Iyini imiphumela yomlingo nemisebenzi ye-urolithin A? Imiphi imikhiqizo eyengezwayo

 I-Urolithin A iyisithako esibalulekile se-bioactive esisetshenziswa kabanzi kwezokwelapha nasekunakekelweni kwezempilo. Iyi-enzyme ekhiqizwa ikakhulukazi izinso futhi inomsebenzi wokuhlakaza amahlule egazi. Imiphumela yomlingo nemisebenzi ye-Urolithin A ibonakala ngokuyinhloko kulezi zici ezilandelayo.

I-Urolithin A ivimbela ukuwohloka kwemisipha

1. Thuthukisa ukuhlanganiswa kwamaprotheni emisipha futhi wenze kusebenze indlela yokusayina ye-mTOR

Ithagethi yezilwane ezincelisayo ye-rapamycin (mTOR) indlela yokusayina iyindlela eyinhloko yokulawula ukuhlanganiswa kwamaprotheni emisipha. I-Urolithin A ingenza kusebenze indlela yokubonisa i-mTOR futhi ikhuthaze ukuhlanganiswa kwamaprotheni kumaseli emisipha.

I-mTOR ingakwazi ukuzwa izimpawu ezifana nezakhamzimba nezinto zokukhula kumaseli. Uma icushiwe, izoqala uchungechunge lwama-molecule akhombisayo ezansi nomfula, njenge-ribosomal protein S6 kinase (S6K1) kanye ne-eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). I-Urolithin A yenza kusebenze i-mTOR, i-phosphorylating S6K1 ne-4E-BP1, ngaleyo ndlela iphromotha ukuqaliswa kokuhumusha kwe-mRNA nokuhlanganisa i-ribosome, futhi kusheshiswe ukuhlanganiswa kwamaprotheni.

Isibonelo, ekuhlolweni ngamaseli emisipha e-in vitro cultured, ngemva kokwengeza i-urolithin A, kwaphawulwa ukuthi amazinga we-phosphorylation we-mTOR kanye nama-molecule ayo okubonisa engezansi akhuphuka, futhi ukubonakaliswa kwama-muscle protein synthesis markers (njenge-myosin heavy chain) kwanda.
Ilawula ukuvezwa kwesici sokulotshwa okuqondile kwemisipha

Urolithin A ingalawula ukuvezwa kwezinto ezibhalwe ngemisipha ezithize ezibalulekile ekuhlanganiseni amaprotheni emisipha kanye nokuhlukaniswa kwamaseli emisipha. Isibonelo, ingakwazi ukulawula ukubonakaliswa kwe-myogenic differentiation factor (MyoD) ne-myogenin.

I-MyoD ne-Myogenin ingakhuthaza ukuhlukaniswa kwamangqamuzana e-muscle stem abe amangqamuzana emisipha futhi isebenze ukuvezwa kwezakhi zofuzo eziqondene nemisipha, ngaleyo ndlela ikhuthaze ukuhlanganiswa kwamaprotheni emisipha. Emfanekisweni we-muscle atrophy, ngemuva kokwelashwa kwe-urolithin A, ukubonakaliswa kwe-MyoD ne-Myogenin kwanda, okusiza ukugcina isisindo somzimba nokuvimbela ukwehla kwemisipha.

2. Vimbela ukuwohloka kwamaprotheni emisipha futhi uvimbele uhlelo lwe-ubiquitin-proteasome (UPS)

I-UPS ingenye yezindlela eziyinhloko zokuwohloka kwamaprotheni emisipha. Phakathi ne-muscle atrophy, amanye ama-E3 ubiquitin ligases, njenge-muscle atrophy F-box protein (MAFbx) kanye ne-muscle RING finger protein 1 (MuRF1), ayasebenza, angamaka amaprotheni emisipha nge-ubiquitin bese ewehlisa nge-proteasome.

I-Urolithin A ingavimbela inkulumo nomsebenzi walawa ma-E3 ubiquitin ligases. Ezivivinyweni zemodeli yezilwane, i-urolithin A inganciphisa amazinga e-MAFbx ne-MuRF1, inciphise uphawu lokutholakala kwendawo yonke yamaprotheni emisipha, ngaleyo ndlela ivimbele ukuwohloka kwamaprotheni emisipha e-UPS-mediated futhi ivimbele ngempumelelo ukwehla kwemisipha.

Ukuguqulwa kwesistimu ye-autophagy-lysosomal (ALS)

I-ALS idlala indima ekuvuseleleni amaprotheni emisipha nama-organelles, kodwa ukusebenza ngokweqile kungaholela ekuwohlokeni kwemisipha. I-Urolithin A ingalawula i-ALS ibe sezingeni elifanele. Ingavimbela i-autophagy ngokweqile futhi ivimbele ukuwohloka ngokweqile kwamaprotheni emisipha.
Isibonelo, i-urolithin A ingalawula ukubonakaliswa kwamaprotheni ahlobene ne-autophagy (njenge-LC3-II), ukuze ikwazi ukugcina i-homeostasis yemvelo yeseli ye-muscle ngenkathi igwema ukuvunyelwa ngokweqile kwamaprotheni emisipha, ngaleyo ndlela isiza ukugcina imisipha yemisipha.

3. Thuthukisa amandla e-metabolism yamangqamuzana emisipha

Ukuncipha kwemisipha kudinga amandla amaningi, futhi i-mitochondria iyindawo eyinhloko yokukhiqiza amandla. I-Urolithin A ingathuthukisa ukusebenza kwe-muscle cell mitochondria futhi ithuthukise ukusebenza kahle kokukhiqizwa kwamandla. Ingakhuthaza i-mitochondrial biogenesis futhi ikhulise inani le-mitochondria.

Isibonelo, i-urolithin A ingakwazi ukusebenzisa isamukeli esenziwe i-peroxisome proliferator-activated γ coactivator-1α (PGC-1α), eyisilawuli esiyinhloko se-mitochondrial biogenesis, ekhuthaza ukuphindaphinda kwe-DNA ye-mitochondrial kanye nokuhlanganiswa kwamaprotheni ahlobene. Ngesikhathi esifanayo, i-urolithin A ingabuye ithuthukise umsebenzi weketanga lokuphefumula le-mitochondrial, ikhulise ukuhlanganiswa kwe-adenosine triphosphate (ATP), inikeze amandla anele okugoqa kwemisipha, futhi inciphise ukwehla kwemisipha okubangelwa amandla anganele.

Ilawula ushukela kanye ne-lipid metabolism futhi isekele ukusebenza kwemisipha

I-Urolithin A ingalawula i-glucose ne-lipid metabolism yamaseli emisipha. Mayelana ne-glucose metabolism, ingathuthukisa ukumuncwa kanye nokusetshenziswa kwe-glucose ngamangqamuzana emisipha, futhi iqinisekise ukuthi amangqamuzana emisipha anezingxenye ezanele zamandla ngokuvula indlela yokubonisa i-insulin noma ezinye izindlela zokubonisa ezihlobene nokuhamba kweglucose.

Ngokuphathelene ne-lipid metabolism, i-urolithin A ingakhuthaza i-fatty acid oxidation, inikeze omunye umthombo wamandla wokugoqa kwemisipha. Ngokwandisa i-glucose ne-lipid metabolism, i-urolithin A igcina ukutholakala kwamandla kwamaseli emisipha futhi isiza ukuvimbela ukwehla kwemisipha.

I-Urolithin A ithuthukisa imetabolism

1. Lawula i-metabolism kashukela futhi uthuthukise ukuzwela kwe-insulin
I-Urolithin A ingathuthukisa ukuzwela kwe-insulin, okubalulekile ekugcineni ushukela wegazi uzinzile. Ingasebenza kuma-molecule abalulekile endleleni yokubonisa i-insulin, njengamaprotheni e-insulin receptor substrate (IRS).

Esimeni sokumelana ne-insulin, i-tyrosine phosphorylation ye-IRS protein iyavinjwa, okuholela ekwehlulekeni kwendlela yokusayina ye-phosphatidylinositol 3-kinase (PI3K) engezansi ukuze isebenze ngokujwayelekile, futhi ukuphendula kweseli ku-insulin kuba buthaka.

I-Urolithin A ingaphromotha i-tyrosine phosphorylation yephrotheni ye-IRS, ngaleyo ndlela ivule indlela yokusayina ye-PI3K-protein kinase B (Akt), ivumele amaseli ukuthi amunce kangcono futhi asebenzise i-glucose. Isibonelo, ekuhlolweni kwemodeli yezilwane, ngemva kokuphathwa kwe-urolithin A, ukuzwela kwezicubu ze-muscle ne-adipose ku-insulin kwathuthukiswa kakhulu, futhi amazinga kashukela egazini alawulwa ngokuphumelelayo.

Ilawula ukwakheka kwe-glycogen nokuwohloka

I-Glycogen iyindlela eyinhloko yokugcina ushukela emzimbeni, ikakhulukazi egcinwe esibindini nasezicubu zemisipha. I-Urolithin A ingalawula ukwakheka nokubola kwe-glycogen. Ingenza kusebenze i-glycogen synthase, ikhuthaze ukwakheka kwe-glycogen, futhi ikhulise indawo yokugcina i-glycogen.

Ngasikhathi sinye, i-urolithin A ingaphinda ivimbele ukusebenza kwama-enzyme e-glycogenolytic, njenge-glycogen phosphorylase, futhi yehlise inani le-glycogen eboliswe ibe yi-glucose futhi ikhishwe egazini. Lokhu kusiza ukuzinzisa amazinga kashukela egazini futhi kuvimbele ukushintshashintsha ngokweqile kushukela wegazi. Ocwaningweni lwemodeli yesifo sikashukela, ngemuva kokwelashwa kwe-urolithin A, okuqukethwe kwe-glycogen esibindini nasemisipha kwanda, nokulawulwa kukashukela egazini kwaba ngcono.

2. Lungiselela i-lipid metabolism futhi uvimbele ukuhlanganiswa kwe-fatty acid

I-Urolithin A inomphumela ovimbelayo enqubweni ye-lipid synthesis. Esibindini nasezicubu ze-adipose, ingavimbela ama-enzyme abalulekile ku-fatty acid synthesis, njenge-fatty acid synthase (FAS) ne-acetyl-CoA carboxylase (ACC).

I-FAS ne-ACC zingama-enzyme abalulekile okulawula ku-de novo synthesis yamafutha acid. I-Urolithin A inganciphisa ukuhlanganiswa kwamafutha acid ngokuvimbela umsebenzi wabo. Isibonelo, kumodeli yesibindi esinamafutha esibangelwa ukudla okunamafutha amaningi, i-urolithin A inganciphisa umsebenzi we-FAS ne-ACC esibindini, inciphise ukuhlanganiswa kwe-triglycerides, futhi ngaleyo ndlela inciphise ukunqwabelana kwe-lipid esibindini.

Ithuthukisa i-fatty acid oxidation

Ngaphezu kokuvimbela ukuhlanganiswa kwe-fatty acid, i-urolithin A ingaphinde ikhuthaze ukubola kwe-oxidative yama-fatty acids. Ingenza kusebenze izindlela zokubonisa kanye nama-enzyme ahlobene ne-fatty acid oxidation. Isibonelo, ingaphakamisa umsebenzi we-carnitine palmitoyltransferase-1 (CPT-1).

I-CPT-1 iyi-enzyme eyinhloko ku-fatty acid β-oxidation, enesibopho sokuthutha ama-fatty acids ku-mitochondria ukuze kuhlanjululwe i-oxidative. I-Urolithin A ikhuthaza i-β-oxidation yama-fatty acids ngokwenza kusebenze i-CPT-1, yandisa ukusetshenziswa kwamandla kwamafutha, isiza ukunciphisa ukugcinwa kwamafutha omzimba, futhi ithuthukise i-lipid metabolism.

3. Thuthukisa amandla e-metabolism futhi uthuthukise umsebenzi we-mitochondrial

I-Mitochondria "yizimboni zamandla" zamaseli, futhi i-urolithin A ingathuthukisa ukusebenza kwe-mitochondria. Ingakwazi ukulawula i-mitochondrial biogenesis futhi ikhuthaze ukuhlanganiswa kwe-mitochondrial nokuvuselela. Isibonelo, ingenza i-peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) isebenze.

I-PGC-1α iyisilawuli esiyinhloko se-mitochondrial biogenesis, engakhuthaza ukuphindaphinda kwe-DNA ye-mitochondrial kanye nokuhlanganiswa kwamaprotheni ahlobene ne-mitochondrial. I-Urolithin A inyusa inombolo nekhwalithi ye-mitochondria futhi ithuthukisa ukusebenza kahle kokukhiqizwa kwamandla kwamaseli ngokuvula i-PGC-1α. Ngasikhathi sinye, i-urolithin A ingabuye ithuthukise ukusebenza kweketango lokuphefumula le-mitochondria futhi ikhulise ukwakheka kwe-adenosine triphosphate (ATP).

4. Ukulawula Ukuhlelwa Kabusha Kwe-Cellular Metabolic

I-Urolithin A ingaqondisa amangqamuzana ukuthi ahlele kabusha i-metabolic, yenze i-metabolism yeseli isebenze kahle. Ngaphansi kwengcindezi ethile noma izimo zesifo, iphethini ye-metabolic yeseli ingase ishintshe, okubangele ukunciphisa ukusebenza kahle ekukhiqizweni kwamandla nasekuhlanganiseni izinto.

I-Urolithin A ingalawula izindlela zokusayina ze-metabolic kumaseli, njenge-AMP-activated protein kinase (AMPK) indlela yokusayina. I-AMPK "inzwa" ye-cell metabolism yamandla. Ngemuva kokuthi i-urolithin A isebenze i-AMPK, ingakwazi ukukhuthaza amaseli ukuthi asuke ku-anabolism aye ku-catabolism, enze ukusetshenziswa kahle kwamandla nemisoco, ngaleyo ndlela kuthuthukiswe ukusebenza kwawo wonke umzimba.

Ukusetshenziswa kwe-urolithin A akugcini emkhakheni wezokwelapha. Iphinde ithole ukunakwa kancane kancane emikhiqizweni yezempilo nezimonyo. I-Urolithin A yengezwa emikhiqizweni eminingi yezempilo ukuthuthukisa ukungatheleleki, ukuthuthukisa ukujikeleza kwegazi nokukhuthaza umzimba. Le mikhiqizo imvamisa isesimweni samaphilisi, amaphilisi noma uketshezi, alungele izidingo zamaqembu ahlukene abantu.

Emkhakheni wezimonyo, i-urolithin A isetshenziswa kabanzi emikhiqizweni yokunakekelwa kwesikhumba ngenxa yokuvuselelwa kabusha kwamaseli kanye nezindawo zokulwa nokuguga. Ingathuthukisa ukujikeleza kwegazi esikhumbeni futhi ikhuthaze ukwakheka kwe-collagen, ngaleyo ndlela ithuthukise ukunwebeka kwesikhumba nokukhanya. Izinhlobo eziningi zokunakekelwa kwesikhumba ezisezingeni eliphezulu seziqalile ukusebenzisa i-urolithin A njengesithako esiwumgogodla ukwethula imikhiqizo elwa nokuguga, yokulungisa kanye neyomswakama ukuze ihlangabezane nokuphishekela kwabathengi isikhumba esihle.

Sengiphetha, njenge-bioactive substance enemisebenzi eminingi, i-urolithin A ibonise amathemba okusebenza abanzi emkhakheni wezokwelapha, ukunakekelwa kwezempilo kanye nobuhle. Ngokujula kocwaningo lwesayensi, inkambu yokusetshenziswa kwe-urolithin A izoqhubeka nokukhula, inikeze izinketho eziningi zempilo nobuhle babantu.