Imethylene blue nehormesis: kutheni iigophe zedosi nempendulo zinokutshintsha icala

Enye impuku ifumana iimiligram ezi-4 ngekhilogram zemethylene blue emva kokufunda ukuqaphela into, ize ngosuku olulandelayo iyikhumbule. Enye impuku ifumana ezingama-50, ize kube nzima nokujikelezisa ivili layo lokubaleka. Imolekyuli iyafana. Icala lesiphumo alifani. Nabani na ofunde ngaphezu kwamaphepha ambalwa emethylene blue sele edibene nolu tshintsho, yaye lunegama: ihormesis, impendulo enezigaba ezibini apho ukuchanabeka okuphantsi nokuphezulu kutyhalela umlinganiselo ofanayo wesiphumo kumacala achaseneyo.

Eli gama liluncedo kuphela xa uyazi into eliyithembisayo nengayithembisiyo. Eli nqaku lihamba kwiiseti ezine zedatha yemethylene blue ezipapashiweyo, nganye inomlinganiselo wayo wesiphumo, uluhlu lwemiyinge neemeko zovavanyo, lize libonise ukuba kutheni imichiza yale dayi isenza olo tshintsho lube nokwenzeka. Liqukumbela ngesilumkiso esinyanzeliswa yidatha: igophe elifikelela encotsheni kuvavanyo olunye lichaza olo vavanyo, aliyondlela yokukhetha idosi yomntu.

Le pateni inegama, yaye intsingiselo yalo incinci kunokuba livakala

Igama elithi hormesis laqanjwa ngo-1943 nguSoutham noEhrlich, laza lanikwa inkcazelo yalo yanamhlanje enokulinganiswa nguCalabrese noBaldwin: impendulo yokuziqhelanisa enezigaba ezibini, eyenzeka ngokuthe ngqo okanye ngokuzama ukubuyisela ulungelelwano emva kokuphazamiseka kwe-homeostasis. Qaphela into engekhoyo kuloo nkcazelo. Igama elithi kuluncedo aliveli. Ihormesis ithetha ukuba igophe litshintsha icala, akukho nto ingaphaya koko.

Imilo oyibonayo ixhomekeke kumlinganiselo wesiphumo obekwe kwi-axis ethe nkqo. Xa umlinganiselo wesiphumo ungumsebenzi olungileyo, njengokusebenza kwe-enzyme, ukusetyenziswa kweoksijini okanye amanqaku enkumbulo, ukukhuthazwa yidosi ephantsi okulandelwa kukuthintelwa yidosi ephezulu kuzoba u-U oguqulweyo. Xa umlinganiselo wesiphumo uyinto embi, njengokuvela kwesifo, ukucinezelwa yidosi ephantsi okulandelwa kukwandiswa yidosi ephezulu kuzoba u-J okanye u-U. Ulwalamano luyafana, kodwa umlinganiselo kwi-axis ethe nkqo wohlukile. Uninzi lomsebenzi wemethylene blue lulinganisa imisebenzi elungileyo, ngoko eli nqaku lithetha ngeegophe ezingu-U oguqulweyo, kuqondwa ukuba unobumba wealfabhethi ngumbandela wendlela yokuzoba igrafu.

Uphononongo luka-2008 olwaqokelela iimpendulo zehormesis zemethylene blue lucacisa ubungakanani bazo. Kwindlela yokuziphatha, ekusebenzeni komzimba nakwimichiza yezinto eziphilayo, iimpendulo ezikwindawo yokukhuthazwa zifikelela malunga ne-130 ukuya kwi-160 ekhulwini lomlinganiselo weqela lolawulo, zibe nomndilili okufutshane ne-140, ngaphambi kokuba zibuyele kumlinganiselo weqela lolawulo zize zehle ngaphantsi kwawo njengoko idosi iqhubeka inyuka. Olo luhlu sisishwankathelo sovavanyo oluninzi, asilophawu lwemolekyuli. Igophe ngalinye elingezantsi linencopho yalo kwiiyunithi zalo.

Kutheni le molekyuli ngokukodwa inokutshintsha icala

Imethylene blue ayingomnikeli wee-elektroni nje. Ingumthuthi osebenza macala omabini. Imo yayo eluhlaza e-oxidized yamkela ii-elektroni, iguquke ibe yimo engenambala e-reduced, yaye le mo i-reduced inokuzidlulisela ezo elektroni kwinqanaba elilandelayo. Ukudluliselwa kwee-elektroni okubangela ezi gophe kuchazwe kwingcaciso yendlela imethylene blue ehambisa ngayo ii-elektroni, yaye lo msebenzi wokuzithutha ngundoqo wayo yonke into apha.

Kwimiyinge ephantsi, loo mjikelo unika ukuphefumla kweeseli enye indlela. Idayi ekwimo e-reduced inokwenziwa i-oxidized kwi-cytochrome oxidase, i-enzyme yokugqibela yekhonkco lokuthuthwa kwee-elektroni, inyuse isantya sokusebenza kwayo kunye nokusetyenziswa kweoksijini namandla okuphefumla kweeseli. Kwimiyinge ephezulu, kwaloo michiza inomdla wokwamkela ii-elektroni iqalisa ukukhuphisana nekhonkco eliqhelekileyo endaweni yokulinceda: iphambukisa ii-elektroni kwindlela yazo eqhelekileyo, isebenzisa ioksijini ngokuthe ngqo, ize ivelise iintlobo zeoksijini ezisebenzayo ngokwekhemikhali endaweni yamandla aluncedo. Umthuthi omncinane osebenza njenge-catalyst, ukuhamba okungakumbi; indawo egqithisileyo ekhuphisanayo efunxa ii-elektroni, ukuhamba okuncinane. Le michiza yenza ukutshintsha kwecala kube nokwenzeka, nangona ingaqinisekisi ukuba nawuphi na umlinganiselo wesiphumo uya kufikelela phi encotsheni.

Ubungqina obuzimeleyo bokuxhomekeka kumyinge buvela kwiiseli ezingenazo kwaphela iimitochondria. Kuvavanyo lweeseli ezibomvu zegazi luka-1976, umyinge ophantsi we-1 micromolar wakhuthaza indlela ye-hexose monophosphate ngendlela eyayixhomekeke kakhulu kwi-oxyhemoglobin, ngoxa umyinge ophindwe kalikhulu ophezulu we-0.1 millimolar wawungachatshazelwa kakhulu bubukho be-oxyhemoglobin, waza wavelisa ihydrogen peroxide kuzo zontathu iindlela zokulinganisa ezasetyenziswayo. Idayi enye, iindlela ezimbini zokusebenza, ezahlulwe ngumahluko kumyinge. Iiseli ezibomvu zegazi azikwazi ukuphefumla ngeemitochondria, ngoko eli asilogophe lweemitochondria, kodwa libonisa ukutshintsha kwesimo semichiza ye-redox yedayi njengoko umyinge unyuka, kanye into efunwa yingcaciso yeemitochondria.

Iigophe ezine, iimeko zovavanyo ezine

Umfanekiso ongezantsi uzoba kwakhona iiseti ezine zedatha ecaleni kwenye. Iphaneli nganye igcina ii-axis zayo neemeko zayo, kuba ukuzidibanisa kwisikali esinye ibiya kuba bubuxoki bokuqala obunokuthethwa leli nqaku. Umzobo ngumfuziselo; amaxabiso achanekileyo neemeko zikwisicatshulwa.

Iphaneli A: i-cytochrome oxidase kumxube owenziwe ngokutyunyuzwa kwengqondo yempuku. Elona gophe licacileyo leemitochondria lifumaneka ngokungathanga ngqo, lizotywe kuphononongo kusetyenziswa idatha yomxube owenziwe ngokutyunyuzwa kwengqondo yempuku: malunga ne-138 ekhulwini lomsebenzi weqela lolawulo kwi-0.5 micromolar, ukubuyela kumlinganiselo weqela lolawulo kufutshane ne-5 micromolar, ukuhla ngaphantsi komlinganiselo wokuqala kufutshane ne-10 micromolar, apho ababhali bacebisa ukuba idayi ithatha ii-elektroni kwizakhiwo eziqhelekileyo zekhonkco. Umxube owenziwe ngokutyunyuzwa, micromolar, uvavanyo lokulinganisa ngokufunxwa kokukhanya. Eso sivakalisi sichaza yonke imeko, yaye igophe alithethi nto ngaphandle kwayo.

Iphaneli B: inkumbulo yeempuku nokubaleka kwivili. Kuphononongo lwenkumbulo yeempuku, iinaliti ezinikwe kanye emva koqeqesho zavavanywa kwiiyure ezingama-24 kamva. Iidosi zeemiligram ezi-1 ukuya kwezili-10 ngekhilogram zashiya ukuhamba nokutya kungahlukanga koko kwakwiqela elanikwa isisombululo setyuwa, ngoxa iimiligram ezingama-50 ukuya kwezili-100 ngekhilogram zanciphisa kakhulu ukubaleka kwivili (ixabiso eliphakathi laliyi-35 xa lithelekiswa nokujikeleza okungama-279), yaye eyona dosi iphezulu yabangela ukuphakama koboya, ukuhamba okungalungelelananga nokufa kwempuku enye. Idosi yeemiligram ezi-4 ngekhilogram yaphucula ukuqhelana nokuqaphela izinto: iimpuku ezazinikwe idayi zachitha phantse imizuzwana eli-10 engakumbi kwinto entsha. Ukusetyenziswa kweoksijini yingqondo kwanyuka kumxube owenziwe ngokutyunyuzwa owachanabekwa kwidayi e-reduced kwimiyinge ephantsi ye-micromolar, nakwiingqondo ezathathwa kwiiyure ezingama-24 emva kokunikwa imiligram e-1 ngekhilogram emzimbeni ophilayo. Qaphela ukwahlukana: indlela yokuziphatha yavavanywa ngeedosi ezazinikwa umzimba wonke emva koqeqesho, ukusetyenziswa kweoksijini kwavavanywa ngemiyinge kumxube owenziwe ngokutyunyuzwa kunye nedosi enye emzimbeni ophilayo, yaye ezi zilingo zimbini, hayi igophe elinye.

Iphaneli C: indlela ye-zebrafish emile njengo-T. Uphononongo lwe-zebrafish lwantywilisa iintlanzi eziqeqeshiweyo kwiiyure ezili-12 emva koqeqesho emanzini anemiyinge emiselweyo ye-0.1, 0.5, 5.0 okanye 10.0 micromolar, kuthelekiswa neqela lolawulo elanikwa idayi yokutya eluhlaza. Iqela le-0.5 micromolar laqhuba kakuhle kakhulu, iqela le-5.0 lafana neqela lolawulo, laza iqela le-10.0 laqhuba kakubi kunamaqela eedosi eziphantsi. Kukho izilumkiso ezibini kule phaneli. Umyinge we-micromolar emanzini awungomyinge we-micromolar egazini okanye engqondweni; ukusasazeka nokuqokelelana kwenzeka phakathi kwamanzi etanki nezicubu. Yaye ubungqina bamanani bubuthathaka kunokuba imilo ibonisa: idosi ephezulu yahlukile kumaqela eedosi eziphantsi, kodwa akukho minye imahluko ebalulekileyo ngokwezibalo phakathi kwamaqela eyaxelwayo. Igophe liyinyani kodwa alichanekanga ngokupheleleyo.

Iphaneli D: indlela esecaleni kwiiseli ezibomvu zegazi. UMetz noogxa bakhe bathelekisa i-1 micromolar ne-0.1 millimolar kwiiseli ezibomvu zegazi lomntu phantsi komoya, icarbon monoxide, nomxube owawusenza phantse yonke ihemoglobin ibe yicarboxyhemoglobin kuxinzelelo lweoksijini oluqhelekileyo lomzimba. Ukukhuthazwa yidosi ephantsi kwaphela ngaphandle kwe-oxyhemoglobin; ukukhuthazwa yidosi ephezulu akuzange kuchatshazelwe kangako. Iperoxide yavela kuphela kwidosi ephezulu. Le phaneli ifanele ukuba secaleni kwezinye njengobungqina bemichiza, ingabi yindawo yesine kwigophe elinye elikhulu: akukho mitochondria, umsantsa wemiyinge ophindwe kalikhulu, nemixube yeegesi etshintshwe kuvavanyo.

Kutheni iincopho zingangqamani, yaye zingafanelanga kungqamana

Iincopho ezine zikwi-0.5 micromolar kumxube owenziwe ngokutyunyuzwa, kwiimiligram ezi-4 ngekhilogram ezitofwe emva koqeqesho, kwi-0.5 micromolar emanzini etanki, nakwisibini somyinge ophantsi nophezulu esahlulwe ngumahluko ophindwe kalikhulu kwiiseli ezibomvu zegazi. Ukuthatha nawaphi na amabini kula maxabiso njengenani elifanayo yimpazamo yokudibanisa izinto ezingezizo ezodidi olunye. Umlinganiselo wesiphumo ngamnye unegophe lawo: owona myinge ulungele inkumbulo akufuneki ungqamane nowona ulungele umsebenzi we-oxidase, ukusetyenziswa kweoksijini, ukuhamba okanye ukuveliswa kweperoxide. Iyunithi nganye yomlinganiselo ithetha into eyahlukileyo: i-micromolar kumxube owenziwe ngokutyunyuzwa, i-micromolar emiselweyo emanzini, iimiligram ngekhilogram ezinikwa umzimba wonke, nemiyinge kwiplasma, engqondweni nakwiimitochondria zizixa ezahlukileyo, yaye utyekelo lwemethylene blue lokuqokelelana kwiimitochondria nasengqondweni luzigcina zahlukile. Imodeli nganye yongeza indlela yayo yokufunxwa, ukusasazwa nokususwa kwemichiza emzimbeni: uhlobo lwesilwanyana, indlela yokunikezelwa nexesha zigqiba ukuba sesiphi isicubu esidibana nedayi engakanani kangangexesha elingakanani.

Kulapha apho indima yedosi nendlela yokunikezelwa kukhuseleko lwemethylene blue ibaluleka khona, kuba iziphumo zeedosi eziphezulu kula maphepha — ukucinezelwa kokuhamba, ukuhamba okungalungelelananga, impuku enye efileyo, ukuveliswa kweperoxide — zizalathisi zobutyhefu kwiimeko zazo zovavanyo, azingomida yokhuseleko yakhe nabani na omnye. Yaye nabani na ohendelwa ekuguquleni iimiligram ezi-4 ngekhilogram kwimpuku zibe yinkqubo yokunikwa umntu kufuneka aqale afunde indlela iziphumo zezilwanyana ezinxulumene ngayo nobungqina babantu: ukuguqula ngokulula iimiligram ngekhilogram phakathi kweentlobo zezilwanyana akwanelanga.

Impazamo ekufuneka uyiphephe

U-U oguqulweyo uyahenda kuba ukhangeleka njengeqhosha lokulungelelanisa idosi eliphawulwe eyona ndawo ifanelekileyo. Akunjalo. Ihormesis ichaza into eyenzekileyo kumlinganiselo wesiphumo omnye kwiimeko zovavanyo olunye. Dibanisa iinkcazelo ezine ezinjalo uze ufumane iincopho ezine kwiinkqubo ezine zeeyunithi, nto leyo ichasene neqhosha lokulungelelanisa. Ukusetyenziswa ngokunyanisekileyo kwezi gophe kukuthelekisa nokulumkisa: lindela ukuba iziphumo zitshintshe icala xa umyinge utshintsha, lindela ukuba umlinganiselo wesiphumo ngamnye utshintshe kwindawo yawo, yaye ungathembi naliphi na ibango eliboleka incopho yovavanyo olunye ukuthethelela idosi kolunye uhlobo lwesilwanyana, kwenye indlela yokunikezelwa, kwesinye isicubu okanye kwenye injongo. Umahluko phakathi kweepateni zovavanyo nezigqibo zedosi yomntu ngundoqo weli nqaku lonke, ophinda uchazwe ukuze ungaphoswa.

Indlela yokufunda iphepha elilandelayo ledosi nempendulo

Imibuzo emine ifanele phantse lonke igophe lemethylene blue oya kudibana nalo. Ngowuphi umlinganiselo wesiphumo okwi-axis ethe nkqo, yaye ngaba ukutshintsha kwawo icala kungazoba u-U okanye u-J. Ngowuphi umyinge ochazwa ngokwenene yi-axis ethe tye: umyinge omiselweyo emanzini, kumxube owenziwe ngokutyunyuzwa, kwiplasma, uqikelelo lwengqondo, okanye idosi enikwe umzimba wonke. Yeyiphi imodeli namaxesha ayivelisileyo: umxube owenziwe ngokutyunyuzwa, iiseli ezikhuliswe elebhu izibane zivuliwe okanye zicinyiwe, izilwanyana eziqeqeshiweyo ezinikwe idosi ngaphambi okanye emva koqeqesho, zavavanywa nini. Yaye yintoni eyasetyenziswa kulawulo: isisombululo setyuwa, idayi yokutya eluhlaza, isithwali, nokuba izibalo zephepha ziyalixhasa na ibango ngalinye lothelekiso lwezibini okanye zixhasa kuphela imilo iyonke. Iphepha eliphendula yomine liyalifanele ixesha lakho. Elixela incopho ngaphandle kwayo likunike inani elingenadilesi.