Txhais Metabolic Reprogramming rau hauv Cov Hom Phiaj Tshiab Rau Raum Cancer
Feb 25, 2022
Omran Abu Abouda thiab Robert H. Weiss,b,c,∗ua al
Abstract.Nyob rau hauv lub hnub nyoog ntawm bioinformatics thiab nrog lub advent ntawm high-powered xam nyob rau hauv lub xyoo caum dhau los los yog li ntawd cov toj roob hauv pes ntawm biomedical kev tshawb fawb tau ua radically hloov. Thaum ib tiam dhau los, cov neeg tshawb xyuas yuav kawm txog lawv cov "nyiam" cov protein lossis cov noob thiab ua kom tiav lub luag haujlwm ntawm cov khoom sib xyaw no hauv lawv cov kab mob ntawm kev txaus siab, cov tsos ntawm omics tau hloov lub ntsej muag ntawm cov tshuaj xws li ntau ntawm kev txiav ntug (thiab nyiaj txiag! ) Kev tshawb fawb kho mob tam sim no ntsuas cov kab mob biology ze li ntawm nws tag nrho. Ua ke qhov no nrog lub realization uasraummob qog noj ntshavyog "tus kab mob metabolic" vim nws ntau yam derangements nyob rau hauv biochemical txoj kev [1, 2], thiab ntshiab cell renal cell carcinoma (ccRCC) ua siav rau cov ntaub ntawv mining siv ntau yam omics mus kom ze.
Cistancheyog ib tug ntawm cov huab tais nyiam tributes nyob rau hauv ancient sij hawm. Nws muaj lub koob npe nrov ntawm "suab puam ginseng". Vim li cas huab tais nyiamCistanche? Tom qab tag nrho, muaj peb txhiab beauties nyob rau hauv lub harem.Cistanchemuaj cov teebmeem ntawm invigorating lublub raum, nourishing lub ntsws, invigorating lub essence, nourishing lub plab, thiab laxatives. Nyob rau tib lub sijhawm, nws kuj tuaj yeem siv rau kev noj haus. Thaum ua noj porridge, yuav tsum tau ntxiv ib qho nyiaj ntawm Cistanche, uas tseem siv tau rau cov poj niam cev xeeb tub uas tsis muaj kev cai lij choj thiab tom qab yug me nyuam cov ntshav tsis txaus cem quav, hemorrhoid prolapse, thiab los ntshav.
Ntsiab lus:Lub raummob qog noj ntshav, metabolomics, cistanche,kho cov hom phiaj, reprogramming
Hu rau:joanna.jia@wecistanche.com/ WhatsApp: 008618081934791
Cistanche tubulosa tiv thaiv kab mob raum, nyem qhov no kom tau txais cov qauv
Lub cev
Nws paub zoo txawm tias los ntawm qhov uas twb tau sau rau hauv nplooj ntawv ntawm Phau Ntawv Xov Xwm tshiab no tias ccRCC yog ib tus kab mob uas tsis muaj kev xaiv kho mob txaus. Thaum yav dhau los kev tshawb nrhiav cov tshuaj khomob tshiab hauv kev mob qog noj ntshav (thiab ntau yam kab mob) tau ua ib qho kev tawm dag zog hauv brute force sim-thiab-yuam kev mus kom ze ntawm cov tshuaj lom neeg tshiab, thiab muaj hmoo heev ntawm tus neeg mob thiab nws tus kws kho mob. , tam sim no peb muaj peev xwm kwv yees seb yuav ua li cas rau txhua tus neeg mob tus kab mob raws li genomics lossis kev txheeb xyuas kev hloov pauv tshwj xeeb (raws li tau hais rau ntau xyoo) thiab, tsis ntev los no, ntawm metabolomics. Txawm hais tias kev hloov pauv tau raug tsom mus rau lwm cov qog nqaij hlav uas muaj kev vam meej, qhov no tsis yog qhov teeb meem rau ccRCC thiab yuav tsis tham ntxiv hauv cov lus qhia no. Ntawm qhov tod tes, qhov kev tshawb pom feem ntau siv omics technologies ntawm reprogrammed metabolism ua ib feem thiab parcel ntawm tus kab mob metabolic no tau ua rau ntau txoj hauv kev uas tsis "ua raws li txoj cai" thiab yog li ntawd yog los yog yuav yog, siv rau cov kev kho mob tshiab uas yuav nyob deb. toxicity tsawg dua li cov kev kho mob uas tsis yog tshwj xeeb brute force. Cov txheej txheem no yuav tau tham hauv qee qhov kev nthuav dav tom qab hauv kab lus no.
Lawm, thaum nrhiav tau thiab validating tshiab los yog reprogrammed metabolism, cov txheej txheem feem ntau yuav yields tshiab insights yog hais tias ntawm metabolomics raws li daim teb no cuam tshuam nrog cov kos npe ntawm qhov tseem ceeb ntawm tag nrho cov txheej txheem metabolic tam sim no thiab ntsuas tau [3, 4]. Raws li nrog txhua txoj hauv kev omics, kev coj ua ntawm metabolomics ("tsis yog lub hom phiaj" hauv nws qhov kev siv tau zoo tshaj plaws) nrhiav kom pom tag nrho cov metabolites me me tam sim no hauv cov txheej txheem lom neeg, tab sis tau kawg, tsuas yog ib feem me me ntawm cov no yuav. tiag tiag yuav pom thiab chemically txheeb xyuas. Tom qab kev siv tshuaj lom neeg (piv txwv li hauv cov kab lis kev cai los yog, zoo dua, hauv tag nrho cov kab mob), cov metabolites uas pom tau tias hloov pauv tuaj yeem kawm hauv cov ntsiab lus ntawm lawv cov neeg nyob ib puag ncig sab saud thiab hauv qab [5]. Thaum qhov no ua tiav siv ntau qhov kev lag luam muaj software, tsim thiab tshiab reprogrammed txoj hauv kev tuaj yeem ua rau pom uas yuav ua rau, ntawm kev soj ntsuam, mus rau txoj kev sib koom ua ke lossis "nodes" ua rau muaj kev cuam tshuam. Hauv ntau qhov xwm txheej no, ntawm kev tshuaj xyuas cov npe ntawm cov khoom me me uas tau pom tias muaj kev cuam tshuam ntau txoj hauv kev, nws tuaj yeem pom tias txoj hauv kev no yav dhau los tau kawm thiab tsom los ntawm cov kws tshuaj tsim los rau lwm yam kab mob thiab, ntau zaus, tau raug. pov tseg ntev [6]. Rau cov laj thawj no, nws yog qhov ncaj ncees hais tias metabolomics coj mus rau reprogramming kev nkag siab uas ua rau cov hom phiaj kho tshiab.
Thaum tsim txoj hauv kev reprogrammed hauv RCC siv cov metabolomics yog ib txoj hauv kev muaj zog heev nrog cov txiaj ntsig kho mob siab, nws yog cov txheej txheem nrog ntau tshaj nws qhov kev sib koom ntawm qhov tsis zoo hauv lub ntsiab vim qhov tseeb tias, nrog rau nws cov khoom lag luam, nws tau yooj yim muaj. Vim tias ib tus neeg tshawb nrhiav muaj cov ntaub so ntswg thiab / lossis cov qauv biofluid (thiab cov nyiaj txaus!) tuaj yeem, hauv txoj kev xav, ua cov kev tshawb fawb ntawm cov pob txha pob txha metabolomics thiab yog li tsim cov kev xav, nws yog ib qho tseem ceeb ua ntej tshaj tawm txoj hauj lwm rau tus neeg tshawb xyuas kom muaj kev paub txog kev noj qab haus huv. Cov kev tshawb pom uas siv hauv vitro lossis hauv vivo systems tsam qhov kev tshawb pom tom qab pom tias tsuas yog artefactual lossis tsawg los tsis muaj qhov tseem ceeb lom. Yog li, kev loj hlob ntawm cov ntaub ntawv metabolomics nthuav tawm qhia txoj hauv kev tshiab thiab biomarkers yuav tsum tau soj ntsuam nrog lub qhov muag tseem ceeb thiab qhib siab.
Nyob rau hauv lub teeb pom kev tsis ntev los no hais tias RCC yog nyob rau hauv qhov tseeb ib tug kab mob metabolic, raws li tau hais los saum toj no, muaj ib tug xov tooj ntawm zoo-tsim omics kev tshawb fawb siv RCC ntaub so ntswg thiab biofluids qhia tshiab thiab reprogrammed metabolic txoj kev (Fig. 1). Peb xaus cov kev tshawb fawb tseem ceeb tshaj plaws uas ua rau muaj peev xwm kho tau tshiab hauv kab lus hauv qab no.
Glycolysis
Clear cell RCC (ccRCC) yog tam sim no tsim tau zoo los siv Warburg metabolism. Kev tshawb fawb ntawm ccRCC hlwb thiab cov ntaub so ntswg los ntawm nas thiab cov neeg mob siv metabolomics [7, 8], proteomics [8–10], thiab transcriptomics [11] tau pom muaj zog kos npe ntawm nce glycolysis hauv ccRCC. Qib ntawm cov enzymes koom nrog hauv glycolysis xws li hexokinase-1 (HK-1), pyruvate kinase (PK-2), thiab lactate dehydrogenase A (LDH-A) tau nce ntxiv hauv ccRCC hlwb thiab paj ntaub [9]. Thaum cov tshuaj hloov kho cov piam thaj analog 2- deoxy-D-glucose (2-DG) ua lub substrate los inhibit hexokinase [12], 3-bromopyruvate (3-BrPa) yog ntseeg los cuam tshuam
ncaj qha nrog HK enzymatic kev ua si thiab khi rau hexokinase 2 [13]. Hauv ccRCC, HIF tab tom ua lub luag haujlwm tseem ceeb hauv kev ua kom LDH-A, uas yog ib qho tseem ceeb enzyme hauv glycolysis. Cov kev tshawb fawb tsis ntev los no tsom rau HIF siv PT2385 ua rau inhibition ntawm qog loj hlob nyob rau hauv ntau yam RCC cell kab [7] thiab tam sim no tau raug sim hauv kev sim tshuaj [14].
Fatty acid oxidation thiab lipid synthesis
Cov kev tshawb fawb metabolomics hauv ccRCC tau qhia txog kev siv cov roj fatty acids ntau ntxiv [15]. Tseeb tiag, inhibitors ntawm fatty acids oxidation xws li PPAR antagonist tau sim hauv ccRCC qauv thiab pom tias inhibit qog loj hlob [16, 17]. Tsis tas li ntawd, fatty acid synthase (FASN) uas koom nrog hauv kev tsim cov kab mob ntev fatty acids thiab cov roj (cholesterol) tau pom tias muaj ntau dhau hauv ccRCC thiab cuam tshuam nrog qog nqaij hlav thiab qhov tsis zoo ntawm tus kab mob no [18]. Inhibition ntawm FASN los ntawm cerulin los yog nws cov derivative C75 induced ceev ceev nyob rau hauv malonyl-CoA nrog ib tug cim txo nyob rau hauv lipogenesis nyob rau hauv ntau yam mob qog noj ntshav, nrog rau RCC hlwb [19, 20].
Tryptophan
Tryptophan yog ib qho tseem ceeb amino acid thiab yog catabolized los ntawm txoj kev kynurenine los ntawm tus nqi txwv enzyme kev ua ntawm indoleamine 2,3-dioxygenase (IDO) [21]. Ib qho ntawm feem ntau tshaj tawm cov teebmeem ntawm tryptophan metabolism yog kev tiv thaiv kab mob raws li qhov tshwm sim ntawm tryptophan depletion [22] nrog rau kev nce hauv cov tshuaj tiv thaiv kab mob metabolites hauv txoj kev kynurenine [23]. Hauv ccRCC, qib ntawm tryptophan raug txo, qhia txog kev txhim kho ntawm txoj kev no ua rau kev tiv thaiv kab mob [10]. Inhibition ntawm IDO tiv thaiv cov purported immunosuppressive
cov nyhuv thiab ua rau T-cell ua rau hauv murine RCC qauv [24]. Kev xaiv IDO inhibitor epacadostat tau sim hauv ccRCC thiab pom los txhim kho lub peev xwm lytic ntawm cov qog-antigen-tshwj xeeb T hlwb hauv cov qauv preclinical [25].
Glutamine
Ntau qhov kev tshawb fawb ywj pheej tau pom tias kev siv glutamine tau nce hauv ccRCC piv rau cov ntaub so ntswg hauv lub raum [10, 11, 26]. Lub hom phiaj ntawm cov enzymes koom nrog hauv glutamine metabolism, xws li glutaminase (GLS) raug kuaj. Hauv kev sim tshuaj, qhov me me molecule inhibitor ntawm glutaminase, CB-839, ib leeg lossis ua ke nrog mTOR inhibitor everolimus, tau pom cov txiaj ntsig zoo rau cov neeg mob ccRCC [27]. Tsis tas li ntawd, glutamine nyob rau hauv ccRCC yog pub rau glutathione / oxidized glutathione txoj kev (GSH / GSSG), ib txoj hauv kev tseem ceeb rau neutralizing ROS hauv hlwb [10, 11]. Inhibitors ntawm NADPH synthesis xws li KPT-9274 tau pom cov qog nqaij hlav hauv RCC tus qauv [28].
Arginine
Argininosuccinate synthase-1 (ASS1) yog tus nqi txwv enzyme rau kev hloov pauv ntawm citrulline rau arginine rau ammonia detoxification los ntawm urea voj voog hauv lub raum [29]. Hauv ccRCC, ASS1 tsis tau qhia lossis raug txo qis hauv cov qog [30]. Qhov kev tshawb pom no tau lees paub hauv txhua qib ccRCC hauv kev tshawb fawb proteomic [9]. Raws li tus qauv no, arginine deprivation inhibited qog loj hlob hauv RENCA nas qauv ntawm RCC [30]. Daim ntawv pegylated ntawm arginine deaminase (ADI-PEG20) tuaj yeem siv rau deplete arginine los ntawm deamination ntawm arginine rau citrulline [30, 31].
Hauv cov ntsiab lus, kev txawj ntse siv cov txheej txheem muaj zog ntawm metabolomics rau kev tshawb pom thiab kev siv tau ntawm reprogrammed metabolic txoj hauv RCC tau ua rau tam sim no ua rau ntau lub hom phiaj kho mob tshiab rau cov kab mob uas lawv tsis txaus. Muab hais tias xws li hloov biochemical txoj hauv kev yog feem ntau nyob rau hauv cov qog thiab tsis tseem ceeb rau ib puag ncig cov ntaub so ntswg ua rau muaj kev cuam tshuam rau cov kev no los ntawm cov phiaj xwm kho mob yuav tsis ua rau muaj kev phom sij loj. Yog li, theem tam sim no tau teeb tsa rau kev sim tshuaj ntawm cov tshuaj tshiab no ib leeg lossis ua ke nrog cov kev kho mob tsim. Txawm hais tias muaj kev pheej hmoo siab me ntsis vim tias muaj ntau qhov kev ua haujlwm ntawm reprogramming hauv cov ntaub so ntswg ib txwm tsis paub, qhov muaj peev xwm nce mus rau thaj chaw ntawm txoj kev no muaj peev xwm los ua kev hloov pauv thiab qhib cov kev kho tshiab.
ib lub Division of Nephrology, University of California Davis, Davis, CA, USA
b Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA
c Medical Service, VA Northern California Health Care System, Sacramento, CA, USA
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