Multi-Tim Hom Tshuaj Rau Cov Kab Mob Raum
Apr 20, 2023
Abstract
Cov kab mob raum xws li AKI, CKD, thiab GN tuaj yeem ua rau kev lim ntshav thiab xav tau kev hloov raum. Cov kab mob ntawm lub raum yog qhov nyuaj heev, nce ntawm cov nqi sib txawv, thiab koom nrog ntau hom cell thiab cov xov tooj ntawm tes taw qhia txoj hauv kev. Cov kab mob hauv lub raum nyuaj xav tau cov kev kho mob uas tuaj yeem ua rau ntau lub hom phiaj. Hauv kaum xyoo dhau los, kev tsim tshuaj-rau-ib-chip tau ua rau kev loj hlob sai ntawm ntau hom tshuaj los ntawm lub tswv yim mus rau qhov tseeb. Ntau lub hom phiaj siv tshuaj tiv thaiv AA txoj hauv kev thiab cov kev hloov pauv tau siv tau zoo los kho cov kab mob inflammatory, fibrotic, thiab cov kab mob metabolic. Cov tshuaj ntau hom phiaj kuj tau pom muaj peev xwm zoo rau kev kho mob ntshav qab zib nephropathy thiab fibrotic nephropathy. Cov tshuaj no ua los ntawm kev txo lub raum TGF-b signaling, o, mitochondrial dysfunction, thiab oxidative kev nyuaj siab. Muaj ob peb lwm yam tsis ntev los no tau tsim ntau tus neeg ua haujlwm uas tsis tau sim rau lawv lub peev xwm los tiv thaiv kab mob raum. Zuag qhia tag nrho, muaj peev xwm zoo rau cov tshuaj ntau lub hom phiaj los ua rau ntau hom cell thiab qhia txoj hauv kev los kho mob raum.
Nyem qhov no kom paub tias Cistanche yog dab tsi thiab cov teebmeem ntawm Cistanche
Nws kwv yees tias 37 lab tus tib neeg hauv Tebchaws Meskas muaj kab mob raum thiab Medicare siv ntau dua $ 130 nphom los kho mob raum. Hom kab mob raum muaj xws li AKI, CKD, thiab GN. Yam tseem ceeb uas yuav ua rau mob raum yog mob ntshav siab, ntshav qab zib, thiab keeb kwm ntawm tsev neeg. Kab mob plawv thiab mob siab heev thiab kev tuag yog txuam nrog rau mob raum. Txawm hais tias muaj mob raum mob hnyav, kev kho mob muaj tsawg thiab ntau tus neeg mob yuav tsum tau lim ntshav thiab hloov lub raum.
AKI, CKD, thiab kab mob glomerular muaj ntau yam etiologies. Ua rau AKI suav nrog tshuaj toxicity, thoracic phais ischemia, thiab kab mob septic. Lub pathophysiology ntawm AKI suav nrog cov kab mob hypotension, systemic hypoxia, thiab txo cov ntshav oxygen vim kev cuam tshuam ntawm cov pa oxygen hauv zos xa mus rau lub raum. Kev taw qhia thiab cov txheej txheem metabolic nyob rau hauv lub raum tubular ntu thiab cov hlwb epithelial suav nrog kev ua kom cov hypoxia-inducible yam, ua kom cov peroxisome proliferator-activated receptor g (PPARg) -PPARg coactivator 1a (PGC-1a) txoj kev, mitochondrial signaling, thiab fructokinase activation.CKD feem ntau yog vim muaj ntshav siab thiab ntshav qab zib mellitus ua rau lub raum puas tsuaj los ntawm cov txheej txheem ntawm tes sib txawv. Mob ntshav qab zib nephropathy tshwm sim los ntawm oxidative kev nyuaj siab, o, mitochondrial tsis ua hauj lwm, thiab fatty acid metabolism ua rau lub raum fibrosis uas impairs raum tubular thauj, raum hemodynamics, thiab glomerular pom. Cov kab mob Glomerular, xws li glomerulonephritis, pib nrog kev raug mob glomerular, uas tuaj yeem ua rau mob ntxiv glomerular lub raum raug mob. Cov tshuaj tiv thaiv kab mob thiab cov khoom ntxiv, xws li C3 thiab C5, tuaj yeem ua rau glomerular inflammatory cell infiltration. Glomerular thylakoid hlwb, podocytes, thiab endothelial hlwb puas lawm, thiab ib qho ntxiv cellular matrix ua rau glomerulosclerosis. Tom qab ntawd, cov txheej txheem tsis tiv thaiv kab mob ua rau lub raum puas tsuaj ua rau muaj kev cuam tshuam ntawm fibrosis. Zuag qhia tag nrho, cov kab mob hauv lub raum yog qhov nyuaj heev vim tias lawv koom nrog ntau hom cellular, thiab ntau lub xov tooj ntawm tes taw qhia txoj hauv kev, thiab kev nce qib ntawm cov nqi sib txawv.
Cistanche ntxiv
Qhov nyuaj ntawm lub raum kab mob yuav tsum tau txhim kho txoj kev kho mob uas tuaj yeem ua rau ntau lub hom phiaj (Daim duab 1). Cov kab mob hauv lub raum, xws li AKI, mob ntshav qab zib nephropathy, CKD, FSGS, GN, thiab ESKD, koom nrog ntau hom kab mob raum thiab kab mob kev loj hlob nyob ntawm kev hloov pauv hauv ntau txoj hauv kev qhia xov tooj ntawm tes. Nyob rau hauv xyoo tas los no, qhov tshwm sim ntawm ntau hom tshuaj tau ua rau cov kev kho tshiab rau kev kho mob raum kab mob.
Tsim Multi-Target Small-Molecule Drug rau Cov Kab Mob Raum
Kev xav thiab tsim nyog tsim cov tshuaj rau ntau lub hom phiaj tau txais lub zog nyob rau hauv kaum xyoo dhau los. Cov kab ke lom neeg muaj cov cuab yeej ua haujlwm them nyiaj ua haujlwm thiab ua haujlwm tsis tu ncua uas tso cai rau lawv tiv thaiv kev cuam tshuam ib leeg; Yog li, cov kab mob feem ntau tshwm sim los ntawm ntau yam caj ces thiab / lossis ib puag ncig uas ua rau tsis ua haujlwm ntawm lub cev. Cov kab mob nyuaj, xws li cov kab mob metabolic, kab mob fibrotic, AKI, CKD, thiab cov kab mob glomerular, feem ntau yuav raug kho los ntawm kev hloov kho ib txhij ntawm ntau lub hom phiaj.
Kev pom zoo ntawm sulpiride / valsartan, kev sib xyaw ntawm neprilysin thiab angiotensin type 1 (AT1) receptor inhibitor rau kev kho mob plawv tsis ua hauj lwm, tau tshoov siab lub tswv yim ntawm kev tsim dual-acting molecules rau kev kho mob raum kab mob. Peb pab pawg thiab lwm tus tau tsom mus rau txoj hauv kev molecular rau ob-ua yeeb yam me me molecules tsom rau hauv nruab nrog cev fibrosis thiab kab mob raum ua rau lub neej. Cov tshuaj ntau lub hom phiaj no muaj peev xwm ntau dua li ib lub hom phiaj thiab cov tshuaj tshwj xeeb vim yog (1) kev hloov kho cov kab mob zoo dua, (2) cov tshuaj ntxiv thiab / lossis kev sib koom ua ke, (3) cov tshuaj muaj txiaj ntsig ntau dua li kev kho ua ke, (4) ) Lub sijhawm siv tau ntev dua, thiab (5) txo qis kev cuam tshuam rau kev siv tshuaj (Table 1). Nws tau paub ntau ntxiv tias kev sib npaug ntawm ob lub hom phiaj tuaj yeem muab kev kho mob zoo dua thiab cov kev mob tshwm sim.
Hom Tshuaj Ntau Hom Tshuaj
Ib qho kev sib tw loj hauv kev tsim cov tshuaj ntau lub hom phiaj (tseem hu ua cov tshuaj ntau ligand) yog qhov yuav tsum tau ua kom zoo dua cov tshuaj rau ntau lub hom phiaj lom neeg thaum tswj cov tshuaj tsim nyog. Qhov nruab nrab, cov tshuaj ntau lub hom phiaj muaj cov molar wattage ntau dua thiab muaj lipophilic ntau dua li cov ntsiab lus tsim los hloov kho ib lub hom phiaj. Txawm hais tias cov tshuaj ntau lub hom phiaj tau tsim nrog cov khoom tsim nyog zoo li cov tshuaj, ib qho tseem ceeb ntawm kev tsim tshuaj thiab kev txhim kho cov txheej txheem yog xaiv cov hom phiaj lom neeg. Cov cuab yeej suav thiab cov ntaub ntawv tsim qauv tso cai rau kev tsim cov tshuaj pharmacophore, ua kom muaj kev tsim cov tshuaj ntau hom phiaj uas xaiv rau lub hom phiaj lom neeg. Kev txiav txim siab qhov yuav tsum tau ua kom muaj nuj nqis, ntsuas cov tshuaj pharmacological thiab kev xaiv lub hom phiaj lom neeg yog lwm qhov kev sib tw loj hauv kev tsim cov tshuaj ntau lub hom phiaj.
Cov tshuaj ntau lub hom phiaj tuaj yeem muab faib ua peb pawg tseem ceeb: txuas, fused, thiab ua ke cov tshuaj pharmacophore (Daim duab 2). Linked multi-target tshuaj muaj ob yam sib txawv pharmacophores rau txhua lub hom phiaj uas txuas los ntawm ib tug linker. Cov tshuaj txuas ntau lub hom phiaj no yuav muaj qhov hnyav dua molar. Sulbactrim / valsartan yog ib qho piv txwv ntawm cov tshuaj sib txuas ntau lub hom phiaj nrog cov tshuaj pharmacophore tshwj xeeb uas inhibits neprilysin enzyme thiab cov tshuaj pharmacophore tshwj xeeb uas tawm tsam AT1 receptor. Txo qhov loj ntawm qhov sib txuas ntawm cov tshuaj sib txuas sib txuas ua ke nws thiaj li ua rau qhov tseem ceeb ntawm kev sib cuag ntawm cov tshuaj pharmacophore, uas ua rau muaj cov tshuaj sib xyaw ua ke. Yog li, fused multitargeted tshuaj muaj ntau pawg pharmacodynamic uas tsis sib cais los ntawm kev sib txuas. Qhov tsis zoo ntawm kev sib txuas thiab fused multitargeted tshuaj yog qhov hnyav molar loj thiab dav lipophilicity. Cov tshuaj sib xyaw ua ke ntau lub hom phiaj yog raws li kev sib koom ua ke, cov tshuaj pharmacophore tsim los koom nrog lub hom phiaj lom neeg ntawm kev txaus siab thaum muaj qhov hnyav molar thiab ua tau raws li lwm yam ntawm Lipinski txoj cai. Kev tsim thiab kev ua kom zoo ntawm ntau lub hom phiaj ua ke cov tshuaj pharmacophore tau nyuaj tshaj plaws rau hnub no. Qhov tshwm sim ntawm cov qauv tshuaj tsis meej-kev sib raug zoo los ntawm cov ntaub ntawv x-ray cov qauv thiab microarray tsim ntawm cov hom phiaj protein tuaj yeem pab nrhiav qhov pib ntawm kev sib koom ua ke ntau hom tshuaj. Ob peb cov tshuaj uas muaj kev sib txuas, fused, lossis ua ke cov tshuaj pharmacophores tau tsim thiab sim rau lawv lub peev xwm los tawm tsam cov kab mob raum siv cov qauv ntawm tes thiab tsiaj.
Kev nce qib nrog ntau hom tshuaj rau raum kab mob
Ib kauj ruam tseem ceeb hauv kev tsim cov tshuaj ntau lub hom phiaj rau cov kab mob raum yog kev txheeb xyuas cov hom phiaj molecular. Lub hom phiaj yuav tsum yog kev hloov kho kab mob uas tawm tsam cov kev taw qhia sib txawv lossis tib txoj kev taw qhia los ntawm ntau lub ces kaum. Piv txwv li, nyob rau hauv lub raum kab mob, ib tug mechanism ntawm kev txaus siab yog thaiv TGF-b signaling uas ua rau fibrosis. Lub ntsiab lus tseem ceeb ntawm cov lus teb cascade feem ntau yog pib los ntawm TGF-b tab sis kuj suav nrog cov kab mob cytokines thiab cov cim qhia cov molecules uas txhawb nqa cov lus teb pro-fibrotic hauv myofibroblasts thiab yog lub hom phiaj kho mob. Vim tias TGF-b ua lub luag haujlwm tseem ceeb hauv kev tsim fiber ntau, nws tau pib xav tias lub hom phiaj TGFb tuaj yeem tswj cov kabmob hauv nruab nrog cev. Hmoov tsis zoo, txoj hauv kev no ua tsis tiav vim tias TGF-b tseem ua lub luag haujlwm tseem ceeb hauv ntau cov txheej txheem lom neeg tseem ceeb, xws li kev tiv thaiv kab mob thiab kev loj hlob ntawm tes. Yog li ntawd, txoj hauv kev zoo tshaj plaws los kho cov mob fibrotic nephropathy yog los hloov kho ob peb nqes dej tsis muaj kev thaiv cov txheej txheem tseem ceeb TGF-b-tswj cov txheej txheem lom neeg. Cov tshuaj ntau lub hom phiaj rau cov kab mob raum lub hom phiaj kev hloov pauv, AA metabolites, lom zem g protein-coupled receptors, thiab renin-angiotensin system.
Cistanche extract
Nyob rau hauv 5 xyoo dhau los, kev ntsuam xyuas ntawm ntau hom tshuaj tiv thaiv kab mob raum tau nthuav dav. Cov kev siv zog no tau tsom mus rau ntshav qab zib thiab ntshav siab CKD thiab lub raum fibrosis. Cov tshuaj ntau lub hom phiaj tuaj yeem kho tsis tau tsuas yog mob raum tab sis kuj mob ntshav qab zib, kab mob metabolic, thiab kub siab ib txhij. Qhov no yog ua tiav los ntawm kev sib piv thawj zaug ntawm cov tshuaj ntau lub hom phiaj nrog lawv txoj hauv kev ib hom phiaj hauv cov enzymes lossis cellular systems. Vim hais tias cov hom phiaj sib xyaw ua ke hauv CKD koom nrog ib tus neeg lub hom phiaj qhia nyob rau hauv cov ntaub so ntswg sib txawv ntawm lub cev, hauv vivo validation ntawm anti-CKD ntau hom tshuaj yuav tsum tau. Qhov no yog ib qho teeb meem tseem ceeb, vim tias mus txog qib no yuav tsum muaj kev siv tshuaj chemistry tseem ceeb los tsim cov tshuaj ntau lub hom phiaj uas xaiv los hloov cov hom phiaj ntawm cov neeg nyiam thaum tswj hwm cov khoom tsim tshuaj pharmacokinetic. Zoo siab heev, txoj kev pheej hmoo siab, muaj txiaj ntsig zoo ntawm cov tshuaj ntau lub hom phiaj rau kev kho mob raum tau ua rau muaj tus lej ntawm cov neeg ua haujlwm pheej hmoo tuaj txog lossis twb nyob hauv tib neeg kev sim tshuaj.
Cov tshuaj uas hloov pauv txoj hauv kev AA muaj cov tshuaj tiv thaiv kab mob, tiv thaiv fibrotic, tiv thaiv ntshav siab, thiab tiv thaiv ntshav qab zib thiab muaj peev xwm kho mob raum. Ib txoj hauv kev tseem ceeb uas siv rau hauv ntau lub hom phiaj yog txoj kev cyclooxygenase. Inhibition ntawm enzyme soluble epoxide hydrolase (sEH) tau siv ua ke nrog cyclooxygenase (COX) inhibition lossis transcription factor agonism. sEH enzymes txhawb nqa cov hydrolysis ntawm AA metabolite epoxy dicarbonyl trienoic acids (EETs) rau cov khoom siv hluav taws xob tsawg tsawg (DHETEs). Los ntawm inhibiting sEH, EET theem tau nce siab. EET yog eicosanoid tseem ceeb hauv tib neeg lub raum thiab muaj cov tshuaj tiv thaiv kab mob. Kev nthuav qhia sEH siab lossis txo qis EET qib hauv lub raum tau cuam tshuam nrog kev kub siab, ntshav qab zib, thiab kab mob raum. Inhibition ntawm sEH kuj tiv thaiv lub raum mob thiab interstitial fibrosis los ntawm inhibiting kev hloov ntawm endothelial hlwb mus rau mesenchymal hlwb thiab kev qhia ntawm ib tug du nqaij actin thiab TGF-b. Yog li, sEH inhibition ua ke nrog lwm lub hom phiaj kho mob tuaj yeem kho mob ntshav siab lossis ntshav qab zib thaum sib ntaus cov kab mob raum.
Standardized Cistanche
Cov txiaj ntsig ntawm Cistanche ntawm Kev Tswj Xyuas Kev Noj Qab Haus Huv ntawm Kev Hloov Raum
Ib qho kev sib tw loj tshaj plaws rau cov tib neeg uas tau hloov lub raum yog qhov kev pheej hmoo ntawm kev tsis lees paub thiab kis kab mob. Nws yog ib qho tseem ceeb rau cov neeg mob no kom muaj kev noj qab nyob zoo, nrog rau kev noj zaub mov zoo thiab kev tawm dag zog, los txhawb lawv lub cev tiv thaiv kab mob thiab pab tiv thaiv cov teeb meem tom qab kev phais. Cistanche, tshuaj ntsuab suav tshuaj, tau kawm txog nws cov txiaj ntsig kev noj qab haus huv thiab nws cov txiaj ntsig hauv kev txhawb nqa lub raum noj qab haus huv.
Cov kev tshawb fawb tau pom tias Cistanche tuaj yeem ua kom muaj peev xwm antioxidant thiab txo oxidative kev nyuaj siab hauv lub cev, ua rau lub raum ua haujlwm tau zoo. Tsis tas li ntawd, Cistanche tau pom tias muaj cov tshuaj tiv thaiv kab mob, uas tuaj yeem pab tiv thaiv cov ntaub so ntswg puas thiab txhawb kev kho mob tom qab kev phais mob raum.
Ib txoj kev tshawb fawb tau ua rau cov neeg tau txais kev hloov hauv lub raum pom tau tias cov neeg siv cov tshuaj Cistanche tau txo qis ntawm creatinine thiab ntshav urea nitrogen (BUN), qhia tau hais tias lub raum ua haujlwm tau zoo. Lawv kuj tau ntsib cov kab mob tsawg dua piv rau pawg tswj hwm uas tsis noj tshuaj ntxiv.
Txawm li cas los xij, nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias yuav tsum muaj kev tshawb fawb ntxiv kom nkag siab txog qhov ua tau zoo thiab kev nyab xeeb ntawm Cistanche ua ib qho ntxiv rau cov neeg mob hloov lub raum. Raws li nrog ib qho ntxiv, nws raug pom zoo kom cov tib neeg sab laj nrog lawv tus kws kho mob ua ntej ntxivCistanchelos yog lwm yamtshuaj ntsuab ntxivmus rau lawv txoj haujlwm.
Hauv kev xaus, Cistanche tuaj yeem tuav cov lus cog tseg ua ib qho khoom ntxiv los txhawb kev tswj hwm kev noj qab haus huv ntawm cov neeg mob hloov lub raum. Kev tshawb fawb ntxiv yog xav tau kom nkag siab txog nws cov txiaj ntsig zoo thiab muaj peev xwm txaus ntshai, tab sis cov kev tshawb fawb thawj zaug qhia tias nws tsim nyog xav txog kev ua ib feem ntawm txoj hauv kev los tswj lub raum noj qab haus huv.
Cov ntaub ntawv
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John D. Imig1 , Daniel Merk2thiab Eugen Proschak2
1 Drug Discovery Center thiab Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
2 Lub Tsev Kawm Ntawv Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Lub Tebchaws Yelemees
