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Cov hmoov Ban-Lan-Gen ua rau cov kab mob dextran sodium sulfate ua rau mob plab hnyuv rov qab los hauv cov nas los ntawm kev hloov kho cov kab mob hauv plab thiab rov qab tsim cov SCFA Derived-GLP-1 hauv plab.
Jiao Peng,1-3,*Li Xi,4,*Zheng Lin,3,5 Duan Lifang,1 Gao Zhengxian,2,5 Diehu,1 Li Jie,6 Li Xiaofeng,6 Shen Xiangchun,5 Xiao Haitao21Peking University Shenzhen Tsev Kho Mob Chav Haujlwm Tshuaj, Shenzhen, Neeg Suav Teb; 2Shenzhen University Health Science Center Tsev Kawm Ntawv Tshuaj, Shenzhen, Neeg Suav Teb; 3Guizhou Medical University Engineering Technology Research Center of Ethnic Medicine and Traditional Chinese Medicine Development and Application Ministry of Education, Guizhou Provincial Key Laboratory of Pharmacy, Guizhou Medical University, Guiyang, Neeg Suav Teb; 4 Chav Haujlwm Gastroenterology, Peking University Shenzhen Tsev Kho Mob, Shenzhen, Neeg Suav Teb; 5 Tsev Kawm Ntawv Tshuaj, Guizhou Medical University, Lub Xeev Chav Haujlwm Tshuaj thiab Kev Siv, Guiyang; 6 Chav Haujlwm Saib Xyuas Kev Kho Mob Hauv Chaw Kuaj Mob, Tsev Kho Mob Peking University Shenzhen, Shenzhen, Suav Teb [email protected] Shen Xiangchun, Tsev Kawm Ntawv Tshuaj, Tsev Kawm Ntawv Kho Mob Guizhou, Guizhou, Tib Neeg Lub Tebchaws Suav Teb, 550004, Email [email protected] Lub Hom Phiaj: Kev kho mob raws li GLP-1 yog ib txoj kev kho mob tshiab rau kab mob plab hnyuv. Ban-Lan-Gen (BLG) granules yog ib hom tshuaj antiviral TCM uas paub tias muaj peev xwm tiv thaiv kev o hauv kev kho mob ntawm ntau yam mob o. Txawm li cas los xij, nws cov txiaj ntsig tiv thaiv kev o ntawm colitis thiab nws txoj kev ua haujlwm tseem tsis meej. TXOJ KEV: Txhawm rau tsim kom muaj dextran sodium sulfate (DSS)-induced chronic relapsing colitis hauv nas. Cov cim qhia txog kev ua haujlwm ntawm kab mob, cov cim qhia txog kev raug mob, thiab cov qib proinflammatory cytokine tau ua los ntsuas qhov cuam tshuam ntawm BLG. Cov teebmeem ntawm BLG rau cov kab mob hauv plab thiab plab hnyuv tau piav qhia los ntawm cov theem serum GLP-1 thiab colonic Gcg, GPR41, thiab GRP43 kev qhia tawm, cov kab mob hauv plab, cov theem fecal SCFAs, thiab GLP-1 tso tawm los ntawm nas thawj. Cov hlwb epithelial colonic SCFA-tau los ntawm GLP-1 ntau lawm. Cov txiaj ntsig: Kev kho mob BLG txo qhov hnyav ntawm lub cev, DAI, txoj hnyuv luv, cov nqaij ntawm txoj hnyuv puas tsuaj, thiab cov cytokine proinflammatory ntawm TNF-α, IL-1β, thiab IL-6 hauv cov nqaij ntawm txoj hnyuv. Tsis tas li ntawd, kev kho mob BLG tuaj yeem kho cov colonic Gcg, GPR41 thiab GRP43 kev qhia tawm thiab cov ntshav GLP-1 hauv cov nas colitis, thiab los ntawm kev nce cov kab mob SCFA xws li Akkermansia thiab Prevotellaceae_UCG-001, thiab txo cov kab mob xws li Eubacterium_xylanophilum_group, Ruminococcaceae_UCG-014, Intestinimonas thiab Oscillibacter. Tsis tas li ntawd, kev kho mob BLG tuaj yeem ua rau cov SCFAs ntau ntxiv hauv cov quav ntawm cov nas colitis. Tib lub sijhawm, kev sim hauv vitro kuj qhia tau tias cov quav extract ntawm cov nas kho BLG tuaj yeem txhawb nqa cov hlwb me me Murine colonic epithelial secrete GLP-1. Xaus Lus: Cov kev tshawb pom no qhia tias BLG muaj cov nyhuv tiv thaiv kab mob plab hnyuv. BLG muaj peev xwm tsim tau los ua kev kho mob, tsawg kawg yog ib feem los ntawm kev hloov kho cov kab mob hauv plab thiab rov qab tsim cov SCFA-derived GLP-1 hauv plab. Cov tshuaj zoo rau kev mob plab hnyuv rov qab los. Cov lus tseem ceeb: colitis, Ban-Lan-Gen granules, plab hnyuv microbiota, cov roj fatty acid luv luv, GLP-1
Kab mob plab hnyuv (Ulcerative colitis - UC) yog ib yam kab mob uas mob ntev ntev ntawm txoj hnyuv loj thiab lub qhov quav uas muaj xws li raws plab rov qab los, mob plab, poob phaus, thiab cov quav ntshav mucopurulent.1 Tsis ntev los no, qhov tshwm sim ntawm UC tau nce ntxiv hauv cov tebchaws uas yav dhau los tsis tshua muaj, suav nrog Suav teb, nrog rau kev nyiam ntawm cov neeg sab hnub poob.2 Qhov kev nce ntxiv no ua rau muaj teeb meem loj rau kev noj qab haus huv pej xeem thiab muaj kev cuam tshuam loj rau cov neeg mob lub peev xwm ua haujlwm thiab lub neej zoo. Qhov tseem ceeb, qhov pathogenesis ntawm UC tseem tsis meej, tab sis feem ntau lees txais tias cov noob caj noob ces, cov yam ntxwv ib puag ncig, cov kab mob hauv plab, thiab lub cev tiv thaiv kab mob txhua tus pab txhawb rau kev loj hlob ntawm UC.3 Txawm tias tam sim no, tsis muaj kev kho rau UC, thiab lub hom phiaj ntawm kev kho mob yog kev kho mob los tswj cov tsos mob hauv kev kho mob, ua rau thiab tswj kev zam txim, txhawb kev kho mob mucosal, thiab txo qhov rov tshwm sim. Kev kho mob ib txwm muaj xws li aminosalicylates, corticosteroids, immunosuppressants, thiab biologics. Txawm li cas los xij, cov tshuaj no tsis tuaj yeem ua tiav qhov txiaj ntsig xav tau vim lawv cov kev phiv ntau yam.4 Tsis ntev los no, ntau qhov kev tshawb fawb tau qhia tias tshuaj suav tshuaj (TCM) tau pom tias muaj peev xwm zoo hauv pab txo qhov mob UC uas tsis muaj tshuaj lom, qhia tias kev tsim cov kev kho mob TCM tshiab yog ib txoj kev kho mob zoo rau UC.5-7
Banlangen Granules (BLG) yog ib hom tshuaj suav tshuaj uas ua los ntawm cov dej ntawm Banlangen cag.8 Ntxiv rau nws cov tshuaj tua kab mob, BLG muaj peev xwm tiv thaiv kev o thiab kev kho mob ntawm ntau yam mob o.9,10 Ntxiv rau, glucosinolates (R,S-goitrin, progoitrin, epiprorubin thiab glucoside tau raug rho tawm thiab txheeb xyuas los ntawm cov dej ntawm Radix isatidis) thiab nucleosides (hypoxanthine, adenosine, uridine thiab guanosine) thiab indigo alkaloids xws li indigo thiab indirubin.11,12 Cov kev tshawb fawb yav dhau los tau sau tseg zoo tias cov tshuaj adenosine, uridine thiab indirubin muaj peev xwm tiv thaiv kab mob colitis hauv ntau hom tsiaj ntawm colitis.13-17 Txawm li cas los xij, tsis muaj kev tshawb fawb raws li pov thawj tau ua los ntsuas qhov ua tau zoo ntawm BLG hauv colitis. Hauv kev tshawb fawb tam sim no, peb tau tshawb xyuas qhov cuam tshuam tiv thaiv ntawm BLG rau dextran sodium sulfate (DSS)-induced chronic relapsing colitis hauv C57BL/6 nas thiab pom tias kev noj tshuaj ntawm BLG ua rau DSS-induced mob plab hnyuv hauv nas mob, nws cov txheej txheem tswj hwm yog cuam tshuam nrog kev hloov pauv ntawm cov kab mob hauv plab thiab kev kho dua tshiab ntawm cov khoom tsim los ntawm glucagon-zoo li peptide-1 (GLP-1).
Cov hmoov BLG (tsis muaj qab zib, NMPA-pom zoo Z11020357; Beijing Tongrentang Technology Development Co., Ltd., Beijing, Suav teb; tus lej batch: 20110966) tau yuav los ntawm cov khw muag tshuaj. DSS (Molecular Weight: 36,000–50,000 Daltons) tau yuav los ntawm MP Biologicals (Santa Ana, Tebchaws USA). Sulfasalazine (SASP) (≥ 98% purity), hematoxylin thiab eosin tau yuav los ntawm Sigma-Aldrich (St. Louis, MO, Tebchaws USA). Nas TNF-α, IL-1β thiab IL-6 luminex Elisa assay kits tau yuav los ntawm R&D systems (Minneapolis, MN, Tebchaws USA). Acetic acid, propionic acid, thiab butyric acid tau yuav los ntawm Aladdin Industries (Shanghai, Suav teb). 2-Ethylbutyric acid tau yuav los ntawm Merck KGaA (Darmstadt, Lub Tebchaws Yelemees).
Tus nas C57BL/6 tus txiv neej hnub nyoog 6-8 lub lis piam (qhov hnyav ntawm lub cev 18-22 g) tau yuav los ntawm Beijing Wetahe Laboratory Animal Technology Co., Ltd. (Beijing, Suav teb) thiab nyob hauv ib puag ncig ntawm 22 ± 2 °C nrog 12 teev lub voj voog kaj/ tsaus ntuj. Cov nas tau noj zaub mov nas ib txwm muaj nrog kev nkag mus rau dej haus dawb rau ib lub lim tiam kom hloov mus rau ib puag ncig tshiab. Cov nas tau raug faib ua plaub pawg: pawg tswj, pawg qauv DSS, pawg kho SASP (200 mg/kg, noj) thiab pawg kho BLG (1 g/kg, noj). Raws li pom hauv Daim Duab 1A, raws li peb txoj kev tshawb fawb yav dhau los, kev sim mob plab hnyuv rov qab los tau ua rau cov nas los ntawm peb lub voj voog ntawm 1.8% DSS rau 5 hnub, ua raws li dej distilled rau 7 hnub, raws li peb txoj kev tshawb fawb yav dhau los.18 Cov nas hauv pawg kho SASP thiab BLG tau kho nrog SASP thiab BLG, raws li, txhua hnub pib txij hnub 0. Raws li kev sim ua ntej, cov koob tshuaj ntawm BLG tau teem rau ntawm 1 g/kg. Lub caij no, cov koob tshuaj ntawm SASP tau teem rau ntawm 200 mg/Kg raws li cov ntaub ntawv sau tseg.4 Cov pawg tswj hwm thiab cov qauv DSS tau txais tib lub ntim dej thoob plaws hauv kev sim.
Daim Duab 1 BLG kho DSS-induced mob plab hnyuv rov qab mob hauv nas. (A) Kev tsim qauv sim ntawm mob plab hnyuv rov qab mob thiab kev kho mob, (B) kev hloov pauv ntawm lub cev qhov hnyav, (C) cov qhab nia ntawm cov kab mob (DAI), (D) qhov ntev ntawm txoj hnyuv loj, (E) daim duab sawv cev ntawm txoj hnyuv loj, (F) H&E staining Colon (magnification, ×100) thiab (G) cov qhab nia histological. Cov ntaub ntawv tau nthuav tawm ua qhov nruab nrab ± SEM (n = 6). ##p < 0.01 lossis ###p < 0.001 vs pawg tswj (Con); *p < 0.05 lossis **p < 0.01 lossis ***p < 0.001 vs pawg DSS.
Qhov hnyav ntawm lub cev, qhov sib xws ntawm cov quav, thiab cov ntshav hauv qhov quav tau sau tseg txhua hnub. Cov ntsuas kev ua haujlwm ntawm tus kab mob (DAI) tau txiav txim siab los ntawm kev sib xyaw cov qhab nia ntawm qhov hnyav ntawm lub cev, qhov sib xws ntawm cov quav, thiab cov ntshav hauv qhov quav raws li tau piav qhia ua ntej.19 Thaum kawg ntawm kev sim, tag nrho cov nas tau raug tua pov tseg thiab cov ntshav, cov quav thiab cov hnyuv loj tau raug sau rau kev sim ntxiv.
Cov nqaij ntawm txoj hnyuv tau kho nrog formalin thiab muab tso rau hauv paraffin. Cov ntu 5-micron tau ua thiab pleev xim nrog hematoxylin-eosin (H&E), tom qab ntawd dig muag thiab ntsuas raws li tau piav qhia ua ntej.19
Tag nrho RNA ntawm cov nqaij mos ntawm txoj hnyuv tau rho tawm los ntawm Trizol reagent (Invitrogen, Carlsbad, CA), ua raws li cDNA rho tawm nrog reverse transcriptase (TaKaRa, Kusatsu, Shiga, Nyiv). Kev ntsuas PCR tau ua tiav siv lub sijhawm tiag tiag PCR system nrog SYBR Green Master (Roche, Basel, Switzerland). Cov ntawv sau txog cov noob caj noob ces tau hloov kho kom zoo rau β-actin thiab cov ntaub ntawv tau soj ntsuam siv txoj kev 2-ΔΔCT. Cov kab ke gene primer tau qhia hauv Rooj 1.
Kev rho tawm thiab kev cog qoob loo ntawm cov nas colonic epithelial cell thawj zaug tau ua raws li tau piav qhia ua ntej.20 Hauv luv luv, cov colonic ntawm cov nas uas muaj hnub nyoog 6-8 lub lis piam tau raug txiav tawm thawj zaug tom qab tua los ntawm kev hloov pauv ntawm lub caj dab, tom qab ntawd qhib ntev, kho nrog Hanks Balanced Salt Solution (HBSS, tsis muaj calcium thiab magnesium) thiab txiav ua tej daim me me 0.5-1 hli. Tom qab ntawd, cov ntaub so ntswg tau zom nrog 0.4 mg / mL collagenase XI (Sigma, Poole, UK) hauv DMEM nruab nrab dawb thiab centrifuged ntawm 300 xg rau 5 feeb ntawm chav tsev kub. Rov ua dua cov pellet hauv DMEM nruab nrab (ntxiv nrog 10% fetal bovine serum, 100 Units / mL penicillin, thiab 100 µg / mL streptomycin) ntawm 37 ° C thiab dhau los ntawm nylon mesh (qhov loj me ~ 250 µm). Cov aliquots ntawm cov colonic epithelial cell tau muab tso rau hauv cov tais iav hauv qab thiab incubated nrog acetic acid, propionic kua qaub, butyric acid, thiab nas cov quav rho tawm rau 2 teev ntawm 37°C, 5% CO2.
Cov nqaij ntawm txoj hnyuv tau sib xyaw nrog PBS, thiab cov theem ntawm cytokines IL-6, TNF-α thiab IL-1β hauv cov nqaij ntawm txoj hnyuv tau raug kuaj pom siv cov khoom siv luminex ELISA assay (R&D systems, Minneapolis, MN, USA). Ib yam li ntawd, cov theem GLP-1 hauv cov ntshav thiab cov kab lis kev cai ntawm cov hlwb epithelial murine thawj zaug tau txiav txim siab nrog cov khoom siv ELISA (Bioswamp, Wuhan, Tuam Tshoj) raws li cov lus qhia ntawm cov chaw tsim khoom.
Tag nrho cov DNA los ntawm cov quav tau raug rho tawm siv cov khoom siv rho tawm DNA (Tiangen, Tuam Tshoj). Qhov zoo thiab qhov ntau ntawm DNA tau ntsuas ntawm qhov sib piv ntawm 260 nm/280 nm thiab 260 nm/230 nm, raws li. Tom qab ntawd, siv txhua cov DNA uas tau rho tawm ua tus qauv, cov primers tshwj xeeb 338F (ACTCCTACGGGAGGCAGCAG) thiab 806R (GGACTACHVGGGTWTCTAAT) tau siv los ua kom cov cheeb tsam V3-V4 ntawm 16S rRNA gene loj dua hauv cov cheeb tsam sib txawv. Cov khoom PCR tau raug ntxuav siv QIAquick Gel Extraction Kit (QIAGEN, Lub Tebchaws Yelemees), ntsuas los ntawm PCR tiag tiag, thiab sequenced siv IlluminaMiseq PE300 sequencing platform (Illumina Inc., CA, USA). Rau kev tshuaj xyuas bioinformatics, kev ua cov ntaub ntawv tau ua raws li cov txheej txheem tau tshaj tawm yav dhau los.21,22 Hauv ntej, siv Cutadapt (V1.9.1) los lim cov ntaub ntawv raw express.OTUs tau clustered siv UPARSE (version 7.0.1001) nrog qhov kev txiav tawm zoo sib xws ntawm 97%, thiab UCHIME tau siv los tshem tawm cov kab ke chimeric. Kev tshuaj xyuas thiab kev faib tawm hauv zej zog tau ua tiav los ntawm kev siv RDP classifier (http://rdp.cme.msu.edu/) raws li SILVA ribosomal RNA gene database.
Cov theem ntawm cov roj fatty acid luv luv (acetic acid, propionic acid, thiab butyric acid) tau ntsuas raws li Tao et al. tau piav qhia ua ntej, nrog qee qhov kev hloov kho.23 Hauv luv luv, 100 mg ntawm cov quav tau raug ncua ua ntej hauv 0.4 mL ntawm dej deionized, ua raws li 0.1 mL ntawm 50% sulfuric acid thiab 0.5 mL ntawm 2-ethylbutyric acid (tus qauv sab hauv), tom qab ntawd homogenized thiab cua sov ntawm 4 ° C. Siv lub tshuab centrifuge ntawm 12,000 rpm rau 15 feeb ntawm C. Cov supernatant tau rho tawm nrog 0.5 mL ntawm ether thiab txhaj rau hauv GC rau kev tshuaj xyuas. Rau kev tshuaj xyuas roj chromatography (GC), cov qauv tau tshuaj xyuas siv GC-2010 Plus roj chromatograph (Shimadzu, Inc.) nruab nrog lub tshuab ntes hluav taws ionization (FID). Kev sib cais tau ua tiav siv ZKAT-624 kem, 30 m × 0.53 mm × 0.3 μm (Lanzhou Zhongke Antai Analytical Technology Co., Ltd., Tuam Tshoj). Cov ntaub ntawv tau txais los ntawm kev siv GC solution software (Shimadzu, Inc.). Qhov sib piv sib cais yog 10: 1, cov roj nqa yog nitrogen, thiab tus nqi ntws yog 6 mL / feeb. Qhov ntim txhaj tshuaj yog 1 μL. Qhov kub ntawm lub tshuab txhaj tshuaj thiab lub tshuab ntes yog 300 ° C. Qhov kub ntawm qhov cub tau tuav ntawm 140 ° C rau 13.5 feeb, tom qab ntawd nce mus txog 250 ° C ntawm tus nqi ntawm 120°C/feeb; qhov kub tau tuav rau 5 feeb.
Cov ntaub ntawv raug nthuav tawm ua qhov nruab nrab ± qhov yuam kev txheem ntawm qhov nruab nrab (SEM). Qhov tseem ceeb ntawm cov ntaub ntawv tau raug soj ntsuam los ntawm ib txoj kev ANOVA ua raws li Duncan's multiple range test. GraphPad Prism 5.0 software (GraphPad Software Inc., San Diego, CA, USA) tau siv rau txhua qhov kev xam thiab p < 0.05 tau suav tias yog qhov tseem ceeb ntawm kev suav lej.
Nws paub zoo tias UC yog ib yam kab mob colitis uas rov qab mob dua nrog mob plab hnyav, raws plab thiab los ntshav. Yog li ntawd, DSS-induced chronic relapsing colitis hauv nas tau tsim los ntsuam xyuas qhov ua tau zoo ntawm BLG tiv thaiv kab mob colitis (Daim Duab 1A). Piv nrog rau pawg tswj, nas hauv pawg qauv DSS tau txo qhov hnyav ntawm lub cev thiab DAI siab dua, thiab cov kev hloov pauv no tau thim rov qab tom qab 24 hnub ntawm kev kho BLG (Daim Duab 1B thiab C). Kev luv ntawm txoj hnyuv yog ib qho cim tseem ceeb ntawm UC. Raws li pom hauv Daim Duab 1D thiab E, qhov ntev ntawm txoj hnyuv ntawm nas uas tau txais DSS tau luv dua, tab sis tau txo los ntawm kev kho BLG. Tom qab ntawd, kev tshuaj xyuas histopathological tau ua los ntsuam xyuas kev o ntawm txoj hnyuv. H&E cov duab stained thiab cov qhab nia pathological qhia tau hais tias kev tswj hwm DSS cuam tshuam rau cov qauv colonic thiab ua rau muaj kev puas tsuaj ntawm crypt, thaum kev kho BLG txo qis kev puas tsuaj ntawm crypt thiab cov qhab nia pathological (Daim Duab 1F thiab G). Qhov tseem ceeb, qhov cuam tshuam ntawm BLG ntawm koob tshuaj ntawm 1 g / Kg yog sib piv rau SASP ntawm koob tshuaj ntawm 200 mg/Kg. Ua ke, cov kev tshawb pom no qhia tau tias BLG muaj txiaj ntsig zoo hauv kev txo qhov hnyav ntawm DSS-induced chronic relapsing colitis hauv nas.
TNF-α, IL-1β thiab IL-6 yog cov cim qhia tseem ceeb ntawm kev mob plab hnyuv. Raws li pom hauv Daim Duab 2A, DSS ua rau muaj kev nce ntxiv ntawm cov noob caj noob ces ntawm TNF-α, IL-1β thiab IL-6 hauv plab hnyuv piv rau pawg tswj. Kev tswj hwm ntawm BLG tuaj yeem thim rov qab cov kev hloov pauv DSS no. Tom ntej no, peb siv ELISA los txiav txim siab cov theem ntawm cov cytokines inflammatory TNF-α, IL-1β, thiab IL-6 hauv cov nqaij plab hnyuv. Cov txiaj ntsig kuj qhia tau tias cov theem colonic ntawm TNF-α, IL-1β, thiab IL-6 tau nce ntxiv ntau hauv cov nas kho nrog DSS, thaum kev kho BLG txo cov kev nce no (Daim Duab 2B).
Daim Duab 2 BLG tiv thaiv kev qhia tawm thiab kev tsim cov gene cytokines proinflammatory TNF-α, IL-1β thiab IL-6 hauv cov hnyuv loj ntawm cov nas kho DSS. (A) Colonic gene kev qhia tawm ntawm TNF-α, IL-1β thiab IL-6; (B) cov protein colonic ntawm TNF-α, IL-1β thiab IL-6. Cov ntaub ntawv tau nthuav tawm ua qhov nruab nrab ± SEM (n = 4–6). #p < 0.05 lossis ##p < 0.01 lossis ###p < 0.001 vs pawg tswj (Con); *p < 0.05 lossis **p < 0.01 vs pawg DSS.
Kev ua haujlwm tsis zoo ntawm txoj hnyuv yog qhov tseem ceeb hauv kev mob UC.24 Txhawm rau tshawb nrhiav seb BLG puas hloov kho cov kab mob hauv plab ntawm cov nas uas tau kho nrog DSS, 16S rRNA sequencing tau ua los tshuaj xyuas cov kab mob hauv plab. Daim duab Venn qhia tau hais tias peb pawg sib koom 385 OTUs. Tib lub sijhawm, txhua pawg muaj OTUs tshwj xeeb (Daim Duab 3A). Ntxiv mus, Chao1 index thiab Shannon index qhia hauv Daim Duab 3B thiab C qhia tau hais tias qhov sib txawv ntawm cov kab mob hauv plab tau txo qis hauv cov nas uas tau kho nrog BLG, vim tias Shannon index tau txo qis hauv pawg uas tau kho nrog BLG. Kev tshuaj xyuas cov khoom tseem ceeb (PCA) thiab kev tshuaj xyuas cov khoom tseem ceeb (PCoA) tau siv los txiav txim siab cov qauv sib sau ua ke ntawm peb pawg thiab qhia tau hais tias cov qauv hauv zej zog ntawm cov nas uas tau kho nrog DSS tau sib cais meej meej tom qab kev kho nrog BLG (Daim Duab 3D thiab E). Cov ntaub ntawv no qhia tau hais tias kev kho nrog BLG tau cuam tshuam rau cov qauv hauv zej zog ntawm cov nas uas muaj DSS-induced colitis.
Daim Duab 3 BLG hloov pauv qhov sib txawv ntawm cov kab mob hauv plab hauv cov nas uas muaj DSS-induced colitis. (A) Daim duab Venn ntawm OTU, (B) Chao1 index, (C) Shannon's richness index, (D) Principal Component Analysis (PCA) qhab nia ntawm OTU, (E) OTU Principal Coordinate Analysis (PCoA) qhab nia Daim Duab. Cov ntaub ntawv raug nthuav tawm ua qhov nruab nrab ± SEM (n = 6). **p < 0.01 vs DSS pawg.
Txhawm rau ntsuam xyuas cov kev hloov pauv tshwj xeeb hauv cov kab mob hauv plab, peb tau tshuaj xyuas cov khoom sib xyaw ntawm cov kab mob hauv plab ntawm txhua qib kev faib tawm. Raws li pom hauv Daim Duab 4A, cov phyla tseem ceeb hauv txhua pawg yog Firmicutes thiab Bacteroidetes, ua raws li Verrucomicrobia. Qhov sib piv ntawm Firmicutes thiab Firmicutes / Bacteroidetes tau nce ntxiv ntau hauv cov zej zog microbial fecal ntawm cov nas kho DSS piv rau cov nas tswj, thiab cov kev hloov pauv no tau thim rov qab ntau tom qab kev kho mob BLG. Tshwj xeeb, kev kho mob BLG tau nce ntxiv qhov sib piv ntawm Verrucobacterium hauv cov quav ntawm cov nas uas muaj DSS-induced colitis. Ntawm theem tsev neeg, cov zej zog microbial fecal tau nyob los ntawm Lachnospiriaceae, Muribaculaceae, Akkermansiaceae, Ruminococcaceae thiab Prevotellaceae (Daim Duab 4B). Piv nrog rau pawg DSS, kev poob ntawm BLG ua rau muaj ntau ntawm Akkermansiaceae, tab sis txo qis qhov ntau ntawm Lachnospiraceae thiab Ruminococcaceae. Qhov tseem ceeb, ntawm genus theem, cov kab mob hauv cov quav tau nyob hauv Lachnospira_NK4A136_group, Akkermansia thiab Prevotellaceae_UCG-001 (Daim Duab 4C). Qhov kev tshawb pom no kuj tau qhia tias kev kho mob BLG tau thim rov qab qhov tsis sib npaug ntawm cov kab mob hauv cov lus teb rau DSS kev sib tw, uas yog tus yam ntxwv los ntawm kev txo qis hauv Eubacterium_xylanophilum_group, Ruminococcaceae_UCG-014, Intestinimonas thiab Oscillibacter, thiab kev nce ntxiv hauv Akkermansia thiab Prevotellaceae_UCG-001.
Daim Duab 4 BLG hloov pauv qhov muaj ntau ntawm cov kab mob hauv plab hauv cov nas uas ua rau mob plab hnyuv DSS. (A) Muaj ntau ntawm cov kab mob hauv plab ntawm theem phylum; (B) Muaj ntau ntawm cov kab mob hauv plab ntawm theem tsev neeg; (C) Muaj ntau ntawm cov kab mob hauv plab ntawm theem genus. Cov ntaub ntawv tau nthuav tawm ua qhov nruab nrab ± SEM (n = 6). #p < 0.05 lossis ###p < 0.001 vs pawg tswj (Con); *p < 0.05 lossis **p < 0.01 lossis ***p < 0.001 vs pawg DSS.
Xav txog tias cov roj fatty acid luv luv (SCFAs) yog cov metabolites tseem ceeb ntawm Akkermansia thiab Prevotellaceae_UCG-001, thaum acetate, propionate thiab butyrate yog cov SCFAs ntau tshaj plaws hauv txoj hnyuv, 25-27 peb tseem nyob hauv peb txoj kev tshawb fawb. Raws li pom hauv Daim Duab 5, fecal acetate, propionate, thiab butyrate concentrations tau txo qis hauv pawg DSS-kho, thaum BLG kev kho mob feem ntau tuaj yeem tiv thaiv qhov kev txo qis no.
Daim Duab 5. BLG ua rau cov SCFAs ntau ntxiv hauv cov quav ntawm cov nas uas muaj mob plab hnyuv loj vim DSS. (A) Cov ntsiab lus acetic acid hauv cov quav; (B) cov ntsiab lus propionic acid hauv cov quav; (C) cov ntsiab lus butyric acid hauv cov quav. Cov ntaub ntawv tau nthuav tawm ua qhov nruab nrab ± SEM (n = 6). #p < 0.05 lossis ##p < 0.01 vs pawg tswj (Con); *p < 0.05 lossis **p < 0.01 vs pawg DSS.
Peb ntxiv xam qhov Pearson correlation coefficient ntawm genus-level differential SCFA thiab fecal microbiota. Raws li pom hauv Daim Duab 6, Akkermansia muaj feem cuam tshuam zoo nrog kev tsim cov propionic acid (Pearson = 0.4866) thiab butyric acid (Pearson = 0.6192). Hauv kev sib piv, ob qho tib si Enteromonas thiab Oscillobacter muaj feem cuam tshuam tsis zoo nrog kev tsim cov acetate, nrog Pearson coefficients ntawm 0.4709 thiab 0.5104, raws li. Ib yam li ntawd, Ruminococcaceae_UCG-014 muaj feem cuam tshuam tsis zoo nrog kev tsim cov propionic acid (Pearson = 0.4508) thiab butyric acid (Pearson = 0.5842), raws li.
Daim Duab 6 Kev tshuaj xyuas kev sib raug zoo ntawm Pearson ntawm cov SCFAs sib txawv thiab cov kab mob colonic. (A) Enteromonas nrog acetic acid; (B) Concussion bacillus nrog acetic acid; (C) Akkermansia vs propionic acid; (D) Ruminococcus_UCG-014 nrog propionic acid; (E) Akkermansia nrog butyric acid; (F)) Ruminococcus _UCG-014 nrog butyric acid.
Glucagon-zoo li peptide-1 (GLP-1) yog ib yam khoom tshwj xeeb tom qab kev txhais lus ntawm proglucagon (Gcg) nrog cov khoom tiv thaiv kev o.28 Raws li pom hauv Daim Duab 7, DSS ua rau muaj kev txo qis ntawm Gcg mRNA kev qhia. Kev kho mob plab hnyuv thiab BLG tuaj yeem thim rov qab qhov kev txo qis ntawm DSS-induced Gcg piv rau pawg tswj (Daim Duab 7A). Tib lub sijhawm, qib ntawm GLP-1 hauv cov ntshav tau txo qis hauv pawg kho DSS, thiab kev kho mob BLG tuaj yeem tiv thaiv qhov kev txo qis no (Daim Duab 7B). Vim tias cov roj fatty acid luv luv tuaj yeem txhawb GLP-1 secretion los ntawm G-protein-coupled receptor 43 (GRP43) thiab G-protein-coupled receptor 41 (GRP41) activation, peb kuj tau tshuaj xyuas GPR41 thiab GRP43 hauv plab hnyuv ntawm cov nas colitis thiab pom tias qhov kev qhia tawm ntawm GRP43 thiab GPR41 tau txo qis tom qab DSS kev sib tw, thiab kev kho mob BLG tuaj yeem cawm tau cov kev txo qis no (Daim Duab 7C thiab D).
Daim Duab 7 BLG ua rau cov theem GLP-1 hauv cov ntshav thiab cov Gcg, GPR41 thiab GRP43 mRNA hauv cov nas uas tau kho nrog DSS nce ntxiv. (A) Gcg mRNA hauv cov nqaij ntawm cov hnyuv loj; (B) GLP-1 hauv cov ntshav; (C) GPR41 mRNA hauv cov nqaij ntawm cov hnyuv loj; (D) GPR43 mRNA hauv cov nqaij ntawm cov hnyuv loj. Cov ntaub ntawv tau nthuav tawm ua qhov nruab nrab ± SEM (n = 5–6). #p < 0.05 lossis ##p < 0.01 vs pawg tswj (Con); *p < 0.05 vs pawg DSS.
Vim tias kev kho mob BLG tuaj yeem ua rau cov theem GLP-1 hauv cov ntshav nce ntxiv, kev qhia tawm ntawm colonic Gcg mRNA, thiab cov theem SCFA hauv cov nas uas tau kho nrog DSS, peb tau tshuaj xyuas ntxiv txog acetate, propionate, thiab butyrate nrog rau los ntawm kev tswj (F-Con), DSS colitis (F-Con) -DSS) thiab BLG-kho colitis (F-BLG) nas ntawm kev tso tawm GLP-1 los ntawm cov hlwb epithelial murine thawj zaug. Raws li pom hauv Daim Duab 8A, cov hlwb epithelial nas thawj zaug kho nrog 2 mM acetic acid, propionic acid, thiab butyric acid, feem, tau txhawb nqa GLP-1 tso tawm, sib xws nrog cov kev tshawb fawb yav dhau los.29,30 Ib yam li ntawd, txhua F-Con, F-DSS, thiab F-BLG (sib npaug rau 0.25 g ntawm cov quav) tau txhawb nqa kev tso tawm GLP-1 los ntawm cov hlwb epithelial murine thawj zaug. Qhov tseem ceeb, qhov ntau ntawm GLP-1 tso tawm los ntawm cov hlwb epithelial nas thawj zaug kho nrog F-DSS qis dua li ntawm Cov hlwb epithelial ntawm nas thawj zaug uas tau kho nrog F-Con thiab F-BLG. (Daim Duab 8B). Cov ntaub ntawv no qhia tias kev kho nrog BLG tau kho cov kab mob GLP-1 uas tau los ntawm SCFA hauv plab hnyuv kom rov qab zoo li qub.
Daim Duab 8 BLG-derived SCFA txhawb GLP-1 tso tawm los ntawm cov hlwb epithelial murine thawj zaug. (A) Acetic acid, propionic acid, thiab butyric acid txhawb kev tso tawm ntawm GLP-1 los ntawm cov hlwb epithelial murine thawj zaug; (B) cov quav extracts F-Con, F-DSS thiab F-BLG txhawb cov hlwb epithelial murine thawj zaug Tus nqi ntawm GLP-1 tso tawm. Cov cell epithelial colonic tau muab tso rau hauv cov tais petri iav-hauv qab thiab kho nrog 2 mM acetic acid, propionic acid, butyric acid, thiab cov quav extracts F-Con, F-DSS, thiab F-BLG (sib npaug rau 0.25 g quav), raws li. 2 teev ntawm 37°C, 5% CO2, raws li. Tus nqi ntawm GLP-1 tso tawm los ntawm cov hlwb murine colonic epithelial thawj zaug tau kuaj pom los ntawm ELISA. Cov ntaub ntawv tau nthuav tawm ua qhov nruab nrab ± SEM (n = 3). #p < 0.05 lossis ##p < 0.01 vs. dawb paug lossis F-Con; *p < 0.05 vs. F-DSS.
Cov Lus Luv: Ace, acetic acid; Pro, propionic acid; txawm li cas los xij, butyric acid; F-Con, fecal extract los ntawm cov nas tswj; F-DSS, fecal extract los ntawm cov nas colitis; F-BLG, los ntawm BLG-kho mob plab hnyuv Cov tshuaj rho tawm ntawm cov nas inflammatory.
Lub Koom Haum Ntiaj Teb Kev Noj Qab Haus Huv tau teev npe ua tus kab mob refractory, UC tab tom dhau los ua qhov txaus ntshai thoob ntiaj teb; txawm li cas los xij, cov txheej txheem zoo rau kev kwv yees, tiv thaiv, thiab kho tus kab mob tseem tsawg. Yog li ntawd, muaj qhov xav tau ceev ceev los tshawb nrhiav thiab tsim cov tswv yim kho mob tshiab thiab muaj txiaj ntsig zoo rau UC. Kev npaj tshuaj suav suav yog qhov kev xaiv zoo vim tias ntau cov tshuaj suav suav tau pom tias muaj txiaj ntsig zoo rau kev kho mob UC hauv cov pej xeem Suav dhau ntau pua xyoo, thiab lawv txhua tus yog cov organic organic thiab cov khoom siv ntuj uas feem ntau tsis muaj teeb meem rau tib neeg thiab tsiaj txhu.31,32 Txoj kev tshawb fawb no tsom mus nrhiav kev npaj tshuaj suav suav uas muaj kev nyab xeeb thiab muaj txiaj ntsig zoo rau kev kho mob UC thiab los tshawb nrhiav nws cov txheej txheem ua haujlwm.BLG yog cov tshuaj ntsuab Suav uas paub zoo siv los kho tus mob khaub thuas.8,33 Kev ua haujlwm hauv peb lub chaw kuaj mob thiab lwm tus tau qhia tias indigo, cov khoom lag luam tshuaj suav suav uas ua tiav los ntawm cov khoom siv raw li BLG, qhia txog kev ua tau zoo hauv kev kho mob UC hauv tib neeg thiab tsiaj txhu.4,34 Txawm li cas los xij, cov teebmeem tiv thaiv kab mob plab ntawm BLG thiab nws cov teebmeem Lub txheej txheem tsis meej. Hauv kev tshawb fawb tam sim no, peb cov txiaj ntsig qhia tau tias BLG ua rau DSS-induced colonic o, uas cuam tshuam nrog kev hloov pauv ntawm plab hnyuv. microbiota thiab kho dua tshiab ntawm txoj hnyuv GLP-1 ntau lawm.
Nws paub zoo tias UC yog tus cwj pwm los ntawm lub sijhawm rov qab los nrog cov yam ntxwv kho mob ib txwm muaj, xws li poob phaus, raws plab, los ntshav ntawm qhov quav, thiab kev puas tsuaj ntawm cov hnyuv mucosal loj heev.35 Yog li, mob plab hnyuv rov qab los tau muab los ntawm kev muab peb lub voj voog ntawm 1.8% DSS rau tsib hnub, ua raws li xya hnub ntawm dej haus. Raws li pom hauv Daim Duab 1B, kev poob phaus thiab cov qhab nia DAI hloov pauv qhia tau tias ua tiav kev ua rau mob plab hnyuv rov qab los. Cov nas hauv pawg kho nrog BLG tau pom tias rov zoo los ntawm hnub 8, uas txawv ntawm hnub 24. Cov kev hloov pauv tib yam kuj tau pom hauv DAI qhab nia, qhia txog kev txhim kho hauv kev txhim kho kev kho mob ntawm mob plab hnyuv. Hais txog kev raug mob plab hnyuv thiab kev mob, qhov ntev ntawm plab hnyuv, kev puas tsuaj ntawm cov nqaij ntawm plab hnyuv, thiab kev qhia tawm thiab kev tsim cov cytokines proinflammatory TNF-α, IL-1β, thiab IL-6 hauv cov nqaij ntawm plab hnyuv kuj tau zoo dua tom qab kev kho mob BLG. Ua ke, cov txiaj ntsig no qhia meej meej tias BLG muaj txiaj ntsig zoo hauv kev kho mob ntawm mob plab hnyuv rov qab los hauv nas.
BLG ua li cas nws cov teebmeem pharmacological? Ntau txoj kev tshawb fawb yav dhau los tau qhia tias cov kab mob hauv plab ua lub luag haujlwm tseem ceeb hauv kev mob UC, thiab microbiome-based thiab microbiome-targeted therapies tau tshwm sim ua ib txoj hauv kev zoo heev rau kev kho mob UC. Hauv kev tshawb fawb tam sim no, peb tau qhia tias kev kho mob BLG ua rau muaj kev hloov pauv tseem ceeb hauv cov kab mob hauv plab, qhia tias qhov kev tiv thaiv ntawm BLG tiv thaiv DSS-induced colitis yog cuam tshuam nrog kev hloov pauv ntawm cov kab mob hauv plab. Qhov kev soj ntsuam no yog sib xws nrog lub tswv yim tias kev rov ua dua qhov homeostasis ntawm cov kab mob hauv plab yog ib txoj hauv kev tseem ceeb rau kev nkag siab txog kev ua haujlwm ntawm TCM npaj.36,37 Qhov tseem ceeb, Akkermansia yog Gram-negative thiab nruj me ntsis anaerobic bacterium uas nyob hauv cov txheej mucus ntawm plab, uas rhuav tshem cov mucins, tsim cov propionic acid, txhawb kev sib txawv ntawm goblet cell, thiab tswj cov mucosa.26 Ntau cov ntaub ntawv kho mob thiab tsiaj qhia tias Akkermansia muaj feem cuam tshuam nrog kev noj qab haus huv mucosa,38 thiab kev noj Akkermansia spp. tuaj yeem txhim kho qhov mob ntawm cov hlab ntsha hauv lub plab.39 Peb cov ntaub ntawv tam sim no qhia tias qhov muaj ntau ntawm Akkermansia tau nce ntxiv tom qab kev kho mob BLG. Tsis tas li ntawd, Prevotellaceae_UCG-001 yog ib hom kab mob uas tsim SCFA.27 Ntau txoj kev tshawb fawb qhia tau tias Prevotellaceae_UCG-001 tau pom muaj tsawg heev hauv cov quav ntawm cov tsiaj uas muaj mob plab.40,41 Peb cov ntaub ntawv tam sim no kuj qhia tau tias kev kho mob BLG tuaj yeem ua rau muaj ntau ntawm Prevotellaceae_UCG-001 hauv cov hnyuv ntawm cov nas uas tau kho DSS. Hauv kev sib piv, Oscillibacter yog ib hom kab mob mesophilic, anaerobic bacterium.42 tau tshaj tawm tias qhov muaj ntau ntawm Oscillibacter tau nce ntxiv hauv cov nas UC thiab muaj feem cuam tshuam zoo nrog IL-6 thiab IL-1β thiab cov qhab nia pathological.43,44 Qhov tseem ceeb, kev kho mob BLG tau txo qhov muaj ntau ntawm Oscillibacter hauv cov quav ntawm cov nas uas tau kho DSS. Qhov tseem ceeb, cov kab mob BLG-hloov pauv no yog cov kab mob uas tsim SCFA ntau tshaj plaws. Ntau txoj kev tshawb fawb yav dhau los tau tau qhia txog cov txiaj ntsig zoo ntawm SCFAs rau kev mob plab hnyuv thiab kev tiv thaiv kev ncaj ncees ntawm txoj hnyuv epithelial.45,46 Peb cov ntaub ntawv tam sim no kuj tau pom tias qhov concentration ntawm SCFA acetate, propionate, thiab butyrate hauv cov quav kho DSS tau nce ntxiv ntau hauv cov nas kho BLG. Thaum muab ua ke, cov kev tshawb pom no qhia meej meej tias kev kho BLG tuaj yeem ua rau cov kab mob tsim SCFA los ntawm DSS hauv cov nas uas muaj mob plab hnyuv rov qab los.
GLP-1 yog ib qho incretin feem ntau tsim tawm hauv ileum thiab colon thiab ua lub luag haujlwm tseem ceeb hauv kev ncua lub plab zom mov thiab txo cov ntshav qab zib tom qab noj mov.47 Cov pov thawj qhia tias dipeptidyl peptidase (DPP)-4, GLP-1 receptor agonist, thiab GLP-1 nanomedicine tuaj yeem ua rau kom txo tau qhov mob plab hnyuv hauv nas.48-51 Raws li tau tshaj tawm hauv kev tshawb fawb yav dhau los, cov SCFA siab tau cuam tshuam nrog cov ntshav GLP-1 hauv tib neeg thiab nas.52 Peb cov ntaub ntawv tam sim no qhia tau tias tom qab kev kho mob BLG, cov ntshav GLP-1 thiab Gcg mRNA kev qhia tau nce ntxiv ntau heev. Ib yam li ntawd, GLP-1 secretion tau nce ntxiv ntau heev hauv cov kab lis kev cai colonic tom qab kev txhawb nqa nrog cov quav extracts los ntawm BLG-kho mob colitis nas piv rau kev txhawb nqa nrog cov quav extracts los ntawm DSS-kho mob colitis nas. SCFAs cuam tshuam li cas rau kev tso tawm ntawm GLP-1?Gwen Tolhurst et al. tau tshaj tawm tias SCFA tuaj yeem txhawb nqa GLP-1 secretion los ntawm GRP43 thiab GPR41.29 Peb cov ntaub ntawv tam sim no kuj qhia tau tias kev kho mob BLG ua rau muaj kev qhia mRNA ntawm GRP43 thiab GPR41 ntau ntxiv hauv cov hnyuv ntawm cov nas uas tau kho DSS. Cov ntaub ntawv no qhia tias kev kho mob BLG tuaj yeem rov qab tau SCFA-txhawb nqa GLP-1 ntau lawm los ntawm kev ua kom GRP43 thiab GPR41.
BLG yog ib hom tshuaj uas siv tau ntev thiab tsis tas yuav muaj ntawv yuav tshuaj (OTC) hauv Suav teb. Qhov ntau tshaj plaws uas siv tau ntawm BLG hauv cov nas Kunming yog 80g/Kg, thiab tsis muaj kev lom heev.53 Tam sim no, qhov ntau tshaj plaws uas pom zoo ntawm BLG (tsis muaj qab zib) rau tib neeg yog 9-15 g/hnub (3 zaug hauv ib hnub). Peb txoj kev tshawb fawb qhia tau tias BLG ntawm 1g/Kg tau kho DSS-induced chronic relapsing colitis hauv nas. Qhov ntau tshaj plaws no ze rau qhov ntau tshaj plaws ntawm BLG uas siv hauv kev kho mob. Peb txoj kev tshawb fawb kuj pom tias nws txoj kev ua haujlwm yog los ntawm, tsawg kawg yog ib feem, los ntawm kev hloov pauv hauv cov kab mob hauv plab, tshwj xeeb tshaj yog cov kab mob tsim SCFA, xws li Akkermansia thiab Prevotellaceae_UCG-001, los kho cov kab mob hauv plab GLP-1. Cov kev tshawb pom no qhia tau tias BLG tsim nyog tau txais kev txiav txim siab ntxiv ua tus neeg sawv cev kho mob rau kev kho mob colitis. Txawm li cas los xij, txoj hauv kev tseeb uas nws hloov cov kab mob hauv plab tseem yuav tsum tau lees paub los ntawm cov nas uas tsis muaj microbiota thiab kev hloov cov kab mob hauv quav.
Ace, acetic acid; tab sis, butyric acid; BLG, pandan; DSS, dextran sodium sulfate; DAI, cov ntsuas kev ua haujlwm ntawm tus kab mob; DPP, dipeptidyl peptidase; FID, nplaim taws ionization ntes; F-Con, tswj Fecal extracts ntawm nas; F-DSS, fecal extracts ntawm DSS colitis nas; F-BLG, fecal extracts ntawm BLG-kho colitis nas; GLP-1, glucagon-zoo li peptide-1; Gcg, glucagon; roj chromatography, roj chromatography; GRP43, G protein-coupled receptor 43; GRP41, G protein-coupled receptor 41; H&E, hematoxylin-eosin; HBSS, Hanks' Balanced Salt Solution; OTC, OTC; PCA, kev tshuaj xyuas cov khoom tseem ceeb; PCoA, kev tshuaj xyuas cov khoom tseem ceeb; Pro, propionic acid; SASP, sulfasalazine; SCFA, luv-saw fatty acids; tshuaj suav, tshuaj suav ib txwm muaj; UC, mob plab hnyuv.
Txhua txoj kev sim tau pom zoo los ntawm Pawg Neeg Saib Xyuas Kev Ncaj Ncees ntawm Tsiaj ntawm Peking University Shenzhen-Hong Kong University of Science thiab Technology Medical Center (Shenzhen, Suav teb) raws li Cov Lus Qhia Txog Lub Tsev Kawm Ntawv thiab Cov Cai Tswjfwm Tsiaj (tus lej kev ncaj ncees A2020157).
Txhua tus kws sau ntawv tau ua cov txiaj ntsig tseem ceeb rau kev xav thiab tsim qauv, kev nrhiav cov ntaub ntawv, lossis kev tshuaj xyuas cov ntaub ntawv thiab kev txhais lus; koom nrog kev sau tsab xov xwm lossis kho dua cov ntsiab lus tseem ceeb ntawm kev txawj ntse; pom zoo xa daim ntawv sau rau phau ntawv xov xwm tam sim no; thaum kawg pom zoo rau qhov version rau kev tshaj tawm; Lub luag haujlwm rau txhua yam ntawm kev ua haujlwm.
Txoj haujlwm no tau txais kev txhawb nqa los ntawm National Natural Science Foundation of China (81560676 thiab 81660479), qhov project thawj chav kawm ntawm Shenzhen University (86000000210), Shenzhen Science thiab Technology Innovation Committee Fund (JCYJ20210324093810026), thiab Guangdong Provincial Medical Science thiab Technology Research Fund (A2020157 thiab A2020272), Guizhou Medical University Pharmacy Guizhou Province Funded by Key Laboratory (YWZJ2020-01) thiab Peking University Shenzhen Hospital (JCYJ2018009).
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