Targeting Cathepsin B By Cycloastragenol Enhances Antitumor Immunity Of CD8 T Cells Via Inhibiting MHC-I Degradation Part 2

CAG inhibits CTSB-mediated MHC-I lysosomal degradation

Glycoside ntawm cistanche tuaj yeem ua rau muaj kev ua haujlwm ntawm SOD hauv plawv thiab daim siab cov ntaub so ntswg, thiab txo cov ntsiab lus ntawm lipofuscin thiab MDA hauv txhua cov ntaub so ntswg, tshem tawm ntau yam reactive oxygen radicals (OH-, H₂O₂, thiab lwm yam) thiab tiv thaiv DNA puas. los ntawm OH-radicals. Cistanche phenylethanoid glycosides muaj peev xwm tshem tawm cov dawb radicals, muaj peev xwm txo tau ntau dua li cov vitamin C, txhim kho cov haujlwm ntawm SOD hauv cov phev ncua, txo cov ntsiab lus ntawm MDA, thiab muaj qee yam kev tiv thaiv ntawm cov phev ua haujlwm. Cistanche polysaccharides tuaj yeem txhim kho kev ua haujlwm ntawm SOD thiab GSH-Px hauv erythrocytes thiab ntsws cov ntaub so ntswg ntawm cov nas senescent sim los ntawm D-galactose, nrog rau txo cov ntsiab lus ntawm MDA thiab collagen hauv lub ntsws thiab ntshav, thiab nce cov ntsiab lus ntawm elastin, muaj Cov nyhuv scavenging zoo ntawm DPPH, ncua lub sijhawm ntawm hypoxia hauv cov nas senescent, txhim kho cov haujlwm ntawm SOD hauv cov ntshav, thiab ncua lub physiological degeneration ntawm lub ntsws hauv kev sim cov nas nrog cellular morphological degeneration, kev sim tau pom tias Cistanche muaj peev xwm antioxidant zoo. thiab muaj peev xwm los ua ib qho tshuaj tiv thaiv thiab kho cov kab mob ntawm daim tawv nqaij laus. Nyob rau tib lub sijhawm, echinacoside hauv Cistanche muaj lub peev xwm tseem ceeb txhawm rau txhawm rau DPPH dawb radicals thiab muaj peev xwm tshem tawm cov pa oxygen reactive thiab tiv thaiv dawb radical-induced collagen degradation, thiab kuj muaj kev kho zoo ntawm thymine dawb radical anion puas.

Nyem rau ntawm maca ginseng cistanche hiav txwv nees

【Yog xav paub ntxiv:george.deng@wecistanche.com / WhatApp:8613632399501 】

Cov kev tshawb fawb yav dhau los tau ua pov thawj tias MHC-I feem ntau yog degraded hauv lysosomes thaum lub sij hawm qog nqaij hlav, ua rau cov qog tiv thaiv kab mob khiav tawm. . Peb thawj zaug siv RNA cuam tshuam los cuam tshuam qhov kev qhia ntawm CTSB hauv MC38 cell kab, thiab cov txiaj ntsig tau pom tias cov noob thiab cov protein qhia qib ntawm H2-k1 tau nce ntxiv tom qab CTSB (daim duab 5A, B). Ib yam li ntawd, tom qab knockdown thiab overexpression ntawm CTSB nyob rau hauv tib neeg HCT-116 kab ntawm tes, mRNA los yog protein qhia theem ntawm HLA-A nce (daim duab 5C, D) thiab txo (daim duab 5E, F), feem. Nyob rau tib lub sijhawm, peb pom tias cov qog hlwb nrog kev qhia siab ntawm CTSB qhia qis HLA-A qib, thaum lub hlwb tom qab CTSB knockdown nce qhov kev qhia ntawm HLA-A (daim duab 5G). Cov txiaj ntsig no qhia tau tias CTSB ua rau muaj kev tswj hwm tsis zoo ntawm kev qhia ntawm MHC-I. Tom qab ntawd, peb tau kho MC38 xov tooj ntawm tes nrog CAG thiab pom tias CAG txhawb nqa qhov kev qhia ntawm MHC-I thiab tsis muaj kev cuam tshuam rau CTSB (daim duab 5H, I), uas tau ua raws li cov txiaj ntsig yav dhau los ntawm kev tshawb fawb ntawm cov qog nqaij hlav. Ntxiv mus, peb pom tias tom qab kev kho CAG, H2-Kd tau sau los ntawm lub xovtooj ntawm tes mus rau nws daim nyias nyias (daim duab 5J), uas tau ua pov thawj ntxiv rau peb qhov kev xav tias CAG tuaj yeem cuam tshuam qhov degradation ntawm MHC-I molecule thiab ua kom nws sib sau ua ke ntawm cell membrane, uas yog yooj yim mus ntes los ntawm lub cev tiv thaiv kab mob. Txhawm rau kom ua tiav peb qhov kev xav, peb siv Co-IP kev sim los tshawb xyuas seb CTSB khi rau MHC-I thiab ua rau nws qhov kev puas tsuaj. Peb pom tias CAG tuaj yeem cuam tshuam kev khi ntawm CTSB thiab MHC hauv nas MC38 hlwb (daim duab 5K), thiab kev qhia ntawm MHC-I kuj nce ntxiv. Peb kuj tau pom tib qhov tshwm sim hauv tib neeg HCT116 hlwb (daim duab 5L). Tom ntej no, txhawm rau paub meej ntxiv seb CAG txhawb nqa MHC-I kev qhia thiab cell membrane sib sau los ntawm CTSB, peb tau hloov CTSB mutant plasmid rau hauv tib neeg HCT-116 hlwb. Cov txiaj ntsig tau pom tias tom qab hloov pauv Y75A, A77V, thiab G198V mutant plasmids, CAG txoj haujlwm ntawm kev txhim kho CD74 thiab HLA-A noob qhia tau raug rhuav tshem (daim duab 5M), thiab MHC-I molecules aggregated ntawm cell membrane mus rau lysosomes (daim duab 5N). Qhov txiaj ntsig no tau pom tias CAG inhibited qhov degradation ntawm MHC-I hauv lysosomes kho los ntawm CTSB thiab txhawb nqa cov reaggregation ntawm MHC-I mus rau lub cell membrane.

Kev sib xyaw ua ke ntawm CAG thiab PD-1 cov tshuaj tiv thaiv zoo txhim kho cov qog-tua muaj peev xwm ntawm CD8 ntxiv rau T hlwb

Kev tiv thaiv qog noj ntshav yog tshwm sim los ntawm kev poob ntawm cov qog cell antigen kev nthuav qhia muaj nuj nqi thiab inhibition ntawm lub cev tiv thaiv kab mob. Raws li peb cov txiaj ntsig, peb tau kwv yees seb CAG puas tuaj yeem siv ua ke nrog PD-1 cov tshuaj tiv thaiv kab mob los tua cov qog, ob qho tib si los daws qhov tsis zoo ntawm cov qog antigen nthuav qhia thiab daws qhov depletion ntawm CD8 ntxiv rau T hlwb tshwm sim los ntawm PD{ {2}}/ PD-L1 txoj kev. Yog li, peb tau hloov MC38 cov qog nqaij hlav cancer rau hauv cov nas C57BL/6 thiab tsim ib pawg ua ke ntawm PD-1 tshuaj tiv thaiv thiab CAG. Cov txiaj ntsig tau pom tias pawg sib xyaw ua ke ntawm CAG thiab PD-1 cov tshuaj tiv thaiv tau nthuav tawm cov nyhuv antitumor zoo dua li CAG thiab PD-1 pawg (daim duab 6A–D). Tsis tas li ntawd, peb tau pom qhov nce ntxiv ntawm cov neeg nkag mus hauv H2-Kd ntxiv rau cov hlwb, CD45 ntxiv rau cov hlwb, thiab CD8 ntxiv rau cov hlwb hauv cov qog nqaij hlav (daim duab 6E–G), thiab kev qhia ntawm cov tshuaj tiv thaiv kab mob ntsig txog cov noob caj noob ces. H2-K1, Psmb8, thiab B2m kuj tau txhim kho (daim duab 6H–J). Lub caij no, kev qhia ntawm Ifng thiab Tnf noob tau txhim kho zoo ib yam nkaus (daim duab 6K, L), thiab cov tshuaj tiv thaiv kab mob ua rau pom tias qhov kev qhia ntawm H2-Kd tau nce ntau (daim duab 6M).

Yog li, txoj kev tshawb no feem ntau qhia meej txog cov tshuaj tiv thaiv kab mob ntawm CAG, feem ntau yog los ntawm inhibiting degradation ntawm MHC-I mediated los ntawm CTSB, txhawb kev sib sau ntawm MHC-I molecules rau cell membrane, thiab tom qab ntawd txhim kho cov antigen kev nthuav qhia muaj peev xwm ntawm cov qog nqaij hlav cancer. Ntxiv mus, ua ke nrog PD-1 antibody, nws tuaj yeem tua cov qog nqaij hlav cancer zoo heev (daim duab 6N).

CAG txhawb nqa MHC-I kev qhia hauv cov kab mob qog nqaij hlav hauv plab hnyuv thiab txhim kho kev tua muaj peev xwm ntawm CD8 T hlwb

Txhawm rau tshawb xyuas ntxiv seb puas muaj cov tshuaj pharmacological ntawm CAG tuaj yeem siv rau kev kho mob, tib neeg cov kab mob qog noj ntshav tau siv. Peb pom tias cov organoids incubated nrog CAG txhim kho qhov kev qhia ntawm MHC-I (daim duab 7A), thiab qhov kev qhia ntawm antigen-kev nthuav qhia txog cov noob ANXA1, B2M, thiab HLA-A kuj nce ntxiv (daim duab 7B). Hauv kev sim yav dhau los, peb pom tias CAG txhim kho cov nyhuv tua ntawm CD8 T hlwb los ntawm kev txhawb nqa cov tshuaj tiv thaiv antigen ntawm cov qog hlwb, thiab cov nyhuv zoo dua thaum ua ke nrog PD-1 antibody. Txhawm rau txheeb xyuas ntxiv cov txiaj ntsig no, peb tau sau cov ntshav peripheral ntawm cov neeg noj qab haus huv thiab cais CD8 T hlwb, thiab tom qab ntawd incubated nrog CAGstimulated organoids rau 24 teev (daim duab 7C). Cov txiaj ntsig tau pom tias piv nrog pab pawg DMSO, CD8 T hlwb hauv cov qog nqaij hlav organoids kho nrog CAG tsis tau ploj mus lawm tab sis tau muaj ntau dua nyob rau saum npoo ntawm organoids; tib lub sijhawm, muaj tsawg dua tawm ntawm CD8 T hlwb hauv CAG thiab PD-1 pawg (daim duab 7D). Peb pom tias IFN-G secreted los ntawm activated CD8 T hlwb tau raug txhim kho (daim duab 7E–H).

Txog tam sim no, peb pom tias CAG txhawb nqa cov tshuaj tiv thaiv kab mob qog noj ntshav los txhim kho cov nyhuv antitumor ntawm CD8 T hlwb, thiab kev sib xyaw ntawm CAG thiab PD-1 cov tshuaj tiv thaiv muaj txiaj ntsig zoo tshaj plaws antitumor. Ntxiv mus, peb tau tshuaj xyuas cov ntaub ntawv mob qog noj ntshav hauv cov ntaub ntawv Cancer Genome Atlas (TCGA) thiab pom tias cov tshuaj tiv thaiv kab mob ntsig txog cov noob HLA-A, HLA-B, HLA-C, CD74, thiab B2M tau qhia qis qis hauv cov qog, thiab Qhov ciaj sia taus ntawm cov noob no nrog kev qhia qis yog qhov tsis zoo (daim duab 7I, J, daim duab 7A-H).

Yog li ntawd, peb pom tau hais tias kev tswj hwm ntawm HLA-A, CD74, thiab lwm cov noob los ntawm CAG tau txais txiaj ntsig zoo rau cov neeg mob qog. Tsis tas li ntawd, peb pom tias cov neeg mob uas muaj kev qhia siab ntawm HLA-A, nrog rau IFNG, muaj kev muaj sia nyob ntau dua (daim duab 7K); Cov neeg mob uas muaj kev qhia siab ntawm HLA-A thiab kev qhia qis ntawm PDCD1 kuj muaj qhov muaj sia nyob zoo dua (daim duab 7L). Tag nrho cov kev tshawb pom no qhia tias CAG yuav yog tshuaj-tus neeg sib tw rau kev kho mob qog noj ntshav hauv plab.

Kev sib tham

Kev tiv thaiv kev tiv thaiv yog qhov laj thawj tseem ceeb rau qhov tsis ua haujlwm ntawm lub cev tiv thaiv kab mob los tswj cov qog loj hlob, tab sis yuav ua li cas kev khiav tawm txawv txav tshwm sim thaum immunotherapy tseem to taub tsis zoo.34 Cov kev tshawb fawb tau pom tias qhov poob ntawm cov qog antigen-presenting muaj nuj nqi, kev hloov pauv ntawm epigenetic, kev qhia ntawm antiapoptotic. proteins, thiab immunosuppressive receptors yog ze ze rau cov qog tiv thaiv kab mob. 6 7 35–37 Nyob rau hauv xyoo tas los no, txawm hais tias immunotherapy uas sawv cev los ntawm PD-1 cov tshuaj tiv thaiv kab mob tau ua rau muaj kev cuam tshuam zoo, qhov tshwm sim ntawm kev tiv thaiv tshuaj thiab kev kho mob tsis zoo ntawm cov qog nqaij hlav hauv plab tau ua rau muaj kev tsis txaus siab loj heev. 38 39 Yog li ntawd, nrhiav cov tshuaj uas tuaj yeem txhawb cov qog antigen nthuav qhia thiab ua haujlwm nrog PD-1 cov tshuaj tiv thaiv kab mob tuaj yeem tiv thaiv qog tiv thaiv kab mob kom zoo dua.

Cov kev tshawb fawb tsis ntev los no tau pom tias cov active molecules los ntawm cov tshuaj suav tshuaj ua lub luag haujlwm zoo hauv kev kho cov kab mob, xws li celastrol hauv kev kho mob metabolic syndrome, 32 andrographolide hauv colitis thiab mob qog noj ntshav, 40 baicalin hauv lipid-txo thiab trifolirhizin hauv kev tswj cov qog. 41 42 CAG yog ib qho active molecule hauv A. membranaceus thiab muaj lub luag haujlwm ntawm cov kab mob plawv, tiv thaiv daim siab, tiv thaiv kab mob, thiab kho mob plab aortic aneurysm.18 43-45 Txawm li cas los xij, muaj kev tshawb fawb me me txog nws hauv thaj chaw ntawm mob qog nqaij hlav hauv plab. Yog li ntawd, peb tsom mus soj ntsuam seb puas thiab CAG inhibits kev loj hlob ntawm murine nyuv qog noj ntshav

Txoj kev loj hlob ntawm scRNA-seq thiab scATAC-seq technologies tau zoo heev rau kev tshawb fawb ntawm cov kab mob.46-48 Yog li ntawd, peb siv ib leeg-cell multi-omics technology los soj ntsuam cov antitumor mechanism ntawm CAG. Nws tau pom tias CAG txhawb kev ua haujlwm antigen-tam sim no ntawm cov qog nqaij hlav qog noj ntshav, thiab cov haujlwm ntawm CD8 ntxiv rau T hlwb, CD4 ntxiv rau T hlwb, thiab NK hlwb hauv lymphocytes tau txhim kho mus rau qhov sib txawv. Ntawm qhov tod tes, Spp1 ntxiv rau TAM cov hlwb hauv cov hlwb myeloid tau xav ntau dua rau kev hloov pauv ntawm cov lus teb, thiab cov teeb liab hypoxia tau cuam tshuam loj heev tom qab kho CAG. Cov txiaj ntsig no zoo ib yam nrog cov txiaj ntsig tau tshaj tawm hauv cov kev tshawb fawb yav dhau los, qhov inhibition ntawm Spp1 ntxiv rau TAM hypoxia teeb liab thiab txhim kho cov lus teb inflammatory tuaj yeem inhibit qhov kev loj hlob ntawm cov qog.49 Yog li ntawd, peb xav tias CAG txhawb cov antigen-presenting muaj nuj nqi ntawm cov qog nqaij hlav cancer, yog li. CD8 ntxiv rau T hlwb thiab macrophages tuaj yeem paub thiab tua cov qog nqaij hlav cancer zoo. Peb txuas ntxiv txheeb xyuas peb qhov kev xav nrog kev sim hauv vitro. Flow cytometry tsom xam kuj tau pom tias CAG nce qhov nkag mus ntawm CD45 lub cev tiv thaiv kab mob, suav nrog CD8 ntxiv rau T hlwb thiab NK hlwb. Tsis tas li ntawd, lub peev xwm ntawm IFN- thiab GZMB zais los ntawm CD8 ntxiv rau T hlwb kuj tseem txhim kho los ntawm CAG. Txhawm rau txiav txim siab seb CD8 T hlwb lossis macrophages ua lub luag haujlwm tseem ceeb hauv kev sim tshuaj tiv thaiv kab mob CAG, peb tau sim peb qhov kev xav nrog cov qog hlav hauv cov nas liab qab. Vim qhov kev loj hlob tsis zoo ntawm T hlwb tshwm sim los ntawm kev txhaj tshuaj ntawm thymus hauv cov nas liab qab thaum lub luag haujlwm ntawm macrophages tseem muaj. Txawm li cas los xij, cov txiaj ntsig tau pom tias CAG tsis tuaj yeem tua cov qog hloov hauv cov nas liab qab. Cov txiaj ntsig no qhia tias CAG tuaj yeem txhim kho cov nyhuv tua ntawm CD8 ntxiv rau T hlwb ntawm cov qog los ntawm kev txhawb nqa cov tshuaj tiv thaiv kab mob qog noj ntshav.

Tom ntej no, peb tau tshawb nrhiav seb CAG txhawb nqa cov tshuaj tiv thaiv kab mob qog noj ntshav li cas los ntawm TRAP thev naus laus zis los nrhiav cov hom phiaj protein ntawm CAG los piav qhia qhov tshwm sim. CTSB yog ib qho cysteine ​​hydrolase, uas tuaj yeem cuam tshuam nrog lwm cov proteins thiab degrade hauv lysosomes.50 Peb xav tias nws yuav cuam tshuam nrog antigen nthuav qhia cov proteins uas ua rau nws degradation. Thiab nws tau raug tshaj tawm tias MHC-I molecule yog degraded hauv lysosomes, ua rau cov qog cell antigen-presenting function.13 Yog li ntawd, peb xav tias CTSB yuav khi rau MHC-I molecule thiab ua rau nws degradation hauv lysosomes. Peb tau txheeb xyuas qhov kev xav no tias CAG tuaj yeem tiv thaiv kev degradation ntawm MHC-I los ntawm inhibiting kev cuam tshuam ntawm CTSB thiab MHC-I. Organoids yog ib qho qauv zoo los kawm txog kev nce qib ntawm cov kab mob qog thiab muaj qhov tseem ceeb los txhawb kev kho mob ntawm cov neeg mob qog nqaij hlav los ntawm kev tshawb xyuas cov txiaj ntsig ntawm cov tshuaj rau kev loj hlob ntawm cov qog organoids thiab cov txheej txheem tshwj xeeb.51 52 Los ntawm peb cov kev sim, peb pom tias ua ke nrog CAG thiab PD-1 cov tshuaj tiv thaiv kab mob muaj peev xwm tiv thaiv cov qog loj hlob txawm tias nyob rau hauv nas hloov qog cov qauv lossis tib neeg cov kab mob qog noj ntshav. Qhov tsis txaus ntawm qhov kev tshawb fawb no yog qhov txwv ntawm xenograft cov qauv thiab cov neeg mob organoids. Txawm hais tias muaj cov lus xaus zoo sib xws ntawm cov qauv murine thiab tib neeg organoids, xav tau kev tshawb nrhiav ntxiv.

Ntawm no, peb piav qhia txog cov txheej txheem tshwj xeeb uas CAG inhibits kev loj hlob ntawm cov qog nqaij hlav hauv plab, feem ntau los ntawm inhibiting degradation ntawm MHC-I mediated los ntawm CTSB, los txhim kho cov tshuaj tiv thaiv kab mob ntawm CD8 ntxiv rau T hlwb. Ntawm qhov tod tes, nws txhawb nqa qhov kev nthuav qhia antigen ntawm cov qog nqaij hlav cancer, thiab ntawm qhov tod tes, nws relieves lub xeev depletion ntawm CD8 ntxiv rau T hlwb. Cov txiaj ntsig kev sim kuj tau lees paub tias kev sib xyaw ntawm CAG thiab PD-1 cov tshuaj tiv thaiv kab mob muaj txiaj ntsig zoo tshaj plaws antitumor.

Hauv kev xaus, rau qhov zoo tshaj plaws ntawm peb txoj kev paub, cov kev tshawb pom no qhia tias CTSB downregulation confers antitumor tiv thaiv. Peb cov kev tshawb fawb kuj tau piav qhia txog cov txheej txheem tshwj xeeb ntawm CAG hauv inhibiting kev loj hlob ntawm cov qog nqaij hlav hauv plab. Nws yog tsim nyog hais tias CAG muaj peev xwm zoo li cov khoom noj qab haus huv hauv European thiab Asmeskas kev lag luam. Peb cov kev tshawb fawb tau muab cov tshuaj tiv thaiv kab mob muaj peev xwm.

Cov kws sau ntawv koom nrog

1 Lub Xeev Tseem Ceeb Laboratory ntawm Pharmaceutical Biotechnology, Chemistry thiab Biomedicine Innovation Center (ChemBIC), Department of Biotechnology thiab Pharmaceutical Sciences, Lub Tsev Kawm Ntawv ntawm Kev Tshawb Fawb Txog Lub Neej, Nanjing University, Nanjing, Jiangsu, Suav

2 Bioinformatics Department of Predictive Medicine, Lub koom haum ntawm Biomedical Informatics, Cell Signal Transduction Laboratory, Lub Tsev Kawm Ntawv ntawm Kev Kho Mob Sciences, Henan University, Kaifeng, Henan, Tib Neeg Lub Tebchaws ntawm Tuam Tshoj

3 Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, First Clinical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, Suav teb

4 Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China

5 Jiangsu Provincial Key Laboratory ntawm Tshuaj Metabolism thiab Pharmacokinetics, Lub Xeev Lub Chaw Haujlwm Tseem Ceeb ntawm Cov Tshuaj, Tuam Tshoj Pharmaceutical University, Nanjing, Jiangsu, Suav

6 Genergy Bio-technology (Shanghai) Co., Ltd., Shanghai, Suav

7 Jiangsu Key Laboratory ntawm Kev Tshawb Fawb Tshuaj Tshiab thiab Cov Tshuaj Kho Mob, Xuzhou Medical University, Xuzhou, Jiangsu, Suav

Cov koom tesYS, HC, thiab DS tau tsim txoj haujlwm no thiab tsim txoj kev kawm. GD, BW, thiab XS tau ua qhov kev sim thiab tshuaj xyuas cov ntaub ntawv. LZ thiab HC txheeb xyuas cov ntaub ntawv scRNA-seq thiab scATAC-seq. DS thiab HC tau muab cov txheej txheem kev txhawb nqa thiab cov tswv yim tswv yim. YS thiab GD sau cov ntawv sau. YS, raws li tus neeg lav, muaj lub luag haujlwm tag nrho rau kev ua haujlwm thiab / lossis kev coj ua ntawm txoj kev tshawb fawb thiab muaj cai nkag mus rau cov ntaub ntawv thiab tswj kev txiav txim siab tso tawm.

Nyiaj txiagTxoj haujlwm no tau txais kev txhawb nqa los ntawm National Key Research and Development Project (2017YFC1700602), National Natural Science Foundation of China (Nos. 81930117, 81872877, 82074318), Qhov Tseem Ceeb Kev Kawm Txuj Ci Kev Txhim Kho ntawm Jiangsu Higher Education Institutions thiab Mountain-Climbing Nanj University Project (N/A), Natural Science Foundation Project ntawm Shanghai, Scientific thiab Technological Innovation Action Plan (No. 22ZR1447400).

Kev nyiam sib twTsis muaj leej twg tshaj tawm.

Tus neeg mob tso cai rau kev tshaj tawmTsis siv tau.

Kev pom zoo ntawm EthicsTxoj kev tshawb fawb tib neeg txoj hnyuv organoids tau pom zoo los ntawm Pawg Neeg Tshawb Fawb thiab Kev Ncaj Ncees ntawm Lub Tsev Kho Mob Affiliated ntawm Nanjing University of Chinese Medicine thiab ua raws li tag nrho cov kev cai coj ncaj ncees (2020-NL-094- 02). Cov neeg koom nrog tau txais kev pom zoo los koom nrog hauv txoj kev kawm ua ntej koom nrog

Kev txheeb xyuas thiab kev txheeb xyuasTsis ua haujlwm; sab nraud cov phooj ywg-saib xyuas.

Cov ntaub ntawv muaj nyobTag nrho cov ntaub ntawv cuam tshuam rau txoj kev tshawb no suav nrog hauv tsab xov xwm lossis muab tso ua cov ntaub ntawv ntxiv hauv online.

Cov khoom siv ntxivCov ntsiab lus no tau muab los ntawm tus kws sau ntawv. Nws tsis tau raug soj ntsuam los ntawm BMJ Publishing Group Limited (BMJ) thiab tej zaum yuav tsis tau raug tshuaj xyuas. Txhua qhov kev xav lossis cov lus pom zoo tau tham tsuas yog cov neeg sau ntawv nkaus xwb thiab tsis pom zoo los ntawm BMJ. BMJ tsis lees paub txhua qhov kev lav phib xaub thiab lub luag haujlwm uas tshwm sim los ntawm kev tso siab rau cov ntsiab lus. Qhov twg cov ntsiab lus suav nrog cov ntaub ntawv txhais lus, BMJ tsis lees paub qhov raug thiab kev ntseeg siab ntawm cov kev txhais lus (xws li tab sis tsis txwv rau cov kev cai hauv zos, cov txheej txheem kho mob, cov lus siv, cov npe tshuaj, thiab cov tshuaj ntau npaum li cas), thiab tsis muaj lub luag haujlwm rau qhov yuam kev thiab/ los yog omissions tshwm sim los ntawm kev txhais lus thiab adaptation los yog lwm yam.

Qhib nkagQhov no yog ib tsab xov xwm qhib tau muab faib los ntawm Creative Commons Attribution Non-Commercial (CC BY-NC 4.{0) daim ntawv tso cai, uas tso cai rau lwm tus los faib, rov ua dua, hloov kho, tsim los ntawm txoj haujlwm no tsis yog lag luam, thiab tso cai rau lawv cov derivative ua hauj lwm nyob rau hauv cov nqe lus sib txawv, yog hais tias tus thawj ua hauj lwm yog muab hais kom raug, credit tsim nyog, muaj kev hloov pauv tau qhia, thiab kev siv tsis yog lag luam.

REFERENCES

1 Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA A Cancer J Clinicians 2022; 72:7–33.

2 Kuipers EJ, Grady WM, Lieberman D, et al. mob qog nqaij hlav hauv plab. Nat Rev Dis Primers 2015; 1:15065.

3 Biller LH, Schrag D. Kev kuaj mob thiab kev kho mob qog nqaij hlav hauv plab hnyuv loj. JAMA 2021; 325: 669–85.

4 Oliveira AF, Bretes L, Furtado I. Kev tshuaj xyuas ntawm PD-1/PD-L1 inhibitors hauv metastatic dMMR/MSI-H mob qog noj ntshav. Pem Hauv Ntej Oncol 2019; 9: 396.

5 Das M, Zhu C, Kuchroo VK. Tim-3 thiab nws lub luag haujlwm hauv kev tswj cov tshuaj tiv thaiv kab mob. Immunol Rev 2017; 276:97–111.

6 Jiang X, Wang J, Deng X, et al. Lub luag hauj lwm ntawm cov qog microenvironment hauv PD-L1/PD-1- kho cov qog tiv thaiv kab mob tawm. Hmoob Cancer 2019; 18:10.

7 Dhatchinamoorthy K, Colbert JD, Rock KL. Kev tiv thaiv kab mob qog noj ntshav los ntawm kev poob ntawm MHC chav kawm I antigen nthuav qhia. Pem Hauv Ntej Immunol 2021; 12: 636568.

8 Zhu Y, Qian Y, Li Z, et al. Neoantigen-reactive T cell: lub luag haujlwm tseem ceeb hauv kev siv tshuaj tiv thaiv kab mob hauv cellular. MedComm 2021; 2:207–20.

9 Vries JE, Yssel H, Spits H. Interplay ntawm TCR/CD3 complex thiab CD4 los yog CD8 nyob rau hauv lub activation ntawm cytotoxic T lymphocytes. Immunol Rev 1989; 109:119–42.

10 Huang J, Meyer C, Zhu C. T cell antigen recognition ntawm cell membrane. Mol Immunol 2012; 52:155–64.

11 Allison JP. CD28-B7 kev sib cuam tshuam hauv T-cell ua kom. Curr Opin Immunol 1994; 6:414–9.

12 Liu X, Bao X, Hu M, et al. Inhibition ntawm PCSK9 potentiates tiv thaiv kab mob qog noj ntshav. Xwm Txheej 2020;588:693–8.

13 Yamamoto K, Venida A, Yano J, et al. Autophagy txhawb kev tiv thaiv kev tiv thaiv kab mob qog noj ntshav los ntawm kev txo qis MHC-I. Xwm Txheej 2020;581:100–5.

14 Chen X, Zhao Y, Luo W, et al. Celastrol induces ROS-mediated apoptosis ntawm ncaj qha tsom peroxiredoxin -2 hauv cov qog nqaij hlav plab. Theranostics 2020; 10:10290–308.

15 Kong N, Chen X, Feng J, et al. Baicalin induces ferroptosis hauv zais zis hlwb los ntawm downregulating FTH1. Acta Pharm Sin B 2021; 11:4045–54.

16 Teng G, Chen W, Wang P, et al. Inhibition ntawm NLRP3 inflammasome-mediated pyroptosis nyob rau hauv macrophage los ntawm cycloastragenol pab txhawb rau amelioration ntawm imiquimod-induced psoriasis zoo li daim tawv nqaij o hauv nas. Int Immunopharmacol 2019; 74: 105682.

17 Li M, Li S-chun, Dou B-kai, et al. Cycloastragenol upregulates SIRT1 qhia, txo qis apoptosis, thiab suppresses neuroinflammation tom qab lub hlwb ischemia. Acta Pharmacol Sin 2020; 41:1025–32.

18 Chen C, Ni Y, Jiang B, et al. Anti-aging derivatives ntawm cycloastragenol ua los ntawm biotransformation. Nat Prod Res 2021; 35:2685–90.

19 Fauce SR, Jamieson BD, Chin AC, et al. Telomerase-based pharmacologic txhim kho ntawm cov tshuaj tiv thaiv kab mob ntawm tib neeg CD8 ntxiv rau T lymphocytes. J Immunol 2008; 181:7400–6.

20 Wang B, Wang Y, Sun X, et al. CXCR6 yog qhov yuav tsum tau ua rau cov tshuaj tiv thaiv kab mob ntawm intratumoral CD8 ntxiv rau T hlwb. J Immunother Cancer 2021; 9:e003100.

21 Butler A, Hoffman P, Smibert P, thiab al. Kev koom ua ke ib leeg-cell transcriptomic cov ntaub ntawv nyob rau hauv ntau yam mob, technologies, thiab hom. Nat Biotechnol 2018; 36:411–20.

22 Yu G, Wang G, Han Y, et al. clusterProfiler: ib pob R rau kev sib piv cov ntsiab lus lom neeg ntawm pawg noob. OMICS: A Journal of Integrative Biology 2012; 16:284–7.

23 Stuart T, Butler A, Hoffman P, et al. Kev sib xyaw ua ke ntawm cov ntaub ntawv ntawm ib leeg. Cell 2019; 177:1888–902.

24 Granja JM, Corces MR, Pierce SE, et al. ArchR yog ib pob software uas muaj peev xwm ua tau rau kev sib koom ua ke ntawm ib leeg-cell chromatin nkag mus rau kev txheeb xyuas. Nat Genet 2021; 53:403–11.

25 Korsunsky I, Millard N, Fan J, et al. Fast, rhiab, thiab raug kev koom ua ke ntawm ib leeg-cell cov ntaub ntawv nrog kev sib haum xeeb. Nat Methods 2019; 16:1289–96.

26 Trapnell C, Cacchiarelli D, Grimsby J, et al. Cov dynamics thiab regulators ntawm cell destiny txiav txim siab yog qhia los ntawm pseudo-temporal ordering ntawm ib lub hlwb. Nat Biotechnol 2014; 32:381–6.

27 Qiu X, Hill A, Packer J, et al. Ib leeg-cell mRNA kom muaj nuj nqis thiab kev txheeb xyuas qhov sib txawv nrog kev suav pej xeem. Nat Methods 2017; 14:309–15.

28 Qiu X, Mao Q, Tang Y, et al. Reversed graph embedding daws teeb meem ib leeg-cell trajectories. Nat Methods 2017; 14:979–82.

29 Patel AP, Tirosh I, Trombetta JJ, et al. Ib leeg-hlwb RNA-seq qhia txog intratumoral heterogeneity hauv thawj glioblastoma. Science 2014; 344: 1396–401.

30 Subramanian A, Tamayo P, Mootha VK, et al. Gene teem enrichment tsom xam: ib txoj hauv kev paub txog kev txhais cov genome-wide qhia profiles. Proc Natl Acad Sci USA 2005; 102:15545–50.

31 Tian Y, Wan N, Ding M. Chemoproteomics maps glycolytic tsom ib co hauv cov qog nqaij hlav cancer. bioRxiv 2020.

32 Zhu Y, Wan N, Shan X, et al. Celastrol lub hom phiaj adenylyl cyclase-associated protein 1 kom txo tau cov macrophage-mediated o thiab ameliorate high-fat diet-induced metabolic syndrome hauv nas. Acta Pharm Sin B 2021; 11:1200–12.

33 Driehuis E, Kretzschmar K, Clevers H. Tsim kom muaj cov kab mob qog noj ntshav los ntawm tus neeg mob rau kev siv tshuaj tshuaj. Nat Protoc 2020; 15:3380–409.

34 Lin KY, Lu D, Hung CF, et al. Ectopic qhia ntawm vascular cell adhesion molecule -1 raws li ib tug tshiab mechanism rau qog tiv thaiv evasion. Cancer Res 2007; 67:1832–41.

35 Kriegsman BA, Vangala P, Chen BJ, et al. Feem ntau poob ntawm IRF2 hauv cov qog nqaij hlav ua rau lub cev tsis muaj zog los ntawm kev txo qis MHC chav kawm I antigen thiab nce PD-L1 qhia. Xyoo 2019; 203: 1999-2010.

36 Gomez S, Tabernacki T, Kobyra J, et al. Kev sib xyaw ua ke ntawm epigenetic thiab kev tiv thaiv kab mob kom kov yeej kev mob qog noj ntshav. Semin Cancer Biol 2020; 65:99–113.

37 Mandal R, Barrón JC, Kostova I. Caspase-8: rab ntaj ob sab. Biochim Biophys Acta Rev Cancer 1873; 2020: 188357.

38 Qin S, Xu L, Yi M, et al. Novel immune checkpoint hom phiaj: tsiv dhau PD-1 thiab CTLA-4. Mol Cancer 2019; 18:155.

39 Lizardo DY, Kuang C, Hao S, et al. Immunotherapy kev ua tau zoo ntawm kev kho qhov tsis sib haum xeeb-tsis muaj mob qog noj ntshav: los ntawm lub rooj ntev zaum mus rau sab txaj. Biochim Biophys Acta Rev Cancer 2020; 1874: 188447.

40 Guo W, Sun Y, Liu W, et al. Me me molecule-driven mitophagy-mediated NLRP3 inflammasome inhibition yog lub luag haujlwm rau kev tiv thaiv kab mob qog noj ntshav. 2014; 10:972–85.

41 Dai J, Liang K, Zhao S, et al. Chemoproteomics qhia baicalin activates hepatic CPT1 rau ameliorate noj cov zaub mov vim rog rog thiab hepatic steatosis. Proc Natl Acad Sci USA 2018; 115: E5896–905.

42 Sun D, ​​Tao W, Zhang F, et al. Trifolirhizin induces autophagy-dependent apoptosis nyob rau hauv txoj hnyuv mob cancer ntawm AMPK / mTOR signaling. Sig Transduct Target Ther 2020; 5:174.

43 Gu M, Zhang S, Zhao Y, et al. Cycloastragenol txhim kho hepatic steatosis los ntawm activating farnesoid X receptor signaling. Pharmacological Research 2017; 121:22–32.

44 Wang J, Wu ML, Cao SP, et al. Cycloastragenol ameliorates kev sim plawv puas hauv nas los ntawm kev txhawb nqa myocardial autophagy ntawm inhibition ntawm AKT1-RPS6KB1 signaling. Biomed Pharmacother 2018; 107: 1074–81.

45 Wang Y, Chen C, Wang Q, et al. Inhibitory teebmeem ntawm cycloastragenol ntawm lub plab aortic aneurysm thiab nws cov txheej txheem cuam tshuam. Br J Pharmacol 2019; 176:282–96.

46 Lee JJ, Bernard V, Semaan A, et al. Elucidation ntawm qog-stromal heterogeneity thiab ligand-receptor interactome los ntawm ib leeg-cell transcriptomics nyob rau hauv lub ntiaj teb no tiag-lub ntiaj teb no pancreatic biopsies. Clin Cancer Res 2021; 27:5912–21.

47 Zhang L, Li Z, Skrzypczynska KM, et al. Ib leeg-Cell tsom xam qhia txog cov txheej txheem ntawm Myeloid-Targeted therapies nyob rau hauv txoj hnyuv loj. Cell 2020; 181:442–59.

48 Gao J, Wu Z, Zhao M, et al. Allosteric inhibition qhia SHP2-kev kho mob qog nqaij hlav hauv cov qog nqaij hlav hauv plab los ntawm ib leeg-cell transcriptomics. Acta Pharm Sin B 2022; 12:149–66.

49 Wei J, Chen Z, Hu M, et al. Tus cwj pwm kev sib txuas lus ntawm cov qog nqaij hlav qog nqaij hlav nthuav tawm SPP1 ntxiv rau cov qog-mob macrophage nthuav dav hauv hypoxia thiab txhawb kev mob qog noj ntshav los ntawm ib leeg-cell RNA-Seq Cov ntaub ntawv. Pem Hauv Ntej Cell Dev Biol 2021; 9: 749210.

50 Chen X, Yu C, Kang R, et al. Cellular degradation systems hauv ferroptosis. Cell Tuag txawv 2021; 28:1135–48.

51 Puschhof J, Pleguezuelos-Manzano C, Martinez-Silgado A, et al. Lub plab hnyuv organoid cocultures nrog microbes. Nat Protoc 2021; 16:4633–49.

52 Lee SH, Hu W, Matulay JT, et al. Cov qog evolution thiab tshuaj teb nyob rau hauv tus neeg mob-derived organoid qauv ntawm zais zis cancer. Cell 2018; 173:515–28.

【Yog xav paub ntxiv:george.deng@wecistanche.com / WhatApp:8613632399501 】