Chii chinonzi Alzheimer's and Geroprotectors (GNPs)

Alzheimer's ndiyo inonyanya kukonzeresa kuora mwoyo, imhando ye dementia inokonzeresa matambudziko nekurangarira, kufunga uye maitiro. Zviratidzo zvinowanzo kukura zvishoma nezvishoma uye zvichitowedzera kuwedzera nekufamba kwenguva, zvichiva zvakaomarara zvakakwana kupindira nemabasa ezuva nezuva.Chirwere cheAlzheimer nhoroondo dze60 muzana kusvika ku80 muzana yekutengesa kwemangwana. Uye kukwegura ndiyo yakanyanya ngozi panjodzi dzezvirwere zvakawanda, kusanganisira chirwere cheAlzheimer (AD) uye kenza.

Geroprotectors, inonzi senotherapeutic inopindira kukanganisa iyo inokonzera kukwegura uye zvirwere zvine chokuita nezera, uye nekudaro nekuwedzera nguva yeupenyu hwemhuka. Tsvakurudzo itsva yeSalk yave ichitsvaga chikamu chakasiyana-siyana chezvikamu izvi, zvinonzi geroneuroprotectors (GNPs), izvo zviri AD vachengeti vezvinodhaka uye vanononoka kukwegura mumakonzo.

 

Alzheimers drug (AD drug) vakatsvaga J147 CMS121 CAD31

 

Chikonzero chechirwere cheAlzheimer

Vatsvagiri vanotenda kuti hapana chimwe chikonzero chechirwere cheAlzheimer. Unowana sei chirwere cheAlzheimer? Chirwere ichi chinogona kukura kubva pane zvakawanda zvinhu, senge genetics, mararamiro uye nharaunda. Masayendisiti akaona zvinhu zvinowedzera njodzi yeAlzheimer's. Kunyange zvimwe zvinhu zvine njodzi - zera, nhoroondo yemhuri uye nhaka - zvisingachinjike, humbowo huri kubuda hunoratidza kuti panogona kunge paine zvimwe zvinhu zvatinogona kukurudzira.

-Age

Iyo inonyanya kuzivikanwa njodzi kune Alzheimer's iri kuwedzera zera, asi Alzheimer's haisi yakajairwa chikamu chekweguru. Kunyange zera richiwedzera njodzi, hachisi chikonzero chakanangana neAlzheimer's.

Vazhinji vanhu vane chirwere ava makumi matanhatu nemashanu zvichikwira. Mushure memakore makumi matanhatu nemashanu, njodzi yeAlzheimer inopetwa kaviri pamakore mashanu. Mushure memakore makumi masere nemashanu, njodzi inosvika chinenge chetatu.

-Family history

Imwe ngozi yakasimba inguva yemhuri. Vaya vane mubereki, hama kana hanzvadzi neAlzheimer zvinowanzoita kuti zvirwere zvirwere. Ngozi inowedzera kana kupfuura imwe yemhuri yako ine chirwere.

-VaGenesis (hutano)

Masayendisiti anoziva mageneti anowanikwa muAlzheimer's. Zvikamu zviviri zvejenisi zvinopesana kana munhu ari kurwara nechirwere: njodzi dzejeni uye deterministic jenesi.

-Kukuvadzwa

Iko kune hukama pakati pekukuvara kwemusoro uye ramangwana njodzi yekuora mwoyo. Dzivirira huropi hwako nekusunga bhandi rako remumagaro, kupfeka ngowani yako paunenge uchiita zvemitambo, uye "kudonhedza-pasi" imba yako.

-Iye-musoro-kubatana

Humwe humwe uchapupu hwakasimba hunobatanidza hutano hwehuropi nemoyo weutano. Izvi zvinonzwisisika, nokuti uropi hunochengetedzwa nemimwe mitambo yakawanda yemuviri yemidziyo yeropa, uye mwoyo inokonzerwa nekupura ropa kuburikidza nemidziyo yeropa kuuropi.

Alzheimer's drug (AD drug) candidates: J147, CMS121, CAD31

Nhasi, Alzheimer's iri pamberi pekutsvaga kwetsika. Vatsvagiri vari kushanda kuti vafumure akawanda maficha echirwere cheAlzheimer uye mamwe madhenda sezvazvinogona. Kumwe kwekufambira mberi kunoshamisa kwakajekesa kuti Alzheimer's inobata sei huropi. Tariro iyi iyi nzwisiso irinani inotungamira kumarapirwo matsva. Dzakawanda nzira dzinogona kuitika parizvino dziri kuongororwa pasi rese.

Kurema kwehutachiona hwechirwere 2,4-Dinitrophenol (DNP) inobatsira mukuvaka muviri

Salk's Cellular Neurobiology Laboratory yakatanga nemakemikari maviri akawanikwa mumiti yakaratidza mishonga: fisetin, chigadzirwa chechisikigo chinobva kunezvibereko nemiriwo, uye curcumin, kubva pamuchero we-curry spice turmeric. Kubva izvi, boka racho rakagadzira zvitatu AD zvinodhaka vanobvumirana vanovakirwa pamusana pekukwanisa kwavo kudzivirira neuroni kubva kune dzakawanda zvinodhaka zvinokonzerwa nehutano hwehuchembera. Irobhu yakaratidza kuti idzi nhatu dzakagadziriswa (dzinonzi CMS121, CAD31 uye J147), pamwe chete ne fisetin uye curcumin, yakaderedza ma molecular marker ekukwegura, pamwe nekuora mwoyo, uye akawedzera upenyu hwemukati hweveve kana nhunzi.

Zvinonyanya kukosha, boka racho rakaratidza kuti maitiro e molecular anobatanidzwa nevaya vakadanwa neAIDS vane zvimwe zvakafanana nezvimwe zviviri zvakanyatsotsvakurudzwa zvakagadzirirwa maitiro ayo anozivikanwa kuwedzera upenyu hwemhuka dzakawanda. Nokuda kwechikonzero ichi, uye zvichibva pamigumisiro yezvidzidzo zvavo zvekare, boka rinotaura kuti fisetin, curcumin uye vatatu veDD zvinodhaka zvinosangana neshoko rekuve geroneuroprotectors.

Zvimwe zvidzidzo mubhuku iri zvinosarudza kana izvi zvinokonzerwa nemigumisiro kune nhengo dzisiri kunze kweuropi. "Kana madhiragi aya ane zvigaro kune mamwe masangano emumuviri, akadai sekuchengetedza mafungiro epfungwa uye hutano hwehutano hwemasumbu, hunogona kushandiswa mune dzimwe nzira dzokurapa kana kudzivirira zvirwere zvekukwegura," anodaro Schubert.

- Alzheimer's drug (AD drug) musarudzo: J147

Curcumin, icho chinonyanya kushandiswa kweIndia curry spice turmeric, inowanikwa mumataundi akawanda anodzikisa kuputika, rOS production, amyloid toxicity, uye excitotoxicity, uye inoshanda zvikuru mumidhori yemhando dze AD. Zvisinei, curcumin ine yakanyanya kwazvo neurotrophic activity, mashoma bioavailability, uye urombo husina kunaka hwekurota. Kuvandudza basa re-neurotrophic uye kugadzikana kwemagetsi kwe curcumin, takashandisa SAR inotungamirirwa nekushandura makemikari kunatsiridza mapepa emagetsi panguva imwechete kuwedzera simba rayo uye zvimwe zvezvinhu zvayo zvehupenyu. Pakutanga i-labile diketo system ye curcumin yakashandurwa ku pyrazole kuti iite CNB-001, nekugadzikana kwakadzikama uye neuroprotective basa pamusoro pe curcumin. Kuongororwa kwemaitiro emapoka pazvinhu zvitatu zve phenyl zve CNB-001 zvakaratidza kuti mapoka e-hydroxyl haafaniri kuitwa mumabasa manomwe ekuongorora. Kuwedzerwa kwemaviri emamethyl kusvika ku pyrazole yakabatana nepenyl ring yakaita kuti CNB-023 iwedzere kuwedzera pamusoro pe CNB-001. Zvisinei, CNB-023 inonyanya kuongororwa (cLogP = 7.66), uye inobatanidza nepamusoro yepopophilicity ine zvikwereti zvakawanda. Kuti kuderedze lipophilicity uye kuziva kuti zvigadziriswa zvidimbu zvekuita basa, rimwe remapoka maviri e cinnamyl rakabviswa uye huwandu hwekugadzirisa hunoita kuti huve duku duku J147. J147 ndeye 5-10 nguva dzakawanda pane dzose dzekuongorora maitiro se CNB-001, nepo curcumin ine zvishoma kana kusina basa mune imwe nzira ipi zvayo. J147 haisi yakasimba chete asi inewo yakanaka ye physicochemical properties (MW = 350, cLogP = 4.5, tPSA = 42). J147 (1146963-51-0) yakadzidzwa zvakanyanya muvanhu vakwegura vakwegura uye AD mienzaniso iyo ine maitiro akanaka ekurapa.

Alzheimers drug (AD drug) vakatsvaga J147 CMS121 CAD31

Mumwe munhu anonetsekana anoita J147 inogona kudzikisirwa kune anonhuwirira amines / hydrazines ayo anogona kunge ari carcinogenic. Kuti uongorore mukana uyu, kugadzikana kwemagetsi kweJ147 kwakadzidzwa mumicrosomes, mune mbeva plasma, uye mu vivo. Zvakaratidzwa izvozvo J147 (1146963-51-0) haisi yakasvibiswa kunonhuwira amines kana hydrazines, kuti scaffold yakanyarara, uye kuti yakashandurwa kuviri kana matatu metabolite ye-oxidative mumunhu, mutsva, runa, monkey, uye imbwa microsomes. Kuti tiongorore kuchengetedzwa kwemasabetiti aya, takaita hutachiona hwevanhu vatatu hutachiona hwemabetabolite uye tinoedza kuite zvehupenyu muhutachiona hwehutachiona. Hapana chimwe chemasaboliti aya ane chepfu, uye akawanda emetabolites ane mabasa ezvinyorwa zvakafanana neaya aJ147.

- Alzheimer's drug (AD chinodhaka) musarudzo: CMS121

CMS121 ndiyo yakabva fisetin. Mumakore mashoma apfuura, isu takaratidza kuti iyo flavonoid fisetin inoshanda nemuromo, neuroprotective, uye cognition-inosimudzira mamorekuru mune dzinoverengeka mhuka mhando dze CNS kusagadzikana. Fisetin ine yakanangana antioxidant chiitiko uye inogona kuchengetedza epamukati maseru eGSH pasi pekushushikana. Uye zvakare, fisetin ine zvese neurotrophic uye anti-kupisa basa. Aya akasiyana siyana ezviito zvinoratidza kuti fisetin inokwanisa kudzikisa kurasikirwa kwehuropi basa rakabatana neakawanda matambudziko. Zvisinei, iyo yakakwirira EC50 mumasero akaedzwa (2-5 μM), low lipophilicity (cLogP 1.24), yakakwirira tPSA (107), uye hurombo bioavailability vane fisetin yakaganhurirwa yekufambira mberi kwekuwedzera semumiriri wemishonga.

Alzheimers drug (AD drug) vakatsvaga J147 CMS121 CAD31

Chinetso chaiva chokuvandudza fiti ye fisetin mune dzimwe nzira dzisingabvumirwi neuroprotective pathways uye panguva imwechete ichichinja mafungiro ayo ekugadzirisa kuti zvive zvakanyatsoenderana neaya akabudirira CNS madhiragi (molecular kuwanda ≤ 400, cLogP ≤ 5, tPSA ≤ 90, HBD ≤ 3, HBA ≤ 7) .Zvirevo zvakasiyana zvakashandiswa pakuvandudza fisetin. Mukutanga, mazana e-hydroxyl akasiyana-siyana akashandurwa nenzira yakarongeka kuti abvise sulfate / glucuronidate metabolites. Mukuswedera kwechipiri, flavone scaffold yakachinjwa kuva quinoline, panguva imwe chete ichichengetedza maitiro makuru ezvinyorwa zve fisetin.Ukushandisa nzira dzedu dzekutsvaga zvinodhaka zvinodhaka, takaita zvinhu zvakasiyana-siyana zvakagadziriswa nemabasa akawedzerwa zvakanyanya muurouroprotective oxytosis uye vitro ischemia zviyero. Zvimwe zvinhu zvitatu zvefisetin zvakachengetwa mune zvigadzirwa, kusanganisira kugadziriswa kweGSH, kuvharirwa kwebhakitiriya lipopolysaccharide (LPS) kwakakonzera microglial activation, uye PC12 chikamu kusiyana, chiyero cheurourotrophic. Flavone yakagadzirwa CMS-140 uye quinolone inokonzerwa CMS-121 ndeye 600 uye 400 nguva dzinowedzera zvakanyanya, zvakasiyana, kupfuura fisetin mumutambo we ischemia (Mufananidzo.) Saka, zvinokwanisika kuchengetedza unhu hukuru hwepolphenol uye uchivandudza zvose zvechimirochemical uye pharmacological properties yekombundi.

- Alzheimer's drug (AD chinodhaka) musarudzo: CAD31

Zvose zvezvipembenene zviitiko zveCAD31 zvaifadza mumamiriro ekudzivirira zvimwe zviitiko zvinotyisa muhutano hunosangana nehutachiona hwehutano.

CAD31 chirwere cheAlzheimer (AD) mukwikwidzi wezvinodhaka uyo akasarudzwa pahwaro hwekugona kwawo kumutsidzira kudzokororwa kwemunhu embryonic stem cell-yakatorwa neural preursor maseru pamwe neAPMPswe / PS1ΔE9 AD mbeva. Kufambisa CAD-31 kuenda kukiriniki, kuyedza kwakaitwa kuti itsvage neuroprotective uye pharmacological zvivakwa, pamwe nekuyedza kwayo kurapa kushanda mune yakasarudzika mbeva modhi yeAD.

CAD31 ine simba neuroprotective zvinhu mumatanhatu matanhatu akasiyana-siyana masero esayeri esayira ayo anofanana neaxicity akaonekwa muuropi hwekare. Zvokurapa uye zvekare zvinotyisa zvinoratidza kuti CAD31 inopinda muuropi uye inogona kunge yakachengeteka. Kana uchinge wapiwa zvokudya zvekare, zviratidzo zve APPswe / PS1ΔE9 AD mice kubva pamwedzi ye10 yemwedzi ye3 yakawedzerwa mune imwe nzira yekurapa kwechirwere ichi, pakanga pane kuderedza kusakanganwa kwepfungwa uye kuputika kwepfungwa, pamwe nekuwedzera kwekutaura synaptic proteins. Doro-molecule deta yemashoko kubva muuropi uye plasma yakaratidza kuti mhedziso huru yeCAD-31 inowanikwa pamafuta asidi metabolism nekuputika. Nzira yekuongorora kwemazwi ekutaura kwenhau yakaratidza kuti CAD-31 yakave nemigumisiro yakawanda pamasikirwo ekugadzira uye AD masimba emagetsi emagetsi.

mhedziso

Bhuku rekutsvakurudza ikozvino rinotarisa kuwana maGNP maviri mumatambudziko ekugadzirira vanhu. Iko fisetin inogadzirwa, CMS121, ikozvino mune zvidzidzo zvekunyadzisa zvemhuka zvinotarisirwa kuti FDA igamuchire kutanga matanho emakiriniki. The curcumin derivative, J147, iri pasi peRWB rekudzokorora kwekubvumira kutanga matanho emakiriniki AD kutanga gore rakatevera. Iboka racho rinoronga kuisa zviratidzo zvehupenyu hwehutano hwekukwegura mumakiriniki ekuedzwa kuti uongorore kuti zvinokonzerwa nehutachiona hwehutachiona.Vatsvakurudzi vanoti kuwanikwa kwevashandi veAIDS vanoshandisa mishonga inovimbisa nzira yekutsvaga mishonga yavakagadzirisa senzira inofadza yekuziva zvimwe GNP compounds izvo zvichabatsira kukurudzira kukwegura kwakanaka. Izvi zvinogona kukurumidza kuwedzera pipeline yemishonga yekurapa zvirwere zvekukwegura izvo zvisiri ikozvino kuporesa.

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