Yintoni i-Alzheimer's and Geroprotectors (i-GNPs)

Isifo i-Alzheimer sesona sizathu siphambili sokudodobala kwengqondo, luhlobo lwesifo sengqondo esixhalabisayo esidala iingxaki kwimemori, ukucinga nasekuziphatheni. Iimpawu zihlala zikhula kancinci kwaye ziye zisiba mandundu ngokuhamba kwexesha, ziba nzima ngokwaneleyo ukuba zingaphazamisa imisebenzi yemihla ngemihla.Isifo se-Alzheimer i-akhawunti ye-60 ipesenti kwi-80 ipesenti zeengxaki ze-dementia. Yaye ukuguga kukuyona ingozi enkulu kwizifo ezininzi, kubandakanya isifo se-Alzheimer (AD) nomhlaza.

I-Geroprotectors, yi-senotherapeutic enenjongo yokuchaphazela imbangela yokuguga kunye nezifo ezinxulumene neminyaka, kwaye ngokunjalo zandisa ixesha lobomi bezilwanyana. Uphando olutsha lwe-Salk sele lufumene i-subclass ekhethekileyo yale mihla, ebizwa ngokuba yi-geroneuroprotectors (i-GNPs), abaviwa be-AD kunye nokucotha inkqubo yokuguga kwiimicebe.

 

Izidakamizwa ze-Alzheimer (izidakamizwa ze-AD) J147 CMS121 ICAD31

 

Unobangela wesifo sika-Alzheimer

Abaphandi bakholelwa ukuba akukho sizathu sinye sesifo se-Alzheimer. Usifumana njani isifo se-Alzheimer? Esi sifo sinokuvela kwizinto ezininzi, ezinje ngemfuza, indlela yokuphila kunye nokusingqongileyo. Izazinzulu zichonge izinto ezonyusa umngcipheko we-Alzheimer's. Ngelixa ezinye izinto ezinobungozi-ubudala, imbali yosapho kunye nelifa-elingenakutshintshwa, ubungqina obuvelayo bucebisa ukuba zinokubakho ezinye izinto esinokuba nefuthe kuzo.

-Age

Owona mngcipheko mkhulu we-Alzheimer's uyanda ubudala, kodwa i-Alzheimer's ayisiyonto iqhelekileyo yokuguga. Ngelixa ubudala bonyusa umngcipheko, ayingonobangela ngqo we-Alzheimer's.

Uninzi lwabantu abanesi sifo baneminyaka engama-65 nangaphezulu. Emva kweminyaka engama-65, umngcipheko we-Alzheimer's iphindwe kabini kwiminyaka emihlanu. Emva kweminyaka engama-85, umngcipheko ufikelela phantse kwisinye kwisithathu.

-Imbali yamabhinqa

Enye into ebalulekileyo yengozi yembali yentsapho. Labo abanomzali, umzalwana okanye udade nge-Alzheimers banokuthi bahlakulele isifo. Umngcipheko ukwandisa ukuba ngaphezu kwelinye ilungu lentsapho linokugula.

-Genetics (ubudala)

Izazinzulu ziyazi ukuba izakhi zofuzo zibandakanyeka kwi-Alzheimer's. Iindidi ezibini zentsholongwane zichaphazela ukuba umntu udala isifo: izakhi zeengcipheko zegciwane kunye nezakhi zofuzo.

-Bala inxeba

Kukho ikhonkco phakathi kokulimala kwentloko kunye nomngcipheko wexesha elizayo wesifo sengqondo esixhalabisayo. Khusela ingqondo yakho ngokubopha ibhanti yakho yokuhlala, nxiba isigcina-ntloko sakho xa uthatha inxaxheba kwezemidlalo, kwaye "uwisa ubungqina" kwikhaya lakho.

Ukuxhamla kwentloko

Olunye ubungqina obuqineleyo lubandakanya impilo yengqondo kwimpilweni. Olu qhagamshelo lunengqiqo, ngenxa yokuba ingqondo ikondliwa ngenye yeenethiwekhi ezicebileyo zemithambo yegazi, kwaye intliziyo inomthwalo wokupompa igazi ngale mida yegazi kwingqondo.

Izilwanyana ze-Alzheimer (izidakamizwa ze-AD): J147, i-CMS121, iCAD31

Namhlanje, i-Alzheimer iphambili kuphando lwezinto eziphilayo. Abaphandi basebenzela ukufumanisa uninzi lwemiba yesifo se-Alzheimer kunye nezinye i-dementias ngokunokwenzeka. Olunye lwenkqubela phambili ebalaseleyo lukhanyisile malunga nendlela i-Alzheimer's echaphazela ngayo ingqondo. Ithemba lokuba oku kuqondwa ngcono kuya kukhokelela kunyango olutsha. Iindlela ezininzi ezinokubakho ziphantsi kophando kwihlabathi liphela.

Isisindo sokulahlekelwa kwezidakamizwa i-2,4-Dinitrophenol (DNP) inzuzo ekwakheni umzimba

I-Salk's Cellular Neurobiology Laboratory yaqala ngeekhemikhali ezimbini ezifunyenwe kwizityalo ezibonakalise iimpawu zonyango: i-fisetin, umkhiqizo wemvelo ovela kwiziqhamo nemifuno, kunye ne-curcumin, kwi-curry spice. Ukusuka kula maqela, iqela laqulunqa ezintathu AD iziyobisi abaviwa abaxhomekeke ekubeni banakho ukukhusela i-neurons kwizinto ezininzi ezinobungozi ezinxulumene nobuchopho obuguga. Lebhu ibonise ukuba aba baphathi abathathu abaqulunqwayo (ababizwa ngokuba yiCMS121, iCAD31 kunye J147), kunye ne-fisetin kunye ne-curcumin, zanciphisa iimpawu ze-molecular ze-aging, kunye ne-dementia, kwaye zandisa ubomi obuphakathi kwamagundane okanye iimpukane.

Kubaluleke kakhulu, iqela libonise ukuba iindlela zee molecular ezibandakanyeka ngaba baviwa bezidakamizwa ze-AD zifana nezinye iimveliso eziphandiweyo eziphandiweyo ezichanekileyo eziyaziwayo ukuba zandisa ubomi bezilwanyana ezininzi. Ngenxa yesi sizathu, kwaye ngokusekelwe kwiziphumo zezifundo zabo zangaphambilini, iqela lithi i-fisetin, i-curcum kunye nabaviwa abathathu bezidakamizwa ze-AD bahlangabezana nencazelo yokuba yi-geroneuroprotectors.

Ezinye izifundo kwilebhu zichonga ukuba ngaba ezi zinto zineziphumo kwizitho ezingaphandle kwengqondo. "Ukuba la mayeza aneenzuzo kwezinye iinkqubo zomzimba, ezifana nokugcina umsebenzi wezintso kunye nempilo yonke yemisipha, zingasetyenziswa ngeendlela ezongezelelweyo zokunyanga okanye ukukhusela izifo zokuguga," utshilo u-Schubert.

-Ichiza lika-Alzheimer (iziyobisi ze-AD) abagqatswa: J147

Curcumin, isithako esiyinhloko se-Indian curry spice turmeric, i-multitgetget composound eyanciphisa ukuvuvukala, ukuveliswa kweROS, i-amyloid yetyhefu, kunye ne-excitotoxicity, kwaye isebenza kakuhle kwiimodeli ze-AD. Nangona kunjalo, i-curcumin inomsebenzi ophantsi kakhulu we-neurotrophic activity, ukungabikho kobuhlwempu kunye nokungena ebuchosheni. Ukuphucula umsebenzi we-neurotrophic and stability of stability ye-curcumin, sasebenzisa i-SAR eqhutywe nge-chemistry yokuphucula ukuphucula izixhobo ze-pharmacological ngeli xesha likhula ukwanda kwayo kunye nemisebenzi yemisebenzi yezinto eziphilayo. Ekuqaleni i-labile diketo inkqubo ye-curcumin yaguqulwa kwi-pyrazole ukwenza i-CNB-001, ngokuzinza okuzinzileyo kunye nomsebenzi ongenasiphelo kwi-curcumin. Ukuhlolisiswa kwamagqabantshintshi kwinqanaba elithathu le-phenyl le-CNB-001 lityhila ukuba amaqela e-hydroxyl ayimfuneko ekusebenziseni iimvavanyo eziyisixhenxe zokuhlola. Ukongezwa kwamacandelo amabili e-methyl kwi-pyrazole eqhotyoshelweyo i-phenyl ring yikhokelela ku-CNB-023 ngokuphucula amandla kwi-CNB-001. Nangona kunjalo, i-CNB-023 iphezulu ye-lipophilic (cLogP = 7.66), kwaye ihlanganiswe neepoplicity ephezulu ineemfanelo ezininzi. Ukunciphisa i-lipophilicity kunye nokuchonga iimfuno ezincinane zokwenza umsebenzi, enye yamacandelo ama-cinnamyl isuswe kwaye ukuqhutyelwa phambili kuqhutywe kwikholeji encinci kakhulu J147. I-J147 i-5-10 amaxesha amaninzi kuwo onke amalinge okuhlola okufana ne-CNB-001, ngelixa i-curcumin inomsebenzi omncinci okanye akukho naliphi na isilingo. I-J147 ayinamandla nje kuphela kodwa nayo inezixhobo ezintle ze-physicochemical (MW = 350, cLogP = 4.5, tPSA = 42). J147 (1146963-51-0) uye wafundiswa ngokubanzi kwiimodeko eziqhelekileyo ze-AD kunye ne-AD apho zineempembelelo ezigqithiseleyo zokwelapha.

Izidakamizwa ze-Alzheimer (izidakamizwa ze-AD) J147 CMS121 ICAD31

Umntu oxhalabileyo owenza i-J147 unokuthotywa amine / hydrazines ezinamakha ezinokubangela i-carcinogenic. Ukuphonononga oku kunokwenzeka, uzinzo lwe-J147 lwafundwa kwii-microsomes, kwi-plasma yegundane, nakwi-vivo. Kwaboniswa ukuba J147 (I-1146963-51-0) ayihlaziyikiyo kumamine amnandi okanye i-hydrazines, ukuba i-scaffold isisigxina kakhulu, kwaye iguqulelwe kwi-metabolites ezimbini okanye ezintathu kwi-metabolites, i-mouse, i-rat, i-monkey kunye ne-dog microsomes. Ukuhlolisisa ukhuseleko lwezi metabolites, senze zonke izilwanyana ze-metabolite zesibindi zezilwanyana kwaye zizilinga ukwenza umsebenzi wezinto eziphilayo kwiimvavanyo ze-neuroprotection. Akukho nanye kula ma-metabolites anetyhefu, kwaye ezininzi zeemetabolithi zinemisebenzi ye-biological efana neY147.

-Ichiza lika-Alzheimer (iziyobisi ze-AD) abagqatswa: CMS121

I-CMS121 yikamva fisetin. Kule minyaka imbalwa idlulileyo, sibonisile ukuba i-flavonoid fisetin iyasebenza ngomlomo, isebenza nge-neuroprotective, kunye ne-molecule eyonyusa ukuqonda kwiimodeli ezininzi zezilwanyana zokuphazamiseka kwe-CNS. I-Fisetin inemisebenzi ethe ngqo yokulwa ne-antioxidant kwaye inokugcina amanqanaba e-intracellular ye-GSH phantsi koxinzelelo. Ukongeza, i-fisetin inemisebenzi ye-neurotrophic kunye ne-anti-inflammatory. Olu luhlu lubanzi lwezenzo lubonisa ukuba i-fisetin inesakhono sokunciphisa ukuphulukana nomsebenzi we-neurological onxulumene nokuphazamiseka okuninzi. Nangona kunjalo, i-EC50 yayo iphakame kakhulu kwizilingo ezisekwe kwiseli (2-5 μM), lipophilicity ephantsi (cLogP 1.24), tPSA ephezulu (107), kunye nokungafumaneki kakuhle kwe-bioavailability kuthintele i-fisetin yophuhliso olungaphezulu njengomgqatswa weziyobisi.

Izidakamizwa ze-Alzheimer (izidakamizwa ze-AD) J147 CMS121 ICAD31

Umceli mngeni yayikukuphucula amandla e-fisetin kwiindlela ezininzi ze-neuroprotective pathways ngelixa kwangaxeshanye ziguqula iipropathi zayo ze-physicochemical ukuze zihambelane ngakumbi nezo ziphumeleleyo iziyobisi ze-CNS (ubunzima bemolekyuli ≤ 400, cLogP-5, tPSA-90, HBD-3, Iindlela ezimbini ezahlukeneyo zasetyenziselwa ukuphucula i-fisetin. Okokuqala, amaqela ahlukeneyo e-hydroxyl aguqulwe ngendlela echanekileyo yokuphelisa i-sulfate / glucuronidate metabolites. Kwindlela yesibini, i-flavone scaffold yatshintshwa yaba yi-quinoline, ngelixa kwangaxeshanye kugcinwa izinto eziphambili ze-fisetin.Ukusebenzisa indlela yethu yokufumanisa iziyobisi, sivelise inani lezinto ezinemisebenzi ephuculweyo kwi-neuroprotective oxytosis nakwi Vitro ischemia uvavanyo. Imisebenzi emithathu eyongezelelweyo ye-fisetin igcinwe kwiziphumo, kubandakanya ukugcinwa kwe-GSH, inhibition ye-bacterial lipopolysaccharide (LPS) eyenze ukuba kusebenze i-microglial activation, kunye ne-PC7 cell umahluko, umlinganiso womsebenzi we-neurotrophic. I-Flavone evela kwi-CMS-12 kunye ne-quinolone evela kwi-CMS-140 ngama-121 kunye nama-600 amaxesha anamandla ngakumbi, ngokulandelelana, kune-fisetin kulingo lwe-ischemia (Umzobo . Yiyo loo nto kunokwenzeka ukugcina iimpawu ze-polyphenol ngelixa uphucula imeko ye-physiochemical kunye ne-pharmacological yecomputer.

-Ichiza lika-Alzheimer (iziyobisi ze-AD) abagqatswa: CAD31

Zonke iziphumo zomzimba ze-CAD31 ziyakulungeleka kumxholo wokuthintela ezinye iziganeko ezinobungozi kwizifo ezithintekayo ezindala.

I-CAD31 sisifo se-Alzheimer's (AD) umgqatswa weziyobisi okhethwe ngenxa yesakhono sayo sokukhuthaza ukuphindaphindwa kweseli ye-embryonic stem yeeseli zangaphambi kweseli kunye nakwii-APPswe / PS1ΔE9 iimpuku. Ukuhambisa i-CAD-31 isiya eklinikhi, kwenziwa amalinge okumisela iipropathi zayo zokuthintela ukhuseleko kunye neekhemesti, kunye nokuvavanya ukusebenza kwayo kunyango kwimodeli ye-AD engqongqo.

I-CAD31 inezixhobo ezinamandla ezinonophelo lwe-neuroprotective kwiimvavanyo zeeseliti ze-nerve ezihlukeneyo ezi-6 ezifanisa nezobisi ezibonwe kwingqondo yobudala. Izifundo ze-Pharmacological kunye neyokuqala zonyango zibonisa ukuba i-CAD31 isingeniso sengqondo kunye nokuba ikhuselekile. Xa zondliwa kumdala, iimpawu ze-APPswe / PS1ΔE9 AD ezisuka kwiinyanga ze-10 zeenyanga ze-3 ezongezelelweyo kwindlela yokwelapha yesi sifo, kukho ukunciphisa ubunzima beememori kunye nokuvutha kwengqondo, kunye nokwanda kwindlela proteins. Idatha ye-molecule yamatafula ephuma kwingqondo kunye ne-plasma ibonise ukuba umphumo omkhulu we-CAD-31 usekelwe kwi-fatty acid metabolism kunye nokuvuvukala. Uhlalutyo lwendlela yokubonakalisa i-gene expression data lubonise ukuba i-CAD-31 ineempembelelo ezinkulu kwi-synapse ukwakheka kunye ne-AD yamandla emitha.

isiphelo

Iqela lophando ngoku lijolise ekufumaneni i-GNP ezimbini kwiilingo zabantu. I-fisetin, i-CMS121, okwangoku kwizifundo zeengxubevange zezilwanyana ezifunekayo kwi-FDA imvume yokuqala iimvavanyo zeklinikhi. I-curcumin evela J147, ngaphantsi kokuhlaziywa kwe-FDA yesibonelelo sokuqala uvavanyo lweekliniki ngo-AD ekuqaleni konyaka ozayo. Eli qela liceba ukubandakanya abamakishi be-biochemical ukuguga kwiimvavanyo zeclini ukuzama ukuvavanya iziphumo ezinokuthi zenze i-geroprotective impembelelo. Abaphandi bathi ukufumanisa kwabaviwa beziyobisi be-AD baqinisekisa indlela yokufumanisa izidakamizwa eziye zaphuhliswa njengendlela ecacileyo yokuchonga GNP izixhobo eziza kukunceda ukuguga okunempilo. Oku kunokukhawulezisa kakhulu umbhobho wamachiza ukuphatha izifo zokuguga okwangoku akukho unyango.

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