ICurcumin Derivative J-147 yonyango i-AD, yokuguga, yoxinzelelo kuxinzelelo (MDD)

Uphengululo lweJ-147

ICurcumin yipolyphenol kunye necandelo elisebenzayo leTurmeric kunye neGinger.Curcumin inezibonelelo ezininzi ezingqiniweyo ekunyangeni izifo ezininzi, kodwa ngenxa yokungakwazi kwayo ukuwela iBarrier-Brain Barrier (BB), kukho imida ecacileyo.

Ngokusisiseko, J147 (CAS:1146963-51-0Isiphumo seCurcumin kunye neCyclohexyl-Bisphenol A (CBA) esisisiyobisi esinamandla se-neurogenic kunye ne-neuroprotective. Yenzelwe ukusetyenziswa kokunyanga iimeko ze-neurodegenerative ezinxulumene nokwaluphala. I-J147 inokuwela i-BBB iye kwingqondo (yomelele) kwaye inyuse imveliso yeseli ye-neuronal.

Ngokungafaniyo neziyobisi ezikhoyo ezivunyiweyo ze-Alzheimer's Disease, i-J147 ayisiyo-acetylcholinesterase inhibitor okanye i-phosphodiesterase inhibitor, kodwa yona inyusa ukuqonda ngonyango lwexesha elifutshane.

Kule posi, siza kuthetha ngendlela i-curcumin evela kwi-J147 inyanga ngayo isifo se-Alzheimer's (AD), isifo esikhulu sokudakumba (MDD) kunye nokuGuga.

Nantsi imixholo:

1. Funda ngakumbi malunga neJ-147 Work (Mechanism)
2. Jonga ngokukhawuleza iZibonelelo zikaJ-147
3. J-147 Phatha isifo se-Alzheimer's (AD)
4. J-147 Phatha ingxaki yokuguga
5. I-J-147 Phatha ingxaki enkulu yoxinzelelo (MDD)
6. Olunye uphando malunga noJ-147
7. Apho unokuthenga khona i-J-147 Powder

Funda ngakumbi malunga neJ-147 Work (Mechanism)

Kude kube ngowama-2018, isiphumo se-J-147 kwiseli sihlale singummangaliso de iZiko leSalk Neurobiologists liyichaze iphazili. Iyeza lisebenza ngokubopha kwi-ATP synthase. Le proteni ye-mitochondrial imodareyitha ukuveliswa kwamandla eselula, yiyo loo nto kulawula inkqubo yokuguga.Ubukho bongezelelo lwe-J-147 kwinkqubo yomntu kuthintela iityhefu ezinxulumene nobudala ezibangelwa kukungasebenzi kakuhle kwemitochondria kunye nokuveliswa kakhulu kwe-ATP.

Inkqubo ye-J-147 yokusebenza iya kukonyusa amanqanaba eeurotransmitters ezahlukeneyo kubandakanya i-NGF kunye ne-BDNF. Ngaphandle koko, isebenza kumanqanaba e-beta-amyloid, ahlala ephezulu kwizigulana ezine-Alzheimer's kunye ne-dementia. Iziphumo ze-J-147 zibandakanya ukucothisa ukuqhubela phambili kwe-Alzheimer's, ukuthintela ukusilela kwememori, kunye nokwandisa imveliso yeeseli ze-neuronal.

Jonga ngokukhawuleza iZibonelelo zikaJ-147

Ukuphucula ukusebenza kweMitochondrial kunye nokuPhila ixesha elide

Ithintela isifo se-Alzheimer

Ro Ukuphucula iMemori

Ukukhula kobuchopho

Khusela iiNeurons

❻ Singasiphucula isifo seswekile

❼ Ukulwa iintlungu kunye ne-Neuropathy

❽ Ngamana angaphucula ukuxhalaba

J-147 Nyanga Isifo se-Alzheimer (AD)

J-147 kunye no-AD: Imvelaphi 

Okwangoku, iparadigm enkulu yokufumanisa iziyobisi kwizifo ze-neurodeergenerative isekwe kwimigangatho ephezulu yokuhlangana kwezijoliso zesifo esinye. Kwisifo i-Alzheimer's (AD), kugxilwe kwi-amyloid beta peptide (Ass) edibanisa usapho lwezifo zesifo i-Alzheimer's. Nangona kunjalo, ngenxa yokuba ubudala yeyona nto ingumngcipheko we-AD, siphonononge enye inkqubo yokufumanisa iziyobisi esekwe ekusebenzeni kwiimodeli ezininzi zenkcubeko yeeseli ezinxulumene nobudala kunokuba zenziwe kuphela kwimetabolism ye-amyloid. Sisebenzisa le ndlela, sichonge imolekyuli ye-neurotrophic enamandla, esebenza ngomlomo ehambisa imemori kwiintonga eziqhelekileyo, kwaye ithintela ukulahleka kweeproteni ze-synaptic kunye nokwehla kwengqondo kwimodeli yegundane ye-transgenic.

J 147 kunye no-AD: Uhlalutyo lokuvavanywa kokuvela kwiimpuku

INTSHAYELELO: Ngaphandle kweminyaka yophando, akukho ziyobisi ziguqula isifo se-Alzheimer's (AD), isifo esibulalayo, esidala nobudala. Ukuvavanywa kweyeza ezinokubakho kunyango lweemodeli zeentonga ze-AD ngokubanzi kuxhomekeke ekuvavanyeni iikhompawundi ngaphambi kokuba isifo sibe khona, ngaloo ndlela sibonisa ukuthintela izifo endaweni yokuguqula izifo. Ngaphaya koko, le ndlela yokuhlola ayibonisi inkcazo yeklinikhi yezigulana ze-AD ezinokuthi zichaze ukusilela kokuguqula iikhompawundi ezichongwe njengeziluncedo kwiimodeli zezilwanyana kwizifo eziguqula iikhompawundi kuvavanyo lweklinikhi. Ngokucacileyo indlela ebhetele yokuvavanywa kwangaphambili kweziyobisi kwi-AD iyafuneka.

IINDLELA: Ukubonakalisa ngokuchanekileyo useto lweklinikhi, sisebenzise esinye isicwangciso sokujonga esibandakanya unyango lweempuku ze-AD kwinqanaba lesifo xa isifo sele sihambile. Iigundane ze-AD ezigugileyo (iinyanga ezingama-20 ubudala) ze-transgenic AD (i-APP / swePS1DeltaE9) zondliwe ngokukhethekileyo, ukusebenza ngomlomo, ukuphucula imemori kunye nemolekyuli ye-neurotrophic ebizwa ngokuba yi-J147. Ukuvavanywa kokuziphatha kwengqondo, i-histology, i-ELISA kunye ne-Western blotting zazisetyenziselwa ukuvavanya isiphumo se-J147 kwimemori, i-amyloid metabolism kunye neendlela ze-neuroprotective. I-J147 iphinde yaphandwa kwimodeli yokunyusa inkumbulo kwi-C57Bl / 6J iimpuku xa kuthelekiswa ne-donepezil. Iinkcukacha kwi-pharmacology kunye nokhuseleko lwe-J147 zikwabandakanywa.

IINKCUKACHA: Idatha eboniswe apha ibonisa ukuba i-J147 inako ukuhlangula ukusilela kwengqondo xa ilawulwa kwinqanaba lesifo. Amandla e-J147 ukuphucula inkumbulo kwiimpuku ze-AD ezindala zihambelana nokudityaniswa kwezinto ze-neurotrophic ze-NGF (ukukhula kwe-nerve factor) kunye ne-BDNF (ubuchwephesha obufunyenwe yi-neurotrophic factor) kunye neeproteni ezininzi eziphendulayo ze-BDNF ezibalulekileyo ekufundeni nakwimemori. Thelekisa phakathi kwe-J147 kunye ne-donepezil kwimodeli ye-scopolamine ibonakalise ukuba ngelixa zombini ezi zinto zinokuthelekiswa nokusindisa imemori yexesha elifutshane, i-J147 ibiphezulu ekuhlanguleni inkumbulo yendawo kunye nokudityaniswa kwezi zimbini zisebenze kakuhle kwimemori yokuma kunye nememori.

Isiphelo kwi-J-147 ye-AD

I-J147 yindawo entsha enomdla enamandla kakhulu, ekhuselekileyo kwizifundo zezilwanyana kunye nokusebenza ngomlomo. I-J147 yinto enokubakho kunyango lwe-AD ngenxa yokukwazi kwayo ukubonelela ngokukhawuleza Izibonelelo zokuqonda, kwaye ikwanakho ukumisa kwaye mhlawumbi ibuye umva ukukhula kwesifo kwizilwanyana ezinempawu njengoko kubonisiwe kwezi zifundo.

J-147 Phatha ingxaki yokuguga

J-147 kunye Ukuguga: Imvelaphi 

Iimpuku eziphathwe nge-J147 zazinememori engcono kunye nokuqonda, imithambo yegazi esempilweni kwingqondo kunye nezinye izinto eziphuculweyo zomzimba…

"Ekuqaleni, inkuthazo yayikukuvavanya eli chiza kwimodeli yenoveli yezilwanyana eyayifana kakhulu ne-99% yezigulo ze-Alzheimer," utshilo u-Antonio Currais, olilungu leLabhoratri yeSeli yeNeurobiology yeNzululwazi uDavid Schubert eSalk. “Khange sixele kwangaphambili ukuba siza kulubona olu hlobo ukuguga kodwa iJ147 yenza iimpuku ezindala zibukeke ngathi zincinci, ngokusekwe kumanqanaba athile omzimba. ” "Ngelixa uninzi lwamachiza aveliswe kule minyaka ingama-20 idlulileyo ajolise kwiiplathi ze-amyloid kwingqondo (eziyimpawu yesi sifo), akukho nanye ebonakalise ukuba iyasebenza ekliniki," utshilo uSchubert.

Kwiminyaka eliqela eyadlulayo, uSchubert kunye noogxa bakhe baqala ukusondela kunyango lwesi sifo kwinqanaba elitsha. Endaweni yokujolisa kwi-amyloid, ilebhu igqibe kwelokuba ingoyena mngcipheko ubalulekileyo wokuguga. Sebenzisa izikrini ezisekwe kwiseli ngokuchasene nobudala obudityaniswa nobutyhefu obunxulumene nengqondo, bahlanganisa i-J147.

Ngaphambili, iqela lafumanisa ukuba i-J147 inokuthintela kwaye iphinde ibuyisele ukuphulukana nenkumbulo kunye ne-Alzheimer's pathology kwiimpuku ezinenguqulo yohlobo oluyifumene njenge-Alzheimer's, imodeli yegundane esetyenziswa ngokuxhaphakileyo. Nangona kunjalo, le fomu yesi sifo ine-1% kuphela yamatyala e-Alzheimer's. Kubo bonke abanye abantu, ukuguga yeyona nto iphambili emngciphekweni, utsho uSchubert. Iqela lifuna ukuphonononga iziphumo zomgqatswa weziyobisi kuhlobo lweempuku ezikhula ngokukhawuleza kwaye namava e-dementia efana kakhulu nengxaki yokunxibelelana kwabantu enxulumene nobudala.

J-147 kunye nokuGuga: Uvavanyo lokutholwa kokuvavanywa kwiimpuku

Kulo msebenzi wakutshanje, abaphandi basebenzise iseti ebanzi yokulinganisa ukubonakaliswa kwazo zonke iintlobo zofuzo kwingqondo, kunye nangaphezulu kwe-500 iimolekyuli ezincinci ezibandakanyeka kwimetabolism kwingqondo kunye negazi lamaqela amathathu eempuku eziguga ngokukhawuleza. Amaqela amathathu eempuku ezigugayo ngokukhawuleza afaka iseti enye ebisencinci, iseti enye ebindala kunye neseti endala kodwa isondla i-J147 njengoko bekhulile.

Iimpuku ezindala ezafumana i-J147 zenze ngcono kwimemori nakwezinye iimvavanyo zokuqonda kwaye zabonisa nokunyakaza okungaphezulu kweemoto. Iimpuku eziphathwe nge-J147 zazineempawu ezimbalwa zesifo se-Alzheimer's kwingqondo yazo. Ngokubalulekileyo, ngenxa yedatha enkulu eqokelelweyo kumaqela amathathu eempuku, kunokwenzeka ukubonisa ukuba uninzi lwezinto zokubonisa zofuzo kunye nemetabolism kwiimpuku ezindala ezondliwe iJ147 zazifana kakhulu nezilwanyana ezincinci. Oku kubandakanya amakishayo okonyusa amandla emetabolism, ukunciphisa ukudumba kwengqondo kunye namanqanaba ancitshisiweyo e-acid ene-asidi kwingqondo.

Esinye isiphumo esaziwayo yayikukuba i-J147 ithintele ukuvuza kwegazi kwi-microvessels kwingqondo yeempuku ezindala. "Imithambo yegazi eyonakalisiweyo yinto eqhelekileyo yokuguga ngokubanzi, kwaye kwiAlzheimer's, iba mbi kakhulu," utshilo uCurrais.

Isiphelo kwi-J-147 yengxaki yokuguga

Iimpuku ezondla i-J147 ziye zandisa amandla emetabolism kwaye zanciphisa ukuvuvukala kwengqondo. Iziphumo ezichasene nokwaluphala kwizilwanyana.

Iqela elivela kwi-Salk Institute libonise ukuba umgqatswa weziyobisi usebenze kakuhle kwimodeli yokuguga engasetyenziswanga kuphando lwe-Alzheimer's. Xa ezi mpuku zaphathwa nge-J147, zazinememori engcono kunye nokuqonda, imithambo yegazi esempilweni kwingqondo kunye nezinye izinto eziphuculweyo zomzimba.

I-J-147 Phatha ingxaki enkulu yoxinzelelo (MDD)

J-147 kunye ne-MDD: Imvelaphi

Ingxaki enkulu yokudandatheka (MDD) sisifo sengqondo esomeleleyo esihambelana nokusilela kwee-monoamine neurotransmitters, ngakumbi ukungahambi kakuhle kwe-5-HT (5-hydroxytryptamine, serotonin) kunye ne-receptors zayo. Isifundo sethu sangaphambili sicebise ukuba unyango olunzima ngenoveli Isiphumo se-curcumin J147 bonisa iimpembelelo ezinje ngoxinzelelo ngokunyusa inqanaba le-neurotrophic factor (BDNF) kwinqanaba le-hippocampus yeempuku. Uphononongo lwangoku lwandisiwe kwiziphumo zethu zangaphambili kwaye saphanda ngeziphumo ezichasene noxinzelelo lwe-J147 yeentsuku ezi-3 kwiimpuku zamadoda ze-ICR kunye nokuhambelana kwayo okunokwenzeka kwi-5-HT1A kunye ne-5-HT1B receptors kunye nomqondiso we-CAMP-BDNF.

J-147 kunye ne-MDD: Uhlalutyo lokuvavanywa kokuvela kwiimpuku

Iindlela: I-J147 ngeedosi ze-1, 3, kunye ne-9 mg / kg (nge-gavage) yenziwa iintsuku ezi-3, kunye nexesha lokuchasana nokudada nokunyanzelwa kovavanyo lokumiswa komsila (i-FST kunye ne-TST) yabhalwa. I-rayoligand yokubopha i-assay yayisetyenziselwa ukumisela ukudibana kwe-J147 ukuya kwi-5-HT1A kunye ne-5-HT1B receptor. Ngaphaya koko, i-5-HT1A okanye i-5-HT1B agonist okanye umchasi wayo wasetyenziselwa ukumisela ukuba yeyiphi i-5-HT receptor subtype ebandakanyekayo kwiziphumo ezinje ngoxinzelelo lwe-J147. Iimolekyuli ezisezantsi ezisezantsi ezinje nge-CAMP, PKA, pCREB, kunye ne-BDNF nazo zalinganiswa ukumisela indlela yokusebenza.

iziphumo: Iziphumo zabonisa ukuba unyango olunganyangekiyo olunamandla lwe-J147 linciphise ngokumangalisayo ixesha lokuhamba kuzo zombini i-FST kunye ne-TST ngendlela exhomekeke kwidosi. I-J147 ibonakalise ukuhlangana okuphezulu kwi-vitro ukuya kwi-5-HT1A receptor elungiselelwe kwiimpuku zeethishu kwaye yayingenamandla kangako kwi-5-HT1B receptor. Ezi ziphumo ze-J147 zavalwa kukungaphambi kokunyanga nge-5-HT1A antagonist NAD-299 kwaye yaphuculwa yi-5-HT1A agonist 8-OH-DPAT. Nangona kunjalo, i-5-HT1B ye-receptor antagonist i-NAS-181 ayitshintshanga ngokwenyani iziphumo zeJ147 kwindlela yokuziphatha enokudakumba. Ngaphaya koko, ukunyanzelwa kwangaphambili nge-NAD-299 kuthintele ukonyuka okunyanzelweyo kwe-J147 kwi-CAMP, i-PKA, i-pCREB, kunye ne-BDNF expression kwi-hippocampus, ngelixa i-8-OH-DPAT iphucule iziphumo ze-J147 kwezi ntetho zeproteni.

Isiphelo kwi-J-147 yoxinzelelo olukhulu lokudakumba (MDD)

Iziphumo zicebisa ukuba i-J147 induces ngokukhawuleza iziphumo ezinje ngoxinzelelo ngexesha leentsuku ezi-3 zonyango ngaphandle kokubangela ukunyamezelwa kweziyobisi. Ezi ziphumo zinokulamla nge-5-HT1A-exhomekeke kwi-CAMP / PKA / pCREB / BDNF signaling.

Olunye uphando malunga noJ-147

T-006: Uyenza njani le ndlela iphuculweyo iye kwi-J-147

※ I-J147 yiphenyl hydrazide ethathwe kwi-curcumin yendalo.

※ I-J147 ine-half-life of 2.5 hrs in the brain, 1.5 hrs in plasma, 4.5min in microsomes yabantu, kunye <4min kwii-microsomes zegundane.

Unyango olunganyangekiyo lomlomo kunye ne-J147 lukhusele i-nerve ye-sciatic kwiswekile eqhubela phambili yeswekile ye-myelinated conduction velocity ngelixa elinye idosi ye-J147 ikhawuleze yabuya umva i-allodynia ekhutshiweyo.

Unyango lwe-J147 lonyango olulawulwa phantsi, olonyusa i-APP (ukungalunganga kwe-APP ekugqibeleni kunika i-Aβ).

Mit I-mitochondrial α-F1 subunit ye-ATP synthase (ATP5A) njengendawo yokujolisa ephezulu yemolekyuli ye-J147, iprotein efundwe ngaphambili kwimeko yokuguga… ine-inhibition exhomekeke kwi-ATP5a.

※ I-J147 ibuyisele amanqanaba e-acylcarnitines ephakamisa ukusebenza okuhle kwi-mitochondrial dynamics.

Kwii-receptors ze-NMDA, T-006 inhibits Ca2 + yokungena kakhulu.

※ I-T-006 inendima ekhuselayo kule nkqubo yokuthintela indlela ye-MAPK / ERK kunye nokubuyisela umendo we-PI3-K / Akt.

※ Ezinye izinto ezinje nge-3j (i-dicyanovinyl-endaweni ye-J147 analogue) inokuthintela i-oligomerization kunye ne-fibrillation ye-β-amyloid peptides kwaye ikhusela iiseli ze-neuronal kwi-cytotoxicity eyenziwe yi-β-amyloid.

Uyithenga phi ipowder ye-J-147?

Ukusemthethweni kwale nootropic kusekho ithambo lokuxabana kodwa akuyi kukuthintela ekufumaneni iimveliso ezisemthethweni. Emva kwayo yonke loo nto, uvavanyo lweklinikhi lwe-J-147 lwe-Alzheimer luyaqhubeka. Ungawuthenga umgubo kwiivenkile ezikwi-Intanethi njengoko ufumana ilungelo lokuthelekisa amaxabiso e-J-147 kubathengisi abohlukeneyo. Nangona kunjalo, kuya kufuneka uqiniseke ukuba ujikeleza kubathengisi abasebenza kuvavanyo oluzimeleyo lwelebhu.

Ukuba ufuna ezinye J-147 iyathengiswa, ngena kwivenkile yethu. Sinika ii-nootropics ezininzi phantsi kolawulo lomgangatho. Ungathenga ngesixa esikhulu okanye uthenge into enye ngokuxhomekeke kwinjongo yakho yengqondo. Qaphela ukuba, ixabiso le-J-147 linobuhlobo kuphela xa uthenga ngezixa ezikhulu.

isingqiniso

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