Buluugga methylene iyo oksaydhka naytrik: NOS, cGMP, calaamadaynta xididdada

Su'aashu waxay u muuqataa mid fudud: buluugga methylene ma xannibaa oksaydhka naytrik? Shaybaarka dhexdiisa, jawaabtu waxay u kala baxdaa afar su'aalood oo kala gaar ah, mid walbana waxay leedahay tijaabo u gaar ah. Isku qasidda su'aalahan ayaa ah sababta ugu weyn ee qoraallada ku saabsan buluugga methylene iyo oksaydhka naytrik ay ugu muuqdaan kuwo kalsooni leh balse aan caddayn.

Ka fikir calaamadda oksaydhka naytrik sidii silsilad leh afar xiriiriye. Hiddo-side ayaa la qoraa si loo sameeyo ensaymka nitric oxide synthase. Ensaymku wuxuu arginine u beddelaa oksaydhka naytrik. Gaasku wuxuu u gudbaa bartilmaameedkiisa ka hor inta uusan wax kale la falgelin. Soluble guanylate cyclase ayaa dareema oo sameeya GMP wareegsan. Saamaynta buluugga methylene ku leeyahay xiriiriye kasta waa la daabacay, laakiin caddayntu waxay ka timid diyaarino kala duwan, uruurinno kala duwan, iyo noocyo ensaym oo kala duwan. Natiijo laga helay hal xiriiriye ma caddaynayso fal ka dhacay xiriiriye kale.

Silsiladda caadiga ah, oo si fudud loo sheegay

Darbiga xididka dhiigga dhexdiisa, taxanaha caadiga ahi sidan ayuu u dhacaa. Kicin ayaa ku dhacda unugga dahaarka gudaha ee xididka. Endothelial nitric oxide synthase, oo loo yaqaan eNOS ama NOS3, ayaa soo saara qadar yar oo kooban oo oksaydhka naytrik ah. Gaasku wuxuu u gudbaa unugga muruqa siman ee deriska ah, wuxuu ku xirmaa heme-ka birtiisu ku jirto xaalad la dhimay ee soluble guanylate cyclase, wuxuuna dedejiyaa u beddelidda GTP una beddelayo GMP wareegsan. GMP wareegsan ayaa hawlgeliya protein kinase G, maaraynta kaalshiyamku way isbeddeshaa, muruquna wuu dabca.

Waxaa jira silsilad labaad oo mudan in gooni loo kala saaro. Inta lagu jiro infekshan ama soo-gaadhista cytokine, unugyadu waxay qoraan hidde-sidaha ensaym kale, inducible nitric oxide synthase ama iNOS, oo sidoo kale loo yaqaan NOS2. Wuxuu soo saaraa qulqullo oksaydhka naytrik ah oo ka badan kana sii raaga kuwa eNOS. Nooc saddexaad, neuronal NOS ama nNOS, wuxuu ku shaqeeyaa xaalad kale. Marka maqaal cilmiyeed uu yiraahdo nitric oxide synthase isaga oo aan qeexin nooca, joogso oo hubi kii la cabbiray. Dulmarka sida buluugga methylene u gudbiyo elektaroonnada ayaa isla qodobkan ka sheegaya bartilmaameedyada redox guud ahaan: gudbintu keligeed waxba ma qabato, waxaana natiijada go'aamiya walaxda la falgasha ee ku taal daraf kasta.

GMP wareegsan ee la cabbiray sidoo kale waa cabbir isku dhafan, ma aha tijaabo toos ah oo ensaymka lagu sameeyo. Heerkiisu wuxuu ka tarjumayaa samaynta cyclase oo laga jaray burburinta phosphodiesterases, gaar ahaan PDE5 ee muruqa siman ee xididdada. Sidaas darteed, hoos u dhac ku yimaadda GMP wareegsan wuxuu ka dhigan yahay in calaamad yar ay gaadhay dareemaha. Keligiis ma tilmaamayo xiriiriyihii fashilmay.

Xiriiriyaha 1: ensaym iNOS oo ka yar ayaa la sameeyaa

Unugyada macrophage ee jiirka ee lagu kiciyey lipopolysaccharide bakteeriyo, interferon gamma, ama labadaba, buluugga methylene wuxuu ka hortagay kororkii la filayey ee borotiinka iNOS, wuxuuna si xooggan u yareeyey RNA-ga farriinsidaha iNOS ee tijaabooyinka qoraalka hidde-sidaha ee macrophage. Qaybta xogta muhiimka ah bixisa waa waxa aan isbeddelin. Burburinta xannibaha I kappa B alpha, ku daridda kooxaha fosfaytka ee NF kappa B iyo STAT1, iyo u guuritaanka qodobadaas gudaha bu'da unugga ayaa inta badan sidii hore ahaa. Waxa hoos u dhacay waxay ahayd ku-xidhnaantooda DNA, taas oo lagu xaqiijiyey chromatin immunoprecipitation oo muujiyey joogitaan yaraaday oo ka jiray qaybta dhiirrigelisa qoraalka hidde-sidaha iNOS.

Taasi waa saamayn nidaaminta hidde-sidaha oo ka horraysa tirada ensaymka, ma aha xannibaad degdeg ah oo lagu sameeyo ensaym hore u jiray. Waxay ka tirsan tahay calaamadaynta bararka, halkaas oo qodobada qoraalka hidde-siduhu ay tahay inay ku xirmaan qaybta dhiirrigelisa qoraalka ka hor inta uusan borotiinku soo bixin. Wax toos ah kama sheegayso eNOS-ka joogtada ah ee xidid xaalad nasasho ku jira, waana in sidaas loo sharraxaa.

Xiriiriyaha 2: ensaymka NOS ee jira ayaa si gaabis ah u shaqeeya

Daraasad lagu sameeyey jiirka weyn ayaa tijaabisay heer kale. Jiir waaweyn oo lab ah oo miyir qaba ayaa xididka laga siiyey lipopolysaccharide, dabadeed saddex saacadood ka dib waxaa xididka laga siiyey dareere cusbo leh ama buluugga methylene oo ah 3 mg halkii kg. Firfircoonida nitric oxide synthase ee qaybta dhexe ee hoose ee hypothalamus ayaa lagu cabbiray u beddelidda arginine calaamadaysan una beddelayo citrulline ee daraasadda firfircoonida NOS ee hypothalamus. Walbahaarka iyo dareeraha cusbada leh oo keliya ayaa kiciyey xoogaa firfircooni ah oo aan kaalshiyam ku tiirsanayn, lipopolysaccharide-na wuxuu gaadhsiiyey qiyaastii toban jeer heerka kooxda kantaroolka. Buluugga methylene wuxuu meesha ka saaray labada qaybood ee firfircoonida la kiciyey. Firfircoonida joogtada ah ee kaalshiyamka ku tiirsan isma beddelin nudahaas, qadarkaas, iyo waqtigaas cabbirka.

Natiijadaas u akhri sida ay u qoran tahay: firfircoonida la cabbiray ee nooca iNOS ayaa la yareeyey xaaladahaas. Ma aha cabbirka muujinta hidde-sidaha, mana aha caddayn ah in si joogto ah iNOS loo xusho halkii eNOS ama nNOS. Shaqada ensaymka la sifeeyey ayaa sii xoojinaysa taxaddarkaas. Tijaabooyinka tooska ah ee nitric oxide synthase la sifeeyey, buluugga methylene wuxuu si buuxda u xannibay samaynta citrulline marka uruurintu ahayd 30 micromolar, iyadoo uruurinta keenaysa xannibaad kala bar ah ay ku dhowayd 5.3 micromolar marka superoxide dismutase uusan jirin iyo 9.2 micromolar marka uu jiro, sida lagu sheegay isbarbardhigga NOS la sifeeyey iyo guanylate cyclase. Daraasad kale oo nNOS la sifeeyey ah ayaa tilmaantay oksaydhaynta heme-ka ku xiran ensaymka. Casharka wax-ku-oolka ahi waa in xannibaadda tooska ah ee NOS ay dhab ka tahay nidaamyada gooni loo soocay, laakiin natiijada hypothalamus looma fidin karo sheegasho guud oo ah in buluugga methylene uusan saamayn NOS-ka joogtada ah meel kasta.

Xiriiriyaha 3: oksaydhka naytrik ayaa luma ka hor inta uusan gaadhin

Muujinta ugu cad ee ah in wax aan ahayn xannibaadda ensaymku sharxi karaan hoos u dhac ku yimaadda GMP wareegsan waxay ka timid unugyada muruqa siman ee halbowlaha sambabada ee bakaylaha oo lagu koriyey shaybaarka. Qaabka tijaabadu wuxuu gebi ahaanba ka gudbay NOS-ka gudaha ka samaysma iyadoo si toos ah loogu daray walxo sii daaya oksaydhka naytrik, dabadeed waxaa la baaray in buluugga methylene uu weli yareeyo jawaabta GMP wareegsan ee daraasadda superoxide ee muruqa siman ee xididdada.

Saddex walxood oo sii daaya ayaa lagu tijaabiyey uruurinno u dhexeeya 1 ilaa 100 micromolar: S nitroso L cysteine, sodium nitroprusside, iyo walax u dhiganta oo deamination lagu sameeyey oo xasilloon, laguna magacaabo MPANO. Dhammaantood waxay kordhiyeen GMP wareegsan qiyaastii 1.5 jeer ilaa 12 jeer. Buluugga methylene oo ahaa 10 micromolar wuxuu xannibay labadii hore 51 ilaa 100 boqolkiiba, jawaabta MPANO-na isma beddelin. Haddii buluugga methylene uu keliya xannibi lahaa goobta kicinta falcelinta ee cyclase, xulashadan walxaha sii daaya way adkaan lahayd in la sharxo, sababtoo ah saddexduba waxay ku dhammaadaan isla ensaymka ku yaal heerka dambe.

Saddex tijaabo oo kantarool ah ayaa markaas habka ku xidhiidhiyey superoxide. Marka hore, samaynta superoxide ka baxsan unugga iyadoo la isticmaalayo xanthine iyo xanthine oxidase waxay soo celisay isla qaabkii: CYSNO iyo nitroprusside waa la xannibay, MPANO-na lama saamayn. Marka labaad, buluugga methylene wuxuu keenay samaynta superoxide oo ku xidhan qadarka iyo waqtiga, kana timid unugyada muruqa siman, laguna cabbiray dhimista cytochrome c. Marka saddexaad, superoxide dismutase wuxuu si buuxda uga hortagay xannibaadda halka catalase uusan sidaas samayn, taas oo superoxide, halkii hydrogen peroxide, u tilmaamaysa walaxda ugu dhow ee sababta u ah saamaynta diyaarintaas.

Nooca tijaabada ee wada-korinta unugyada wuxuu mudan yahay in la sheego, sababtoo ah wuxuu muujinayaa meesha ay saamayntu ka dhacdo. Unugyada dahaarka gudaha ee ku yaal muraayadaha daboolka ayaa muddo kooban lala koriyey unugyada muruqa siman, sidaas darteed walaxda ka soo baxda dahaarka gudaha ee si joogto ah loo sii daayo waxay GMP wareegsan ee muruqa siman kordhisay saddex ilaa siddeed jeer. In labada qaybood midkood horay loogu daaweeyo buluugga methylene waxay yaraysay calaamaddaas, superoxide dismutase-na wuxuu qayb ahaan soo celiyey calaamaddii ay yaraysay daawaynta hore ee unugyada dahaarka gudaha. Si kale haddii loo dhigo, buluugga methylene uma baahna inuu haba yaraatee ka shaqeeyo gudaha unugga muruqa siman ee dareemaya calaamadda. Wuxuu hoos u dhigi karaa calaamadda isagoo meesha ka saaraya farriinsidaha inta uu jidka ku jiro. Hagaha akhriska cilmi-baarista buluugga methylene wuxuu tan u qaataa xeer guud: sheeg qaybta uu faragelintu ka dhacay ka hor inta aan la magacaabin bartilmaameed molikuyuuleed.

In tan loogu yeedho xannibaadda NOS waxay noqon lahayd khalad. Tallaabo synthase ah looma baahnayn si walxaha sii daayaa u shaqeeyaan, haddana calaamaddu way hoos u dhacday.

Xiriiriyaha 4: dareemaha laftiisa ayaa jawaabtiisu yaraataa

Saamayn toos ah oo ku dhacda soluble guanylate cyclase way jirtaa, laakiin uruurintu waa muhiim. Isbarbardhigga ensaymka la sifeeyey ee kor lagu xusay, cyclase-ka uu kiciyey oksaydhka naytrik wuxuu u baahday qiyaastii 60 micromolar oo buluugga methylene ah si xannibaad kala bar ah loo helo, marka loo eego xannibaadda kala barka ah ee NOS oo ku dhowayd 5 ilaa 9 micromolar; xitaa 1 millimolar wuxuu keenay oo keliya xannibaad ugu sarreysa oo qayb ahaan ah. Taasi waa kala duwanaansho qiyaastii lix ilaa kow iyo toban jeer ah. Sidaas darteed, tijaabo unug oo uruurinteedu tahay micromolar hoose oo yaraysa GMP wareegsan laguma tilmaami karo xannibaad cyclase oo xulasho leh iyadoo lagu salaynayo oo keliya tirada GMP wareegsan.

Daraasad redox oo dambe ayaa ku dartay taxaddar labaad: buluugga methylene wuxuu hawl-beeliyey cyclase-ka uu hawlgeliyey oksaydhka naytrik isaga oo adeegsanaya hab ka duwan oksaydhaynta fudud ee hawadu ku samayso birta heme-ka. Sidaas darteed, dareemaha waa la wiiqi karaa, laakiin kimistariga arrintu weli ma cadda, farqiga uruurintuna wuxuu ka dhigan yahay in saamaynta superoxide iyo NOS ay mudan tahay in marka hore meesha laga saaro marka soo-gaadhistu tahay micromolar hoose. Tani sidoo kale waa meesha ay ku habboon tahay kantaroolka phosphodiesterase. Haddii aan burburinta la cabbirin ama la xannibin, uruurista GMP wareegsan oo yaraata waxay la jaanqaadaysaa samayn yar, burburin dhakhso badan, ama labadaba.

Sababta aan tan loogu soo koobi karin hal sheegasho oo cadaadiska dhiigga ku saabsan

Xiriiriye kasta waxaa lagu xaqiijiyey nidaam ka duwan. Qoraalka hidde-sidaha ee macrophage ma aha firfircoonida ensaymka ee hypothalamus. Firfircoonida hypothalamus ka dib lipopolysaccharide ma aha heerka isku-ururka xididka ee dahaarka gudaha marka uu nasanayo. Walaxda dahaarka gudaha ka timaadda ee si joogto ah loo sii daayo marka unugyada la wada koriyo ma aha ballaadhinta xididdada ee uu kiciyo walax soo-dhoweeye hawlgelisa. Unugyada halbowlaha sambabada ee lagu koriyey shaybaarka kuna jira buluugga methylene oo ah 10 micromolar ma aha wareegga dhiigga qof bani'aadam ah. In dhammaantood loo soo koobo hadal sida buluugga methylene wuxuu kordhiyaa cadaadiska dhiigga isagoo xannibaya oksaydhka naytrik waxay tuuraysaa isla kala duwanaanshaha loo sameeyey tijaabooyinka kantaroolka si loo ilaaliyo.

Saddex hubin ayaa sharraxaadda ka dhigaya mid sax ah. Marka hore, sheeg nooca ensaymka: eNOS oo la xidhiidha heerka isku-ururka xididdada ee xaaladda nasashada, iNOS oo la xidhiidha qulqulka la kiciyey ee bararka, nNOS oo la xidhiidha neerfayaasha iyo qaar ka mid ah xaaladaha ensaymka la sifeeyey. Marka labaad, sheeg sida calaamadda oksaydhka naytrik loo keenay: samayn gudaha ah, sii-daynta joogtada ah ee dahaarka gudaha, ama walax gaar ah oo sii daysa sida CYSNO, nitroprusside, ama MPANO, maadaama walaxda xasilloon ee sii daysaa ay iska caabbiday buluugga methylene halka kuwa aan xasilloonayn aysan sidaas samayn. Marka saddexaad, sheeg uruurinta iyo soo-celinta: soo-celinta superoxide dismutase waxay tilmaamaysaa doorka superoxide, fashilka catalase wuxuu ka hor imanayaa in hydrogen peroxide uu sabab yahay diyaarintaas, ku-dayashada xanthine oxidase waxay muujinaysaa in habkaasi ku filan yahay, tijaabooyinka ensaymka la sifeeyeyna waxay kala saaraan saamaynta tooska ah ee kicinta falcelinta iyo luminta dhacda inta farriintu jidka ku jirto.

Soo koobidda kooban waa tan. Waxaa habboon in buluugga methylene loo arko walax meelo badan ka carqaladaysa calaamadaynta oksaydhka naytrik ilaa GMP wareegsan, halkii loo arki lahaa xannibe cyclase oo xulasho leh. Iyadoo ku xidhan diyaarinta iyo uruurinta, wuxuu yarayn karaa ku-xidhnaanta qodobada qoraalka hidde-sidaha iNOS, si toos ah ayuu u xannibi karaa ensaymyada NOS, wuxuu yarayn karaa helitaanka oksaydhka naytrik isagoo dhalinaya superoxide, wuxuuna wiiqi karaa cyclase-ka uu hawlgeliyo oksaydhka naytrik. Doorka calaamadaynta GMP wareegsan ee daraasadaha xididdada iyo isbarbardhigga walxaha sii daaya oksaydhka naytrik ee loo adeegsado tijaabooyinka unugyada mid walba wuxuu si faahfaahsan u daboolayaa mid ka mid ah laamahaas, halka hababka loo adeegsado kala saaridda saamaynta redox iyo saamaynta ensaymka ay sharraxayaan sababta superoxide dismutase iyo catalase iyo kantarool walax sii daysa oo xasilloon ay marar badan uga muuqdaan qoraalladan cilmiyeed.

Qiime hoose oo GMP wareegsan ah ka dib buluugga methylene wuxuu tilmaamayaa silsilad go'day. Tijaabooyinka kantaroolka oo keliya ayaa sheega xiriiriyihii go'ay.