ICurcumin Derivative J-147

Ukubuyekezwa kwe-J-147

ICurcumin iyi-polyphenol futhi iyinto esebenzayo yeTurmeric neGinger.Curcumin inezinzuzo eziningi ezifakazelwe zokwelapha izifo eziningi, kepha ngenxa yekhono layo elibi lokuwela i-Blood-Brain Barrier (BB), kunemikhawulo ecacile.

Ngokuyinhloko, i-J147 (i-CAS:1146963-51-0) Isithako seCurcumin neCycylohexyl-Bisphenol A (CBA) esingumuthi onamandla we-neurogenic kanye ne-neuroprotective. Yenzelwe ukusetshenziswa kokwelashwa kwezimo ze-neurodegenerative ezihambisana nokuguga. I-J147 ingawela i-BBB iye ebuchosheni (eqinile) futhi yenze ukukhiqizwa kwamaseli we-neuronal stem.

Ngokungafani nemithi yamanje evunyelwe i-Alzheimer's Disease, i-J147 ayiyona i-acetylcholinesterase inhibitor noma i-phosphodiesterase inhibitor, kepha ithuthukisa ukuqonda ngokwelashwa kwesikhashana.

Kulokhu okuthunyelwe, sizoxoxa ngokuthi i-curcumin esuselwe ku-J147 isiphatha kanjani i-Alzheimer's Disease (AD), isifo esikhulu sokucindezeleka (MDD) kanye ne-Anti-aging.

Nakhu okuqukethwe:

  1. Funda kabanzi ngomsebenzi we-J-147 (Mechanism)
  2. Izinzuzo Zokubuka Ngokushesha ze-J-147
  3. I-J-147 Yelapha Izifo Ze-Alzheimer's (AD)
  4. J-147 Phatha Inkinga Yokuguga
  5. I-J-147 Phatha ukucindezeleka okukhulu okucindezelayo (MDD)
  6. Ucwaningo Olwengeziwe Nge-J-147
  7. Lapho Ungathenga khona i-J-147 Powder

ICurcumin Derivative J-147

Funda kabanzi ngomsebenzi we-J-147 (Mechanism)

Kuze kube ngu-2018, umphumela we-J-147 esitokisini uhlala ungaziwa kuze kube yilapho iSalk Institute Neurobiologists isichaze le phazili. Isidakamizwa sisebenza ngokubopha i-ATP synthase. Le protein ye-mitochondrial modulates ukukhiqizwa kwamandla eselula, yingakho, ilawula inqubo yokuguga.Utholakala kwesengezo se-J-147 ohlelweni lomuntu kuvimbela ubuthi obuhlobene nobudala obudalwa yimitochondria engasebenzi kanye nokukhiqizwa ngokweqile kwe-ATP.

Indlela yokusebenza ye-J-147 izokwengeza amazinga ama-neurotransmitter ahlukahlukene afaka i-NGF ne-BDNF. Ngaphandle kwalokho, isebenza kumazinga we-beta-amyloid, ahlala ephakeme kakhulu ezigulini ezine-Alzheimer's and dementia. Imiphumela ye-J-147 ifaka phakathi ukubambezela ukuqhubeka kwe-Alzheimer's, ukuvimbela ukusilela kwememori, nokwengeza ukukhiqizwa kwamaseli we-neuronal.

I-AASraw ingumkhiqizi oqeqeshiwe we-Curcumin Derivative J-147.

Sicela uchofoze lapha ukuthola ulwazi lwesilinganiso: Oxhumana nathi

 

Izinzuzo Zokubuka Ngokushesha ze-J-147

❶ Ithuthukisa Umsebenzi WeMitochondrial Nesikhathi Eside

Kuvimbela isifo se-Alzheimer's

Kuthuthukisa iMemori

❹ Ikhula Ubuchopho

❺ Kuvikela ama-Neurons

❻ Kungenzeka Sithuthukise Isifo Sikashukela

Ights Ilwa Ubuhlungu Ne-Neuropathy

❽ Kwangathi Kungathuthukisa Ukukhathazeka

 

Phatha i-J-147 Isifo i-Alzheimer's (AD)

I-J-147 ne-AD: Ingemuva 

Njengamanje, umbandela omkhulu wokutholwa kwezidakamizwa wezifo ezingenayo i-neurodegenerative usekwe kuma-ligands aphezulu wokuhlangana kwezinhloso eziqonde ngqo zesifo. Ngesifo i-Alzheimer's (AD), kugxilwa i-amyloid beta peptide (Ass) elawula izifo zesifo i-Alzheimer's. Kodwa-ke, uma kubhekwa ukuthi iminyaka yobudala iyinto ebaluleke kakhulu engcupheni ye-AD, sihlolisise enye indlela yokutholakala kwezidakamizwa esekwe ekusebenzeni kahle kwamamodeli amaningi amasiko wama-pathologies ahlobene nobudala hhayi i-amyloid metabolism kuphela. Sisebenzisa le ndlela, sikhombe i-molecule ye-neurotrophic enamandla kakhulu, esebenza ngomlomo, eyenza imemori kumagundane ajwayelekile, futhi ivimbele ukulahleka kwamaprotheni we-synaptic kanye nokwehla kwengqondo kumodeli yegundane le-transgenic AD.

ICurcumin Derivative J-147

 

J 147 no-AD: Ukuhlaziywa kokutholwa kokuhlola kwamagundane

ISINGENISO: Naphezu kweminyaka yocwaningo, azikho izidakamizwa eziguqula izifo zesifo i-Alzheimer's (AD), isifo esibulalayo, esihlobene nobudala se-neurodegenerative disorder. Ukuhlolisiswa kwemithi yokwelashwa engaba khona kumamodeli wama-rodent we-AD ngokuvamile kuthembele kumakhemikhali wokuhlola ngaphambi kokuba i-pathology ibekhona, ngaleyo ndlela kube yimodeli yokuvikela izifo kunokuguqula izifo. Ngaphezu kwalokho, le ndlela yokuhlola ayikhombisi ukwethulwa komtholampilo kweziguli ze-AD ezingachaza ukwehluleka ukuhumusha amakhemikhali akhonjwe njenganenzuzo kumamodeli ezilwane kuya kumakhemikhali aguqula izifo ezivivinyweni zokwelashwa. Ngokusobala indlela engcono yokuhlolwa kwezidakamizwa ngaphambi komtholampilo i-AD iyadingeka.

IZINDLELA: Ukukhombisa ngokunembile ukulungiselelwa komtholampilo, sisebenzise elinye isu lokuhlola elibandakanya ukwelashwa kwamagundane e-AD esigabeni sesifo lapho i-pathology isivele ithuthukile. Amagundane we-transgenic asebekhulile (anezinyanga ezingama-20) we-transgenic (APP / swePS1DeltaE9) anikezwe amandla amakhulu, asebenza ngomlomo, aqinisa inkumbulo kanye ne-molecule ye-neurotrophic ebizwa nge-J147. Ukuhlolwa kokuziphatha kokuqonda, i-histology, i-ELISA kanye ne-Western blotting kusetshenziselwe ukuvivinya umphumela we-J147 kwimemori, i-amyloid metabolism kanye nezindlela ze-neuroprotective. I-J147 iphinde yaphenywa ngemodeli eyenziwe nge-scopolamine yokukhubazeka kwememori ku-C57Bl / 6J amagundane futhi kuqhathaniswa ne-donepezil. Imininingwane nge-pharmacology nokuphepha kwe-J147 nayo ifakiwe.

IZIPHUMA: Imininingwane evezwe lapha ikhombisa ukuthi i-J147 inekhono lokuhlenga ukusilela kokuqonda lapho ilawulwa sekwedlule isikhathi kulesi sifo. Ikhono le-J147 lokuthuthukisa inkumbulo kumagundane ase-AD amadala lihambisana nokufakwa kwalo kwezici ze-neurotrophic NGF (i-nerve grow factor) ne-BDNF (ubuchopho obususelwe ku-neurotrophic factor) kanye namaprotheni amaningi aphendulayo e-BDNF abalulekile ekufundeni nasenkumbulweni. Ukuqhathanisa phakathi kwe-J147 ne-donepezil kumodeli ye-scopolamine kukhombisile ukuthi ngenkathi womabili la makhemikhali efaniswa nokusindisa inkumbulo yesikhashana, i-J147 ibiphakeme ekusindiseni inkumbulo yendawo futhi inhlanganisela yalaba bobabili isebenze kahle kakhulu kwimemori engokomongo neye-cued.

 

Isiphetho ku-J-147 se-AD

I-J147 iyinhlanganisela entsha ethokozisayo enamandla amakhulu, ephephile ezifundweni zezilwane futhi esebenza ngomlomo. I-J147 iyindlela yokwelapha engaba khona ye-AD ngenxa yekhono layo lokuhlinzeka ngokushesha izinzuzo zokuqonda, futhi futhi inamandla okumisa futhi mhlawumbe iguqule ukukhula kwesifo ezilwaneni ezinophawu njengoba kukhonjisiwe kulezi zifundo.

 

J-147 Phatha Inkinga Yokuguga

J-147 futhi Ukuguga ukugugaIsendlalelo 

Amagundane aphathwe nge-J147 abenememori engcono nokuqonda, imithambo yegazi enempilo ebuchosheni nakwezinye izici zomzimba ezithuthukisiwe…

“Ekuqaleni, umfutho kwakuwukuhlola lesi sidakamizwa ngendlela entsha yezilwane eyayicishe ifane ne-99% yeziguli ze-Alzheimer,” kusho u-Antonio Currais, oyilungu leProfesa David Schubert's Cellular Neurobiology Laboratory eSalk. “Asibikezelanga ukuthi sizolubona lolu hlobo anti-ukuguga kodwa i-J147 yenza amagundane amadala abukeke sengathi asemancane, ngokuya ngemingcele ethile yomzimba. ” "Yize iningi lemithi elakhiwe eminyakeni engama-20 edlule libhekise uqweqwe lwama-amyloid ebuchosheni (okuyisici esiveza lesi sifo), asikho nesisodwa esikhombisile ukuthi siyasebenza emtholampilo," kusho uSchubert.

Eminyakeni eminingana edlule, uSchubert nozakwabo baqala ukusondela ekwelashweni kwalesi sifo ngendlela entsha. Esikhundleni sokukhomba i-amyloid, ilebhu yanquma ukungangeni engcupheni enkulu yokuguga kwesifo. Besebenzisa izikrini ezisuselwa kumaseli ngokumelene nobuthi obudala obuhlobene nobuchopho, bahlanganisa i-J147.

Phambilini, ithimba lathola ukuthi i-J147 ingavimbela iphinde iguqule ukulahleka kwememori kanye ne-Alzheimer's pathology kumagundane anohlobo lwefomu le-Alzheimer's, imodeli yegundane esetshenziswa kakhulu. Kodwa-ke, leli fomu lesifo liqukethe kuphela i-1% yamacala e-Alzheimer's. Kubo bonke abanye abantu, ukuguga kuyisici esiyingozi esiyinhloko, kusho uSchubert. Leli thimba belifuna ukuhlola imiphumela yalowo ozobhapathizwa ngezidakamizwa ohlotsheni lwamagundane aneminyaka yobudala ngokushesha futhi abhekane nengqondo yokuwohloka komqondo ecishe ifane kakhulu nenkinga yomuntu ehlobene nobudala.

ICurcumin Derivative J-147

I-J-147 nokulwa nokuguga: Ukuhlaziywa kokutholwa kokuhlola kwamagundane

Kulo msebenzi wakamuva, abacwaningi basebenzise isethi ephelele yezilingo ukukala ukubonakaliswa kwazo zonke izakhi zofuzo ebuchosheni, kanye nama-molecule angaphezu kwama-500 amancane abandakanyeka imetabolism ebuchosheni nasegazini lamaqembu amathathu amagundane aguga ngokushesha. La maqembu amathathu amagundane aguga ngokushesha afaka isethi eyodwa ebisencane, isethi eyodwa ebekade indala nesethi eyodwa ebekade indala kepha yondla i-J147 njengoba bekhula.

Amagundane amadala athola i-J147 asebenze kangcono kwimemori nakwezinye izivivinyo zokuqonda futhi abuye abonise ukunyakaza okunamandla kakhulu kwezimoto. Amagundane aphathwe nge-J147 nawo abe nezimpawu ezimbalwa zokugula ze-Alzheimer's ebuchosheni babo. Okubalulekile, ngenxa yenani elikhulu ledatha eliqoqwe emaqenjini amathathu wamagundane, bekwazile ukukhombisa ukuthi izici eziningi zokuvezwa kofuzo kanye nokwakheka komzimba kumagundane amadala aphakelwe i-J147 ayefana kakhulu nalezo zezilwane ezisencane. Lokhu kufaka phakathi omaka bokukhuphuka kwamandla emandla, ukunciphisa ukuvuvukala kobuchopho namazinga ancishisiwe ama-acid e-oxidized fatty ebuchosheni.

Omunye umphumela ophawulekayo kwaba ukuthi i-J147 ivimbele ukuvuza kwegazi kusuka kuma-microvessels ebuchosheni bamagundane amadala. "Imithambo yegazi elimele iyisici esivamile sokuguga ngokuvamile, kanti e-Alzheimer's, ivame ukuba yimbi kakhulu," kusho uCurrais.

I-AASraw ingumkhiqizi oqeqeshiwe we-Curcumin Derivative J-147.

Sicela uchofoze lapha ukuthola ulwazi lwesilinganiso: Oxhumana nathi

 

Isiphetho ku-J-147 ngenkinga yokuguga

Amagundane aphakelwe i-J147 andise amandla emethabolism futhi anciphisa ukuvuvukala kobuchopho.Abaphenyi bathole ukuthi umuntu ozobhekela izidakamizwa ohlose ukulwa nesifo i-Alzheimer's, esibizwa nge-J147, unenqwaba yezinto ezingalindelekile imiphumela yokulwa nokuguga ezilwaneni.

Iqembu elivela eSalk Institute likhombise ukuthi lowo ozobhapathizwa ngezidakamizwa usebenze kahle kwimodeli yegundane yokuguga engasetshenziswa kakhulu ocwaningweni lwe-Alzheimer's. Lapho la magundane elashwa nge-J147, ayenenkumbulo engcono nokuqonda, imithambo yegazi enempilo ebuchosheni nakwezinye izici zomzimba ezithuthukisiwe.

 

I-J-147 Phatha ukucindezeleka okukhulu okucindezelayo (MDD)

I-J-147 ne-MDD: Ingemuva

Isifo esikhulu sokucindezeleka (MDD) ukuphazamiseka kwengqondo okukhulu okuhlobene nokushoda kwama-monoamine neurotransmitters, ikakhulukazi ukungajwayelekile kwe-5-HT (5-hydroxytryptamine, serotonin) nama-receptors ayo. Isifundo sethu sangaphambilini siphakamise ukuthi ukwelashwa okunamandla ngenoveli okuphuma ku-curcumin i-J147 ukhombise imiphumela efana ne-antidepressant ngokukhulisa izinga lobuchopho elisuselwa ku-neurotrophic factor (BDNF) ku-hippocampus yamagundane. Ucwaningo lwamanje lukhulise kokutholakele kwethu kwangaphambilini futhi luphenye imiphumela efana ne-anti-depressant of the sub-acute treatment of J147 for 3 days in male ICR mice and its relevidence to 5-HT1A and 5-HT1B receptors and downstream cAMP-BDNF signaling.

ICurcumin Derivative J-147

I-J-147 ne-MDD: Ukuhlaziywa kokutholwa kokuhlola kwamagundane

Izindlela: I-J147 ngemithamo ye-1, 3, ne-9 mg / kg (nge-gavage) yanikezwa izinsuku ezingama-3, kwathi isikhathi sokulwa nokungahambi kahle ekuhlolweni okuphoqwayo kokubhukuda nokumiswa komsila (i-FST ne-TST) kwarekhodwa. Ukuhlolwa kwe-radioligand okubophelelayo kusetshenziselwe ukucacisa ukusondelana kwe-J147 ne-5-HT1A ne-5-HT1B receptor. Ngaphezu kwalokho, i-agonist ye-5-HT1A noma i-5-HT1B noma umphikisi wayo isetshenziselwe ukunquma ukuthi iyiphi i-5-HT receptor subtype ebandakanyekayo kwimiphumela efana ne-anti-depressant ye-J147. Ama-molecule asayina ezansi njenge-cAMP, i-PKA, i-pCREB, ne-BDNF nawo alinganiswa ukuthola indlela yokusebenza.

Ezenye: Imiphumela ikhombise ukuthi ukwelashwa okungaphansi kwe-J147 kunciphise ngokumangazayo isikhathi sokungakwazi ukuhamba kuzo zombili i-FST ne-TST ngendlela encike kumthamo. I-J147 ikhombise ukusondelana okuphezulu kwe-vitro ku-5-HT1A receptor elungiselelwe kusuka kumagundane izicubu ze-cortical futhi ibinamandla amancane ku-5-HT1B receptor. Le miphumela ye-J147 ivinjelwe ukwelashwa kwangaphambili nge-5-HT1A antagonist NAD-299 futhi ithuthukiswe yi-5-HT1A agonist 8-OH-DPAT. Kodwa-ke, umphikisi we-5-HT1B receptor NAS-181 akazange ayiguqule ngokwazisa imiphumela ye-J147 ekuziphatheni okufana nokudana. Ngaphezu kwalokho, ukwelashwa kwangaphambili nge-NAD-299 kuvimbele ukwanda okwenziwe nge-J147 ku-CAMP, PKA, pCREB, naku-BDNF expression ku-hippocampus, kuyilapho i-8-OH-DPAT ithuthukise imiphumela ye-J147 kule nkulumo yamaprotheni.

 

Isiphetho ku-J-147 se-Major depress disorder (MDD)

Imiphumela iphakamisa ukuthi i-J147 inciphisa imiphumela esheshayo efana ne-anti-depressant ngesikhathi sokwelashwa kwezinsuku ezintathu ngaphandle kokunciphisa ukubekezelelana kwezidakamizwa. Le miphumela ingahle ilamulelwe ukusayina kwe-cAMP / PKA / pCREB / BDNF encike ku-3-HT5A.

 

Ucwaningo Olwengeziwe Nge-J-147

※ T-006: Ungayenza Kanjani Le Ntuthuko Ethuthukisiwe Ku-J-147

I-J147 iyi-phenyl hydrazide etholakala ku-curcumin yemvelo.

I-J147 ine-half-life of 2.5 hrs ebuchosheni, 1.5 hrs ku-plasma, 4.5min kuma-microsomes womuntu, naku- <4min kuma-microsomes wegundane.

Ukwelashwa okungapheli ngomlomo nge-J147 kuvikele i-nerve ye-sciatic ekunciphiseni okuqhubekayo kwesifo sikashukela okuncishisiwe kwe-myelinated fiber conduction velocity ngenkathi imithamo eyodwa ye-J147 isheshe yaguqula i-allodynia ethintekayo ethintekayo.

Treatment Ukwelashwa kwe-J147 kwe-BACE okulawulwa phansi, ngaleyo ndlela kukhuphule i-APP (ukuhlanzwa okungafanele kwe-APP ekugcineni kunika i-Aβ).

※ I-mitochondrial α-F1 subunit ye-ATP synthase (ATP5A) njengenhloso ephezulu yokusondelana yamangqamuzana ye-J147, iphrotheni ebelifundwa phambilini ngokomongo wokuguga… linokuvimbela umthamo okuncike ku-ATP5a.

※ I-J147 ibuyise amazinga e-acylcarnitines aphakamisa umphumela omuhle kumandla we-mitochondrial.

Receptors Kuma-NMDA receptors, T-006 kuvimbela ukungena ngokweqile kwe-Ca2 +.

※ I-T-006 inendima evikelayo kulolu hlelo ngokusebenzisa zombili izindlela ezivimbela i-MAPK / ERK nokubuyisela indlela ye-PI3-K / Akt.

※ Ezinye izinto ezifana ne-3j (i-analogue ye-dicyanovinyl-esikhundleni se-J147 analogue) ingavimbela i-oligomerization ne-fibrillation yama-peptide e-β-amyloid futhi ivikele amaseli we-neuronal kusuka ku-cytotoxicity eyenziwe nge-β-amyloid.

 

Ungawuthengaphi Powder we-J-147?

Ukuba semthethweni kwale nootropic kuseyithambo lombango kepha ngeke kukuvimbe ekutholeni imikhiqizo esemthethweni. Ngemuva kwakho konke, izivivinyo zokwelashwa ze-J-147 Alzheimer's ziyaqhubeka. Ungathenga i-powder ezitolo eziku-inthanethi njengoba uthola ilungelo lokuqhathanisa amanani we-J-147 kubathengisi abahlukahlukene. Kodwa-ke, kufanele uqiniseke ukuthi uthenga kusuka kubahlinzeki abavumelekile ngokuhlolwa okuzimele kwelabhoratri.

Uma ufuna ezinye J-147 iyathengiswa, ngena esitolo sethu. Sinikezela ngama-nootropics amaningi ngaphansi kokulawulwa kwekhwalithi. Ungathenga ngobuningi noma wenze ukuthenga okukodwa ngokuya ngomgomo wakho we-psychonautic. Qaphela ukuthi, intengo ye-J-147 inobungane kuphela uma uthenga ngobuningi.

I-AASraw ingumkhiqizi oqeqeshiwe we-Curcumin Derivative J-147.

Sicela uchofoze lapha ukuthola ulwazi lwesilinganiso: Oxhumana nathi

 

Izikhombo

[1] Ngaphambi kukaM, et al. Isakhi se-neurotrophic J147 siguqula ukukhubazeka kokuqonda kumagundane esifo esidala i-Alzheimer's. I-Alzheimers Res Ther. 2013 uMeyi 14; 5 (3): 25.

[2] UChen Q, et al. Isidakamizwa senoveli se-neurotrophic sokuthuthukisa ukuqonda kanye nesifo se-Alzheimer's. Ama-PLoS One. 2011; 6 (12): e27865.

[3] I-Currais A, i-Goldberg J, i-Farrokhi C, i-Chang M, i-Prior M, i-Dargusch R, i-Daugherty D, i-Armando A, i-Quehenberger O, i-Maher P, i-Schubert D: Indlela ebanzi yama-multomics ekuqondeni ubudlelwano phakathi kokuguga nokuwohloka komqondo. Ukuguga (i-Albany NY). 2015 Nov; 7 (11): 937-55. i-doi: 10.18632 / ukuguga.100838. [I-PubMed: 26564964]

[4] UDaugherty DJ, uMarquez A, uCalcutt NA, uSchubert D: I-curcumin yenoveli etholakala ekwelapheni i-neuropathy yesifo sikashukela. I-Neuropharmacology. 2018 Feb; 129: 26-35. i-doi: 10.1016 / j.neuropharm.2017.11.007. I-Epub 2017 Nov 6. [I-PubMed: 29122628]

[5] J. Goldberg, A. Currais, M. Ngaphambi, W. Fischer, C. Chiruta, E. Ratliff, D. Daugherty, R. Dargusch, K. Finley, PB Esparza-Molto, JM Cuezva, P. Maher, M. UPetrascheck, D. Schubert

[6] USolomon B (Okthoba 2008). "I-Filamentous bacteriophage njengethuluzi lokwelapha lokwelapha ukwelashwa kwezifo ze-Alzheimer". Ijenali Yesifo Se-Alzheimer's. 15 (2): 193–8. I-PMID 18953108.

[7] UWang M, et al. Ukuhlanganiswa kokuqala kwe- [11C] J147, i-ejenti entsha engaba yi-PET yokufanekisa isithombe se-Alzheimer's. I-Bioorg Med Chem Lett. 2013 uJan 15; 23 (2): 524-7.

[8] Ngaphambi kukaM, et al. Ukukhetha amandla we-neurogenic njengenye indlela yokutholakala kwesidakamizwa se-Alzheimer's. I-Alzheimers Dement. 2016 Juni; 12 (6): 678-86.

 

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