Cistanche: Echinacoside txo qis Pancreatic Adenocarcinoma Cell loj hlob los ntawm Inducing Apoptosis ntawm Mitogen-activated Protein Kinase Pathway

Hu rau: Audrey Hu Whatsapp / hp: 0086 13880143964 Email:audrey.hu@wecistanche.com

WEI WANG, JINBIN LUO, YINGHUI LIANG thiab XINFENG LI

Abstract.

Daim ntawv thov kev kho mob ntawm cov khoom ntuj tsim los ntawm cov tshuaj suav tshuaj tau txais kev saib xyuas hauv kev kho mob qog noj ntshav.Echinacoside(ECH), ib qho ntawm cov phenylethanoids, cais tawm ntawm stems ntawmCistanche(ib cov tshuaj suav tshuaj ntsuab) muaj cov ntaub so ntswg-tiv thaiv thiab tiv thaiv apoptotic cuam tshuam rau hauv nruab nrab paj hlwb. Txawm li cas los xij, nws tseem tsis tau paub ntau ntxiv seb ECH puas muaj cov qog nqaij hlav. Hauv txoj kev tshawb fawb tam sim no, nws tau pom tias ECH tuaj yeem cuam tshuam qhov kev loj hlob ntawm pancreatic adenocarcinoma hlwb los ntawm kev tsim cov pa oxygen reactive hom thiab kev cuam tshuam ntawm mitochondrial membrane muaj peev xwm thiab yog li ua rau apoptosis. Tsis tas li ntawd, nws tau qhia meej tias ECH(Echinacoside)represses qog cell loj hlob los ntawm modulating MAPK kev ua ub no. Hauv kev xaus, txoj kev tshawb no qhia txog kev ua haujlwm tshiab ntawm ECH (Echinacoside) hauv kev tiv thaiv kev mob qog noj ntshav, thiab txhais tau hais tias kev siv ECH tuaj yeem yog lub peev xwm tshuaj khomob rau kev mob qog noj ntshav.

Taw qhia

Lub p53 qog suppressor txoj hauv kev los ntawm induction ntawm cov qog suppressor, ARF mitigates oncogenic E3-ligase nas ob feeb (MDM)2-mediated p53 degradation (3). Qhov no yog ib qho kev tswj hwm nws tus kheej, tiv thaiv tus kheej uas tiv thaiv cov hlwb los ntawm kev hloov pauv tsis zoo. Qhov tseem ceeb, p53 tuaj yeem ua rau Myc kev ua si los ntawm kev ua kom muaj zog, piv txwv li, miR-145 uas lub hom phiajMycmRNA rau kev txhais lus ntsiag to (4,5), yog li tsim cov lus tawm tswv yim tsis zoo.

Lub tswv yim ncaj ncees thiab zoo tshaj plaws los kho mob qog noj ntshav yog tua cov qog nqaij hlav cancer. Feem ntau siv cov tshuaj tiv thaiv kab mob, xws li cisplatin (6), actinomycin D (7), thiab adriamycin (8) tau pom tias inhibit qog loj hlob los ntawm kev txhawb nqa apoptosis. Tsis ntev los no, cov pov thawj loj hlob tau pom tias muaj ntau yam khoom siv ntuj tsim thiab cov khoom siv los ntawm cov nroj tsuag, tshwj xeeb tshaj yog los ntawm cov nroj tsuag tshuaj siv hauv cov tshuaj suav tshuaj (TCM), nthuav tawm cov qog-tshuaj tua kab mob los ntawm inducing apoptosis ntawm cov qog nqaij hlav cancer thiab muaj peev xwm siv tshuaj kho mob. hauv kev kho mob qog noj ntshav (9). Piv txwv li, lub ntuj anthraquinone emodin yog cais los ntawm ntau hom qog nqaij hlav cancer (10,11). Camptothecin, muab los ntawm Suav 'zoo siab tsob ntoo',Camptotheca acuminate, yog ib yam khoom muaj txiaj ntsig zoo uas inhibits ligation ntawm DNA tom qab topo I-mediated strand so (12). Hauv lwm qhov kev tshawb fawb rov qab los ntawm cov pej xeem-raws li kev tshawb fawb ntawm tag nrho 729 cov neeg mob uas mob qog noj ntshav siab, nws tau pom tias kev kho TCM tuaj yeem pab kho mob qog noj ntshav. Ntawm pawg neeg no, 115 tus neeg mob yog cov neeg siv TCM thaum 614 tus neeg mob tsis siv TCM. Kev txheeb xyuas ntau yam qhia tau hais tias, piv nrog cov tsis siv neeg, kev siv TCM tau cuam tshuam nrog kev pheej hmoo ntawm kev tuag tag nrho (13). Txhua qhov kev tshawb pom saum toj no tau qhia tias TCM yog ib qho tseem ceeb ntxiv thiab lwm yam tshuaj uas tuaj yeem siv rau hauv kev kho mob qog noj ntshav.

nas nrog mob ntsws mob (16,17). Tsis tas li ntawd, ECH(Echinacoside)tau pom tias muaj kev tiv thaiv ntawm cov paj hlwb thiab txhim kho kev coj tus cwj pwm tsis zoo hauv murine qauv ntawm Parkinson's disease (18). Qhov tseem ceeb, nws tau pom tias ECH txhawb nqa cell proliferation thiab inhibits apoptosis hauv nas plab hnyuv epithelial MODE-K hlwb (19). Txog tam sim no, txawm li cas los xij, tsis tshua muaj kev saib xyuas rau lub luag haujlwm ntawm ECH hauv kev tiv thaiv kabmob kheesxaws.

Hauv qhov kev tshawb fawb no, nws tau tshawb xyuas seb kev kho ECH puas cuam tshuam rau cov qog cell loj hlob thiab kev loj hlob thiab seb ECH(Echinacoside)induces apoptosis, elevates zus tau tej cov reactive oxygen hom (ROS) thiab txo mitochondrial membrane peev xwm (MMP), thiab thiaj li suppresses qog cell loj hlob. Tsis tas li ntawd, txoj kev tshawb fawb tam sim no tsom los txheeb xyuas cov txheej txheem molecular lub luag haujlwm rau ECH-mediated cell loj hlob inhibition.

Khoom siv thiab txoj kev

Cell kab, reagent, thiab tshuaj tiv thaiv.SW1990 pancreatic adenocarcinoma cells (ATCC, Manassas, VA, USA) tau coj mus kuaj hauv Dulbecco's modified Eagle medium supplemented nrog 10 feem pua ​​​​fetal bovine serum, 50 U/ml penicillin thiab 0.1 mg/ml streptomycin ntawm a 37˚C. 5% CO2 humidified huab cua. ECH(Echinacoside)tau yuav los ntawm Jrdun Biotechnology Corp. (Shanghai, Suav). Antibodies tiv thaiv AKT, P-AKT, ERK, P-ERK, JNK, p-JNK, P38, p-P38, thiab GAPDH tau yuav los ntawm Cell Signaling Technology (Danvers, MA, USA); anti-Bax thiab anti-Bcl-2 tau yuav los ntawm Santa Cruz Biotechnology Inc. (Santa Cruz, CA, USA); thiab anti-Caspase{10}} tau yuav los ntawm Abcam (Shanghai, Suav).

Cell kev vam meejsoj ntsuam. Txhawm rau ntsuas tus nqi ntawm cov qog cell loj hlob, Cell suav cov khoom siv {{{0}}} (CCK-8; Dojindo Molecular Technologies, Rockville, MD, USA) tau siv raws li cov chaw tsim khoom cov lus qhia. Cell ncua kev kawm tau noob ntawm 5, 000 cov cell ntawm ib qhov dej nrog ECH kev kho mob rau 0, 12, 24, 48 lossis 72 h hauv 96 - cov kab lis kev cai zoo. Kev tiv thaiv kev loj hlob ntawm tes tau txiav txim siab los ntawm kev ntxiv WST-8 reagent los ntawm cov khoom siv CCK-8 ntawm qhov kawg ntawm 10 feem pua ​​​​rau txhua qhov dej, thiab qhov nqus ntawm cov qauv tau ntsuas ntawm 450 nm siv lub microplate nyeem ntawv (Multiskan MK3; Thermo Fisher Scientific, Inc., Waltham, MA, USA).

Hoechst 33342 staining.Cells (60 feem pua ​​confluence) tau kho nrog Hoechst 33342 (Beyotime Institute of Biotechnology, Haimen, Tuam Tshoj) ntawm qhov kawg concentration ntawm 1µg / ml, incubated nyob rau hauv 37˚C incubator rau 15 min, ntxuav nrog phosphate-buffered saline ob zaug, tsau nyob rau hauv 4 feem pua ​​paraformaldehyde rau 30 min ntawm chav tsev kub, thiab mounted rau slides. Cov kev hloov pauv morphological ntawm cov cell nuclei tau pom nyob rau hauv lub fluorescence microscope (Olympus BX51, Melville, NY, USA). Cov nuclei ib txwm yog puag ncig thiab stained lub teeb xiav, thaum lub apoptotic nuclei tau shrunken thiab stained ci xiav.

Fluorescence-activated cell kev xaiv (FACS) kev tshuaj xyuas.Rau kev ntsuam xyuas ntawm apoptosis, fluorescein isothiocyanate (FITC)-Annexin V Apoptosis Detection kit (BD Biosciences, Shanghai, China) tau siv raws li cov chaw tsim khoom cov lus qhia. Luv luv, 5x104 lub hlwb raug ntxuav nrog dej khov-txias PBS, rov ua dua hauv 0.1 ml binding buffer (Beyotime Institute of Biotechnology), thiab stained nrog 10 ml ntawm FITC-conjugated Annexin V (10 mg / ml) thiab 10 ml propidium iodide (PI) (50 mg / ml). Tom qab incubation rau 15 min nyob rau hauv chav tsev kub nyob rau hauv qhov tsaus ntuj nti thiab qhov sib ntxiv ntawm 400 ml binding tsis, lub hlwb tau soj ntsuam los ntawm ib tug txaus cytometer (C6; BD Biosciences, Shanghai, Tuam Tshoj).

Kev ntsuas ntawm reactive oxygen hom (ROS).Txhawm rau ntsuas kev tsim khoom ntawm ROS, cov khoom siv Reactive Oxygen Species Assay (Vigorous Biotechnology, Beijing, Tuam Tshoj) tau siv raws li cov chaw tsim khoom cov lus qhia. Luv luv, cov hlwb (80 feem pua ​​​​ntawm cov confluence) tau sau thiab ntxuav nrog PBS ua ntej staining nrog dihydroethidium (DHE) tov (Beyotime Institute of Biotechnology). Cells tau txheeb xyuas los ntawm kev ntsuas cytometric flow.

Kev ntsuas ntawm mitochondrial daim nyias nyias peev xwm (MMP).

Ib qho tetramethylrhodamine methyl ester (TMRM) Assay kit (ImmunoChemistry Technologies, Bloomington, MN, USA) tau siv los txheeb xyuas cov kev hloov hauv MMP. Luv luv, cov hlwb (80 feem pua ​​​​ntawm cov confluence) tau sau, ntxuav nrog PBS thiab stained nrog TMRM rau 15-20 min nyob rau hauv ib tug 37˚C incubator. Cells raug ntxuav ib zaug nrog PBS thiab raug cytometric analyses.

Immunoblottingkev tshuaj xyuas. Cov hlwb (8{10}} feem pua ​​confluence) tau sau thiab lysed hauv RIPA tsis (Jrdun Biotechnology) uas muaj 50 mM Tris-HCl, pH 7.4; 150 mM NaCl, 1 mM EDTA, 1%. Qhov sib npaug ntawm cov cell lysate tau siv rau kev soj ntsuam immunoblotting raws li tau piav qhia dhau los (20).

Kev txheeb cais tsom xam.Cov ntaub ntawv ntau yog qhia raws li qhov nruab nrab ± tus qauv sib txawv. Cov kev sib txawv ntawm kev txheeb cais tau raug soj ntsuam los ntawm cov tub ntxhais kawm qhov kev xeem t-test uas tsis tau ua ke uas siv cov ntaub ntawv SPSS 15.0 software. P<0.05 was="" considered="" to="" indicate="" a="" statistically="" significant="">

Cov txiaj ntsig

ECH (Echinacoside)suppresses qog cellkev loj hlob. Txawm hais tias nws tau tshaj tawm tias ECH(Echinacoside)nthuav tawm lub luag haujlwm tiv thaiv los ntawm inhibiting apoptosis thiab inflammatory signals nyob rau hauv somatic hlwb, xws li neuronal thiab plab hnyuv epithelial hlwb (16-19), nws tseem elusive seb ECH tswj kev mob qog noj ntshav thiab proliferation. Txhawm rau kuaj qhov no, kev soj ntsuam kev ciaj sia ntawm tes tau ua los ntawm kev kho SW1990 hlwb, muab los ntawm qib II pancreatic adenocarcinoma, nrog titrated koob tshuaj ECH raws li qhia hauv daim duab 1. Qhov tseem ceeb, nws tau pom tias ECH cuam tshuam cov qog cell proliferation hauv ib koob. -Txoj kev nyob ntawm lub sijhawm 5-hnub kab lis kev cai (Fig. 1).ECH ua rauapoptosis. Raws li kev poob ntawm apoptosis yog ib qho ntawm cov laj thawj tseem ceeb hauv qab kev tswj tsis tau kev loj hlob ntawm cov qog nqaij hlav qog nqaij hlav pancreatic (21), txoj kev tshawb fawb tam sim no tau ua ib txheej kev sim los txiav txim seb ECH ua rau apoptosis. Ua ntej, los ntawm staining lub nuclei ntawm qog hlwb nrog Hoechst 33342, nws tau pom tias ECH ua rau apoptosis nyob rau hauv ib tug npaum li cas ntawm koob tshuaj (Daim duab 2A). Tsis tas li ntawd, FACS kev txheeb xyuas tau ua los ntawm Annexin V / PI staining kom paub meej ntxiv txog cov nyhuv apoptotic ntawm ty ECH (Fig. 2B). Qhov nruab nrab feem pua ​​​​ntawm cov hlwb apoptotic yog 1.1 feem pua ​​​​hauv cov kab lis kev cai ib txwm muaj, thaum qhov feem pua ​​​​ntawm cov kab mob no tau nce mus rau 10.6, 21.4 thiab 51.3 feem pua ​​​​hauv kev teb rau ECH kev kho mob raws li kev siv tshuaj (Daim duab 2C). Cov txiaj ntsig no, ua ke nrog kev soj ntsuam kev muaj peev xwm ntawm tes tau pom hauv daim duab 1, qhia tau tias ECH kev kho mob inhibits qhov loj hlob ntawm cov qog hlwb los ntawm kev ua rau apoptosis.

tsim ethidium uas intercalates nrog DNA, tau siv nyob rau hauv txoj kev tshawb no los soj ntsuam ROS ntau lawm. Nws tau pom tias, zoo ib yam li lwm yam tshuaj tiv thaiv kab mob, ECH kuj txhawb ROS ntau lawm raws li kev siv tshuaj raws li qhia los ntawm kev siv tshuaj fluorescence siab thaum ECH kho (Daim duab 3).

ECH (Echinacoside)txo MMP.Mitochondrial dysfunction tau pom tias muaj feem cuam tshuam rau qhov induction ntawm apoptosis. Kev qhib ntawm mitochondrial permeability hloov pauv pore tau pom tias ua rau muaj kev cuam tshuam ntawm depolarization ntawm lub peev xwm transmembrane thiab tso tawm ntawm cov yam ntxwv pro-apoptotic (23). Yog li, nws tau sim seb ECH puas tuaj yeem ua rau poob ntawm MMP hauv cov qog hlwb los ntawm kev ua TMRM qhov kev ntsuam xyuas, uas yog ib txoj hauv kev tsim tau zoo, vim qhov kev siv ntawm TMRM fluorescence yog proportional rau lub peev xwm membrane. Nws tau pom tias kev kho ECH txo qis MMP raws li kev noj tshuaj (Daim duab 4).ECH tswj qog cell kev loj hlob viav mitogen-activated proteinlub hauv paus molecular ntawm ECH-mediated qog cell tuag, kev ua haujlwm ntawm ntau txoj hauv kev tseem ceeb, xws li MAPK thiab AKT (24,25), uas tswj cov cell ciaj sia thiab tuag tau kuaj xyuas. Cov MAPKs yog evolutionarily conserved, proline-directed Ser/Thr protein kinases, xws li extracellular signal-regulated kinases (ERKs), c-Jun NH2-terminal kinase (JNKs) thiab cov p38 tsev neeg uas tau qhib los ntawm peb- tier kinase signaling cascades (26,27). Nyob rau hauv txoj kev tshawb no, kev qhia ntawm MAPKs thiab AKT, nrog rau lawv cov activated phosphorylated cov ntaub ntawv, tau soj ntsuam thiab nws tau qhia tias ECH cim suppresses JNK thiab ERK1/2 kev ua, tab sis txhim kho p38 kev ua si (Fig. 5). Qhov tseem ceeb, nws tau pom tias kev ua AKT, uas tseem ceeb heev rau kev loj hlob ntawm tes, tsis cuam tshuam los ntawm ECH kev kho mob (Fig. 5). Tsis tas li ntawd, nws tau pom tias kev kho ECH txhawb nqa kev qhia ntawm Bax thiab Caspase-3 thaum txo Bcl-2 qhia (Fig. 5), uas yog raws li daim duab 2. Yog li, cov txiaj ntsig tau qhia tias ECH ua rau qog cell apoptosis ntawm txoj kev MAPK.

Kev sib tham

Rau qhov zoo tshaj plaws ntawm peb txoj kev paub, qhov no yog thawj txoj kev tshawb fawb los qhia tias ECH muaj cov qog-tshuaj tua kab mob los ntawm kev ua rau apoptosis (Fig. 2), txhawb nqa ROS ntau lawm (Fig. 3) thiab inducing mitochondrial membrane muaj peev xwm depolarization (Fig. 4) , yog li ua rau qog cell loj hlob inhibition (Fig. 1). Tsis tas li ntawd, lub hauv paus molecular ntawm ECH-mediated qog cell tuag tau pom tias tshwm sim los ntawm kev tswj MAPK signaling pathways (Fig. 5). Cov kev tshawb pom no pom tau tias muaj kev ua haujlwm tshiab ntawm ECH hauv kev tiv thaiv qog nqaij hlav thiab yog li qhia tias nws yuav yog tus neeg sawv cev rau kev kho mob qog noj ntshav.

Feem ntau ntawm cov tshuaj tiv thaiv kab mob tuaj yeem ua rau qog cell apoptosis, senescence thiab / lossis cell voj voog raug ntes, uas ua rau inhibition ntawm qog cell loj hlob thiab kev loj hlob. Cell voj voog raug ntes yog cov lus teb ntawm tes rau cov teeb meem kev ntxhov siab me me uas tso cai rau cov hlwb los kho DNA puas ua ntej pib rov ua dua DNA synthesis los yog mitosis, qhov apoptosis thiab senescence (mus tas li cell voj voog raug ntes) tshwm sim hauv cov lus teb rau cov teeb meem kev ntxhov siab uas tshem tawm cov hlwb tsis zoo lossis malignant ( 28, 29). Yog li ntawd, tsuas yog cov nyhuv apoptotic ntawm ECH ntawm cov qog hlwb raug soj ntsuam hauv qhov kev tshawb fawb no, vim tias kev tua cov qog nqaij hlav cancer yog qhov tseem ceeb rau kev ntsuam xyuas lub zog ntawm tus neeg sawv cev tiv thaiv kab mob. Qhov tseem ceeb, nws tau pom tias ECH induces qhov kev qhia ntawmBax(Fig. 5), ib tug pro-apoptotic noob, transcriptionally qhib los ntawm lub qog suppressor p53 (30). Yog li, nws tsim nyog los ntsuas seb ECH puas tuaj yeem qhib txoj hauv kev p53. Yog tias muaj, ECH kuj tseem tuaj yeem ua rau p53- nyob ntawm lub voj voog ntawm tes raug ntes, tsis muaj zog, apoptosis lossis autophagy. Nyob rau hauv txoj kev tshawb no, cov qog-suppressive muaj nuj nqi ntawm ECH nyob rau hauv SW1990 pancreatic adenocarcinoma cell kab tau elucidated. Txawm li cas los xij, kev tshawb fawb ntxiv los soj ntsuam kab mob qog noj ntshav pancreatic ntau dua, yuav tsum tau ua. Nws tau pom tias kev hloov pauv hauv oncogenic protein RAS thiab cov qog nqaij hlav p53 cuam tshuam nrog kev loj hlob ntawm pancreatic cancer (31); Txawm li cas los xij, SW1990 xov tooj ntawm tes tsis muaj kev hloov pauv p53, raws li IARC p53 database (http://p53.iarc.fr/CellLines.aspx). Yog li ntawd, nws yog ib qho tseem ceeb uas yuav tsum tau soj ntsuam seb ECH puas tuaj yeem cuam tshuam rau kev loj hlob thiab kev loj hlob ntawm lwm cov kab mob qog nqaij hlav hauv pancreatic nrog cov kev hloov pauv p53 sib txawv. Tsis tas li ntawd, nws yuav nthuav kom txiav txim siab seb ECH puas tuaj yeem txhawb nqa apoptosis thiab inhibit qhov kev loj hlob ntawm lwm hom qog.

ROS nce thiab txo MMP, uas tau tshwm sim los ntawm ECH kev kho mob, tau pom tias yog qhov tseem ceeb hauv apoptosis induction (22). Tsis tas li ntawd, nws tau pom tias ROS tuaj yeem ua rau oxidation ntawm mitochondrial pores uas txhawb kev tso tawm ntawm cytochrome.c, ib qho nruab nrab hauv apoptosis, vim kev cuam tshuam ntawm MMP (22). Yog li, nws tseem yuav tau txiav txim siab seb ECH cuam tshuam MMP ncaj qha los ntawm kev cuam tshuam ntawm ROS. Tsis tas li ntawd, ROS-elicited oxidative kev nyuaj siab kuj tau pom tias muaj kev koom tes hauv kev hloov kho ntau yam ntawm kev loj hlob ntawm tes tswj cov cim, suav nrog p53, NF-κB, HIFs thiab PI3K (32). Nws tseem yuav txiav txim siab seb puas yog thiab, yog tias muaj, ECH tswj cov kev taw qhia tseem ceeb no li cas. Qhov tseem ceeb, oxidative kev nyuaj siab ua rau ntau yam kab mob neurodegenerative vim yog siv cov pa oxygen siab, tsis muaj zog tiv thaiv kab mob thiab cov yam ntxwv ntawm qhov sib txawv ntawm lub hauv paus paj hlwb (33). Txawm li cas los xij, ntau qhov kev tshawb fawb tau pom tias ECH muaj kev tiv thaiv thiab tiv thaiv apoptotic cuam tshuam rau cov paj hlwb. Hauv qhov no, nws yog qhov tsim nyog rau kev xav tias ECH tuaj yeem txo qis ROS ntau lawm hauv lub davhlau ya nyob twg-qhov sib txawv ntawm neural hlwb. Yog li ntawd, nws tseem yuav tsum tau txiav txim siab seb txoj cai ntawm ROS ntau lawm los ntawm ECH yog nyob ntawm qhov sib txawv ntawm tes. Li no, cov txiaj ntsig tam sim no ua ke nrog lwm cov kev tshawb fawb qhia tias ECH, TCM dav siv, tuaj yeem yog ib qho tseem ceeb chemotherapeutic lub tswv yim tsis yog rau kev kho mob ntawm cov kab mob neurodegenerative nkaus xwb tab sis kuj mob qog noj ntshav.

Tsis ntev los no, siv TCM hauv kev kho mob qog noj ntshav tau txais kev saib xyuas ntau dua. Lub peev xwm ntawm cov khoom ntuj tsim los ntawm cov nroj tsuag tshuaj siv hauv TCM tau lees paub los ntawm cov zej zog kev tshawb fawb txawm nyob rau sab hnub poob ntiaj teb (9). Kev siv zog yuav tsum tau piav qhia txog cov txheej txheem hauv qab ntawm kev ua ntawm cov khoom ntuj tsim, uas thaum kawg yuav ua rau kev txhim kho cov tshuaj zoo thiab nyab xeeb rau kev kho mob qog noj ntshav.

Hauv kev xaus, txoj kev tshawb fawb tam sim no tau pom cov qog inhibitory ua haujlwm ntawm ECH thiab tseem piav qhia txog lub hauv paus molecular ntawm ECH-mediated qog suppression, yog li qhia txog kev siv tshuaj kho mob ECH hauv kev kho mob qog noj ntshav.

Kev lees paub

Txoj kev tshawb no tau txais nyiaj txiag thiab txhawb nqa los ntawm Qhov Kev Pabcuam Tseem Ceeb ntawm Kev Tshawb Fawb Txog Kev Tshawb Fawb ntawm FMU (grant no. 09ZD014). Cov kws sau ntawv xav ua tsaug rau Biomedworld (Shanghai, Suav) rau kev pab kho cov ntawv sau.

Cov ntaub ntawv

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