bigenzurwa bigamije kugerageza uburyo ibintu bikora, si kopi z'indwara zidakira. Gutanga ikinyabutabire hamwe n'igitangiza bipima gukumira impinduka itewe n'igerageza, aho gupima gusubiza inyuma indwara yamaze kubaho. Tandukanya iyi nyandiko ku buryo ibintu bikora n'ibisubizo ku barwayi, kandi usuzume buri mwanzuro werekeye ubuzima ushingiye ku bushakashatsi bwakozwe ku barwayi buwushyigikira.