Kodi Alzheimer's and Geroprotectors (GNPs) ndi chiyani?

Chiwopsezo cha Alzheimer ndi chomwe chimayambitsa matenda a dementia, ndi mtundu wa matenda a dementia omwe amachititsa mavuto ndi kukumbukira, kulingalira ndi khalidwe. Zizindikiro kawirikawiri zimayamba pang'onopang'ono ndipo zimaipiraipira patapita nthawi, zimakhala zovuta kwambiri kuti zisawononge ntchito za tsiku ndi tsiku.Matenda a Alzheimer malipiro a 60 peresenti ku 80 peresenti ya matenda a dementia. Ndipo kukalamba ndilo vuto lalikulu la matenda ambiri, kuphatikizapo matenda a Alzheimer (AD) ndi khansa.

Geroprotectors, ndi senotherapeutic yomwe imakhudza mizu yoyambitsa ukalamba ndi matenda okalamba, ndipo motero imatalikitsa moyo wa nyama. Kafukufuku watsopano wa Salk tsopano watulukira gawo lapaderadera la mankhwalawa, omwe amatchedwa geroneuroprotectors (GNPs), omwe ali AD ofuna mankhwala ndi kuchepetsa ukalamba mu mbewa.

Odwala mankhwala a Alzheimers (AD mankhwala) J147 CMS121 CAD31

Chifukwa cha matenda a Alzheimer's

Ochita kafukufuku amakhulupirira kuti palibe chifukwa chimodzi cha matenda a Alzheimer's. Kodi mumalandira bwanji matenda a Alzheimer's? Matendawa amayamba kuchokera ku zinthu zambiri, monga majini, moyo ndi chilengedwe. Asayansi atulukira zinthu zomwe zimawonjezera chiopsezo cha Alzheimer's. Ngakhale zifukwa zina zoopsya - zaka, mbiri ya banja ndi chikhalidwe - sitingasinthe, umboni wotsimikizirika umasonyeza kuti pangakhale zinthu zina zomwe tingasinthe.

-Age

Chodziwika kwambiri chomwe chimachititsa kuti Alzheimer akule msinkhu, koma Alzheimer si gawo lachikulire. Ngakhale kuti zaka zikuwonjezera ngozi, sizomwe zimayambitsa Alzheimer's.

Anthu ambiri omwe ali ndi matendawa ndi 65 ndi okalamba. Pambuyo pa msinkhu wa 65, chiwopsezo cha Alzheimer chiwonjezeka zaka zisanu ndi chimodzi. Pambuyo pa msinkhu wa 85, chiwopsezocho chimafikira pafupifupi gawo limodzi.

-Mbiri yambiri

Chinthu china choopsa choopsa ndicho mbiri ya banja. Amene ali ndi kholo, mchimwene kapena mlongo ndi Alzheimer ndi omwe angathe kukhala ndi matendawa. Vuto limakula ngati oposa mmodzi m'banja ali ndi matendawa.

-Genesis (utsogoleri)

Asayansi amadziwa kuti majeremusi amapezeka mu Alzheimer's. Magulu awiri a majini amachititsa munthu kukhala ndi matenda: majeremusi oopsa komanso majini a deterministic.

Kuvulala kwakukulu

Pali mgwirizano pakati pa kuvulaza mutu ndi tsogolo la chidziwitso cha maganizo. Tetezani ubongo wanu pogwiritsa ntchito lamba lanu, kuvala chisoti chanu mukamagwira nawo masewera, ndi "kugwa-proofing" kwanu.

-Kugwirizanitsa mutu wamutu

Umboni wina wamphamvu kwambiri umakhudza thanzi la ubongo ndi thanzi labwino. Kulumikizana kumeneku kumakhala kosavuta, chifukwa ubongo umadyetsedwa ndi mitsempha yamatumbo yambiri ya thupi, ndipo mtima uli ndi udindo wopopera magazi kudzera mu mitsempha iyi ku ubongo.

Mankhwala osokoneza bongo a Alzheimers (AD mankhwala): J147, CMS121, CAD31

Masiku ano, Alzheimer's ili patsogolo pa kufufuza kwa zachilengedwe. Ochita kafukufuku akuyesetsa kupeza zambiri za matenda a Alzheimer ndi dementias. Zina mwazomwe zimayenda bwino kwambiri zafotokozera momwe Alzheimer imakhudza ubongo. Chiyembekezo ndikumvetsetsa bwinoko komweko kudzatsogolera kuchipatala chatsopano. Njira zambiri zomwe zingayambidwe panopa zikufufuzidwa padziko lonse lapansi.

Kuchepetsa kutaya mankhwala 2,4-Dinitrophenol (DNP) zopindulitsa mukumanga thupi

Salk's Cellular Neurobiology Laboratory inayamba ndi mankhwala awiri omwe amasonyeza mankhwala: fisetin, mankhwala opangidwa kuchokera ku zipatso ndi ndiwo zamasamba, ndi curcumin, kuchokera ku zonunkhira zam'madzi. Kuyambira izi, gululi linapanga atatu AD mankhwala Ovomerezeka chifukwa cha kuthekera kwawo kuteteza mphutsi ku zoopsa zambiri zomwe zimakhudzana ndi ubongo wokalamba. Labu inasonyeza kuti awa atatu opangidwa (omwe amatchedwa CMS121, CAD31 ndi J147), komanso fisetin ndi curcumin, zinachepetsanso zizindikiro za ukalamba, komanso matenda a maganizo, ndipo zimawonjezera moyo wamkati wa mbewa kapena ntchentche.

Chofunika kwambiri, gululo linawonetsa kuti njira za maselo zomwe zimagwiridwa ndi odwala AD izi ndi zofanana ndi mankhwala ena ofufuza bwino omwe amadziwika kuti athe kupatsa moyo wa zinyama zambiri. Pachifukwachi, ndipo pogwiritsa ntchito zotsatira za maphunziro awo akale, timuyi imanena kuti fisetin, curcumin ndi odwala atatu omwe ali ndi mankhwala osokoneza bongo AD ali ndi tanthauzo la kukhala geroneuroprotectors.

Maphunziro ena mu labu akudziwitsani ngati mankhwalawa ali ndi zotsatira pa ziwalo kunja kwa ubongo. "Ngati mankhwalawa ali ndi phindu kwa machitidwe ena a thupi, monga kusunga impso ndi matenda onse a minofu, akhoza kugwiritsidwa ntchito m'njira zina zothandizira kapena kuteteza matenda a ukalamba," anatero Schubert.

- Mankhwala osokoneza bongo a Alzheimers (AD mankhwala): J147

Curcumin, chofunika kwambiri cha Indian curry spice turmeric, ndi mzere wambirimbiri womwe umachepetsa kutupa, kupanga ROS, poizoni wa poizoni, ndi excitotoxicity, ndipo imakhala yogwira mtima kwambiri m'mafano a AD. Komabe, curcumin imakhala ndi zochepetsetsa kwambiri, zosafunika, komanso ubongo wovuta. Kupititsa patsogolo ntchito yokhudzana ndi ubongo komanso kuchepetsa kagayidwe kake, tinagwiritsira ntchito SAR kuyendetsa njira zowonjezeretsa mavitamini kuti izi zitheke kuwonjezera pa mphamvu zake komanso zochitika zake. Poyamba, labile diketo ya curcumin inasinthidwa ku pyrazole kupanga CNB-001, ndi kukhazikika bwino ndi ntchito zopanda ubongo pa curcumin. Kufufuza kwa magulu ozungulira pa mapuloteni atatu a phenyl a CNB-001 akuwulula kuti magulu a hydroxyl si oyenerera kuti achite ntchito zisanu ndi ziwiri zoyesera. Kuwonjezera kwa magulu awiri a methyl ku pyrazole pachokha puloteni ya phenyl inatsogolera CNB-023 ndi mphamvu yabwino ya CNB-001. Komabe, CNB-023 ndi lipophili (cLogP = 7.66), ndipo imagwirizanitsa ndi chikhalidwe chamaphunziro ali ndi zolemba zambiri. Pofuna kuchepetsa lipophilicity ndikuzindikira zochepa zomwe zimafunika kuchita, magulu awiri a cinnamyl adachotsedweratu ndikupangitsanso kukhathamiritsa kambiri kumayambitsa kamolekyu kakang'ono kwambiri J147. J147 ndi nthawi 5-10 yochuluka kwambiri muzoyesa zonse monga CNB-001, pamene curcumin ili ndi zochepa kapena zosachita muyeso iliyonse. J147 sikuti imakhala yamphamvu koma imakhalanso ndi zinthu zabwino (MW = 350, cLogP = 4.5, tPSA = 42). J147 (1146963-51-0) adaphunziridwa mochulukira muzochitika zakale za zakale komanso za AD zomwe zakhala zothandiza kwambiri.

Odwala mankhwala a Alzheimers (AD mankhwala) J147 CMS121 CAD31

Wina amaganizira kuti J147 ingawonongeke kwambiri ndi amadzi / amadzimadzimadzi omwe amawopsa kwambiri. Kuti muwone izi zitheka, kuyimitsa kwa thupi kwa J147 kunaphunziridwa mu microsomes, mu pulasitiki yamagulu, ndi mu vivo. Izo zinawonetsedwa izo J147 (1146963-51-0) sizonyansa kwa amines kapena hydrazines, kuti scaffold ndi yolimba, ndipo kuti amasinthidwa kuti awiri kapena atatu metabolites okosijeni mwa anthu, mbewa, makoswe, monkey, ndi mbatata microsomes. Kupenda chitetezo cha metabolites, tapanga maselo onse atatu a chiwindi a m'magazi ndipo timayesa kuti tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda. Palibe imodzi ya metabolitesyi ndi poizoni, ndipo ambiri a metabolites ali ndi zinthu zofanana ndi za J147.

- mankhwala osokoneza bongo a Alzheimers (AD mankhwala): CMS121

CMS121 ndizochokera ku fisetin. Pazaka zingapo zapitazi, tawonetsa kuti flavonoid fisetin ndi mankhwala okhudza thupi, odzola, komanso ozindikira omwe amachititsa kuti nyama zisawonongeke. Fisetin imakhala yogwira ntchito yowononga antioxidant ndipo imatha kukhala ndi magulu opatsirana a GSH ovutika. Kuphatikiza apo, fisetin ili ndi ntchito yokhala ndi neurotrophic ndi anti-inflammatory. Zochita zambirizi zikusonyeza kuti fisetin ikhoza kuchepetsa kutaya kwa matenda a ubongo wokhudzana ndi matenda ambiri. Komabe, EC50 yapamwamba kwambiri mumaselo owerengeka (2-5 μM), lipophilicity (cLogP 1.24), mkulu tPSA (107), ndi kusowa kwa bioavailability ali ndi fisetin yochepa yopitilira chitukuko monga munthu wogwiritsira ntchito mankhwala.

Odwala mankhwala a Alzheimers (AD mankhwala) J147 CMS121 CAD31

Chovuta chinali kupititsa patsogolo fisetin mu njira zambiri zamagetsi panthawi imodzimodziyo panthawi imodzimodziyo kusinthasintha zinthu zakuthupi kuti zikhale zogwirizana kwambiri ndi zotsatira za CNS mankhwala (maselo olemera ≤ 400, cLogP ≤ 5, tPSA ≤ 90, HBD ≤ 3, HBA ≤ 7). Njira ziwirizo zinagwiritsidwa ntchito pofuna kusintha fisetin. Poyamba, magulu osiyanasiyana a hydroxyl anasinthidwa mwanjira yothetsera kuthetsa ma sulfate / glucuronidate metabolites. Njira yachiwiri, flavone scaffold inasinthidwa kukhala quinoline, komabe panthawi imodzimodziyo yokhala ndi zofunikira za fisetin.Kugwiritsira ntchito njira zathu zamagulu zopezera mankhwala, tapanga zochokera zingapo ndi ntchito zowonjezereka mu neuroprotective oxytosis ndi vitro ischemia mayesero. Ntchito zina zitatu za fisetin zinasungidwa m'zinthu zowonjezera, kuphatikizapo kusungirako GSH, kulepheretsa bakiteriya lipopolysaccharide (LPS) kuyambitsa mphamvu ya microglial, ndi kusiyana kwa maselo a PC12, kuchuluka kwa maselo a neurotrophic. Flavone yotengedwa ndi CMS-140 ndi quinolone yomwe imachokera ku CMS-121 ndi 600 ndi nthawi ya 400 kwambiri, mofanana, kusiyana ndi fisetin mu yesayimia (Figure). Motero, n'zotheka kusunga mikhalidwe yambiri ya polyphenol komanso kupititsa patsogolo thupi mankhwala apamtunda.

- mankhwala osokoneza bongo a Alzheimers (AD mankhwala): CAD31

Zotsatira zambiri za thupi za CAD31 zinali zabwino poletsa zochitika zina zoopsa zokhudzana ndi matenda ozunguza bongo.

CAD31 ndi odwala mankhwala a Alzheimer's (AD) amene adasankhidwa chifukwa cha mphamvu zake zowonjezeretsa kubwezeretsa kwa maselo a embryonic stem-omwe amachokera m'maselo osakanikirana ndi neural komanso APswe / PS1ΔE9 AD mbewa. Kusunthira CAD-31 kupita ku chipatala, kuyesayesa kunachitidwa kuti adziwe momwe amachitira kachipangizo ka mankhwala komanso mankhwala, komanso kuyesa njira yake yothandizira mu njira yogwira ntchito ya AD.

CAD31 imakhala ndi mphamvu zogwiritsira ntchito matendawa m'magazi asanu ndi limodzi omwe amatsutsana ndi zoopsa zomwe zimachitika mu ubongo wakale. Maphunziro azachipatala ndi oyambirira akuwonetsa kuti CAD31 ndi ubongo wa ubongo ndipo mwachiwonekere ndi otetezeka. Pamene udyetsedwa kale, zizindikiro za APPswe / PS1ΔE9 AD makoswe kuyambira m'miyezi ya 10 kwa miyezi yambiri ya 3 mu njira yothandizira ya matenda, kuchepetsa kukumbukira kukumbukira ndi kutupa kwa ubongo, komanso kuwonjezeka kwa mawu mapuloteni a synaptic. Deta yamadzimadzi ya deta ya ubongo ndi plasma inasonyeza kuti zotsatira za CAD-31 zimayambira pa mafuta amchere amadzimadzi ndi kutupa. Kusanthula mwachindunji za chiwerengero cha ma geneti kunasonyeza kuti CAD-31 inali ndi zotsatira zazikulu zowonongeka bwino ndi AD mphamvu zamagetsi.

Kutsiliza

Gulu lofufuzira tsopano likuyang'ana kupeza ma GNP awiri m'mayesero a anthu. Chombo cha fisetin, CMS121, panopa ndi maphunziro a toxicology omwe amafunikira kuti FDA ivomereze kuyambitsa mayesero. Kupangidwa kwa curcumin, J147, ndi pansi pa FDA ndondomeko ya chiwongoladzanja kuti ayambe kuyesedwa kwa AD m'ma oyambirira chaka chino. Gululi likukonzekera kuphatikiza zizindikiro za sayansi ya ukalamba ku ukalamba m'mayesero a zachipatala kuti ayese zotsatira zowonongeka kowopsa. Ofufuzawo amanena kuti kupezeka kwa ogwiritsa ntchito mankhwalawa kwa AD kumatsimikizira njira yomwe anagwiritsira ntchito mankhwala omwe ayamba kukhala njira yodziŵira zina GNP mankhwala zomwe zidzakuthandizira kulimbikitsa ukalamba wathanzi. Izi zikhoza kufulumizitsa kwambiri mapaipi a mankhwala kuti athetse matenda a ukalamba omwe pakalipano palibe mankhwala.

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