Ukuhlola Iqhaza Le-BHB Empilweni Yengqondo: Ukuguqulwa Kwe-Epigenetic Njengokwelashwa Kwengqondo Ye-Metabolic
Isikhathi sokufunda esilinganiselwe: 16 imizuzu
Ngakho-ke uma sikhuluma ngokudla kwe-ketogenic okwenza ama-ketones, futhi lawo ma-ketone ayimizimba yokubonisa amangqamuzana, yilokhu engikushoyo. I-BHB iwumzimba we-ketone ofundwe kahle kakhulu ezincwadini ngalesi sikhathi. Lokho akusho ukuthi ezinye imizimba ye-ketone ayinayo imiphumela yokubonisa amangqamuzana noma amathonya. Kusho nje ukuthi ucwaningo, ngesikhathi salesi sihloko, lugxile kule miphumela ebonwe ku-BHB.
I-BHB yayivame ukubonakala njengomkhiqizo owenziwe nge-metabolic kuphela kodwa iye yazuza umfutho iminyaka eminingana ekuqapheliseni indima yayo enqubweni eyinkimbinkimbi ye-epigenetic modulation, indima enomthelela ojulile ezinkingeni ze-neuropsychiatric.
I-Epigenetics: Umakhi Ocashile weGene Expression
Ngaphambi kokuthi ngingene kwezinye izici ze-BHB, ngicabanga ukuthi kuwusizo ngempela ukuqonda umqondo we-epigenetics. Ukuchaza lokhu, ngingathanda ukusebenzisa isifaniso esivamile somtapo wolwazi kanye nomsebenzi womtapo wolwazi. Cabanga nge-DNA yakho njengomtapo wolwazi omkhulu oneqoqo elikhulu lezincwadi ezigcwele ulwazi lwakho lofuzo. I-Epigenetics ifana nomsebenzi womtapo wolwazi onqumayo ukuthi yiziphi izincwadi ezikhishwa emashalofini ukuze zifundwe futhi ezihlala zishaywe. Umsebenzi waselabhulali unamandla amakhulu kulesi simo, awuvumi? Umsebenzi womtapo wolwazi akaziguquli izincwadi ngokwazo - ukulandelana kwe-DNA kuhlala kungashintshile - kodwa umsebenzi womtapo wolwazi uthonya ukuthi yiziphi izingxenye zekhodi yofuzo ezivezwayo noma "ezifundwayo," futhi iziphi ezingafundiwe. Kulo mtapo wezincwadi, izincwadi (DNA) ziyigugu kangangokuthi azinakususwa. Nokho, uma incwadi ikhethwa ukuthi ifundwe, inqubo ehlukile (okulotshiweyo) idala amakhophi (i-RNA yesithunywa; i-mRNA) yamakhasi adingekayo. Lawa makhophi yiwo ashiya umtapo wezincwadi, ethwele ukwaziswa okudingekayo ukuze ingqamuzana likhiqize amaprotheni.
Ukulandelana kwe-DNA ezakhini zofuzo kuhlala kunjalo kungakhathaliseki ukuthi amathonya e-epigenetic. Ngicabanga ukuthi imiqondo yezakhi zofuzo kanye ne-epigenetics ingabadida abantu abangayijwayele le miqondo. Uma udidwa yilokhu, awuwedwa. Ake sibheke ezinye izibonelo ezisiza ukuqonda kwethu.
Ukudla ukudla okunothe nge-Vitamin B12, njengenyama, ubisi, namaqanda, kungathonya izimpawu ze-epigenetic. Nakuba i-Vitamin B12 ingaguquli ukulandelana kwe-DNA yezakhi zofuzo ezihlobene nempilo yamangqamuzana egazi enzwa, idlala indima ebalulekile ekugcineni amaphethini e-DNA enempilo, abalulekile ekuvezweni okufanele kwalezi zakhi zofuzo.
Ukuchayeka ezintweni ezingcolisayo namakhemikhali, njengezinsimbi ezisindayo, kungaholela ezinguqukweni ze-epigenetic. Lobu buthi abuguquli ukulandelana kwangempela kwe-DNA yezakhi zofuzo, kodwa bangashintsha ukusho kwephethini ye-DNA. Lokhu kuthinta indlela izakhi zofuzo ezivezwa ngayo, okungaba nomthelela empilweni ngaphandle kokushintsha ikhodi yofuzo ngokwayo.
Ukucindezeleka kwengqondo kanye nokuhlangenwe nakho okubuhlungu kungaholela ekuguqulweni kwe-epigenetic. Lokhu okuhlangenwe nakho akuguquli ukulandelana kwe-DNA ngaphakathi kwezakhi zofuzo ezihlobene nokusabela kwengcindezi nempilo yengqondo. Nokho, bangashintsha indlela lezi zakhi zofuzo ezivezwa ngayo ngezindlela ezihlukahlukene. Lesi sisho sofuzo esishintshiwe singaba nomthelela ekuphenduleni kwengcindezi yomzimba futhi sithinte ngisho nokusebenza kwamaselula nokusebenza kwe-mitochondrial njengoba izimpendulo zengcindezi zihlobene eduze nokusetshenziswa kwamandla kanye nempilo yeselula. Ngakho-ke, nakuba ikhodi yofuzo ingashintshiwe, indlela umzimba osabela ngayo ekucindezelekeni ezingeni lamangqamuzana ingashintshwa kakhulu.
Ukuzivocavoca kuthinta ukuvezwa kofuzo lwe-PPARGC1A, okubalulekile kumetabolism yamandla. Ngenkathi umsebenzi ungashintshi i-DNA yangempela yofuzo lwe-PPARGC1A, uthuthukisa umsebenzi wawo. Lokhu kuholela ekwandeni kokukhiqizwa kwe-mitochondrial kumaseli emisipha kanye nokusebenza kahle kwamandla, konke ngokuguqulwa kwe-epigenetic ngaphandle kokushintsha ukulandelana kwe-DNA yofuzo.
Ukulawulwa kwe-gene expression (aka epigenetics) kufezwa ngezindlela ezahlukahlukene. Kulesi sihloko, sizofunda mayelana nokuguqulwa kwe-histone, i-DNA methylations, nama-microRNAs (miRNAs), aziwa nangokuthi ama-RNA angafaki ikhodi. Ekugcineni, uzoqonda kangcono ukuthi imiphumela ye-BHB ithonya kanjani lezi zinqubo ezibalulekile ekuvezeni izakhi zofuzo ngendlela ethonya impilo yobuchopho.
Ukuqonda i-β-Hydroxybutyrate: Ngaphezu Kwesibaseli Nje
Kulabo abasha kubhulogi nokudla kwe-ketogenic, masikukhuphule ngokushesha! I-β-Hydroxybutyrate ingumzimba we-ketone okhiqizwa kakhulu esibindi ngesikhathi sokunciphisa ukudla kwe-carbohydrate, njengokuzila ukudla noma ukunamathela ekudleni kwe-ketogenic. Kulezi zifunda, umzimba uyashintsha ekusebenziseni i-glucose njengomthombo wawo oyinhloko wamafutha kuya kumafutha avuthayo, okuholela ekukhiqizeni i-BHB namanye ama-ketone. Ungenza i-BHB ngokulandela ukudla kwe-ketogenic, noma ungathatha i-BHB njengesengezo noma inhlanganisela yakho kokubili.
Kodwa udinga ukwazi ukuthi indima ye-BHB idlulela ngale kokuba umthombo wamandla ohlukile. Isebenza njenge-molecule ekhombisayo ethonya uchungechunge lwezinqubo zebhayoloji. Phakathi kwezindima zayo ezithakazelisa kakhulu ikhono layo lokushintsha futhi libe nomthelela ekuvezeni izakhi zofuzo ngezindlela ezihlukahlukene ze-epigenetic ezihambisana nemizwa kanye nokusebenza kwengqondo.
Indima ye-β-Hydroxybutyrate (BHB) empilweni yengqondo: Ithonya le-Epigenetic kanye nokusebenzisana kwe-GPCR
Ngakho-ke, ukuze siqonde indima ehlukahlukene ye-β-Hydroxybutyrate (BHB) empilweni yengqondo kuzodingeka sihlole umthelela wayo we-epigenetic, futhi ikakhulukazi ukusebenzisana kwayo nama-G protein-coupled receptors (GPCRs). Ama-GPCR awumndeni omkhulu wama-cell surface receptors adlala indima ebalulekile ekudluliseni amasignali kusuka ngaphandle kweseli kuya ngaphakathi. Zibophezela ngama-ligand athile (njengamahomoni, ama-NTs, kanye nemikhiqizo ye-metabolic efana ne-BHB) futhi lokhu kwenza amaprotheni e-G asebenze.
Amaprotheni e-G, amafushane kumaprotheni abopha i-guanine nucleotide, awumndeni wamaphrotheni asebenza njengokushintshwa kwamangqamuzana ngaphakathi kwamaseli. Zitholakala ohlangothini lwangaphakathi lwe-membrane yeseli futhi zenziwa zisebenze ngama-GPCR.
Uma amaprotheni e-G esenziwe asebenza ngaphakathi kweseli, adala izinyathelo eziningi zokubonisa ama-cascade ahlanganisa ama-molecule abalulekile amaphakathi njengezithunywa zesibili (isb., i-cAMP, i-calcium ion) nama-kinases (ama-enzyme angeza amaqembu e-phosphate kwamanye amaprotheni). Ezinye zezindlela zokubonisa eziqalwe yi-GPCRs zixhumana ngokungaqondile nemishini ye-epigenetic yeseli.
Isibonelo, i-cascade abayisungulayo ingase iholele ekusebenziseni ama-kinases ukuthi izici zokuloba ze-phosphorylate noma amanye amaprotheni ahilelekile ekulawuleni izakhi zofuzo. Ngamagama alula, lapho amaprotheni e-G ecushiwe, aqala ukusabela kweketango, ekugcineni asebenze ama-enzyme athile (isb, kinases). Lawa ma-kinase abe eseguqula amaprotheni abalulekile (njengezinto zokuloba) alawula ukuthi yiziphi izakhi zofuzo ezisebenzayo kuseli. Lena yindlela isignali evela ngaphandle kwengqamuzana (njengehomoni) engaholela ezinguqukweni kulokho ingqamuzana elikwenzayo, okuhlanganisa izinguquko lapho izakhi zofuzo zisebenza khona.
Ngakho, konke lokhu kuyathakazelisa kakhulu, kodwa yini esiyaziyo ngeqhaza le-BHB ekusebenzisaneni nama-GPCR? I-GPR109A ne-GPR41 yizinhlobo ezithile ze-G protein-coupled receptors (GPCRs) lapho imiphumela ethize ye-BHB ikhonjwe ezincwadini zocwaningo.
I-BHB yenza kusebenze i-GPR109A kuma-adipocyte, inciphisa i-lipolysis futhi iphinde ibe namaseli omzimba kanye nama-endothelial. Lokhu kuvula kungaveza imiphumela elwa nokuvuvukala, okungase kunciphise ingozi ye-atherosclerosis. Lokhu kungahumusheka kanjani emiphumeleni eqondile empilweni yobuchopho, ngakho-ke, kuhlinzeke ngemiphumela yokwelashwa kwesifo sengqondo nokuphazamiseka kwemizwa? Nokho, imiphumela elwa nokuvuvukala, njengaleyo ehlinzekwe ngokusebenzisana kwe-BHB kanye nokusebenza kwe-GPR109A kumaseli omzimba namasosha omzimba, ibalulekile ebuchosheni! Ukuvuvukala okungapheli kuyisici esaziwayo ezinkingeni ezihlukahlukene zemizwa, ngakho ukunciphisa ukuvuvukala kungavikela ubuchopho ekuqhumeni kwe-neuroinflammation. Ukusebenza kwe-endothelial okuthuthukisiwe kuthuthukisa ukugeleza kwegazi ebuchosheni futhi kuqinisekisa ukulethwa okungcono komoya-mpilo kanye nezakhi-izindlela ezibalulekile zobuchopho obusebenzayo futhi, ngakho-ke, ukuzinza kwemizwa nokusebenza kwengqondo.
Kodwa-ke, imiphumela ye-BHB iyavimbela noma "iyaphikisana" ekukhulumeni kwe-GPR41. Ukungena kwe-BHB endleleni yokukhuluma kungaba yinzuzo kanjani? Lokho kubonakala kungenangqondo, akunjalo? Ngakho-ke, ake siqale ukuhlola kwethu lokhu kumongo wesifo sikashukela.
Kusifo sikashukela, ukubonakaliswa okungavinjelwe kwe-GPR41 kuhlotshaniswa nokuncipha kokukhiqizwa kwe-insulin. Lokhu kuncipha kucatshangwa ukuthi kunomthelela enseleleni yamangqamuzana e-beta e-pancreatic ekuphenduleni ngokwanele amazinga e-glucose aphakeme, isici esiyinhloko sohlobo 2 sikashukela. Ukwenziwa kusebenze kwe-GPR41 kumaseli e-beta e-pancreatic empeleni kungase kubambe iqhaza ekuvimbeleni ukukhiqizwa kwe-insulin ekhuthazwa yi-glucose efanele ngaphansi kwezimo zesifo sikashukela.
Kodwa-ke, njengoba sekushiwo, i-BHB ibonakale iphikisana nenkulumo ye-GPR41. Kungani lokho kubalulekile? Ngoba ukuphikisa (ukuphikisa noma ukwehlisa ijubane) isisho se-GPR41 singaba nemiphumela enenzuzo ye-metabolic.
Ngokusebenza ngokumelene ne-GPR41, i-BHB ingase ikhulise ukukhiqizwa kwe-insulin, ngaleyo ndlela ithuthukise ukulawulwa kweglucose yegazi. Le nqubo iphakamisa indima ebalulekile ye-BHB ekulawuleni isifo sikashukela, ikakhulukazi ekuthuthukiseni ukubekezelelana kwe-glucose nokuzwela kwe-insulin. Kodwa kuthiwani ngesifo sengqondo kanye nezinkinga zezinzwa eziphawulwa ukungasebenzi kahle kwe-metabolic ebuchosheni? Ngingasho ukuthi le miphumela ibalulekile empilweni yobuchopho.
Ushukela wegazi ozinzile ubalulekile ekusebenzeni kobuchopho, futhi ukulawulwa kwe-glucose okuthuthukisiwe kusekela impilo yengqondo, kunciphisa ubungozi bezifo ze-neurodegenerative, kusiza ukuzinzisa imizwa, futhi kunikeza i-neuroprotection iyonke. Kuye kwaboniswa ukuthi ukuphikiswa kwe-BHB kwe-GPR41 kuthonya ukusetshenziswa kwamandla kanye nomsebenzi wezinzwa ezinozwela. Ukusebenzisana okuphinde kuthinte i-glucose homeostasis ngokulawula ukukhiqizwa kwe-insulin.
Ukuphikiswa kwe-GPR41 nge-BHB nakho kuthonya umsebenzi wezinzwa ezinozwela. Ukulawula umsebenzi wezinzwa ezizwelayo kubalulekile ngoba kuyingxenye yempendulo yomzimba ekucindezelekeni. Ngokulungisa le mpendulo, i-BHB ingaba nethonya ekulawuleni imiphumela ehlobene nokucindezeleka ebuchosheni, esaziyo ukuthi ingaphazamisa ukugaya kobuchopho. Iqhaza lalokhu kusebenzisana ku-glucose homeostasis kanye nokukhiqizwa kwe-insulin kubalulekile empilweni yobuchopho, futhi ukungalingani kungaholela ezinkingeni zemizwa kanye nengqondo kanye nengozi eyengeziwe yezifo ze-neurodegenerative.
I-BHB idlala indima ebalulekile ekuvuvukeni, kwe-neurologic, kanye izifo ze-metabolic njenge-GPCRs ligand engapheli.
He, Y., Cheng, X., Zhou, T., Li, D., Peng, J., Xu, Y., & Huang, W. (2023). I-β-Hydroxybutyrate njenge-epigenetic modifier: Izindlela eziyisisekelo nemithelela. I-heliyon. https://doi.org/10.1016/j.heliyon.2023.e21098
Akunzima ukubona ukuthi imiphumela ye-BHBs kuma-GPCR inethonya elibalulekile empilweni ye-metabolic, ngakho-ke imiphumela eqondile empilweni yobuchopho.
Futhi leyo yimiphumela engaqondile ye-BHB ekukhulumeni kwe-epigenetic ngokusebenzisa ama-GPCR. Ake sikuthuthukise ngezinqubo eziqondile ezihilelekile ukuze uqonde kangcono ukuthi kungani lokhu kuwukwelapha okunamandla kangaka.
I-Methylation 101: Ukusetha Isiteji Sendima Ye-BHB Ku-Gene Regulation
I-BHB inemiphumela enamandla ku-methylation. Ngaphambi kokuba sikhulume ngazo, kufanele sichithe isikhashana sikhuluma ngokuthi iyini i-methylation ngoba iyinqubo eyisisekelo yezinto eziphilayo edlala indima ebalulekile ekulawuleni izakhi zofuzo kanye ne-epigenetics.
Ungalifaki kakhulu leli gama. Kubonakala kusabisa ekuqaleni, kodwa emnyombweni wayo, i-methylation imane nje ihlanganisa amaqembu amancane amakhemikhali abizwa ngokuthi amaqembu e-methyl ezingxenyeni ezithile ze-DNA yethu noma kumaprotheni (ama-histones) lapho i-DNA isongwe khona. Benza 'njengamathegi' angenza kusebenze noma athulise izakhi zofuzo. Uma amaqembu e-methyl engezwa ezifundeni ezithile, 'angacisha' isakhi sofuzo, sivimbele ukuthi sisetshenziselwe ukwakha amaprotheni. Uma la maqembu amancane e-methyl engekho, 'avula' isakhi sofuzo ngokusivumela ukuthi sibhalwe ngokusebenzayo sibe amaprotheni. Amathegi e-Methyl avala izakhi zofuzo, futhi lezo zakhi zofuzo azenzi amaprotheni. Izakhi zofuzo ezingenayo i-methyl tag ziyavula futhi zenze amaprotheni.
Emtapweni wolwazi kanye nesifaniso somtapo wolwazi, i-DNA methylation ingafaniswa nomsebenzi womtapo wolwazi obeka izimpawu ezithile noma omaka ezincwadini ezithile. Lezi zimpawu azikushintshi okuqukethwe ezincwadini (ukulandelana kwe-DNA) kodwa zibonisa ukuthi incwadi kufanele itholakale kalula noma cha. Kulesi sifaniso, uma incwadi imakwe umsebenzi wasemtatsheni wezincwadi (methylation), kuwuphawu lokuthi le ncwadi akufanele ivulwe noma ifundwe okwamanje. Lokhu kufana nendlela i-methylation ku-DNA engacindezela ngayo ukuvezwa kwezakhi zofuzo ezithile. Kunjengokungathi isisebenzi sasemtatsheni wezincwadi sithi, “Le ncwadi ayidingeki njengamanje; asiyigcine eshalofini futhi ingasebenzi.” Ngokuphambene, ukungabikho kwethegi enjalo kusho ukuthi incwadi iyatholakala ukuze ifundwe, kufana nendlela ukuntuleka kwe-methylation kungavumela isakhi sofuzo ukuba sivezwe.
Amazinga aphakeme we-β-Hydroxybutyrate (BHB) angavimbela umsebenzi wama-enzyme afana ne-DNA methyltransferases (DNMTs). I-DNMTs inesibopho sokwengeza amaqembu e-methyl ku-DNA, inqubo eyinhloko ekulawuleni izakhi zofuzo eyaziwa ngokuthi i-methylation. Ngokuvimbela lawa ma-enzyme, i-BHB inganciphisa i-methylation ye-DNA, engaholela ekushintsheni ekukhulumeni kwezakhi zofuzo ezithile.
Ake sinikeze isibonelo sokwenza lula ukufunda kwakho!
I-BHB ivimbela ama-enzyme akhuthaza i-methylation. Lokhu kuvinjelwa kwe-BHB kuvumela isakhi sofuzo se-PGC-1a (PPARG coactivator 1a) ukuthi silawule. Lokhu kuhle ngempela. I-PGC-1a ibalulekile ekusebenzeni kwe-mitochondrial kanye ne-biogenesis. Ukulawulwa kwalesi sakhi sofuzo kudlala indima ebalulekile ekugcineni umsebenzi wokuphefumula we-mitochondrial kanye namazinga e-fatty acid oxidation.
Uma ufuna ukwazi ukuthi yiziphi izakhi zofuzo ezithonywa yimiphumela ye-BHB ku-methylation, khona-ke uzosijabulela ngempela lesi sihloko engibhale ngaso nje!
Kuyaziwa kabanzi ukuthi imizimba ye-ketone ayisebenzi nje kuphela njenge-ancillary fuel esikhundleni se-glucose kodwa futhi idala izici zokulwa ne-oxidative, anti-inflammatory, kanye ne-cardioprotective ngokubophezela kumaprotheni amaningana ahlosiwe, okuhlanganisa i-histone deacetylase (HDAC), noma i-G protein-coupled receptors. (GPCRs)
He, Y., Cheng, X., Zhou, T., Li, D., Peng, J., Xu, Y., & Huang, W. (2023). I-β-Hydroxybutyrate njenge-epigenetic modifier: Izindlela eziyisisekelo nemithelela. I-heliyon. https://doi.org/10.1016/j.heliyon.2023.e21098
Lokhu kubambisana phakathi kwe-DNA methylation kanye nezinguquko ze-histone kuyisihluthulelo sokuvala izakhi zofuzo ezithile. Ukusebenzisana okunjalo okuhleliwe kuyisibonelo senkimbinkimbi yokulawulwa kwe-epigenetic, lapho izinqubo eziningi zisebenza ndawonye ukuze zishunise kahle ukuvezwa kofuzo, ekugcineni kube nomthelela ekusebenzeni kwamaselula.
Ukuhlola Isixhumanisi Phakathi Kwe-BHB ne-HDAC Inhibition
Okulandelayo, sizokhuluma ngento ebizwa nge-Histone Deacetylases (HDACs). Umndeni we-HDAC uqukethe ama-enzyme amaningana, ngalinye likhethwe inombolo ehlukile, njenge-HDAC1, HDAC2, HDAC3, njalonjalo, kuhlanganise ne-HDAC5. Lawa ama-enzyme avame ukususa amaqembu e-acetyl kuma-histones, okuholela ku-DNA egcwele ngokuqinile kanye nokuncipha komsebenzi wofuzo.
I-BHB iboniswe ukuvimbela i-HDAC5, futhi lokhu kuye kwahlotshaniswa nemiphumela ye-neuroprotective, njengoba kusiza ekuvimbeleni izindlela eziholela ekufeni kweseli. Lokhu kuye kwaphakamisa imibuzo mayelana nendima yama-ketones, njenge-BHB, ekwelapheni izifo ezibandakanya ukuhlukahluka kofuzo lwe-HDAC5, njenge-bipolar disorder. Ingabe ukuguquguquka kwe-HDAC5 ngama-ketone kungaba yindlela eyinhloko lapho ukudla kwe-ketogenic kuveza imiphumela yayo yokwelapha ku-bipolar disorder?
Ake sibuyele kumtapo wethu wezincwadi kanye nesifaniso somsebenzi wasemtapweni wolwazi. Cabanga ukuthi umsebenzi waselabhulali (i-epigenetics) usebenzisa ama-HDAC (i-enzyme) ukupakisha izincwadi (ufuzo) ngokuqinile emashalofini (ama-histones). Lokhu kupakishwa okuqinile emashalofini kwenza kube nzima ukukhipha izincwadi ngazinye (sonke sineshelufu lezincwadi elinjengaleli, akunjalo?). Ubunzima obutholwa ekukhipheni incwadi eshalofini kunciphisa amathuba okuthi izofundwa (inkulumo yofuzo). Ama-HDAC ambalwa asho isikhala esiningi kumashalofu ezincwadi kanye nokubuyisa kalula izincwadi (izakhi zofuzo). Ngiyitholile? Kuhle! Asiqhubeke!
Futhi kulabo abangenaso isizinda sebhayoloji, ungase uzibuze ukuthi ingabe i-methylation ngandlela thize ihlobene ne-Histone Deacetylases (HDACs). Abanjalo. Ziyizinqubo ezihluke ngokusobala. Kodwa-ke, zivame ukuxoxwa ndawonye ezihlokweni ezifanayo ngoba lezi zindlela zinemvelo yokubambisana. Izindawo ze-DNA ezithola i-methylation esindayo zingaheha amaprotheni aqaphela lezi zifunda ze-methylated. Lawa maprotheni angakwazi ukuthola ama-HDAC esizeni, osuzofunda ukuthi angaba nemiphumela enamandla.
Kwenzeka lokhu nje i-BHB idlala indima enamandla ekuguquleni i-gene expression ngokuvimbela i-Histone Deacetylases (HDACs). Ukuvinjelwa kwe-BHB kwama-HDAC kuvimbela lokhu deacetylation, okuholela esimweni esikhululekile se-DNA.
Ngiyazi ukuthi igama elithi "khululeka" alijwayelekile kulo mongo. Kodwa angikulungisi. Igama elithi "relaxed" kumongo we-DNA kanye nokuguqulwa kwe-histone lifanelekile futhi livame ukusetshenziswa kubhayoloji yamangqamuzana. Lapho i-DNA “ikhululekile,” ibhekisela esimweni lapho i-DNA ingasongelwe kakhulu eduze kwama-histones. Lokhu kuphumula kubalulekile ekukhulumeni kofuzo, njengoba kuvumela izici zokuloba kanye namanye amaprotheni alawulayo ukufinyelela kalula ezifundeni ezithile ze-DNA.
Lokhu kuphumula kuvumela izakhi zofuzo ezithile, njenge-FOXO3a, isibonelo, ukuthi zisebenze kakhulu. I-FOXO3a ihileleke ezinqubweni ezihlukahlukene zamaselula, okuhlanganisa impendulo yokucindezeleka kanye ne-apoptosis (ukufa kweseli okuhleliwe). Ukuvinjelwa kwe-HDAC nge-BHB kungathuthukisa ukulotshwa kwe-FOXO3a, kube nomthelela ekuphikiseni ukucindezeleka kwamaselula kanye nezindlela zokusinda. Lo mphumela ubaluleke kakhulu kumongo we-neuroprotection, okuwumphumela wokwelapha odingeka kakhulu kulabo abaphethwe ukugula kwengqondo.
Angifuni ucabange ukuthi imiphumela ye-BHBs kuma-HDAC ifanelekela isakhi sofuzo esisodwa kuphela. Esinye isibonelo esibalulekile nesibalulekile sokuthi ukuvinjelwa kwe-HDACs ngokuba khona kwe-BHB njengokuguqulwa kwe-epigenetic kubonakala lapho sibheka i-Brain-Derived Neurotrophic Factor (BDNF)
Imiphumela yethu ibonise ukuthi i-ketone body BHBA ingakhuthaza inkulumo ye-BDNF ekugxiliseni ngaphakathi kwesifunda somzimba (0.02-2 mM) ngaphansi kokunikezwa kwamandla okuvamile.
U-Hu, E., Du, H., Zhu, X., Wang, L., Shang, S., Wu, X., … & Lu, X. (2018). I-Beta-hydroxybutyrate ikhuthaza ukuvezwa kwe-BDNF kuma-hippocampal neurons ngaphansi kokunikezwa kwe-glucose eyanele. Neuroscience, 386, I-315-325. https://doi.org/10.1016/j.neuroscience.2018.06.036
Ukuvinjelwa kwe-BHB kwama-HDAC nakho kuye kwabonakala kuholela ekwandeni kwenkulumo ye-BDNF. I-BDNF iwufuzo olubalulekile ekukhuleni kwe-neuronal, ukusinda, kanye ne-synaptic plasticity. Ngokuvimbela ama-HDAC, i-BHB ikhuthaza isimo se-acetylated sama-histones eduze nofuzo lwe-BDNF, yenza kube lula ukuloba kwayo. Lokhu kulawulwa kwe-BDNF kungaba nemithelela ebalulekile ku-neuroplasticity, ukusebenza kwengqondo, kanye nokwelashwa okunamandla kokudangala nokunye ukuphazamiseka kwemizwelo.
Ukuqonda Ithonya le-BHB ku-MicroRNA Regulation
Enye indlela yokulawula i-epigenetic into ebizwa ngokuthi ama-microRNAs (miRNAs), okungama-molecule e-RNA angafaki amakhodi alawula ukubonakaliswa kofuzo. Asebenza njengemihlahlandlela enganamathisela kusithunywa esithile i-RNA (mRNA) kuseli, futhi lapho enza lokhu, ama-microRNAs (miRNAs) angamisa i-RNA (mRNA) yesithunywa ekwenzeni amaprotheni noma yehlise ukukhiqizwa kwamaprotheni. Siyichaza kanjani indima ye-microRNA ekukhulumeni kwe-epigenetic sisebenzisa isifaniso sethu selabhulali?
Esifanekisweni sethu somtapo wofuzo, lapho izakhi zofuzo ziyizincwadi, futhi umsebenzi womtapo wolwazi umele i-epigenetics, ama-microRNA (miRNAs) afana namanothi amancane afika ngemva kokuba umsebenzi wasemtatsheni wezincwadi esekhethe ukufunda incwadi (ufuzo) kanye namakhophi (mRNA) enziwe. Lawa manothi anikeza isiqondiso sokuthi umsebenzi waselabhulali (i-epigenetics) kufanele aqhubeke kangaki ukufinyelela ezincwadini ezithile (izakhi zofuzo) noma ukuthi ukufinyelela kufanele kukhawulelwe, aqinisekise ukulawula okungcono kokubonakaliswa kofuzo ukuze kuhlangatshezwane nezidingo zeseli.
I-BHB inweba ithonya layo kuma-microRNAs (miRNAs). I-BHB ikwenza kanjani lokhu?Isebenza ngokubophezela kuma-molecule e-RNA (mRNA) yesithunywa esithile, ngokuvamile okuholela ekucindezelweni noma ekucekeleni phansi kwalawo ma-RNA ezithunywa. Njengoba kuchazwe kusifaniso sethu selabhulali, ama-microRNAs (miRNAs) adlala indima ekulawuleni ukubhalwa kwangemuva kokubhala ngokuyinhloko isisho sofuzo esilungisa kahle. Angase aqondise ama-RNA esithunywa esithile (ama-mRNA) ukuze acekelwe phansi noma avimbele ukuhumusha kwawo ukuze kwandiswe noma kuncishiswe ukukhiqizwa kwamaphrotheni athile ngokusabela kuzimfuneko zeseli.
Izinqubo ezinjalo ziyizingxenye ezibalulekile zomthethonqubo wangemva kokubhala okuthonya uchungechunge olubanzi lwezinqubo zamaselula, ezenzeka ezihlanganisa imetabolism.
Ucwaningo olwenziwa kumavolontiya abantu luye lwabonisa ukuthi amaphrofayili e-microRNA expression ashintshwe kakhulu ngemva kwesimiso seviki le-6 ku-Ketogenic Diet (KD), okubonisa ukuthi izinguquko ze-metabolic ezibangelwa i-KD, ezihlanganisa amazinga e-BHB aphakeme, zingaholela ekushintsheni kwe-miRNA. isisho.
Sekukonke, amavolontiya aku-KD abonise ukulawulwa kwe-miRNAs eqondise kuzakhi zofuzo ezithile ezixhumene ne-nutrient metabolism kanye ne-mTOR, i-PPARs, i-insulin, kanye nezindlela zokusayina ze-cytokine.
U-Nasser, S., Vialichka, V., Biesiekierska, M., Balcerczyk, A., & Pirola, L. (2020). Imiphumela yokudla kwe-ketogenic kanye nemizimba ye-ketone ohlelweni lwenhliziyo nemithambo yegazi: Izindaba zokugxila. Ijenali yomhlaba yesifo sikashukela, 11 (12), 584-595. https://doi.org/10.4239/wjd.v11.i12.584
Kodwa ingxenye ethakazelisayo yayiwukuthi i-miRNAs elawulwa yi-Ketogenic Diet (KD) yayiqondise izakhi zofuzo ezithile ezixhumene ne-nutrition metabolism, kanye nezindlela ezibalulekile zokubonisa njenge-mTOR (i-mechanistic target ye-rapamycin), i-PPARs (i-peroxisome proliferator-activated receptors), i-insulin. izimpawu, kanye nezindlela zokubonisa i-cytokine. Lezi izindlela ezibalulekile zempilo yobuchopho ngokumodela i-metabolism yamandla kanye nokulungisa nokunciphisa i-neuroinflammation.
Kungenye nje indlela i-BHB engaba nesandla ngayo ekulungiseni kahle ukubonakaliswa kofuzo, kube nomthelela ekusebenzeni kwamangqamuzana, futhi inikeze imiphumela yokwelashwa engaba khona ezinqubweni zezifo noma ezimeni ze-metabolic.
Isiphetho
Kulesi sihloko, uhlole izindlela ezimbalwa lapho ubukhona be-BHB busebenza njenge-epigenetic modulator ye-gene expression. Uma sibuyela esifanisweni sethu somtapo wolwazi ogcwele izincwadi (izakhi zofuzo) kanye nomsebenzi womtapo wolwazi (i-epigentics), kuba sobala ukuthi i-BHB ithatha indima yomphathi womtapo wolwazi “kumtapo wolwazi” wethu wofuzo.
Ngokufana nomthelela womsebenzi womtapo wolwazi ezintweni eziqukethwe umtapo wolwazi, i-BHB ayiluguquli uchungechunge lwe-DNA eyisisekelo ngokwayo; ishiya ukulandelana kwe-DNA kungashintshile. Kodwa-ke, i-BHB idlala indima ebalulekile ekuthonyeni amamaki e-epigenetic nezinqubo zamangqamuzana ezinquma ukubonakaliswa kwezakhi zofuzo. Ngomthelela wayo ezinkambisweni ezifana nokuguqulwa kwe-histone, i-DNA methylation, nokulawulwa kwe-microRNA, i-BHB ivela njengomlawuli onamandla ezweni eliyinkimbinkimbi ye-epigenetics. Kuthonya kakhulu isimo sethu sokusebenza kwe-metabolic futhi kungaba nomthelela ekubonisweni kwezakhi zofuzo, kube nomthelela ekusebenzeni kwezinhlelo eziningi ezifanele ezithinta impilo yobuchopho. Ngakho-ke ngiyabuza, kungani inganikezeli ngemiphumela yokwelashwa kwesifo sengqondo nokuphazamiseka kwezinzwa?
Ngithemba ngobuqotho ukuthi lesi sihloko sibe usizo ekuqondeni kwakho ukudla kwe-ketogenic. Unelungelo lokwazi zonke izindlela ongazizwa ungcono ngazo, futhi ngemiphumela enamandla ye-molecular signaling ye-ketone ekhonjwa ezincwadini zocwaningo, ungase uthole ukuthi ukudla kwe-ketogenic kungase kube enye yazo.
Okubhekwayo
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Mikami, D., Kobayashi, M., Uwada, J., Yazawa, T., Kamiyama, K., Nishimori, K., … & Iwano, M. (2019). I-β-Hydroxybutyrate, umzimba we-ketone, yehlisa umphumela we-cytotoxic we-cisplatin ngokwenza kusebenze i-HDAC5 kumaseli e-epithelial e-renal cortical. Isayensi yezempilo, 222, 125-132. https://doi.org/10.1016/j.lfs.2019.03.008
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U-Nasser, S., Vialichka, V., Biesiekierska, M., Balcerczyk, A., & Pirola, L. (2020). Imiphumela yokudla kwe-ketogenic kanye nemizimba ye-ketone ohlelweni lwenhliziyo nemithambo yegazi: Izindaba zokugxila. Ijenali Yomhlaba Yesifo Sikashukela, 11(12), i-584-595. https://doi.org/10.4239/wjd.v11.i12.584
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