Mankhwala osokoneza bongo a Alzheimers (AD mankhwala): J147, CMS121, CAD31
1.Kodi Alzheimer's and Geroprotectors(GNPs) ndi chiyani?
Alzheimer's ndiye chomwe chimayambitsa matenda a dementia, ndi mtundu wa dementia womwe umayambitsa mavuto ndi kukumbukira, kuganiza ndi machitidwe. Zizindikiro nthawi zambiri zimayamba pang'onopang'ono ndikuwonjezeka pakapita nthawi, zimakhala zovuta mokwanira kusokoneza 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.
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2.Choyambitsa matenda a Alzheimer
Ochita kafukufuku amakhulupirira kuti palibe chifukwa chimodzi chokha cha matenda a Alzheimer's. Kodi mumadwala matenda a Alzheimer's? Matendawa amayamba chifukwa cha zinthu zingapo, monga chibadwa, moyo ndi chilengedwe. Asayansi apeza zomwe zimawonjezera matenda a Alzheimer's. Ngakhale zina mwaziwopsezo - zaka, mbiri yabanja komanso kubadwa - sizingasinthidwe, umboni womwe ukupezeka ukuwonetsa kuti pangakhale zina zomwe tingakhudze.
-Age
Vuto lodziwika bwino lomwe limayambitsa matenda a Alzheimer's ndikuchulukirachulukira, koma Alzheimer's si gawo lodziwika bwino la ukalamba. Ngakhale zaka zimachulukitsa chiopsezo, sizomwe zimayambitsa matenda a Alzheimer's.
Anthu ambiri omwe ali ndi matendawa ali ndi zaka 65 kapena kupitilira apo. Pambuyo pa zaka 65, chiopsezo cha Alzheimer's chimachulukiranso zaka zisanu zilizonse. Pambuyo pa zaka 85, chiopsezo chimafika pafupifupi gawo limodzi mwa magawo atatu.
-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 kuvulala mutu ndi chiopsezo chamtsogolo cha dementia. Tetezani ubongo wanu pomanga lamba wapampando wanu, kuvala chisoti chanu pochita nawo masewera, ndi "kuteteza kugwa" kunyumba.
-Kugwirizanitsa mutu wamutu
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3. Alzheimer's drug(AD mankhwala) ofuna: J147, CMS121, CAD31
Masiku ano, Alzheimer's ili patsogolo pa kafukufuku wamankhwala. Ofufuzawo akuyesetsa kuti adziwe zambiri zamatenda a Alzheimer's ndi matenda ena amisala momwe angathere. Zina mwazinthu zopita patsogolo kwambiri zawunikira momwe Alzheimer's imakhudzira ubongo. Chiyembekezo ndikumvetsetsa bwino kumeneku kudzatsogolera kuchipatala chatsopano. Njira zambiri zomwe zikuchitika pakadali pano zikufufuzidwa padziko lonse lapansi.
Kuchepetsa kutaya mankhwala 2,4-Dinitrophenol (DNP) zopindulitsa mukumanga thupi
Salk's Cellular Neurobiology Laboratory idayamba ndi mankhwala awiri opezeka muzomera omwe awonetsa mankhwala: fisetin, chilengedwe chachilengedwe. mankhwala zochokera ku zipatso ndi ndiwo zamasamba, ndi curcumin, kuchokera ku curry spice turmeric. Kuchokera pa 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.
Kafukufuku wina mu labu akuwunika ngati mankhwalawa ali ndi zotsatira pa ziwalo zakunja kwa ubongo. "Ngati izi mankhwala ali ndi ubwino kwa machitidwe ena a thupi, monga kusunga impso ndi thanzi labwino la minofu, angagwiritsidwe ntchito m'njira zina zowonjezera kapena kuteteza matenda okalamba, "Schubert akuti.
- Otsatira a Alzheimer's (AD drug) ofuna: 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.
Wodandaula wina yemwe amachita J147 atha kutsitsidwa kuti akhale amine / ma hydrazines onunkhira omwe atha kukhala amtundu wa khansa. Pofufuza kuthekera uku, kukhazikika kwamadzimadzi kwa J147 kunaphunziridwa mu microsomes, mu mbewa plasma, ndi vivo. Zinawonetsedwa kuti 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.
- Otsatira a Alzheimer's (AD drug) ofuna kutsatira: CMS121
CMS121 ndizochokera ku fisetin. Kwa zaka zingapo zapitazi, tawonetsa kuti flavonoid fisetin ndimagwiridwe apakamwa, oletsa kutsekemera, komanso opititsa patsogolo kuzindikira m'mitundu ingapo yamavuto a CNS. Fisetin imagwira ntchito molimbana ndi antioxidant ndipo imatha kupangitsa kuti ma GSH azikhala ovuta. Kuphatikiza apo, fisetin imakhala ndi ma neurotrophic komanso anti-inflammatory. Zochita zingapozi zikuwonetsa kuti fisetin imatha kuchepetsa kuchepa kwa ntchito yamitsempha yokhudzana ndi zovuta zingapo. Komabe, EC50 yake yokwera kwambiri pamayeso oyeserera (2-5 μM), low lipophilicity (cLogP 1.24), high tPSA (107), komanso kupezeka kwa bioavailability kuli ndi fisetin yocheperako yopitilira patsogolo ngati ofuna mankhwala.
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.
- Otsatira a Alzheimer's (AD drug) ofuna: CAD31
Zotsatira zambiri za thupi za CAD31 zinali zabwino poletsa zochitika zina zoopsa zokhudzana ndi matenda ozunguza bongo.
CAD31 ndi omwe amatenga mankhwala osokoneza bongo a Alzheimer's (AD) omwe adasankhidwa chifukwa chokhoza kuyambitsa kubwereza kwa maselo am'mimba am'mimba omwe amachokera m'mimba mwa mbewa komanso mu mbewa za APPswe / PS1ΔE9 AD. Pofuna kusunthira CAD-31 kupita kuchipatala, zoyeserera zidachitika kuti adziwe momwe angatetezere mankhwala ndi mankhwala, komanso kuyesa momwe angathandizire pochita mbewa ya AD.
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4.Conclusion
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, ali pansi pa kuunika kwa FDA kuti alole kuti ayambe kuyesa zachipatala za AD kumayambiriro kwa chaka chamawa. Gululi likukonzekera kuphatikizira zolembera za biochemical zaukalamba m'mayesero azachipatala kuti ayese zotsatira za geroprotective.Ofufuzawo ati kupezedwa kwa anthu ofuna mankhwala a AD kumatsimikizira njira yotulukira mankhwala yomwe apanga ngati njira yodziwikira zina. GNP mankhwala zomwe zidzakuthandizira kulimbikitsa ukalamba wathanzi. Izi zikhoza kufulumizitsa kwambiri mapaipi a mankhwala kuti athetse matenda a ukalamba omwe pakalipano palibe mankhwala.
AASraw ndi katswiri wopanga J147, CMS121, CAD31 powder yomwe ili ndi labu yodziimira ndi fakitale yayikulu monga chithandizo, zonse. Kupanga zidzachitika motsogozedwa ndi CGMP ndikuwongolera kachitidwe kabwino. Dongosolo loperekera ndi lokhazikika, maoda ogulitsa ndi ogulitsa ndi ovomerezeka.Mwalandiridwa kuti mudziwe zambiri za AASraw!
Ndifikitseni TsopanoWolemba nkhaniyi:
Dr. Monique Hong adamaliza maphunziro awo ku UK Imperial College London Faculty of MedicineScientific Journal paper Wolemba:
1. Chen-yi Cheng
Basic Medical School, Xinxiang Medical University, Xinxiang, Henan 453003, China
2. Guoheng Zhong
Bioland Laboratory (Guangzhou Regenerative Medicine ndi Health Guangdong Laboratory), Guangzhou, 510005, China
3. Hanika Rizo
Department of Earth Sciences, Ottawa-Carleton Geoscience Center, Carleton University, Ottawa, ON, K1S 5B6, Canada
4. Bing Z. Carter PhD
University of Texas MD Anderson Cancer Center, Dept of Leukemia, 1515 Holcombe Blvd, Houston, TX 77030, USA
Dipatimenti ya Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA
Dokotala/wasayansiyu savomereza kapena kulimbikitsa kugula, kugulitsa, kapena kugwiritsa ntchito mankhwalawa pazifukwa zilizonse. Aasraw alibe chiyanjano kapena ubale, wonenedwa kapena ayi, ndi dokotala uyu. Cholinga chotchula dokotalayu ndikuvomereza, kuvomereza ndi kuyamika ntchito yofufuza ndi chitukuko yomwe asayansi akugwira ntchitoyi.