5-Amino-1mq Ua kua

Cov khoom yog ib qho cuab yeej siv reagent hauv kev tshawb fawb kab mob qog noj ntshav. Nws yog dav siv nyob rau hauv kev soj ntsuam ntawm tus cwj pwm tseem ceeb ntawm cov qog nqaij hlav cancer ntau yam, suav nrog kev loj hlob, apoptosis, kev tsiv teb tsaws thiab kev ntxeem tau, pab cov kws tshawb fawb qhia meej txog qhov cuam tshuam ntawm NNMT inhibition ntawm cov qog nqaij hlav cancer. Txog niaj hnub no, nws tau siv ntau lub xov tooj ntawm tes xws li mob qog noj ntshav hauv tsev menyuam, glioma, thyroid cancer, mob raum, mob qog noj ntshav thiab qog nqaij hlav hauv plab.

Hauv kev tshawb fawb txog kev mob qog noj ntshav hauv tsev menyuam, kev kho mob ntawm HeLa lub ncauj tsev menyuam qog noj ntshav nrog cov khoom lag luam cuam tshuam cov qog nqaij hlav qog noj ntshav hauv qhov concentration- thiab nyob ntawm lub sijhawm, thaum txo qis kev qhia ntawm phosphorylated AKT (p-AKT) thiab sirtuin 1 (SIRT1).

Ob leeg cov proteins zoo sib xws rau cov qog cell ciaj sia, kev loj hlob thiab kev kho mob, ntxiv kev lees paub txog kev txhawb nqa lub luag haujlwm ntawm NNMT overexpression hauv kev mob qog noj ntshav hauv ncauj tsev menyuam thiab muab kev nkag siab tshiab rau kev kho mob qog noj ntshav.

Thaum lub sij hawm sim, daim ntawv ua kua tso cai rau kev sib koom ua ke sai rau hauv cov kab lis kev cai ntawm tes, kom ntseeg tau tias cov tshuaj sib xyaw ua ke, tsis txhob cuam tshuam cov cellular tsis sib xws los ntawm kev tsis txaus ntawm cov hmoov formulations, thiab txhim kho kev ntseeg siab ntawm cov ntaub ntawv sim.

Hauv kev tshawb fawb glioma, NNMT qhia tau ntau dua hauv thawj glioblastoma (malignant hlwb qog) dua li cov ntaub so ntswg hauv hlwb. Cov khoom no inhibits NNMT kev ua, cuam tshuam cov metabolic tshuav nyiaj li cas ntawm glioma hlwb, txo lub zog, thiab yog li suppresses glioma cell proliferation thiab tsiv teb tsaws, ua ib tug tseem ceeb cuab tam rau metabolic-targeted kev tshawb fawb ntawm glioblastoma.Nyob rau hauv lub zais zis kev tshawb fawb, NNMT tau raug txheeb xyuas raws li ib tug loj regulator ntawm cell migration. Inhibition ntawm NNMT siv cov khoom lag luam tau txo qis kev loj hlob thiab kev tsiv teb tsaws ntawm cov qog nqaij hlav qog nqaij hlav hauv lub zais zis, ntxiv qhov muaj txiaj ntsig zoo ntawm NNMT raws li lub hom phiaj kho mob rau lub zais zis.

Tshaj li kev siv tshuaj tiv thaiv- kev laus thiab kev tshawb fawb metabolic, cov kua no 5-Amino-1mq yog dav siv rau kev soj ntsuam hauv chaw soj nstuam tsom rau cov tshuaj tiv thaiv kab mob qog noj ntshav. Cov tshuaj tiv thaiv tseem yog ib qho ntawm cov kev tsis txaus ntseeg uas ua rau muaj qhov tsis txaus siab rau cov txiaj ntsig kho mob thiab kev kho mob thaum kawg tsis ua haujlwm thaum kho mob qog noj ntshav, thiab ntau cov pov thawj preclinical tau lees paub tias qhov txawv txav NNMT qhia tau zoo sib xws nrog cov tshuaj tiv thaiv thoob plaws ntau yam khoom thiab hematologic malignancies. Hauv qhov cuam tshuam hauv vitro kev sim, cov kws tshawb fawb tswj hwm qhov kev xaiv NNMT inhibitor los tsim cov qauv tshuaj tiv thaiv kab mob qog noj ntshav los tshawb xyuas.

Thaum ua cov kev tshawb fawb preclinical tshawb nrhiav mob qog noj ntshav-txog molecular mechanisms, kua 5-Amino-1mq ua hauj lwm raws li ib tug txhim khu kev qha chaw soj ntsuam cov cuab yeej ua hauj lwm feem ntau validate cov kev cai ntawm NNMT-centered metabolic cascades. Nws pab cov kws tshawb fawb nthuav tawm cov xwm txheej tseem ceeb ntawm cov txheej txheem molecular uas tsav cov qog pib thiab kev loj hlob ntawm malignant, lub sijhawm no pab txhawb kev tshuaj xyuas thiab kev pom zoo ntawm cov phiaj xwm tiv thaiv qog noj ntshav. Nws cov hom tshuaj pharmacological tseem ceeb ntawm kev ua haujlwm hinges ntawm kev xaiv NNMT kev tawm tsam: thaiv cov tshuaj tiv thaiv nicotinamide methylation ntau dhau los ua kom cov tshuaj tiv thaiv endogenous intracellular nicotinamide reserves, txuas ntxiv ua rau qis qis NAD + biosynthesis. Cov NAD + sib sau ua ke ua rau ua rau muaj ntau yam NAD+-reliant signaling cascades,.

Tshwj xeeb, NNMT catalyzes methylation ntawm nicotinamide rau 1-methylnicotinamide. Raws li kev xaiv NNMT inhibitor tsom rau qhov chaw substrate (IC50 rau tib neeg NNMT=1.2 μM),5-amino-1mq kuatshwj xeeb thaiv cov tshuaj tiv thaiv no, ua rau intracellular nicotinamide tsub zuj zuj thiab nce NAD + theem ntawm NAD + txoj kev khaws cia.As ib qho tseem ceeb coenzyme hauv cellular metabolism, NAD + koom nrog ntau cov txheej txheem physiological suav nrog lub zog metabolism, kho DNA thiab apoptosis.

Nce NAD + qib hloov pauv ntau txoj hauv kev qis qis xws li SIRT1 thiab AKT, yog li inhibiting qog nqaij hlav qog noj ntshav, txhawb kev apoptosis, thiab txo cov qog angiogenesis thiab metastasis.

Tsis tas li ntawd, cov khoom siv tuaj yeem siv los tshawb txog kev sib koom ua ke ntawm NNMT thiab cov lus teb inflammatory, yog li qhia meej nws lub luag haujlwm tsis ncaj rau hauv kev txhim kho qog noj ntshav. Cov kev tshawb fawb qhia tias NNMT muaj feem cuam tshuam nrog cov xwm txheej inflammatory; Nws overexpression induces zus tau tej cov thiab tso tawm inflammatory yam, uas yog ib qho tseem ceeb tsav tsheb ntawm carcinogenesis thiab mob qog noj ntshav.Los ntawm xaiv suppressing lub catalytic kev ua si ntawm NNMT enzyme, 5-Amino-1mq kua tau zoo curbs ntau ntau secretion ntawm ntau yam pro-inflammatory cytokines thiab relieves persistent cov ntaub so ntswg. Kev txo qis hauv zos ua rau mob ntxiv rau qhov mob ntxiv -tsav kev hloov pauv ntawm oncogenic thiab txwv tsis pub cov qog nqaij hlav tom ntej thiab kev loj hlob zuj zus.

Cov khoom lag luam tau pom cov koob tshuaj zoo kawg nkaus -nyob ntawm cov qog loj hlob inhibitory cuam tshuam thoob plaws cov qauv tsiaj uas siv tau uas suav nrog ntau yam mob qog noj ntshav. Piv txwv li, nyob rau hauv ib tug classic peritoneal metastasis qauv ntawm tib neeg lub zes qe menyuam qog noj ntshav, cov kws tshawb fawb tau xa txhua hnub intraperitoneal kev tswj hwm ntawm 20 mg / kg / d ntawm cov khoom thiab pom tias nws zoo inhibited metastasis nyob deb thiab loj hlob sai ntawm HeyA8 ntawm zes qe menyuam qog noj ntshav. Tsis muaj qhov pom tseeb ntawm qhov tsis zoo tshwm sim hauv cov tsiaj sim txawm tias qhov koob tshuaj txhua hnub siab txog 60 mg / kg / d, lees paub nws qhov kev ruaj ntseg profile thiab kev kho mob zoo rau kev kho mob qog noj ntshav zes qe menyuam.

Nyob rau hauv cov tsiaj preclinical qauv ntawm gastric cancer, pancreatic cancer, raum mob cancer, thiab ob peb lwm yam malignancies, cov khoom kuj pom zoo raws li ib tug zoo xws li cov qog-suppressive pharmacological teebmeem. Cov kev tshawb fawb tau qhia tias NNMT tau nthuav tawm txawv txav hauv cov qauv mob qog noj ntshav no. Qhov ncauj lossis intraperitoneal kev tswj hwm ntawm cov khoom lag luam txo qis NNMT kev ua haujlwm hauv cov qog nqaij hlav, txhawb cov qib hauv cov cellular NAD +, inhibits qog cell proliferation sai, thiab txiav cov qog ntim thiab qhov hnyav yam tsis muaj kev puas tsuaj rau ib puag ncig ib puag ncig, qhia txog kev ruaj ntseg thiab meej lub hom phiaj.

Tsis tas li ntawd, cov khoom lag luam nthuav tawm qhov tshwj xeeb zoo hauv cov qauv tsiaj ntawm cov qog nqaij hlav rog rog. Kev rog rog yog cuam tshuam nrog kev pheej hmoo ntawm ntau yam qog nqaij hlav, thiab NNMT overexpression ua raws li tus neeg nruab nrab tseem ceeb txuas kev rog thiab mob qog noj ntshav: nyob rau hauv lub xeev rog, nce NNMT kev ua ub no ua rau cov kab mob metabolic thiab txhawb kev mob qog noj ntshav.By inhibiting NNMT kev ua,5-amino-1mq kuatswj cov txheej txheem metabolism, txo cov rog rog, thiab txo qis qhov tshwm sim thiab kev loj hlob ntawm cov qog nqaij hlav rog rog, muab cov tswv yim tshiab rau kev tiv thaiv thiab kho cov qog nqaij hlav. Nws cov qauv ua kua kuj ua rau kev tswj hwm qhov ncauj mus ntev, ua tau raws li qhov yuav tsum tau muaj ntawm kev tshawb fawb txog kev cuam tshuam mus sij hawm ntev rau cov qog nqaij hlav rog rog.

Nyob rau hauv cov qauv qog nqaij hlav qog nqaij hlav hauv lub zais zis, NNMT knockout txo qis lub peev xwm txav chaw ntawm lub zais zis hlwb, thiab cov khoom, raws li NNMT inhibitor, ua tiav cov txiaj ntsig zoo sib xws. Intraperitoneal los yog qhov ncauj tswj xyuas inhibited zais zis qog nqaij hlav qog nqaij hlav thiab ntxeem tau thiab txo cov tsim ntawm nyob deb metastases, los ntawm mechanisms uas muaj cellular metabolic kev tswj thiab downregulation ntawm metastasis-txog proteins.In non-me me cell ntsws cancer qauv, inhibiting NNMT kev ua si kuj markedly suppressed qog metabolic kev loj hlob thiab paub meej tias cov khoom muaj nqis ntawm cov qog nqaij hlav metastasis. kev cuam tshuam.

Tsis tas li ntawd, NNMT tau raug txheeb xyuas tias yog ib qho kev cog lus muaj peev xwm qog nqaij hlav hauv cov qog nqaij hlav hauv plab, qhov ncauj squamous cell carcinoma, thiab ntau lwm yam qog nqaij hlav, nrog rau nws qhov txawv txav txawv txav ze ze rau qhov mob qog nqaij hlav metastasis. Cov khoom lag luam tuaj yeem txo qis qhov kev nthuav dav ntawm cov qog nqaij hlav tshwj xeeb no thiab txwv tsis pub nyob deb ntawm metastasis los ntawm kev xaiv inhibiting NNMT enzymatic kev ua, muab cov lus qhia tseem ceeb tshiab rau kev kuaj mob ntxov thiab kev cuam tshuam metastasis. Nws cov kua tsim tshwj xeeb yog absorbed sai sai hauv cov tsiaj sim, ua tam sim ntawd los thaiv kev tsim thiab kev loj hlob ntawm cov kab mob metastatic.

Hauv kev tshawb fawb txog kev siv tshuaj khomob, cov khoom lag luam txhim kho kev ua haujlwm ntawm cov tshuaj chemotherapeutic thaum txo lawv cov kev mob tshwm sim lom.Piv txwv li, hauv cov qog nqaij hlav qog noj ntshav thiab cov qog nqaij hlav hauv plab, kev sib txuas cov khoom nrog cov tshuaj kws khomob xws li cisplatin thiab 5-fluorouracil txhim kho cov nyhuv tua ntawm cov qog nqaij hlav cancer thiab txo kev puas tsuaj rau lub cev.

Cov txheej txheem muaj feem xyuam rau kev tswj hwm cov txheej txheem metabolic thiab nce chemosensitivity ntawm cov qog nqaij hlav cancer: los ntawm inhibiting NNMT, cov khoom cuam tshuam lub zog ntawm cov qog nqaij hlav cancer, ua rau lawv yooj yim dua rau kev kho mob, thaum tiv thaiv cov metabolic tshuav ntawm cov hlwb ib txwm thiab txo cov kev mob tshwm sim.

Hauv kev tshawb nrhiav kev tiv thaiv kab mob sib xyaw ua ke, cov khoom lag luam txhim kho qhov ua tau zoo ntawm kev tiv thaiv kab mob los ntawm kev hloov kho cov qog microenvironment. Inflammatory teb thiab metabolic ntshawv siab nyob rau hauv lub qog microenvironment suppress lub cev tiv thaiv kab mob kev ua si.

Cov khoom lag luam inhibits NNMT, txo cov qib inflammatory, txhim kho cov qog microenvironment, txhawb kev tiv thaiv kab mob hauv lub cev thiab ua kom muaj zog, thiab yog li txhim kho kev paub thiab tua cov qog hlwb los ntawm cov tshuaj tiv thaiv kab mob, muab lub tswv yim tshiab rau kev tiv thaiv kab mob sib xyaw ua ke.