Hauv kev sib ntaus sib tua ntau pua xyoo ntawm tib neeg thiab mob qog noj ntshav, xwm txheej ib txwm muab cov lus qhia los daws qhov teeb meem hauv txoj kev npaj txhij txog. Nyob rau hauv xyoo tas los no, ib qho zoo li monosaccharide - Mannose - tau dhau los ua qhov tseem ceeb thoob ntiaj teb ntawm kev tshawb fawb txog kev tshawb fawb vim nws cov khoom tshwj xeeb los tiv thaiv qog noj ntshav. Qhov no hexose, uas yog dav pom nyob rau hauv cranberries thiab citrus txiv hmab txiv ntoo, tau sawv los ntawm lub luag hauj lwm txhawb nyob rau hauv lub teb ntawm cov khoom noj khoom haus mus rau lub luag hauj lwm nyob rau hauv lub qog metabolism hauv kev tshawb fawb, qhia ib tug brand-new dimension ntawm qab zib tshuaj nyob rau hauv cov kev cai ntawm lub neej. Tsab ntawv xov xwm no yuav tshawb xyuas tob txog yuav ua li cas mannose hloov kho thaj chaw kho mob qog noj ntshav los ntawm plaub yam: kev tshawb fawb yooj yim, kev ua haujlwm, kev hloov kho kho mob thiab kev cia siab rau kev lag luam.

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Tshooj Ib: Subverting Cognition: Anti-Cancer Awakening of Sweet Molecules

1.1 Paradigm Hloov hauv kev tshawb fawb Carbohydrate

Hauv cov ntsiab lus ib txwm muaj, cov suab thaj (carbohydrates) tau ntev tau suav tias yog "lub zog txiaj". Tshwj xeeb tshaj yog cov piam thaj, raws li lub hauv paus tseem ceeb ntawm kev ua pa ntawm tes, kev sib koom ua ke ntawm nws cov metabolic abnormality thiab kev loj hlob qog nqaij hlav tau ua kom pom tseeb. Txawm li cas los xij, ib txoj kev tshawb fawb tawm los ntawm Cancer Research UK nyob rau hauv phau ntawv journal Nature hauv 2018 ua tiav rov sau cov lus piav qhia no - pab pawg tshawb fawb tau lees paub thawj zaug tias mannose tuaj yeem xaiv inhibit qhov kev loj hlob ntawm cov qog nqaij hlav cancer los ntawm kev cuam tshuam cov qog cov piam thaj metabolism hauv txoj kev, nrog me ntsis cuam tshuam rau cov ntaub so ntswg. Qhov kev tshawb pom no tsis tsuas yog cuam tshuam qhov kev xav tsis zoo uas "tag nrho cov suab thaj txhawb kev mob qog noj ntshav", tab sis kuj qhib qhov kev sib ntaus sib tua tshiab rau kev kho mob metabolic.

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1.2 Biological Traceability ntawm Mannose

Raws li ib qho isomer ntawm qabzib, mannose tau muab faib rau hauv lub xeev pub dawb ntawm lub epidermis ntawm txiv hmab txiv ntoo xws li citrus thiab txiv apples nyob rau hauv cov xwm, los yog koom nyob rau hauv kev tsim kho ntawm biological membranes nyob rau hauv daim ntawv ntawm glycoproteins. Nyob rau hauv tib neeg lub cev, mannose yog phosphorylated los ua mannose-6-phosphate (M6P), uas dhau los ua ib qho tseem ceeb taw qhia molecule rau lysosomal enzyme sorting. Cov kev tshawb fawb soj ntsuam yav dhau los tau nthuav tawm nws cov txheej txheem hauv kev tiv thaiv kab mob urinary: los ntawm kev sib tw los ntawm kev sib tw rau cov adhesion receptors ntawm cov kab mob pathogenic, nws thaiv lawv cov colonization ntawm urothelium. Cov yam ntxwv no tau ua rau muaj ntau yam kev noj zaub mov uas muaj nyob rau ntawm mannose, tab sis qhov kev tshawb pom ntawm nws cov peev xwm tiv thaiv kab mob qog noj ntshav tau ua rau muaj kev nce ntxiv hauv nws cov txiaj ntsig.

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Tshooj 2: Kev txiav txim siab txog science: Triple Offensive ntawm Mannose tawm tsam Cancer

2.1 Metabolic Hijacking: Txiav tawm "qab zib ntxiv" cov saw hlau ntawm cov qog nqaij hlav cancer

Warburg cov nyhuv ntawm cov qog hlwb (uas tseem cia siab rau glycolysis rau lub zog txawm tias nyob rau hauv ib puag ncig uas muaj oxygen) ua rau lawv cov piam thaj nce mus txog kaum npaug ntawm cov hlwb ib txwm muaj. Ib pab neeg Askiv tau tshawb pom los ntawm isotope tracing thev naus laus zis uas tom qab mannose nkag mus rau hauv cov qog nqaij hlav cancer, nws yog catalyzed los ntawm hexokinase los ua M6P thiab accumulates ntau hauv cov hlwb. Qhov no "pseudo-metabolite" tsis tsuas yog nyob hauv cov kab ntawm cov piam thaj thauj mus los (GLUT), tab sis tseem muaj kev sib tw los cuam tshuam cov haujlwm ntawm phosphoglucose isomerase, uas ua rau tsis muaj cov ntsiab lus tseem ceeb hauv glycolysis thiab lub voj voog tricarboxylic acid, thaum kawg ua rau muaj kev kub ntxhov hauv cov qog nqaij hlav cancer (Daim duab 1).

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2.2 Epigenetics: Kho cov qog microenvironment

Ib txoj kev tshawb fawb luam tawm los ntawm Fudan University hauv Cell Metabolism hauv 2023 tau qhia ntxiv tias mannose tuaj yeem thim rov qab cov kab mob qog nqaij hlav hauv cov qog nqaij hlav los ntawm kev tswj hwm qib histone acetylation. Kev sim tau pom tias hauv cov qog nqaij hlav qog noj ntshav kho nrog mannose, qib acetylation ntawm thaj chaw txhawb nqa ntawm oncogene MYC raug txo qis, thiab nws cov haujlwm transcriptional yog inhibited heev. Qhov no epigenetic reprogramming nyhuv tsis muaj zog rau invasive thiab qhuav yam ntxwv ntawm qog hlwb, muab ib tug theoretical fulcrum rau txoj kev loj hlob ntawm ua ke epigenetic tshuaj.

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2.3 Immune Synergy: Tshem tawm "Invisibility Cloak" ntawm PD-L1

Txawm tias muaj kev cuam tshuam ntau dua yog tias tib pab pawg tau tshawb pom tias mannose tuaj yeem tsom lub qog tiv thaiv kab mob khiav tawm. Los ntawm kev tsom xam spectrometry loj, cov kws tshawb fawb tau lees paub tias mannose cuam tshuam qhov tseeb folding thiab membrane localization ntawm PD-L1 protein los ntawm kev cuam tshuam nrog nws cov kev hloov kho N-glycosylation. PD-L1 protein, uas poob lub "tiv thaiv lub kaus" ntawm cov suab thaj, feem ntau yuav ubiquitinated thiab degraded, yog li tshem tawm cov teeb liab inhibitory ntawm T hlwb. Hauv cov qauv melanoma nas, kev sib xyaw ua ke ntawm mannose thiab anti-PD-1 antibody tau nce cov qog regression tus nqi mus rau 78%, deb tshaj qhov kev kho ib leeg (Daim duab 2).

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Tshooj 3: Los ntawm Chav Ua Haujlwm mus rau Chaw Kho Mob: Txoj Kev Hla Dhau ntawm Kev Txhais Lus Tshuaj

3.1 Milestones ntawm kev tshawb fawb preclinical

Hauv ntau qhov kev sim tsiaj, mannose tau pom dav-spectrum anti-cancer muaj peev xwm. Ib pab pawg neeg Askiv tau cuam tshuam cov kab mob qog noj ntshav rau cov nas nrog 20% ??mannose haus dej thiab pom tias cov qog loj hlob qeeb mus txog 40%, thiab tsis muaj lub siab lossis lub raum toxicity. Txawm tias zoo siab tshaj plaws, thaum siv nrog gemcitabine, lub sij hawm ciaj sia ntawm cov nas tau ntev los ntawm 2.3 zaug, qhia txog nws cov tshuaj tua kab mob-sensitizing tus nqi. Kev tshawb nrhiav kev ywj pheej ntawm MD Anderson Cancer Center hauv Tebchaws Meskas tau pom tias mannose muaj txiaj ntsig zoo sib xws rau cov qog nqaij hlav refractory xws li triple-negative cancer mis thiab glioblastoma.

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3.2 Ua tib zoo tshawb nrhiav tib neeg kev sim

Txawm hais tias muaj cov ntaub ntawv tseem ceeb tshaj plaws, kev sim tib neeg ntsib teeb meem tshwj xeeb. Phase I soj ntsuam sim (NCT05220739) pib hauv 2022 yog thawj zaug ntsuas kev nyab xeeb ntawm qhov ncauj mannose hauv cov neeg mob uas muaj cov qog nqaij hlav siab heev. Cov ntaub ntawv ua ntej qhia tau hais tias cov neeg mob nyob rau hauv ib hnub 5g koob tshuaj pab pawg muaj kev kam rau siab zoo, thiab cov qog qog DNA (ctDNA) hauv qee kis tau txo qis. Txawm li cas los xij, thaum cov koob tshuaj nce mus txog 10g, kwv yees li 15% ntawm cov neeg mob tau mob raws plab, qhia tias yuav tsum tau ua kom zoo dua qhov kev siv tshuaj.

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3.3 Technical Barriers rau industrialization

Txawm hais tias ib txwm muab rho tawm mannose muaj kev nyab xeeb, nws yuav tsum tau txhaj tshuaj siab heev kom ncav cuag cov tshuaj tiv thaiv kabmob kheesxaws (sib npaug rau kev noj 5 kilograms ntawm cranberries txhua hnub), uas tau tsav cov thev naus laus zis tshiab hauv cov khoom siv hluavtaws. Tam sim no, genetic engineered Escherichia coli tuaj yeem nce mannose ntau lawm los ntawm 20 zaug, thaum immobilized enzyme catalysis txo cov nqi tsim khoom qis dua $ 50 ib kilogram. Tsis tas li ntawd, nano-liposome encapsulation thev naus laus zis tuaj yeem ua rau muaj kev ua haujlwm ntawm cov qog-taw qhia xa mus rau 80%, tshem tawm txoj hauv kev rau kev hloov kho kho mob.

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Tshooj Plaub Plaub Kev Sib cav thiab xav txog: Kev xav Txias nyob rau hauv Carnival of Science

4.1 "Dawb-edged ntaj" nyhuv ntawm metabolic cuam tshuam

Nws yog tsim nyog sau cia tias mannose tsis yog panacea. Qee cov qog nqaij hlav qog noj ntshav nqa qhov kev hloov pauv ntawm mannose phosphate isomerase (PMI) tuaj yeem hloov mannose-6-phosphate mus rau hauv fructose-6-phosphate, uas hloov pauv cov glycolytic flux. Qhov tshwm sim "metabolic khiav" no tau kuaj pom nyob rau hauv kwv yees li 7% ntawm cov qauv qog nqaij hlav hauv plab, qhia txog qhov yuav tsum tau tsim cov cim ntsuas tus kheej.

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4.2 Ntuj ≠ Kev Nyab Xeeb: Kev Tswj Xyuas Kev Siv Tshuaj

Txawm hais tias mannose tau raug pom zoo siv rau hauv cov zaub mov raws li GRAS (Feem ntau Pom tau tias muaj kev nyab xeeb), nws cov tshuaj toxicity mus sij hawm ntev ntawm cov tshuaj tiv thaiv kab mob tseem yuav tsum tau ua tiag tiag. Cov kev sim tsiaj tau pom tias kev noj tshuaj ntau ntxiv tuaj yeem ua rau mob plab hnyuv, nrog rau kev nplua nuj ntawm qee yam kab mob kis tau zoo (xws li Klebsiella) nce kaum npaug. Qhov no xav kom cov kev tshawb fawb yav tom ntej yuav tsum sib npaug ntawm kev kho mob thiab microecological homeostasis.

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4.3 Qhov Kev Ua Si ntawm Kev Ua Lag Luam Hype thiab Kev Tshawb Fawb Txog Kev Tshawb Fawb

Nrog lub tswv yim ntawm "anti-cancer qab zib" ua nrov, qee cov tub lag luam tau tshaj tawm cov txiaj ntsig kho mob ntawm cov khoom noj qab haus huv mannose. FDA ntawm Tebchaws Meskas tau tshaj tawm tsab ntawv ceeb toom rau peb lub lag luam rau lawv qhov kev tshaj tawm tsis raug cai, hais tias "cov tshuaj noj tsis tuaj yeem hloov kho tshuaj." Cov kws tshawb fawb tab tom hu rau kev tsim kom muaj kev lag luam whitelist los tswj cov ntawv sau npe thiab kev lag luam ntawm cov khoom muaj mannose.

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Xaus: Daim duab yav tom ntej ntawm lub qab zib kiv puag ncig

Kev tiv thaiv kab mob qog noj ntshav ntawm mannose tsis yog tsuas yog kev sib ntsib zoo tshaj plaws ntawm qhov khoom plig thiab tib neeg kev txawj ntse, tab sis kuj yog ib qho qauv ntawm kev sib koom ua ke ntawm kev tsim kho tshiab. Los ntawm metabolic reprogramming mus rau kev hloov kho ntawm lub cev tiv thaiv kab mob microenvironment, los ntawm kev kuaj cov raj mus rau cov chaw muag tshuaj, qhov "qab zib kiv puag ncig" yog rov sau dua cov cai ntawm kev kho mob qog noj ntshav. Txawm hais tias tseem muaj ntau qhov kev sib tw ua ntej, nws tuaj yeem pom tau tias tiam tom ntej ntawm cov tshuaj glyco-based raws li mannose tuaj yeem ua rau lub sijhawm tshiab ntawm kev tiv thaiv kabmob kheesxaws. Ib yam li Nature tau hais tias: "Thaum kev tshawb fawb seev cev nrog xwm, lub doomsday tswb ntawm mob qog noj ntshav tau nrov lawm."

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