Meriana ea Alzheimer (AD drugs): J147, CMS121, CAD31

Posted on 07/10/2022 by Ngaka Monique o ngotse J147.

" Lefu la Alzheimer, e leng sesosa se atileng haholo sa 'dementia', ke mofuta oa 'dementia' o bakang mathata a ho hopola, ho nahana le boitšoaro. Matšoao a atisa ho hlaha butle-butle le ho mpefala ha nako e ntse e ea, qetellong a ba matla hoo a ka sitisang mesebetsi ea letsatsi le letsatsi. ’Me, bakeng sa maloetse a mangata, a kang lefu la Alzheimer (AD) le kankere, botsofali ke sesosa se kotsi ka ho fetisisa. "

1. Alzheimer's and Geroprotectors(GNPs) ke eng?
2.Sesosa sa lefu la Alzheimer
3.Bakhethoa ba lithethefatsi tsa Alzheimer(AD): J147, CMS121, CAD31
4.Conclusion

1. Alzheimer's and Geroprotectors(GNPs) ke eng?

Alzheimer's ke sesosa se tloaelehileng sa 'dementia', ke mofuta oa 'dementia' o bakang mathata mohopolong, menahanong le boits'oarong. Matšoao hangata a hola butle mme a mpefala ha nako e ntse e tsamaea, a ba matla hoo a ka sitisang mesebetsi ea letsatsi le letsatsi.Lefu la Alzheimer e ikarabella bakeng sa karolo ea 60 ho karolo ea 80 ea linyeoe tsa 'dementia'. Le botsofali ke kotsi e kholo ea mafu a mangata, ho akarelletsa lefu la Alzheimer (AD) le kankere.

Li-Geroprotectors, ke senotherapeutic e ikemiselitseng ho ama motso oa botsofali le maloetse a amanang le lilemo, 'me kahoo e lelefatsa bophelo ba liphoofolo. Phuputso e ncha ea Salk e se e fumane karolo e ikhethang ea lik'hemik'hale tsena, tse bitsoang geroneuroprotectors (GNPs), e leng batlatsi ba AD ba nang le lithethefatsi le ho liehisa botsofali litsong tsa litoeba.

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2.Sesosa sa lefu la Alzheimer

Bafuputsi ba lumela hore ha ho na sesosa se le seng sa lefu la Alzheimer's. U ba le lefu la Alzheimer joang? Boloetse bona bo ka hlaha linthong tse ngata, joalo ka lefutso, mokhoa oa bophelo le tikoloho. Bo-rasaense ba supile lintlha tse eketsang kotsi ea Alzheimer's. Le ha mabaka a mang a kotsi - lilemo, nalane ea lelapa le lefutso - li ke ke tsa fetoloa, bopaki bo hlahang bo bontša hore ho ka ba le lintlha tse ling tseo re ka li susumetsang.

-Age

Kotsi e tsebahalang ka ho fetisisa ea lefu la Alzheimer ke lilemo tse ntseng li eketseha, empa Alzheimer's ha se karolo e tloaelehileng ea botsofali. Le ha lilemo li eketsa kotsi, ha se sesosa se tobileng sa Alzheimer's.

Boholo ba batho ba nang le lefu lena ba lilemo li 65 le ho feta. Kamora lilemo tse 65, kotsi ea lefu la Alzheimer e imena habeli ka mor'a lilemo tse ling le tse ling tse hlano. Ka mor'a lilemo tse 85, kotsi e fihla hoo e ka bang karolo ea boraro.

- Histori ea lelapa

Ntho e 'ngoe e matla ea kotsi ke histori ea lelapa. Ba nang le motsoali, mor'abo rona kapa morali'abo rona ea nang le Alzheimer ba ka 'na ba hlaolela lefu lena. Kotsi e eketsa haeba batho ba fetang setho sa lelapa ba e-na le lefu lena.

-Geneti (bolaoli)

Bo-rasaense ba tseba hore liphatsa tsa lefutso li ameha Alzheimer's. Likarolo tse peli tsa liphatsa tsa lefutso li susumetsa hore na motho o hlaseloa ke lefu: liphatsa tsa lefutso tsa likotsi le liphatsa tsa lefutso tsa deterministic.

-Kola kotsi

Ho na le kamano pakeng tsa kotsi ea hlooho le kotsi ea kamoso ea 'dementia'. Sireletsa boko ba hau ka ho itlama ka lebanta la setulo, ho roala helmete ea hau ha u nka karolo lipapaling, le ho "senola" ntlo ea hau.

-Kamellano-hlooho-hlooho

Bo bong ba bopaki bo matla ka ho fetisisa bo ama bophelo bo botle ba boko bo botle ba pelo. Tlhaloso ena e utloahala, hobane boko bo matlafatsoa ke methapo e mengata ka ho fetisisa ea 'mele ea methapo ea mali,' me pelo e ikarabella bakeng sa ho pompa mali ka methapo ena ea mali ho ea boko.

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3.Bakhethoa ba lithethefatsi tsa Alzheimer(AD): J147, CMS121, CAD31

Kajeno, Alzheimer's e ka pele ho lipatlisiso tsa biomedical. Bafuputsi ba ntse ba sebeletsa ho sibolla likarolo tse ngata tsa lefu la Alzheimer's le dementias tse ling kamoo ho ka khonehang. Tsoelo-pele e 'ngoe e makatsang e hlahisitse leseli la hore na Alzheimer's e ama boko joang. Tšepo ke hore kutloisiso ena e betere e tla lebisa liphekolong tse ncha. Mekhoa e mengata e ka bang teng e ntse e etsoa lipatlisiso lefatšeng ka bophara.

Ho lahleheloa ke tefo ea lithethefatsi tsa 2,4-Dinitrophenol (DNP) melemo ea ho haha 'mele

Salk ea Cellular Neurobiology Laboratory e qalile ka lik'hemik'hale tse peli tse fumanoeng limela tse bontšitseng meriana: fisetin, sehlahisoa sa tlhaho se entsoeng ka litholoana le meroho le curcumin, ho tswa ho monate oa li-turmeric. Ho tsoa ho tsena, sehlopha se ile sa etsa lintho tse tharo AD lithethefatsi ba itšetlehileng ka bokhoni ba bona ba ho sireletsa li-neurone lijong tse ngata tse amanang le botsofali bo tsofetseng. Lebu e bontšitse hore likhetho tsena tse tharo (tse tsejoang e le CMS121, CAD31 le J147), hammoho le fisetin le curcumin, li fokolitse mekhoa ea limolek'hule tsa botsofali, hammoho le 'dementia' 'me li atolosa bophelo ba nakoana ea litoeba kapa lintsintsi.

Habohlokoa, sehlopha se ile sa bontša hore litsela tsa limolek'hule tse kopanetsoeng ke batho ba nang le lithethefatsi tsa AD li tšoana le lik'hemik'hale tse ling tsa lipatlisiso tse peli tse tsebahalang ho eketsa nako ea bophelo ba liphoofolo tse ngata. Ka lebaka lena, 'me ho itšetlehile ka liphello tsa lithuto tsa bona tsa pele, sehlopha se re fisetin, curcumin le batlatsi ba bararo ba AD ba sebelisa lintlha tsa ho ba geroneuroprotectors.

Liphuputso tse ling ka laborateng li etsa qeto ea hore na lik'hemik'hale tsena li na le liphello ho litho tse ka ntle ho boko. "Haeba lithethefatsi tsena li na le melemo bakeng sa mefuta e meng ea 'mele, e kang ho boloka liphio le mosebetsi oa bophelo bo botle, li ka sebelisoa ka litsela tse eketsehileng tsa ho phekola kapa ho thibela mafu a botsofali," Schubert o re.

- Bakhethoa ba lithethefatsi tsa Alzheimer's (AD): J147

Curcumin, motsoako o moholo oa Indian curry spice turmeric, ke metsoako e mengata e fokotsang ho ruruha, tlhahiso ea ROS, chefo ea li-amyloid, le excitotoxicity, 'me e sebetsa hantle mefuteng ea AD. Leha ho le joalo, curcumin e na le tšebetso e tlaase ea neurotrophic, ho se be le bothata bo botle ba booa, le ho haelloa ke boko boko. Ho ntlafatsa ts'ebetsong ea methapo ea methapo ea methapo ea methapo ea methapo ea methapo ea morumo, re sebelisitse SAR hore e sebelise mokhoa oa ho ntlafatsa litsebi tsa phepelo ea meriana ka nako e tšoanang ho eketsa potency ea eona le likarolo tsa mesebetsi ea eona ea tlhaho. Qalong le labile diketo tsamaiso ea curcumin e fetotsoe ho pyrazole ho etsa CNB-001, ka ts'ebetso e tsitsitseng le ts'ebetso ea phekolo ea meriana ho feta curcumin. Ho hlahlojoa ha lihlopha tsa lihlopha tse meketeng e meraro ea phenyl ea CNB-001 ho bontšitse hore lihlopha tsa hydroxyl ha lia hlokahale bakeng sa ho sebetsa litlhahlobong tse supileng tsa ho hlahloba. Ho phaella ha lihlopha tse peli tsa methyl ho pyrazole tse khomaretseng lesale la phenyl li lebisitse ho CNB-023 ka potency e ntlafetseng ka CNB-001. Leha ho le joalo, CNB-023 e na le lipophilic (cLogP = 7.66), mme e kopantsoe le lipophilicity e phahameng e na le mekoloto e mengata. E le ho fokotsa lipophilicity le ho lemoha lintho tse fokolang tse hlokahalang bakeng sa tšebetso, lihlopha tse peli tsa cinnamyl li ile tsa tlosoa 'me ho ntlafatsoa ho eketsehileng ho lebisitsoe ho molek'hule e nyane haholo J147. J147 ke linako tse ling tsa 5-10 tse matla ka ho fetisisa litlhahlobo tsa ho hlahloba litlhahlobo joaloka CNB-001, ha curcumin e e-na le tšebetso e fokolang kapa e se nang letho ho tlhahlobo leha e le efe. J147 ha e na matla feela empa e boetse e na le melemo e ntle ea theknoloji (MW = 350, cLogP = 4.5, tPSA = 42). J147 (1146963-51-0) e 'nile ea ithutoa ka ho pharaletseng ka mehlala e tloaelehileng ea batho ba hōlileng le ea AD moo e nang le katleho ea phekolo e ikhethileng.

Ho tšoenyeha ha motho e mong ea etsang J147 ho ka nyenyefatsoa ho li-amine / hydrazine tse nkhang hamonate tse ka bang le kankere. Ho lekola monyetla ona, botsitso ba 'mele ba J147 bo ile ba ithutoa ka li-microsomes, ka plasma ea mouse le ka vivo. Ho ile ha bontšoa seo J147 (1146963-51-0) ha e silafatsoe ke li-amine kapa li-hydrazine, hore scaffold e tsitsitseng ka mokhoa o ts'oarehileng, le hore e fetotsoe ho metabolite tse peli kapa tse tharo tsa methapole e nang le metsoako ea motho, mouse, rat, monkey le dog's microsomes. Ho hlahloba tšireletseho ea metabolites, re sebelisitse metabolite ea methapo e meraro ea sebete ea batho 'me re e leka bakeng sa liketsahalo tsa likokoana-hloko litlhahloking tsa meriana. Ha ho le e 'ngoe ea metabolite e kotsi,' me metabolite e mengata e na le liketsahalo tsa likokoana-hloko tse tšoanang le tsa J147.

- Bakhethoa ba lithethefatsi tsa Alzheimer's (AD): CMS121

CMS121 ke se tsoa ho sona fisetin. Lilemong tse 'maloa tse fetileng, re bontšitse hore flavonoid fisetin ke molek'hule e sebetsang ka molomo, e sireletsang masapo le e matlafatsang kutlo ho mefuta e mengata ea liphoofolo ea mathata a CNS. Fisetin e na le ts'ebetso e tobileng ea antioxidant mme e ka boloka li-intracellular level tsa GSH li le tlasa khatello ea maikutlo. Ntle le moo, fisetin e na le ts'ebetso ea neurotrophic le anti-inflammatory. Liketso tsena tse fapaneng li fana ka maikutlo a hore fisetin e na le bokhoni ba ho fokotsa tahlehelo ea ts'ebetso ea methapo e amanang le mathata a mangata. Leha ho le joalo, EC50 ea eona e batlang e phahame haholo litekong tse thehiloeng ho sele (2-5 μM), low lipophilicity (cLogP 1.24), high tPSA (107), le bioavailability e fokolang e na le fisetin e fokolang bakeng sa nts'etsopele e tsoelang pele joalo ka mokhethoa oa lithethefatsi.

Phephetso e ne e le ho ntlafatsa matla a fisetin ka litsela tse ngata tsa phekolo ea meriana empa ha nako e le 'ngoe e fetola thepa ea eona ea lintho tse phelang e le hore e lumellane haholo le ea katleho ea lithethefatsi (CNS) HBA ≤ 400). Mekhoa e 'meli e fapaneng e ne e sebelisetsoa ho ntlafatsa fisetin. Ka lekhetlo la pele, lihlopha tse fapaneng tsa hydroxyl li fetotsoe ka tsela e tsitsitseng ho felisa metabolites ea sulfate / glucuronidate. Ka tsela ea bobeli, flavone scaffold e fetotsoe ho quinoline, ha ka nako e ts'oanang e boloka lintlha tsa bohlokoa tsa fisetin. Ha re sebelisa mokhoa oa ho fumana lihlahisoa tsa meriana e mengata, re hlahisitse lihlahisoa tse 'maloa ka mesebetsi e ntlafetseng haholo ho oxytosis ea motlakase liteko tsa vitro ischemia. Mesebetsi e meng e meraro ea fisetin e ne e bolokiloe lihlahisoa, ho kenyeletsa tlhokomelo ea GSH, ho thibela kokoana-hloko ea lipterol lipopolysaccharide (LPS), le phapang ea cellphone ea PC5, tekanyo ea liketsahalo tsa neurotrophic. CV-90 e entsoeng ka Flavone le CMS-3 e nkiloeng ke quinolone ke 7 le linako tse ling tsa 12 tse nang le matla a mangata ho feta fisetin ka tekanyo ea ischemia (Setšoantšo.) Kahoo, ho ka khoneha ho boloka litšobotsi tse ngata tsa polyphenol ha ho ntse ho ntlafatsa 'mele metsoako ea phekolo ea metsoako.

- Bakhethoa ba lithethefatsi tsa Alzheimer's (AD): CAD31

Mefuta e mengata ea liphello tsa CAD31 e ne e le molemong oa ho thibela liketsahalo tse chefo lilemong tsa botsofali tse amanang le botsofali.

CAD31 ke mokhethoa oa lithethefatsi oa Alzheimer's (AD) o khethiloeng motheong oa bokhoni ba eona ba ho susumetsa ho ipheta ha lisele tsa "embryonic stem stem" tse tsoang ho "cell" tse tsoang pele le ho litoeba tsa APPswe / PS1ΔE9 AD. Ho tsamaisa CAD-31 ho ea tleliniking, ho ile ha etsoa liteko ho fumana hore na e na le tšireletso ea meriana le meriana, le ho lekola tšebetso ea eona ea kalafo ka mokhoa o thata oa toeba oa AD.

CAD31 e na le methapo e metle ea methapo ea tšoaetso ea methapo e tšeletseng ea methapo e ts'oanang e nang le methapo e ts'oanang le ea likokoana-hloko tse hlokomelang boko ba khale. Liphuputso tsa boipheliso le tsa pele tsa tlhaho li bontša hore CAD31 ke motho ea nang le boko ba 'mele' me mohlomong o sireletsehile. Ha o fepeloa ho tloha khale, matšoao a matšoao a APPswe / PS1ΔE9 AD litoeba tse qalang likhoeli tsa 10 bakeng sa likhoeli tse eketsehileng tsa 3 ka mokhoa oa phekolo oa lefu lena, ho ne ho fokotseha mohopolo oa ho hopola le ho ruruha ha boko, hammoho le keketseho ea polelo ea liprotheine tsa synaptic. Dintlha tse nyenyane tsa molek'hule tse tsoang bokong le plasma li bontšitse hore phello e kholo ea CAD-31 e thehiloe mafura a methapo ea metabolism le ho ruruha. Tsela ea ho hlahloba liphatlalatso tsa liphatsa tsa lefutso e bontšitse hore CAD-31 e na le liphello tse kholo ka sebopeho sa synapse le AD matla a litsela tsa metsoako.

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4.Conclusion

Sehlopha sa lipatlisiso se se se shebane le ho fumana li-GNP tse peli litsing tsa mantlha tsa meriana. Ho fumanoa fisetin, CMS121, hona joale ke lithuto tsa toxicology tsa liphoofolo tse hlokehang bakeng sa tumello ea FDA ho qala liteko tsa kliniki. Ho tsoa ha curcumin, J147, e tlas'a tlhahlobo ea FDA bakeng sa tumello ea ho qala liteko tsa meriana ea AD hoseng selemong se latelang. Sehlopha sena se rera ho kenyelletsa mekhoa ea likokoana-hloko ea botsofali litsing tsa lits'ebeletso tsa meriana ho hlahloba liphello tse ka 'nang tsa e-ba teng ka bongata. Bafuputsi ba re ho fumanoa ha batlatsi bana ba AD ba sebelisa mokhoa oa ho tsebahatsa lisebelisoa tse eketsehileng Lik'hemik'hale tsa GNP e tla thusa ho ntshetsa pele botsofali bo botle. Sena se ka fokotsa pipeline haholo bakeng sa lithethefatsi ho phekola maloetse a botsofali ao hona joale ho se nang pheko.

AASraw ke moetsi ea hloahloa oa J147, CMS121, CAD31 phofo e nang le lab e ikemetseng le fektheri e kholo e le ts'ehetso, tlhahiso eohle e tla etsoa tlas'a taolo ea CGMP le tsamaiso ea tsamaiso ea boleng. Tsamaiso ea phepelo e tsitsitse, litaelo tse peli tsa thekiso le tse rekisoang li amoheleha.Rea u amohela ho ithuta boitsebiso bo eketsehileng ka AASraw!

O mphihlise Joale

Mongoli oa sengoloa sena:

Ngaka Monique Hong o fumane lengolo UK Imperial College London Faculty of Medicine

Sengoli sa pampiri sa Scientific Journal:

1. Chen-yi Cheng
Sekolo sa Bongaka sa Motheo, Univesithi ea Bongaka ea Xinxiang, Xinxiang, Henan 453003, Chaena
2. Guoheng Zhong
Bioland Laboratory (Guangzhou Regenerative Medicine le Health Guangdong Laboratory), Guangzhou, 510005, China
3. Hanika Rizo
Lefapha la Mahlale a Lefatše, Setsi sa Geoscience sa Ottawa-Carleton, Univesithi ea Carleton, Ottawa, ON, K1S 5B6, Canada
4. Bing Z. Carter PhD
Univesithi ea Texas MD Anderson Cancer Center, Lefapha la Leukemia, 1515 Holcombe Blvd, Houston, TX 77030, USA

5.Jeffrey A. Herron

Lefapha la Boenjiniere ba Lik'hemik'hale le Likokoana-hloko, Univesithi ea Wisconsin-Madison, Madison, WI 53706, USA
Ha ho ka tsela leha e le efe ngaka/saense ena e buellang kapa ho buella ho rekoa, thekiso, kapa tšebeliso ea sehlahisoa sena ka lebaka lefe kapa lefe. Aasraw ha e na kamano kapa kamano, ho boleloa kapa ho seng joalo, le ngaka ena. Sepheo sa ho qotsa ngaka ena ke ho ananela, ho ananela le ho babatsa lipatlisiso tse felletseng le mosebetsi oa nts'etsopele o entsoeng ke bo-ramahlale ba sebetsanang le ntho ena.

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