I-hormesis ye-methylene blue: kuchazwa amajika omthamo nempendulo

Igundane elilodwa linikezwa amamiligremu angu-4 ngekhilogremu e-methylene blue ngemva kokufunda ukubona into, bese liyikhumbula ngosuku olulandelayo. Elinye igundane linikezwa angu-50, bese licishe lingalijikisi nhlobo isondo lalo lokugijima. I-molecule iyafana. Isiqondiso somphumela asifani. Noma ubani osefunde amaphepha ocwaningo e-methylene blue angaphezu kwambalwa useke wahlangana nalokhu kuphenduka, futhi kunegama: i-hormesis, impendulo enezigaba ezimbili lapho ukuchayeka okuphansi nokuphezulu kuphusha umphumela ofanayo olinganiswayo eziqondisweni eziphambene.

Leli gama liwusizo kuphela uma wazi ukuthi lithembisani nokuthi alithembisi ini. Lesi sihloko sihlola amasethi amane edatha ye-methylene blue ashicilelwe, ngalinye linomphumela walo olinganiswayo, ibanga lalo lokugxila nezimo zalo zokuhlola, futhi sibonisa ukuthi kungani ikhemistri yalo dayi yenza lokhu kuphenduka kube nokwenzeka. Siphetha ngesexwayiso esigcizelelwa yidatha: ijika elifinyelela esicongweni esivivinyweni esisodwa lichaza leso sivivinyo, aliyona indlela yokukhetha umthamo womuntu siqu.

Le phethini inegama, futhi incazelo yalo incane kunalokho elizwakala likusho

Igama elithi hormesis laqanjwa ngo-1943 nguSoutham no-Ehrlich, kwathi uCalabrese noBaldwin balinikeza incazelo yalo yesimanje esekelwe ezilinganisweni: impendulo yokuzivumelanisa enezigaba ezimbili, ekhiqizwa ngokuqondile noma ngokunxephezela ngemva kokuphazamiseka kwe-homeostasis. Qaphela okungekho kuleyo ncazelo. Igama elithi kuzuzisa aliveli. I-hormesis isho ukuthi ijika lishintsha isiqondiso, akukho okunye.

Ukuma okubonayo kuncike ekutheni yimuphi umphumela olinganiswayo obekwe ku-eksisi eqondile. Uma umphumela uwumsebenzi omuhle, njengokusebenza kwe-enzyme, ukusetshenziswa komoya-mpilo noma amaphuzu enkumbulo, ukukhuthazwa ngomthamo ophansi okulandelwa ukuvinjelwa ngomthamo ophezulu kudweba u-U obheke phansi. Uma umphumela uyinto embi, njengokuvama kwesifo, ukucindezelwa ngomthamo ophansi okulandelwa ukwanda ngomthamo ophezulu kudweba u-J noma u-U. Ubudlelwano obufanayo, kodwa inani elikwi-eksisi eqondile lihlukile. Ucwaningo oluningi lwe-methylene blue lulinganisa imisebenzi emihle, ngakho lesi sihloko sikhuluma ngamajika ka-U obheke phansi, siqonda ukuthi ukukhetha uhlamvu lwezinhlamvu kuyisinqumo sokudweba igrafu.

Ukubuyekezwa kwango-2008 okwaqoqa izimpendulo ze-hormesis ze-methylene blue kwenza ubukhulu balokhu bucace. Ekuziphatheni, ekusebenzeni komzimba nasekhemistri yezinto eziphilayo, izimpendulo ezisendaweni yokukhuthazwa zifinyelela cishe kumaphesenti angu-130 kuya ku-160 ezinga leqembu lokuqhathanisa, ngesilinganiso esiseduze no-140, ngaphambi kokwehla zidlule ezingeni leqembu lokuqhathanisa bese zehla ngaphansi kwalo njengoba umthamo uqhubeka ukhuphuka. Lelo banga liyisifinyezo sezivivinyo eziningi, alisona isici se-molecule. Ijika ngalinye elingezansi linesicongo salo ngamayunithi alo.

Kungani le molecule ngokukhethekile ingashintsha isiqondiso

I-methylene blue ayiwona nje umnikeli wama-electron olula. Ingumthwali oshintsha abuyele esimweni sangaphambili. Isimo esiluhlaza okwesibhakabhaka esifakwe i-oxidation samukela ama-electron, sibe yisimo esingenambala esenziwe i-reduction, bese leso simo singadlulisela lawo ma-electron ezinyathelweni ezilandelayo. Ukudluliselwa kwama-electron okusemuva kwala majika kuchazwa encazelweni yokuthi i-methylene blue iwahambisa kanjani ama-electron, futhi indaba lapha imayelana nalowo mthwali.

Emazingeni aphansi okugxila, lowo mjikelezo unikeza ukuphefumula kwamangqamuzana enye indlela. Udayi osesimweni se-reduction ungafakwa i-oxidation ku-cytochrome oxidase, i-enzyme yokugcina ochungechungeni lokuthuthwa kwama-electron, okwandisa izinga lokusebenza kwayo kanye nokusetshenziswa komoya-mpilo namandla okuphefumula kwamangqamuzana. Emazingeni aphezulu okugxila, yona le khemistri efuna ama-electron iqala ukuncintisana nochungechunge oluvamile esikhundleni sokulusiza: iphambukisa ama-electron endleleni yawo evamile, isebenzise umoya-mpilo ngokuqondile, futhi ikhiqize izinhlobo zomoya-mpilo ezisebenza kakhulu ngokwekhemistri esikhundleni samandla asebenzisekayo. Umthwali omncane osebenza njenge-catalyst wandisa ukugeleza; indawo eyeqile encintisana ngokudonsa ama-electron iyakunciphisa. Ikhemistri yenza ukushintsha kwesiqondiso kube nokwenzeka, kodwa ayiqinisekisi ukuthi noma yimuphi umphumela othile olinganiswayo uzofinyelela kuphi esicongweni.

Ubufakazi obuzimele bokuncika ezingeni lokugxila buvela emangqamuzaneni angenawo nhlobo ama-mitochondria. Ezivivinyweni zamangqamuzana abomvu egazi zango-1976, izinga eliphansi lokugxila elingu-1 micromolar lakhuthaza indlela ye-hexose monophosphate ngendlela eyayincike kakhulu ku-oxyhemoglobin, kuyilapho izinga elingu-0.1 millimolar, eliphakeme ngokuphindwe ngekhulu, lalingathinteki kangako ngokuthi i-oxyhemoglobin ikhona yini futhi lakhiqiza i-hydrogen peroxide ngokwazo zontathu izindlela zokuhlola ezasetshenziswa. Udayi ofanayo, izindlela ezimbili zokusebenza, ezihlukaniswa izinga lokugxila. Amangqamuzana abomvu egazi awakwazi ukuphefumula, ngakho leli akulona ijika lama-mitochondria, kodwa libonisa ukuthi ikhemistri ye-redox yodayi ishintsha isimo njengoba izinga lokugxila likhuphuka, okuyikho kanye okudingwa incazelo yama-mitochondria.

Amajika amane, izimo ezine zokuhlola

Umfanekiso ongezansi udweba kabusha amasethi amane edatha eceleni komunye nomunye. Iphaneli ngalinye ligcina ama-eksisi alo nezimo zalo, ngoba ukuwabeka ndawonye esikalini esisodwa kungaba ngamanga okuqala lesi sihloko esingawakhuluma. Umdwebo uyisifanekiso esilula; amanani aqondile nezimo kutholakala embhalweni.

Iphaneli A: i-cytochrome oxidase kungxube yezicubu zobuchopho begundane ezigayiwe. Ijika lama-mitochondria elicace kakhulu litholakala emthonjeni wesibili, lidwetshwe ekubuyekezweni kusetshenziswa idatha yengxube yezicubu zobuchopho begundane ezigayiwe: cishe amaphesenti angu-138 okusebenza kweqembu lokuqhathanisa ku-0.5 micromolar, libuyela ezingeni leqembu lokuqhathanisa eduze no-5 micromolar, libe ngaphansi kwezinga lokuqala eduze no-10 micromolar, lapho ababhali bephakamisa khona ukuthi udayi ususa ama-electron ezakhiweni ezivamile zochungechunge. Ingxube yezicubu ezigayiwe, micromolar, ukuhlola nge-spectrophotometry. Lowo musho uyisimo sonke salolu cwaningo, futhi ijika alisho lutho ngaphandle kwaso.

Iphaneli B: inkumbulo yamagundane nokugijima esondweni. Ocwaningweni lwenkumbulo yamagundane, imijovo eyodwa ngemva kokuqeqeshwa yahlolwa ngemva kwamahora angu-24. Imithamo yamamiligremu angu-1 kuya ku-10 ngekhilogremu yashiya ukunyakaza nokudla kungahlukile kulokho kweqembu elinikezwe amanzi anosawoti, kuyilapho amamiligremu angu-50 kuya ku-100 ngekhilogremu anciphisa kakhulu ukugijima esondweni (inani eliphakathi lokuzungeza elingu-35 uma liqhathaniswa no-279), kanti umthamo ophezulu kunayo yonke wabangela ukumisa koboya, ukunyakaza okungahlangene nokufa kwegundane elilodwa. Umthamo wamamiligremu angu-4 ngekhilogremu wathuthukisa ukujwayela nokubona izinto: amagundane ayenikezwe wona achitha cishe imizuzwana engu-10 eyengeziwe entweni entsha. Ukusetshenziswa komoya-mpilo ebuchosheni kwakhuphuka kokubili kungxube yezicubu ezigayiwe echayeke kudayi osesimweni se-reduction emazingeni aphansi e-micromolar nasebuchosheni obathathwa ngemva kwamahora angu-24 kunikezwe igundane eliphilayo imiligremu engu-1 ngekhilogremu. Qaphela umehluko: ukuhlolwa kokuziphatha kwasebenzisa imithamo esabalala emzimbeni ngemva kokuqeqeshwa, ukuhlolwa kokusetshenziswa komoya-mpilo kwasebenzisa amazinga okugxila engxubeni yezicubu ezigayiwe kanye nomthamo owodwa esilwaneni esiphilayo, futhi lezi yizivivinyo ezimbili, akulona ijika elilodwa.

Iphaneli C: indlela eyindida emise okuka-T ye-zebrafish. Ucwaningo lwe-zebrafish lwacwilisa izinhlanzi eziqeqeshiwe amahora angu-12 ngemva kokuqeqeshwa emanzini anezinga lokugxila elibekiwe elingu-0.1, 0.5, 5.0 noma 10.0 micromolar, kuqhathaniswa neqembu elinodayi wokudla oluhlaza okwesibhakabhaka. Iqembu le-0.5 micromolar lasebenza kahle kakhulu, iqembu le-5.0 lalingafana neqembu lokuqhathanisa, kanti iqembu le-10.0 lasebenza kabi kunamaqembu emithamo ephansi. Leli phaneli lihambisana nezexwayiso ezimbili. I-micromolar emanzini okucwilisa ayiyona i-micromolar egazini noma ebuchosheni; ukusatshalaliswa nokunqwabelana kuphakathi kwamanzi ethangi nezicubu. Futhi ubufakazi bezibalo bubuthaka kunalokho okuphakanyiswa ukuma kwejika: umthamo ophezulu wawuhlukile emaqenjini emithamo ephansi, kungabikwanga omunye umehluko obalulekile ngokwezibalo phakathi kwamaqembu. Ijika lingokoqobo kodwa alinembile kakhulu.

Iphaneli D: indlela yokuphambukisa kumangqamuzana abomvu egazi. UMetz nozakwabo baqhathanisa i-1 micromolar ne-0.1 millimolar kumangqamuzana abomvu egazi omuntu ngaphansi komoya, i-carbon monoxide, nengxube eyenza cishe yonke i-hemoglobin ibe yi-carboxyhemoglobin ngaphansi kwengcindezi yomoya-mpilo evamile emzimbeni. Ukukhuthazwa ngomthamo ophansi kwehla kakhulu ngaphandle kwe-oxyhemoglobin; ukukhuthazwa ngomthamo ophezulu kwakucishe kungathinteki. I-peroxide yavela kuphela kumthamo ophezulu. Leli phaneli kufanele libe eceleni kwamanye njengobufakazi bekhemistri, hhayi njengephuzu lesine ejikeni elilodwa elihlanganisa konke: akukho ma-mitochondria, amazinga okugxila ahlukaniswe ukuphindeka ngekhulu, nezingxube zamagesi eziguquliwe.

Kungani izicongo zingahambisani, futhi kungani kungafanele zihambisane

Izicongo ezine zitholakala ku-0.5 micromolar engxubeni yezicubu ezigayiwe, kumamiligremu angu-4 ngekhilogremu ajovwe ngemva kokuqeqeshwa, ku-0.5 micromolar emanzini ethangi, nasemazingeni amabili, eliphansi neliphezulu, ahlukaniswe ukuphindeka ngekhulu kumangqamuzana abomvu egazi. Ukuphatha noma yimaphi amabili njengokungathi ayinani elifanayo kuyiphutha lokuhlanganisa izigaba ezingafani. Umphumela ngamunye olinganiswayo unejika lawo: izinga elihle kakhulu lenkumbulo akudingeki lifane nelokusebenza kwe-oxidase, ukusetshenziswa komoya-mpilo, ukunyakaza noma ukukhiqizwa kwe-peroxide. Iyunithi ngayinye yezinga lokugxila isho into ehlukile: i-micromolar engxubeni yezicubu ezigayiwe, i-micromolar ebekiwe emanzini okucwilisa, amamiligremu ngekhilogremu anikezwa emzimbeni wonke, namazinga okugxila ku-plasma, ebuchosheni nakuma-mitochondria kuyizilinganiso ezihlukile, futhi ukuthambekela kwe-methylene blue ekunqwabelaneni kuma-mitochondria nasebuchosheni kukugcina kuhlukene. Imodeli ngayinye yengeza indlela yayo umzimba owamukela, usabalalise futhi ukhiphe ngayo into: uhlobo lwesilwane, indlela yokuyinikeza nesikhathi kunquma ukuthi yiziphi izicubu ezihlangana nodayi ongakanani isikhathi esingakanani.

Yilapha futhi lapho indima yomthamo nendlela yokunikeza ekuphepheni kwe-methylene blue ibaluleka khona, ngoba imiphumela yemithamo ephezulu kula maphepha—ukucindezelwa kokunyakaza, ukunyakaza okungahlangene, igundane elilodwa elifile, ukukhiqizwa kwe-peroxide—iyizimpawu zobuthi ngaphansi kwezimo zayo zokuhlola, hhayi imingcele yokuphepha yanoma ubani omunye. Futhi noma ubani olingeka ukuba aguqule amamiligremu angu-4 ngekhilogremu egundaneni abe wuhlelo lokunikeza umuntu kufanele aqale afunde ukuthi okutholwe ezilwaneni kuhlobana kanjani nobufakazi babantu: ukuguqula nje amamiligremu ngekhilogremu phakathi kwezinhlobo zezilwane akwanele.

Iphutha okufanele ligwenywe

U-U obheke phansi uyaheha ngoba ubukeka njengesilawuli somthamo esiphawulwe indawo ekahle kuso. Akunjalo. I-hormesis ichaza okwenzeka kumphumela owodwa olinganiswayo ngaphansi kwezimo ezithile zokuhlola. Hlanganisa izincazelo ezine ezinjalo uthole izicongo ezine ezinhlelweni ezine zamayunithi, okuyinto ephambene nesilawuli esisodwa. Ukusetshenziswa okuthembekile kwala majika kuwukuqhathanisa nokuxwayisa: lindela ukuthi imiphumela iphenduke lapho izinga lokugxila lishintsha, lindela ukuthi umphumela ngamunye olinganiswayo uphenduke endaweni yawo, futhi ungasethemba noma yisiphi isimangalo esithatha isicongo sesivivinyo esisodwa ukuze sisekele umthamo kolunye uhlobo lwesilwane, enye indlela yokunikeza, ezinye izicubu noma enye injongo. Umehluko phakathi kwamaphethini ezivivinyo nezinqumo zomthamo womuntu siqu yiwona mgogodla walesi sihloko sonke, ushiwo futhi ukuze ungaphuthelwa.

Indlela yokufunda iphepha elilandelayo lomthamo nempendulo

Imibuzo emine isebenza cishe kuwo wonke amajika e-methylene blue ozohlangana nawo. Yimuphi umphumela olinganiswayo okwi-eksisi eqondile, futhi ingabe ukuphenduka kwawo kungadweba u-U noma u-J. Yiliphi izinga lokugxila elibikwa ngempela yi-eksisi evundlile: elibekiwe emanzini okucwilisa, elengxube yezicubu ezigayiwe, ele-plasma, elesilinganiso sobuchopho, noma umthamo onikezwe emzimbeni wonke. Yimuphi umodeli nezikhathi ezalikhiqiza: ingxube yezicubu ezigayiwe, amangqamuzana akhuliswe endaweni yokuhlola kukhanyisiwe noma kucinyiwe, izilwane eziqeqeshiwe ezinikezwe umthamo ngaphambi noma ngemva kokuqeqeshwa, zahlolwa nini. Futhi yini eyasetshenziswa ukuqhathanisa: amanzi anosawoti, udayi wokudla oluhlaza okwesibhakabhaka, into ethwala into ehlolwayo, nokuthi izibalo zephepha zisekela isimangalo ngasinye sokuqhathanisa amaqembu amabili noma ukuma kwejika kukonke kuphela. Iphepha eliphendula yonke le mibuzo emine lisifanele isikhathi sakho. Elibika isicongo ngaphandle kwale mininingwane likunike inombolo engenalo ikheli.