Hormesis ya methylene blue: kufotokoza ma curve a mlingo ndi zotsatira

Khoswe wina amapatsidwa methylene blue ya 4 milligrams per kilogram ataphunzira kuzindikira chinthu, ndipo tsiku lotsatira amachikumbukira. Khoswe wina amapatsidwa 50, ndipo amangoyendetsa pang'ono kwambiri gudumu lake lothamangirapo. Molekyu ndi yomweyo. Koma njira imene zotsatira zikupita si yomweyo. Aliyense amene wawerenga mapepala angapo ofufuza methylene blue waona kusintha kumeneku, ndipo kuli ndi dzina: hormesis, kuyankha kwa magawo awiri kumene kukhudzidwa ndi kuchuluka kochepa ndi kwakukulu kumakankhira chinthu chomwechi choyezedwa m'njira zotsutsana.

Dzinali ndi lothandiza pokhapokha mutadziwa zimene limalonjeza ndi zimene sililonjeza. Nkhaniyi ikufotokoza magulu anayi a deta yofalitsidwa yokhudza methylene blue, lililonse lili ndi chinthu chake choyezedwa, kuchuluka kwake koyesedwa ndi makonzedwe ake oyesera, ndipo ikusonyeza chifukwa chake kapangidwe ka mankhwala a utotowu kamapangitsa kusintha kumeneku kukhala kotheka. Ikumaliza ndi chenjezo limene deta ikusonyeza mosapita m'mbali: curve imene imafika pachimake pa kuyesera kumodzi imafotokoza kuyesera kumeneko, osati njira yosankhira mlingo wa munthu payekha.

Kachitidwe kameneka kali ndi dzina, ndipo tanthauzo lake ndi locheperapo kuposa mmene limamvekera

Dzina lakuti hormesis linayambitsidwa mu 1943 ndi Southam ndi Ehrlich, ndipo Calabrese ndi Baldwin analipatsa tanthauzo lake lamakono loyezeka ndi manambala: kuyankha kwa magawo awiri kodzisintha kuti kugwirizane ndi zinthu, komwe kumachitika mwachindunji kapena kudzera m'kubwezeretsa kusokonekera kwa kukhazikika kwa mkati mwa thupi. Onani chimene sichili m'tanthauzo limenelo. Mawu akuti zothandiza mulibe. Hormesis imangonena kuti curve imasintha njira, palibe china.

Maonekedwe amene mukuona amadalira chinthu choyezedwa chimene chili pa mzere woima wa grafu. Ngati chinthu choyezedwacho ndi ntchito yabwino monga kugwira ntchito kwa enzyme, kugwiritsa ntchito oxygen kapena mphambu ya kukumbukira, kulimbikitsidwa ndi mlingo wochepa kenako kuletsedwa ndi mlingo waukulu kumajambula U wotembenuzidwa. Ngati chinthu choyezedwacho ndi choipa, monga kuchuluka kwa anthu amene akudwala, kuchepetsedwa ndi mlingo wochepa kenako kuwonjezedwa ndi mlingo waukulu kumajambula J kapena U. Ubale ndi womwewo, koma choyezedwa pa mzere woima ndi chosiyana. Kafukufuku wambiri wa methylene blue amayesa ntchito zabwino, choncho nkhaniyi ikugwiritsa ntchito ma curve a U wotembenuzidwa, pozindikira kuti chilembo chimene chimaoneka chimadalira mmene grafu yajambulidwira.

Nkhani yowunikira ya mu 2008 imene inasonkhanitsa mayankho a hormesis a methylene blue imasonyeza kukula kwa zotsatirazi momveka bwino. Pa khalidwe, kagwiridwe ka thupi ndi biochemistry, mayankho omwe ali m'dera lolimbikitsa amafika pafupifupi pa 130 mpaka 160 peresenti ya chiyerekezero, ndi avareji pafupi ndi 140, asanatsike kudutsa pa mlingo wa chiyerekezero kenako kufika pansi pake pamene mlingo ukupitiriza kukwera. Kuchuluka kumeneku ndi chidule cha zoyesera zambiri, osati khalidwe lokhazikika la molekyuyi. Curve iliyonse ili pansipa ili ndi pachimake pake m'mayunitsi ake.

Chifukwa chake molekyu imeneyi ingasinthe njira ya zotsatira

Methylene blue si yongopereka ma electron basi. Ndi yonyamula ma electron mobwerera m'mbuyo ndi kupita patsogolo. Mtundu wake wabuluu wa oxidised umalandira ma electron n'kusanduka mtundu wa reduced wopanda mtundu, ndipo mtundu wa reduced ungapereke ma electron amenewo ku magawo otsatira. Kusamutsa ma electron kumene kuli maziko a ma curve amenewa kwafotokozedwa m'nkhani ya mmene methylene blue imasunthira ma electron, ndipo ntchito yake yonyamula ma electron ndiyo mfundo yonse pano.

Pa kuchuluka kochepa, kuzungulira kumeneku kumapatsa kupuma kwa maselo njira ina. Utoto wa reduced ungakhale oxidised pa cytochrome oxidase, enzyme yomaliza ya unyolo wonyamula ma electron, n'kuwonjezera liwiro la ntchito yake limodzi ndi kugwiritsa ntchito oxygen ndi mphamvu ya kupuma kwa maselo. Pa kuchuluka kwakukulu, khalidwe lomweli lofunitsitsa ma electron limayamba kupikisana ndi unyolo wabwinobwino m'malo mouthandiza: limapatutsa ma electron kuchoka pa njira yawo yanthawi zonse, kugwiritsa ntchito oxygen mwachindunji, ndi kupanga mitundu ya oxygen yochita zinthu mwachangu m'malo mopanga mphamvu yothandiza. Chonyamulira chochepa chothandiza kusintha kwa mankhwala chimawonjezera kuyenda kwa ma electron; chokokera ma electron chochuluka kwambiri chopikisana ndi unyolo chimakuchepetsa. Kapangidwe ka mankhwalaka kamapangitsa kusintha kwa njira kukhala kotheka, koma sikamatsimikizira pamene chinthu chilichonse choyezedwa chidzafike pachimake.

Umboni wodziimira wokha wa kudalira kuchuluka umachokera ku maselo amene alibe mitochondria konse. Mu zoyesera za erythrocyte za mu 1976, kuchuluka kochepa kwa 1 micromolar kunalimbikitsa njira ya hexose monophosphate kudzera m'njira imene inkadalira kwambiri oxyhemoglobin, pamene kuchuluka kokwera ka 100 kwa 0.1 millimolar sikunakhudzidwe kwambiri ndi kukhalapo kapena kusakhalapo kwa oxyhemoglobin ndipo kunapanga hydrogen peroxide malinga ndi njira zonse zitatu zoyezera zomwe zinagwiritsidwa ntchito. Utoto womwewo, njira ziwiri zogwirira ntchito, zosiyanitsidwa ndi kuchuluka. Maselo ofiira a magazi sangachite kupuma kwa maselo, choncho iyi si curve ya mitochondria, koma ikusonyeza kuti khalidwe la redox la utotowu limasintha pamene kuchuluka kukukwera, zomwe n'zofunika kuti kufotokoza kwa mitochondria kugwirizane.

Ma curve anayi, makonzedwe anayi

Chithunzi chili pansipa chikujambulanso magulu anayi a detawa moyandikana. Gawo lililonse likusunga mizere yake ya grafu ndi mikhalidwe yake, chifukwa kuika zonse pa sikelo imodzi kukanakhala bodza loyamba limene nkhaniyi inganene. Chithunzichi ndi chongosonyeza kachitidwe; manambala ndi mikhalidwe yeniyeni zili m'mawu a nkhaniyi.

Gawo A: cytochrome oxidase mu homogenate ya ubongo wa khoswe. Curve yomveka kwambiri ya mitochondria imachokera ku deta yosindikizidwa kale, yojambulidwa m'nkhani yowunikira kuchokera ku deta ya homogenate ya ubongo wa khoswe: pafupifupi 138 peresenti ya ntchito ya chiyerekezero pa 0.5 micromolar, kubwerera pa chiyerekezero pafupi ndi 5 micromolar, ndi kutsikira pansi pa mlingo woyambira pafupi ndi 10 micromolar, pomwe olemba akuganiza kuti utotowu ukuchotsa ma electron ku magulu abwinobwino a unyolo. Homogenate, micromolar, kuyeza pogwiritsa ntchito spectrophotometry. Chiganizo chimenecho chili ndi zonse zofunika kudziwa za makonzedwewo, ndipo curveyo ilibe tanthauzo kunja kwake.

Gawo B: kukumbukira kwa makoswe ndi kuthamanga pa gudumu. Mu kafukufuku wa kukumbukira kwa makoswe, zotsatira za jakisoni umodzi woperekedwa pambuyo pophunzitsidwa zinayesedwa patatha maola 24. Milingo ya 1 mpaka 10 milligrams per kilogram inasiya kuyenda ndi kudya kukhala kosasiyanitsidwa ndi zomwe zinaoneka pa saline, pamene 50 mpaka 100 milligrams per kilogram inachepetsa kwambiri kuthamanga pa gudumu (median ya maulendo 35 poyerekezera ndi 279), ndipo mlingo wapamwamba kwambiri unachititsa ubweya kuimirira, kuyenda mosagwirizana ndi kufa kwa khoswe mmodzi. Mlingo wa 4 milligram per kilogram unawongolera kuzolowera ndi kuzindikira zinthu: makoswe omwe analandira methylene blue anakhala pafupifupi masekondi 10 owonjezera akuyang'ana chinthu chatsopano. Kugwiritsa ntchito oxygen kwa ubongo kunakwera mu homogenate yokhudzidwa ndi utoto wa reduced wa kuchuluka kochepa kwa micromolar komanso mu ubongo womwe unatengedwa patatha maola 24 kuchokera pamene 1 milligram per kilogram inaperekedwa m'nyama yamoyo. Zindikirani kusiyanaku: kuyesa khalidwe kunagwiritsa ntchito milingo yoperekedwa m'thupi lonse pambuyo pophunzitsidwa, pamene kuyesa kugwiritsa ntchito oxygen kunagwiritsa ntchito kuchuluka mu homogenate komanso mlingo umodzi m'nyama yamoyo; zimenezi ndi zoyesera ziwiri, osati curve imodzi.

Gawo C: zebrafish mu njira za T. Kafukufuku wa zebrafish unamiza nsomba zophunzitsidwa m'madzi kwa maola 12 pambuyo pophunzitsidwa, pa kuchuluka kokonzedwa kwa 0.1, 0.5, 5.0 kapena 10.0 micromolar, poyerekezera ndi gulu lomwe linagwiritsa ntchito utoto wabuluu wa chakudya. Gulu la 0.5 micromolar linachita bwino kwambiri, gulu la 5.0 linafanana ndi gulu loyerekezerapo, ndipo gulu la 10.0 linachita moyipa kuposa magulu a milingo yochepa. Pali machenjezo awiri pa gawoli. Micromolar m'madzi omiziramo si micromolar m'magazi kapena mu ubongo; kufalikira ndi kuunjikana zimachitika pakati pa madzi a mu thanki ndi minofu. Ndipo umboni wa ziwerengero ndi wofooka kuposa mmene maonekedwe a curve akusonyezera: mlingo waukulu unasiyana ndi magulu a milingo yochepa, ndipo palibe kusiyana kwina kwa magulu kofunika malinga ndi ziwerengero komwe kunanenedwa. Curveyo ndi yeniyeni koma yosalongosoka bwino.

Gawo D: njira ina ya erythrocyte. Metz ndi anzake anayerekezera 1 micromolar ndi 0.1 millimolar m'maselo ofiira a magazi a munthu ali mu mpweya wamba, carbon monoxide, ndi chisakanizo chomwe chinapangitsa hemoglobin pafupifupi yonse kukhala carboxyhemoglobin pa kuthamanga kwa oxygen kofanana ndi kwa m'thupi. Kulimbikitsidwa pa mlingo wochepa kunachepa kwambiri popanda oxyhemoglobin; kulimbikitsidwa pa mlingo waukulu sikunakhudzidwe kwambiri. Peroxide inaoneka pa mlingo waukulu wokha. Gawoli liyenera kukhala pafupi ndi ena monga umboni wa kagwiridwe ka mankhwala, osati ngati mfundo yachinayi pa curve ina yaikulu yophatikiza zonse: palibe mitochondria, kusiyana kwa kuchuluka ka 100, ndi zosakaniza za mpweya zosinthidwa mwadala.

Chifukwa chake malo a pachimake sakufanana, ndipo sayenera kufanana

Malo anayi a pachimake ali pa 0.5 micromolar mu homogenate, 4 milligrams per kilogram yoperekedwa ndi jakisoni pambuyo pophunzitsidwa, 0.5 micromolar m'madzi a mu thanki, ndi kuyerekeza kwa kuchuluka kochepa ndi kwakukulu kosiyana ka 100 m'maselo ofiira a magazi. Kutenga ziwiri zilizonse mwa izi ngati nambala yomweyo ndi kulakwitsa mwa kusakaniza magulu osiyana. Chinthu chilichonse choyezedwa chili ndi curve yake: mlingo wabwino kwambiri pa kukumbukira suyenera kufanana ndi wabwino kwambiri pa ntchito ya oxidase, kugwiritsa ntchito oxygen, kuyenda kapena kupanga peroxide. Yuniti iliyonse ya kuchuluka ili ndi tanthauzo losiyana: micromolar ya homogenate, micromolar yokonzedwa m'madzi omiziramo, milligrams per kilogram yoperekedwa m'thupi lonse, ndi kuchuluka mu plasma, ubongo ndi mitochondria ndi miyeso yosiyana, ndipo chizolowezi cha methylene blue chounjikana mu mitochondria ndi ubongo chimapitiriza kuzisiyanitsa. Mtundu uliwonse wa choyesedwa umawonjezera kagwiridwe kake ka kuyamwa, kufalitsa ndi kuchotsa mankhwala: mtundu wa nyama, njira yoperekera ndi nthawi zimatsimikizira kuti ndi minofu iti imene ikukhudzidwa ndi utoto wochuluka motani komanso kwa nthawi yayitali bwanji.

Apa n'kumenenso ntchito ya mlingo ndi njira yoperekera pa chitetezo cha methylene blue ili yofunika, chifukwa zotsatira za milingo yayikulu m'mapepala amenewa, kuchepa kwa kuyenda, kuyenda mosagwirizana, khoswe mmodzi wakufa, ndi kupanga peroxide, ndi zizindikiro za kawopsedwe m'makonzedwe awo, osati malire a chitetezo kwa wina aliyense. Ndipo aliyense amene akufuna kutembenuza 4 milligrams per kilogram ya khoswe kukhala ndondomeko yoperekera kwa munthu ayenera kuwerenga kaye mmene zomwe zapezeka m'nyama zikugwirizanirana ndi umboni wa anthu: kungotembenuza milligram-per-kilogram kuchokera ku mtundu wina wa nyama kupita ku wina sikokwanira.

Cholakwika choyenera kupewa

U wotembenuzidwa amakopa chifukwa amaoneka ngati chida chosinthira mlingo chokhala ndi malo abwino kwambiri olembedwapo. Si choncho. Hormesis imafotokoza zimene zinachitika pa chinthu chimodzi choyezedwa m'makonzedwe amodzi. Mukaphatikiza mafotokozedwe anayi oterowo, mumapeza malo anayi a pachimake m'mayunitsi anayi osiyana, zomwe sizofanana ndi chida chosankhira mlingo. Kugwiritsa ntchito ma curve amenewa moona mtima ndi kuwayerekezera ndi kuchenjeza: yembekezerani kuti zotsatira zingasinthe njira pamene kuchuluka kukusintha, yembekezerani kuti chinthu chilichonse choyezedwa chisintha njira pa malo ake, ndipo musakhulupirire zonena zilizonse zomwe zimatenga pachimake pa kuyesera kumodzi kuti zilungamitse mlingo mu mtundu wina wa nyama, njira ina yoperekera, minofu ina kapena cholinga china. Kusiyanitsa pakati pa kachitidwe ka zoyesera ndi zisankho za mlingo wa munthu payekha ndiyo mfundo ya nkhani yonseyi, yobwerezedwanso kuti isaphonyedwe.

Mmene mungawerengere pepala lotsatira la mlingo ndi zotsatira

Mafunso anayi amagwirizana ndi pafupifupi curve iliyonse ya methylene blue yomwe mudzakumane nayo. Ndi chinthu chiti choyezedwa chimene chili pa mzere woima, ndipo kodi kusintha kwa njira yake kungajambule U kapena J. Mzere wopingasa ukusonyeza kuchuluka kwanji kwenikweni: kokonzedwa m'madzi omiziramo, kwa mu homogenate, kwa mu plasma, koyerekezedwa kwa mu ubongo, kapena mlingo woperekedwa m'thupi lonse. Ndi mtundu wanji wa choyesedwa ndi nthawi iti zimene zinapanga curveyo: homogenate, maselo okulitsidwa mu labotale magetsi ali oyaka kapena ozimitsidwa, nyama zophunzitsidwa zopatsidwa mlingo asanaphunzitsidwe kapena ataphunzitsidwa, ndipo zinayesedwa liti. Ndipo choyerekezerapo chinali chiyani: saline, utoto wabuluu wa chakudya, kapena chinthu chonyamulira mankhwala, komanso ngati ziwerengero za pepalalo zikuthandiza zonena za kuyerekeza kulikonse kwa magulu awiri kapena maonekedwe onse a curve okha. Pepala limene limayankha mafunso onse anayi ndi loyenera nthawi yanu. Limene limangonena za pachimake popanda zimenezi lakupatsani nambala yopanda malo ake.