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

I-Alzheimer iyona nto ibangela ukugula komzimba, luhlobo lwesifo sengqondo sokubangela ingxaki engqondweni, ukucinga nokuziphatha. Iimpawu zisoloko zikhula ngokukhawuleza kwaye zenzeke ngakumbi ngexesha, ziba nzima ngokwaneleyo ukuphazamisa imisebenzi yansuku zonke.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

Isizathu sesifo se-Alzheimer

Abaphandi bakholelwa ukuba akukho nto ebangela isifo se-Alzheimer. Ufumana njani isifo se-Alzheimer? Esi sifo sinokuvela kwimimandla emininzi, njenge-genetics, indlela yokuphila nokusingqongileyo. Iingcali zenzululwazi ziye zachonga izinto ezandisa ingozi ye-Alzheimer's. Nangona ezinye izinto ezinobungozi-ubudala, imbali yentsapho kunye nokuzalwa-ayikwazi ukutshintshwa, ubungqina obusakhulayo bubonisa ukuba kukho ezinye izinto esinokuzichaphazela.

-Age

Into eyaziwayo yengozi enkulu ye-Alzheimer iyanda, kodwa i-Alzheimer ayiyinto eqhelekileyo yokuguga. Nangona ubudala buyandisa ubungozi, akusiyo imbangela ngqo ye-Alzheimer's.

Uninzi lwabantu abanezifo zi-65 kwaye zikhulile. Emva kweminyaka eyi-65, umngcipheko we-Alzheimer uphindwe kabini kwiminyaka emihlanu. Emva kweminyaka eyi-85, umngcipheko ufinyelela phantse 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 unxibelelwano phakathi kokulimala kwentloko kunye nomngcipheko we-future dementia. Khusela ingqondo yakho ngokubhinqa ibhande lakho lokuhlala, ugqoke i-helmet yakho xa uthatha inxaxheba kwimidlalo, kwaye "ukuwa phantsi" kwekhaya 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 ihamba phambili ephando lwezolimo. Abaphandi bazama ukufumanisa iinkalo ezininzi ze-Alzheimer's disease kunye nezinye i-dementias ngokunokwenzeka. Ezinye zeyona nkqubela phambili ephawulekayo iye yacacisa indlela i-Alzheimer echaphazela ngayo ingqondo. Ithemba lukuqonda oku bhetele kuya kubakho unyango olutsha. Uninzi lweendlela ezinokuthi zingaphononongo emhlabeni jikelele.

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.

I-Alzheimer's drug (izidakamizwa ze-AD): I-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 ochaphazelekayo okwenza i-J147 ingahlaziywa kumamine / ama-hydrazines anamakhayo anokuthi abe ne-carcinogenic. Ukuhlolisisa oku kwenzeka, ukuzinza kokuxilongwa kweJ147 kwafundwa kwii-microsomes, kwiplasma yamagundane, nakwi-vivo. Kwa boniswa 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.

I-Alzheimer's drug (izidakamizwa ze-AD) abaviwa: CMS121

I-CMS121 yikamva fisetin. Kule minyaka embalwa edluleyo, sibonise ukuba i-florin flavonoid iyasebenza, i-neuroprotective, kunye ne-molocule yokuphucula ukuqonda. I-Fisetin inomsebenzi ochanekileyo we-antioxidant kwaye ingakwazi ukugcina ii-intracellular levels of GSH phantsi kwengcinezelo. Ukongezelela, i-fisetin inomsebenzi wesifo se-neurotrophic and anti-inflammatory. Uluhlu olubanzi lwezenzo lubonisa ukuba i-fisetin inokukwazi ukunciphisa ukulahleka komsebenzi wegazi ochaphazelekayo kunye neengxaki ezininzi. Nangona kunjalo, i-EC50 ephakamileyo kwi-esayini esekelwe kwiseli (2-5 μM), i-lipophilicity ephantsi (cLogP 1.24), i-tPSA ephezulu (107), kunye nokulahleka kwezinto ezinokungabikho kwemvelo kuye kwanciphisa i-fisetin ekuphuhliseni okuqhubekayo njengesigqirha seziyobisi.

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

Umngeni wawukujongana nokuphucula umthamo we-fisetin kwiindlela ezininzi ze-neuroprotective ngenkathi ngexesha elifanayo ukuguqula iipropati ze-physicochemical ukuba zihambelane kakhulu nezo mpahla ze-CNS (ubunzima bomzimba ≤ 400, cLogP ≤ 5, tPSA ≤ 90, HBD ≤ 3, I-HBA ≤ i7) .Iendlela ezimbini ezazisetyenziselwa ukuphucula i-fisetin. Ekuqaleni, amaqela e-hydroxyl ahlukeneyo aguqulwa ngendlela echanekileyo yokuphelisa i-sulfate / glucuronidate metabolites. Kwindlela yesibini, i-flavone scaffold yaguqulwa yaba yi-quinoline, ngoxa ngexesha elifanayo ligcina izinto eziphambili zesakhiwo se-fisetin. Ukusebenzisa indlela yethu yokufumanisa izidakamizwa ze-multitarget, siye savelisa inani elithathwe kwiimveliso eziphuculweyo kwi-oxytosis ye-neuroprotective ii-vitro ischemia. Imisebenzi emithathu eyongezelelweyo ye-fisetin yayigcinwa kwii-derivatives, kubandakanywa nokugcinwa kwe-GSH, ukuvimbela i-lipopolysaccharide ye-bacteria (LPS) yenze i-activation microglial, kunye nokwahlukana kweseli ye-PC12, umlinganiselo wesenzo se-neurotrophic. I-Flavone evela kwi-CMS-140 kunye ne-quinolone evela kwi-CMS-121 yi-600 kunye nama-400 amaxesha angaphezu kwamandla, ngokulandelanayo, kunokuba i-fisetin kwisilingo se-ischemia (Umfanekiso.) Ngoko ke, kunokwenzeka ukugcina iimpawu ze-polyphenol ngelixa ziphucula zombini i-physiochemical Iipropthiki ze-pharmacological zekhampani.

I-Alzheimer's drug (izidakamizwa ze-AD) abaviwa: ICAD31

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

I-CAD31 isifo sesifo se-Alzheimer (AD) umviwa okhethiweyo okhethwe ngokwamandla akhe okukhuthaza ukuphindaphinda kwe-cell embryonic stem cell-derived cell cell preseor cells kunye nakwi-APPswe / PS1ΔE9 AD. Ukuhambisa i-CAD-31 ekliniki, kwenziwa amalinge ukuze kuqinisekiswe iipropati ze-neuroprotective kunye ne-pharmacological, kunye nokuzama ukuphumelela kwindlela yokwelapha ye-AD.

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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