Curcumin Derivative J-147: Chithandizo Cholonjeza cha Matenda a Alzheimer's, Anti-aging, and Major Depressive Disorder (MDD)

Kuwunika kwa J-147

Curcumin ndi polyphenol ndipo ndi gawo logwira ntchito la Turmeric ndi Ginger.Curcumin ili ndi maubwino ambiri otsimikizika pochiza matenda ambiri, koma chifukwa chakulephera kwake kuwoloka Pagazi-Brain Barrier (BB), pali zolephera zomveka.

Kwenikweni, J147 (CAS:1146963-51-0) ndi Curcumin ndi Cyclohexyl-Bisphenol A (CBA) yochokera ku mankhwala amphamvu a neuroogenic ndi neuroprotective. Idapangidwa kuti igwiritsidwe ntchito pochiza matenda a neurodegenerative okhudzana ndi ukalamba. J147 ikhoza kuwoloka BBB mu ubongo (yamphamvu) ndikupangitsa maselo a neuronal stem Kupanga.

Mosiyana ndi mankhwala omwe amavomerezedwa ku matenda a Alzheimer's, J147 si acetylcholinesterase inhibitor kapena phosphodiesterase inhibitor, komabe kumawonjezera kuzindikira ndi chithandizo chanthawi yochepa.

Mu positi iyi, tikambirana momwe chotengera cha curcumin chotengera J147 zimathandizira Matenda a Alzheimer's (AD), vuto lalikulu lachisoni (MDD) ndi Anti-ukalamba.

Nazi izi:

1. Dziwani zambiri za J-147 Work (Mechanism)
2. Zowona Mwachangu Maubwino a J-147
3. J-147 Chitani Matenda a Alzheimer's (AD)
4. J-147 Chitani Vuto Lokalamba
5. J-147 Chitani Matenda Aakulu Achisoni (MDD)
6. Kafukufuku Wambiri Zokhudza J-147
7. Kuti Gulani J-147 Powder

Dziwani zambiri za J-147 Work (Mechanism)

Mpaka 2018, mphamvu ya J-147 pa seloyo idakhalabe yosamvetsetseka mpaka Salk Institute Neurobiologists itasokoneza chithunzicho. Mankhwalawa amagwira ntchito pomanga ATP synthase. Puloteni iyi ya mitochondrial imathandizira kupanga mphamvu zamagetsi, chifukwa chake, kuwongolera ukalamba.Kupezeka kwa chowonjezera cha J-147 m'dongosolo laumunthu kumaletsa poizoni wokhudzana ndi zaka zomwe zimachokera ku mitochondria yosagwira ntchito komanso kuchuluka kwa ATP.

Njira yogwiritsira ntchito J-147 iwonjezeranso milingo yama neurotransmitter angapo kuphatikiza NGF ndi BDNF. Kuphatikiza apo, imagwira ntchito pamagulu a beta-amyloid, omwe nthawi zonse amakhala apamwamba pakati pa odwala omwe ali ndi Alzheimer's and dementia. Zotsatira za J-147 zimaphatikizapo kuchepa kwa matenda a Alzheimer's, kupewa kuchepa kwa kukumbukira, ndikuwonjezera kupanga kwama cell a neuronal.

Zowona Mwachangu Maubwino a J-147

❶ Zimasintha Ntchito Ya Mitochondrial Ndi Moyo Wautali

❷ Imaletsa Matenda a Alzheimer's

❸ Zimasintha Kukumbukira

❹ Kukula Ubongo

Zimateteza Ma Neurons

❻ Angakulitse matenda ashuga

❼ Amalimbana Ndi Zowawa Ndi Neuropathy

❽ Angakulitse Kuda Nkhawa

J-147 Chitani Matenda a Alzheimer's (AD)

J-147 ndi AD: Mbiri 

Pakadali pano, njira yayikulu yopezera mankhwala a matenda a neurodegenerative idakhazikitsidwa pamikhalidwe yogwirizana kwambiri ndi matenda amodzi. Kwa matenda a Alzheimer's (AD), cholinga chake ndi amyloid beta Peptide (Ass) yomwe imayimira matenda a Alzheimer's. Komabe, poganizira kuti zaka ndiye chiwopsezo chachikulu cha AD, ife anafufuza mankhwala ena Njira yodziwira yomwe imachokera pakuchita bwino kwamitundu ingapo yama cell amitundu yokhudzana ndi zaka m'malo mongotengera amyloid metabolism. Pogwiritsa ntchito njirayi, tidazindikira molekyulu yamphamvu kwambiri, yogwira ntchito pakamwa, ya neurotrophic yomwe imathandizira kukumbukira makoswe wamba, ndikuletsa kutayika kwa mapuloteni a synaptic komanso kuchepa kwa chidziwitso mu mtundu wa mbewa wa AD.

J 147 ndi AD: Kusanthula koyeserera kwa mbewa

KUYAMBIRA: Ngakhale zaka zambiri zafukufuku, palibe mankhwala osokoneza bongo a Alzheimer's (AD), matenda owopsa, okhudzana ndi ukalamba. Kuwunika kwa mankhwala omwe angakhalepo mu makoswe a AD nthawi zambiri amadalira kuyesedwa kwa mankhwala matenda asanafike, potero amatengera kupewa matenda m'malo mosintha matenda. Kuphatikiza apo, njirayi yowunikira sikuwonetsera kuwonetsa kwa odwala a AD omwe angafotokozere zakulephera kutanthauzira mankhwala omwe amadziwika kuti ndi othandiza pazinyama zotengera matenda omwe amasintha m'mayesero azachipatala. Zachidziwikire kuti njira yabwinoko yowunikira AD isanachitike zamankhwala imafunika.

ZITSANZO: Kuti tiwonetse bwino zomwe zikuchitika pachipatala, tidagwiritsa ntchito njira ina yowunikira yokhudzana ndi kuchiza mbewa za AD pakadutsa matendawa pomwe matenda ali kale. Makoswe okalamba (azaka 20) transgenic AD (APP / swePS1DeltaE9) adadyetsedwa modabwitsa, yogwira pakamwa, yolimbikitsa kukumbukira ndi ma molekyulu a neurotrophic otchedwa J147. Kuzindikira kwamachitidwe, histology, ELISA ndi Western blotting zinagwiritsidwa ntchito kuyesa momwe J147 imakumbukira, amyloid metabolism ndi neuroprotective pathways. J147 idafufuzidwanso pamtundu wa scopolamine wopangitsa kukumbukira kuwonongeka kwa kukumbukira mu C57Bl / 6J mbewa ndikuyerekeza ndi donepezil. Zambiri pazamankhwala ndi chitetezo cha J147 zimaphatikizidwanso.

ZOKHUDZA: Zambiri zomwe zafotokozedwa pano zikuwonetsa kuti J147 imatha kupulumutsa zoperewera zazidziwitso zikagwiritsidwa ntchito kumapeto kwa matendawa. Kutha kwa J147 kukonza kukumbukira kwa mbewa zakale za AD kumalumikizidwa ndikulowetsedwa kwa ma neurotrophic factor NGF (nerve grow factor) ndi BDNF (brain derived neurotrophic factor) komanso ma protein angapo oyankha a BDNF omwe ali ofunikira pakuphunzira ndi kukumbukira. Kuyerekeza pakati pa J147 ndi donepezil mu mtundu wa scopolamine kunawonetsa kuti ngakhale mankhwala onsewa anali ofanana poteteza kukumbukira kwakanthawi kochepa, J147 inali yopambana poteteza kukumbukira kwa malo ndikuphatikizika kwa ziwirizi zimagwira ntchito bwino pamakumbukidwe azikumbukiro.

Kutsiliza pa J-147 kwa AD

J147 ndi chida chatsopano chomwe chimakhala champhamvu kwambiri, chotetezeka m'maphunziro azinyama komanso pakamwa. J147 ndi njira yothandizira AD chifukwa chokhoza kupereka mwachangu phindu lakuzindikira, imakhalanso ndi mwayi wokhoza kuyimitsa kapena mwina kusintha kufalikira kwa matenda m'zinyama zamankhwala monga akuwonetsera m'maphunzirowa.

J-147 Chitani Vuto Lokalamba

J-147 ndi Kulambala: Mbiri 

Mbewa zochiritsidwa ndi J147 zinali ndi chikumbukiro chabwino komanso kuzindikira, mitsempha yamagazi yathanzi muubongo ndi zina zotukuka ...

“Poyamba, chilimbikitso chinali kutero yesani mankhwalawa m'chitsanzo chatsopano cha nyama chomwe chinali chofanana kwambiri ndi 99% ya odwala Alzheimer's," akutero Antonio Currais, membala wa Pulofesa David Schubert's Cellular Neurobiology Laboratory ku Salk. "Sitinaneneretu kuti tidzawona izi odana ndi ukalamba koma J147 idapangitsa mbewa zakale kuwoneka ngati zazing'ono, kutengera mbali zingapo zakuthupi. ” Schubert akuti: "Ngakhale mankhwala ambiri omwe apangidwa m'zaka 20 zapitazi amayang'ana zikwangwani za amyloid muubongo (zomwe ndizodziwika bwino za matendawa), palibe yomwe yatsimikizika kuti ndi yothandiza kuchipatala," akutero Schubert.

Zaka zingapo zapitazo, Schubert ndi anzawo adayamba kupeza chithandizo cha matendawa mwanjira ina. M'malo molimbana ndi amyloid, labuyo idasankha kuthana ndi chiopsezo chachikulu cha ukalamba. Pogwiritsa ntchito zowonera pakompyuta motsutsana ndi zoopsa zaubongo zokhudzana ndi ukalamba, adapanga J147.

M'mbuyomu, gululo lidapeza kuti J147 imatha kuletsa komanso kubweza kukumbukira kukumbukira komanso matenda a Alzheimer's mu mbewa zomwe zili ndi mtundu wamtundu wa Alzheimer's, womwe umagwiritsidwa ntchito kwambiri ndi mbewa. Komabe, mtundu uwu wa matendawa umangokhala pafupifupi 1% ya matenda a Alzheimer's. Kwa wina aliyense, ukalamba ndiye chinthu chachikulu chowopsa, akutero Schubert. Gululo linkafuna fufuzani zotsatira zake a mbewa zamtundu wa mbewa zomwe zimakalamba mwachangu ndikukhala ndi vuto la dementia lomwe limafanana kwambiri ndi matenda obwera chifukwa cha ukalamba.

J-147 ndi Anti-ukalamba: Kuyesa koyeserera kwa mbewa

Pa ntchito yaposachedwa iyi, ofufuzawa adagwiritsa ntchito mayeso osiyanasiyana kuti athe kuyerekezera mitundu yonse yaubongo muubongo, komanso mamolekyulu opitilira 500 omwe amaphatikizidwa ndi kagayidwe kabongo m'magazi ndi magulu amitundu itatu ya mbewa zokalamba mwachangu. Magulu atatu a mbewa zokalamba mwachangu anali ndi seti imodzi yomwe inali yaying'ono, imodzi yomwe inali yakale ndi imodzi yomwe inali yakale koma idadyetsa J147 akamakalamba.

Makoswe akale omwe adalandira J147 adachita bwino pamakumbukidwe ndi mayeso ena kuti azindikire ndikuwonetsanso mayendedwe olimba amgalimoto. Mbewa zomwe zimathandizidwa ndi J147 zidalinso ndi zizindikilo zochepa za matenda a Alzheimer's muubongo wawo. Chofunika kwambiri, chifukwa cha kuchuluka kwa deta yomwe yasonkhanitsidwa pamagulu atatu a mbewa, zinali zotheka kuwonetsa kuti mbali zambiri zamafotokozedwe amtundu ndi kagayidwe kake mu mbewa zakale zodyetsa J147 zinali zofanana kwambiri ndi ziweto zazing'onozo. Izi zidaphatikizapo zolemba zowonjezera mphamvu zamagetsi, kuchepetsa kutupa kwaubongo ndikuchepetsa kwamafuta amadzimadzi muubongo.

Chodziwika china chinali chakuti J147 idaletsa kutuluka kwa magazi kuchokera ku ma microvessels mu ubongo wa mbewa zakale. "Mitsempha yamagazi yowonongeka ndimakonda kufala kukalamba, ndipo ku Alzheimer's, kumakhala koyipa kwambiri," akutero Currais.

Kutsiliza pa J-147 pamavuto okalamba

Mbewa zomwe zidadyetsa J147 zidachulukitsa mphamvu zamagetsi ndikuchepetsa kutupa kwa ubongo. zotsatira zolimbana ndi ukalamba mu nyama.

Gulu lochokera ku Salk Institute lidawonetsa kuti wopikisana naye mankhwalawa adagwira bwino ntchito ya mbewa yaukalamba yomwe siigwiritsidwe ntchito pakafukufuku wa Alzheimer's. Mbewa izi zikagwidwa ndi J147, anali ndi kukumbukira bwino komanso kuzindikira, mitsempha yathanzi yamaubongo muubongo ndi zina zotukuka.

J-147 Chitani Matenda Aakulu Achisoni (MDD)

J-147 ndi MDD: Mbiri

Matenda aakulu achisokonezo (MDD) ndimavuto amisala okhudzana ndi kuchepa kwa ma monoamine neurotransmitters, makamaka zovuta za 5-HT (5-hydroxytryptamine, serotonin) ndi ma receptors ake. Kafukufuku wathu wam'mbuyomu adanenanso kuti chithandizo chovuta ndi buku zotumphukira za curcumin J147 adawonetsa zodetsa nkhawa monga kukweza kwaubongo komwe kumachokera mu neurotrophic factor (BDNF) mu hippocampus wa mbewa. Kafukufuku wapano adakulitsa zomwe tidapeza m'mbuyomu ndikufufuza zomwe zimayambitsa matenda opatsirana pogonana a J147 masiku atatu mu mbewa zamphongo za ICR komanso kuthekera kwake kwa 3-HT5A ndi 1-HT5B receptors ndi kutsika kwa cAMP-BDNF.

J-147 ndi MDD: Kusanthula koyeserera kwa mbewa

Njira: J147 pamiyeso ya 1, 3, ndi 9 mg / kg (kudzera pa gavage) idaperekedwa kwa masiku 3, ndipo nthawi yolimbana ndi kusunthika pakuyesedwa kokakamizidwa ndi kuyimitsidwa kwa mchira (FST ndi TST) kudalembedwa. Kuyesa kwa radioligand kunagwiritsidwa ntchito kudziwa kuyanjana kwa J147 ku 5-HT1A ndi 5-HT1B receptor. Kuphatikiza apo, 5-HT1A kapena 5-HT1B agonist kapena wotsutsana naye adagwiritsidwa ntchito kuti adziwe mtundu wa 5-HT receptor subtype womwe umakhudzidwa ndi zomwe zimachitika ngati J147. Mamolekyu osonyeza kutsika monga cAMP, PKA, pCREB, ndi BDNF adayesedwanso kuti adziwe momwe angachitire.

Results: Zotsatirazi zidawonetsa kuti chithandizo chochepa kwambiri cha J147 chidachepetsa kwambiri nthawi yopanda kuyenda mu FST ndi TST m'njira yodalira mlingo. J147 idawonetsa kuyanjana kwambiri mu vitro kupita ku 5-HT1A receptor yokonzedwa kuchokera ku mbewa zamtundu wama mbewa ndipo inali yopanda mphamvu pa 5-HT1B receptor. Zotsatirazi za J147 zidatsekedwa ndikunyengerera ndi 5-HT1A wotsutsana NAD-299 ndikuwonjezeredwa ndi 5-HT1A agonist 8-OH-DPAT. Komabe, 5-HT1B wolandila wotsutsana NAS-181 sanasinthe moyamikira zotsatira za J147 pamakhalidwe okhumudwa. Kuphatikiza apo, kunyengerera koyambirira ndi NAD-299 kutsekereza kuwonjezeka kwa J147 komwe kunapangitsa kuchuluka kwa cAMP, PKA, pCREB, ndi BDNF mu hippocampus, pomwe 8-OH-DPAT idakulitsa zotsatira za J147 pamawonedwe a mapuloteniwa.

Kutsiliza pa J-147 ya Major Depression Disorder (MDD)

The Zotsatira zimasonyeza kuti J147 imayambitsa zotsatira zowonongeka mofulumira pa nthawi ya chithandizo cha masiku atatu popanda kuchititsa kulolerana kwa mankhwala. Zotsatirazi zitha kulumikizidwa ndi 3-HT5A-yodalira cAMP/PKA/pCREB/BDNF siginecha.

Kafukufuku Wambiri Zokhudza J-147

-T-006: Momwe Mungapangire Njira Yina Yotukuka Ili J-147

147 JXNUMX ndi phenyl hydrazide yochokera ku curcumin yachilengedwe.

147 J2.5 ili ndi theka la theka la maola 1.5 muubongo, 4.5 hrs mu plasma, 4min mu microsomes ya anthu, ndi <XNUMXmin mu mbewa microsomes.

Treatment Chithandizo chamankhwala cham'mimba ndi J147 chidateteza mitsempha ya sciatic kuchokera ku matenda opatsirana ndi matenda ashuga omwe amachepetsa kuchepa kwamphamvu kwa myelinated fiber conduction velocity pomwe miyezo imodzi ya J147 mwachangu komanso posakhalitsa idasinthira allodynia yokhudzidwa.

Treatment Chithandizo cha J147 chothandizidwa ndi BACE, motero kukulitsa APP (zolakwika za APP pomalizira pake zimapangitsa Aβ).

Mitundu ya mitochondrial α-F1 ya ATP synthase (ATP5A) monga mgwirizano wapakatikati wa J147, puloteni yomwe idaphunziridwa kale pakukalamba ... imakhala ndi choletsa kutengera ATP5a.

147 JXNUMX idabwezeretsa milingo ya acylcarnitines yomwe ikusonyeza zotsatira zabwino pamphamvu za mitochondrial.

※ Mu othandizira a NMDA, T-006 Imaletsa kuchuluka kwambiri kwa Ca2 +.

-T-006 ili ndi gawo loteteza m'dongosolo lino kudzera munjira zonse zolepheretsa MAPK / ERK ndikubwezeretsanso PI3-K / Akt njira.

Der Zina zotumphukira monga 3j (dicyanovinyl-m'malo mwa J147 analogue) zitha kulepheretsa oligomerization ndi kufinya kwa ma peptide a β-amyloid ndikuteteza ma cell a neuronal ku t-amyloid-cytotoxicity.

Mungagule Kuti Powonjezera la J-147?

Zovomerezeka za nootropic iyi ikadali fupa la mikangano koma sikudzakulepheretsani kupeza zinthu zovomerezeka. Kupatula apo, mayeso azachipatala a J-147 Alzheimer akuchitika. Mutha kugula poda pa intaneti masitolo mukamapeza mwayi wofananiza mitengo ya J-147 kwa ogulitsa osiyanasiyana. Komabe, muyenera kuwonetsetsa kuti mukugula kuchokera kwa ogulitsa omwe ali ndi mayeso odziyimira pawokha a labotale.

Ngati mukufuna zina J-147 yogulitsa, fufuzani ndi sitolo yathu. Timapereka zambiri nootropics pansi pa khalidwe labwino. Mutha gulani zochuluka kapena gulani kamodzi kutengera cholinga chanu cha psychonautic. Dziwani kuti, mtengo wa J-147 ndi wochezeka pokhapokha mutagula zochuluka.