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Toxoplasma gondii ke kokoana-hloko ea intracellular protozoan e fetolang tikoloho e nyenyane ea motho ea tšoaelitsoeng 'me e tsejoa e amahanngoa le ketsahalo ea ho hōla ha hlahala bokong.Thutong ena, re nahana hore exosomal miRNA-21 ho tsoa ho ts'oaetso ea Toxoplasma e khothalletsa kholo ea hlahala bokong.Li-exosomes tse tsoang ho Toxoplasma-infected BV2 microglia li ile tsa khetholloa 'me ho kenngoa ka hare ho lisele tsa glioma tsa U87 ho netefalitsoe.Li-profiles tsa Exosomal microRNA expression li ile tsa hlahlojoa ho sebelisoa mefuta ea microRNA le microRNA-21A-5p e amanang le Toxoplasma gondii le ho hlopha tumor.Re boetse re fuputsa maemo a mRNA a liphatsa tsa lefutso tse amanang le tumor liseleng tsa glioma tsa U87 ka ho fetola maemo a miR-21 ho li-exosomes le phello ea li-exosome ho ata ha lisele tsa glioma tsa U87.Ho li-exosomes tsa lisele tsa glioma tsa U87 tse tšoaelitsoeng ke Toxoplasma gondii, polelo ea microRNA-21 e eketseha mme mosebetsi oa liphatsa tsa lefutso tsa antitumor (FoxO1, PTEN, le PDCD4) oa fokotseha.Li-exosomes tse nkiloeng ho BV2 tse tšoaelitsoeng ke Toxoplasma li etsa hore ho be le ho ata ha lisele tsa glioma tsa U87.Li-Exosomes li khothalletsa kholo ea lisele tsa U87 ka mohlala oa tumor ea mouse.Re fana ka maikutlo a hore ho eketseha ha exosomal miR-21 ho toxoplasma-infected BV2 microglia e ka bapala karolo ea bohlokoa e le motšehetsi oa kholo ea lisele tsa U87 glioma ka ho theola liphatsa tsa lefutso tsa antitumor.
Ho hakanngoa hore linyeoe tse fetang limilione tse 18.1 tsa mofetše o tsoetseng pele li ile tsa fumanoa lefatšeng ka bophara ka selemo sa 2018, 'me ho fumanoa lihlahala tse ka bang 297,000 tsa tsamaiso ea methapo ea bohareng selemo se seng le se seng (1.6% ea lihlahala tsohle) 1.Patlisiso e fetileng e bonts'itse hore mabaka a kotsi a ho nts'etsapele lihlahala tsa boko ba motho a kenyelletsa lihlahisoa tse fapaneng tsa lik'hemik'hale, nalane ea lelapa, le mahlaseli a ionizing a tsoang lisebelisoa tsa kalafo le tlhahlobo ea hlooho.Leha ho le joalo, ha ho tsejoe hantle hore na sesosa sa lefu lena ke sefe.Hoo e ka bang 20% ​​ea mefuta eohle ea kankere lefatšeng ka bophara e bakoa ke likokoana-hloko, libaktheria le likokoana-hloko3,4.Likokoana-hloko tse tšoaetsanoang li senya mekhoa ea liphatsa tsa lefutso tsa sele e amohelang, joalo ka tokiso ea DNA le potoloho ea lisele, 'me e ka lebisa ho ruruha ho sa feleng le ho senya sesole sa' mele5.
Likokoana-hloko tse tšoaetsanoang tse amanang le mofetše oa motho ke likokoana-hloko tse atileng haholo tsa kokoana-hloko, ho kenyeletsoa human papillomaviruses le hepatitis B le C.Likokoana-hloko li ka boela tsa bapala karolo e ka bang teng ho nts'etsopele ea mofetše oa batho.Mefuta e mengata ea likokoana-hloko, e leng Schistosoma, Opishorchis viverrini, O. felineus, Clonorchis sinensis le Hymenolepis nana, e 'nile ea ameha mefuteng e sa tšoaneng ea kankere ea batho 6,7,8.
Toxoplasma gondii ke protozoan ea intracellular e laolang tikoloho ea lisele tse nang le tšoaetso.Kokoana-hloko ena ho hakanngoa hore e tšoaetsa hoo e ka bang karolo ea 30 lekholong ea baahi ba lefatše, e leng se behang baahi bohle kotsing9,10.Toxoplasma gondii e ka tšoaetsa litho tsa bohlokoa, ho kopanyelletsa le tsamaiso ea methapo e bohareng (CNS), 'me ea baka mafu a tebileng a kang meningitis e bolaeang le encephalitis, haholo-holo ho bakuli ba immunocompromised9.Leha ho le joalo, Toxoplasma gondii e ka boela ea fetola tikoloho ea moeti ea tšoaelitsoeng ka ho fetola kholo ea lisele le likarabo tsa 'mele ho batho ba nang le immunocompetent, e leng se lebisang tlhokomelong ea tšoaetso e sa foleng e sa foleng9,11.Hoa thahasellisa hore ho fanoe ka kamano pakeng tsa ho ata ha T. gondii le ho ata ha hlahala bokong, litlaleho tse ling li fana ka maikutlo a hore liphetoho tsa tikoloho ea vivo ka lebaka la tšoaetso e sa foleng ea T. gondii li tšoana le hlahala microenvironment.
Li-exosomes li tsejoa e le li-intercellular communicators tse fanang ka litaba tsa likokoana-hloko, ho akarelletsa le liprotheine le li-nucleic acid, tse tsoang liseleng tsa boahelani16,17.Li-exosomes li ka ama lits'ebetso tsa tlhaho tse amanang le hlahala joalo ka anti-apoptosis, angiogenesis, le metastasis sebakeng sa tikoloho ea tumor.Haholo-holo, li-miRNAs (miRNAs), li-RNA tse nyenyane tse se nang khouto tse ka bang bolelele ba li-nucleotide tse 22, ke li-post-transcriptional gene regulator tse laolang ho feta 30% ea mRNA ea batho ka mochine oa ho khutsisa o entsoeng ke miRNA (miRISC).Toxoplasma gondii e ka senya ts'ebetso ea tlhaho ka ho laola polelo ea miRNA ho batho ba tšoaelitsoeng.Li-miRNAs tse amohelang li na le matšoao a bohlokoa bakeng sa ho laola lits'ebetso tsa baeloji ho fihlela leano la pholoho la likokoana-hloko.Ka hona, ho ithuta liphetoho ho boemo ba moeti miRNA holim'a tšoaetso ea T. gondii ho ka re thusa ho utloisisa tšebelisano pakeng tsa moamoheli le T. gondii ka ho hlaka.Ka 'nete, Thirugnanam et al.15 e ile ea fana ka tlhahiso ea hore T. gondii e khothalletsa kankere ea boko ka ho fetola polelo ea eona ho li-miRNA tse khethehileng tse amanang le ho hōla ha hlahala 'me li fumane hore T. gondii e ka baka li-glioma liphoofolong tsa liteko.
Boithuto bona bo shebane le phetoho ea exosomal miR-21 ho microglia e tšoaelitsoeng ke Toxoplasma BV2.Re hlokometse karolo e ka bang teng ea exosomal miR-21 e fetotsoeng kholong ea lisele tsa glioma tsa U87 ka lebaka la ho bolokoa khubung ea FoxO1/p27, e leng sepheo sa miR-21 e fetelletseng.
Li-exosomes tse nkiloeng ho BV2 li ile tsa fumanoa ho sebelisoa centrifugation e fapaneng 'me ea netefatsoa ke mekhoa e fapaneng ea ho thibela tšilafalo ka likarolo tsa cellular kapa li-vesicles tse ling.SDS-polyacrylamide gel electrophoresis (SDS-PAGE) e bontšitse mekhoa e fapaneng pakeng tsa liprotheine tse nkiloeng ho lisele tsa BV2 le li-exosomes (Figure 1A), 'me lisampole li ile tsa hlahlojoa bakeng sa boteng ba Alix, e ileng ea hlahlojoa ke Bophirimela ho phunya matšoao a protheine ea exosomal ho.Ho ngolla ha Alix ho fumanoe ka liprotheine tse sa tloaelehang empa eseng ka liprotheine tsa BV2 cell lysate (setšoantšo sa 1B).Ho feta moo, RNA e hloekisitsoeng ho tsoa ho li-exosomes tse nkiloeng ho BV2 e ile ea hlahlojoa ho sebelisoa bioanalyzer.18S le 28S li-subunits tsa ribosomal li ne li sa hlokomeloe ka mokhoa oa ho falla oa exosomal RNA, tse bontšang bohloeki bo ka tšeptjoang (Setšoantšo sa 1C).Qetellong, phetiso elektrone microscopy ile a bontša hore exosomes hlokomela ba ne ba ka bang 60-150 nm ka boholo 'me o na le kopi-joaloka sebopeho tloaelehileng ea exosome morpholoji (sa feiga. 1D).
Tšobotsi ea li-exosomes tse tsoang liseleng tsa BV2.(A) Leqephe la leqephe la polokeho.Liprotheine li ne li arohane le lisele tsa BV2 kapa li-exosomes tse nkiloeng ho BV2.Mekhoa ea protheine e fapana lipakeng tsa lisele le li-exosomes.(B) Tlhahlobo ea blot ea Bophirimela ea letšoao la exosomal (Alix).(C) Tlhahlobo ea RNA e hloekisitsoeng ho tloha liseleng tsa BV2 le li-exosomes tse nkiloeng tsa BV2 tse sebelisang bioanalyzer.Ka hona, li-subunits tsa 18S le 28S tsa ribosomal liseleng tsa BV2 li ne li sa fumanehe ka seoelo ho exosomal RNA.(D) Transmission electron microscopy e bontšitse hore li-exosomes tse arohaneng le lisele tsa BV2 li ne li silafalitsoe hampe ka 2% ea uranyl acetate.Li-Exosomes li ka ba 60-150 nm ka boholo le sebopeho sa kopi (Pina le Jung, data e sa phatlalatsoang).
Ho kenngoa ha liselefouno tsa li-exosome tse nkiloeng ho BV2 ka har'a lisele tsa glioma tsa batho tsa U87 ho ile ha hlokomeloa ho sebelisoa confocal microscopy.Li-exosomes tse ngotsoeng ka PKH26 li fumaneha sebakeng sa cytoplasm ea lisele tsa U87.Li-nuclei li ne li silafalitsoe ke DAPI (setšoantšo sa 2A), se bontšang hore li-exosomes tse entsoeng ka BV2 li ka kenngoa ka hare ho lisele tse amohelang 'me tsa susumetsa tikoloho ea lisele tse amohelang.
Ho kenella ka hare ho li-exosomes tse nkiloeng ho BV2 ka har'a lisele tsa glioma tsa U87 le li-exosomes tse nkiloeng ho BV2 tse tšoaelitsoeng ke Toxoplasma RH li entse hore ho be le ho ata ha lisele tsa U87 glioma.(A) Li-Exosomes tse kenngoeng ke lisele tsa U87 tse lekantsoeng ka microscopy ea confocal.Lisele tsa glioma tsa U87 li ne li kentsoe ka li-exosomes tse ngotsoeng PKH26 (e khubelu) kapa ntle le taolo bakeng sa lihora tse 24.Li-nuclei li ne li silafalitsoe ke DAPI (e putsoa) ebe li hlokomeloa tlas'a microscope e kopanetsoeng (scale bar: 10 μm, x 3000).(B) Ho ata ha lisele tsa glioma tsa U87 ho ile ha khethoa ka tlhahlobo ea ho ata ha lisele.Lisele tsa glioma tsa U87 li ile tsa phekoloa ka li-exosomes bakeng sa nako e boletsoeng. *P <0.05 e fumanoe ka tlhahlobo ea t ea Seithuti. *P <0.05 e fumanoe ka tlhahlobo ea t ea Seithuti. *P < 0,05 получено по t-критерию Стьюдента. *P <0.05 ka tlhahlobo ea t ea Seithuti. *P <0.05 通过学生t 检验获得. *P <0.05 * P < 0,05, полученный с помощью t-критерия Стьюдента. * P <0.05 e fumanoe ho sebelisoa tlhahlobo ea t ea Seithuti.
Ka mor'a ho netefatsa ho kenngoa ha li-exosomes tse entsoeng ka BV2 ka har'a lisele tsa glioma tsa U87, re ile ra etsa liteko tsa ho ata ha lisele ho batlisisa karolo ea BV2 e entsoeng ka Toxoplasma e entsoeng ka li-exosome ho nts'etsopele ea lisele tsa glioma tsa motho.Kalafo ea lisele tsa U87 tse nang le li-exosomes tse tsoang liseleng tsa BV2 tse nang le tšoaetso ea T. gondii li bontšitse hore li-exosomes tse tsoang ho T. gondii tse nang le tšoaetso ea BV2 li bakile ho ata haholo ha lisele tsa U87 ha li bapisoa le taolo (setšoantšo sa 2B).
Ho phaella moo, ho hōla ha lisele tsa U118 ho bile le liphello tse tšoanang le tsa U87, kaha Toxoplasma e ile ea susumetsa li-exosomes e baka maemo a phahameng ka ho fetisisa a ho ata (data e sa bontšoang).Ho latela lintlha tsena, re ka bonts'a hore li-exosomes tse tšoaelitsoeng ke BV2 tse nang le tšoaetso ea Toxoplasma li bapala karolo ea bohlokoa ho ata ha lisele tsa glioma.
Ho batlisisa phello ea li-exosomes tse tsoang ho BV2 tse tšoaelitsoeng ke Toxoplasma ho nts'etsopele ea hlahala, re ile ra kenya lisele tsa glioma tsa U87 ka har'a litoeba tse hlobotseng bakeng sa mohlala oa xenograft le li-exosomes tse nkiloeng ho BV2 kapa li-exosomes tse nkiloeng ke BV2 tse nang le RH.Ka mor'a hore lihlahala li hlahe ka mor'a beke ea 1, sehlopha se seng le se seng sa liteko tsa litoeba tsa 5 se ile sa aroloa ho ea ka boholo ba hlahala ho fumana sebaka se tšoanang sa ho qala, 'me boholo ba hlahala bo ne bo lekantsoe ka matsatsi a 22.
Ka litoeba tse nang le mohlala oa U87 xenograft, boholo bo boholo ba hlahala le boima ba 'mele bo ile ba hlokomeloa ho sehlopha sa exosome se entsoeng ka RH se nang le tšoaetso ea BV2 letsatsing la 22 (Setšoantšo sa 3A, B).Ka lehlakoreng le leng, ho ne ho se na phapang e khōlō ka boholo ba tumor pakeng tsa sehlopha sa exosome se nkiloeng ho BV2 le sehlopha sa taolo ka mor'a phekolo e makatsang.Ho phaella moo, litoeba injected le lisele glioma le exosomes pono bontshiweng kholo ka ho fetisisa hlahala bophahamo ba modumo sehlopheng sa RH-tshwaetso BV2-nkiloeng exosomes (sa feiga. 3C).Liphetho tsena li bonts'a hore li-exosomes tse tšoaelitsoeng ke BV2 tse tsoang ho Toxoplasma li baka kholo ea glioma moetsong oa tumor ea toeba.
Oncogenesis (AC) ea li-exosome tse nkiloeng ho BV2 ka mokhoa oa U87 xenograft mouse.Boholo ba hlahala (A) le boima ba 'mele (B) bo ile ba eketseha haholo ho BALB / c litoeba tse hlobotseng tse tšoaroang ka li-exosome tse nang le tšoaetso ea RH tse nkiloeng ho BV2.BALB/c litoeba tse hlobotseng (C) li ne li kenngoa ka tlas'a letlalo ka lisele tse 1 x 107 tsa U87 tse emisitsoeng motsoako oa Matrigel.Matsatsi a ts'eletseng ka mor'a ente, 100 μg ea li-exosomes tse nkiloeng ho BV2 li ile tsa phekoloa ka litoeba.Boholo ba hlahala le boima ba tsona li ne li lekanngoa ka matsatsi a bontšitsoeng le ka mor'a sehlabelo, ka ho latellana. *P <0.05. *P <0.05. *Р <0,05. *P <0.05. *P <0.05. *P <0.05. *Р <0,05. *P <0.05.
Lintlha li bontšitse hore 37 miRNAs (16 overexpressed le 21 downexpressed) e amanang le ho itšireletsa mafung kapa nts'etsopele ea hlahala e fetotsoe haholo ka microglia ka mor'a tšoaetso ea Toxoplasma RH strain (Fig. 4A).Maemo a amanang le polelo ea miR-21 har'a li-miRNA tse fetotsoeng a netefalitsoe ke RT-PCR ea nako ea nnete ho li-exosomes tse nkiloeng ho BV2, li-exosomes tse tšoaroang ka lisele tsa BV2 le U87.Polelo ea miR-21 e bontšitse keketseho e kholo ea li-exosomes tse tsoang liseleng tsa BV2 tse tšoaelitsoeng ke Toxoplasma gondii (RH strain) (setšoantšo sa 4B).Maemo a amanang le polelo ea miR-21 ho BV2 le U87 liseleng a ile a eketseha ka mor'a ho kenngoa ha li-exosomes tse fetotsoeng (setšoantšo sa 4B).Maemo a lekanyelitsoeng a polelo ea miR-21 ka har'a lisele tsa boko ba bakuli ba hlahala le litoeba tse tšoaelitsoeng ke Toxoplasma gondii (ME49 strain) e ne e phahame ho feta taolong, ka ho latellana (sa feiga. 4C).Liphetho tsena li amana le phapang lipakeng tsa maemo a polelo a li-microRNA tse boletsoeng esale pele le tse netefalitsoeng ka har'a vitro le in vivo.
Liphetoho polelong ea exosomal miP-21a-5p ho microglia e tšoaelitsoeng ke Toxoplasma gondii (RH).(A) E bontša liphetoho tse kholo ho siRNA e amanang le ho itšireletsa mafung kapa nts'etsopele ea hlahala ka mor'a tšoaetso ea T. gondii RH.(B) Maemo a amanang le maikutlo a miR-21 a ile a fumanoa ke RT-PCR ea nako ea sebele ho li-exosomes tse nkiloeng ho BV2, li-exosomes tse tšoaroang ke BV2, le lisele tsa U87.(C) Maemo a amanang le maikutlo a miR-21 a ile a fumanoa liseleng tsa boko ba bakuli ba hlahala (N = 3) le litoeba tse tšoaelitsoeng ke Toxoplasma gondii (ME49 strain) (N = 3). *P <0.05 e fumanoe ka tlhahlobo ea t ea Seithuti. *P <0.05 e fumanoe ka tlhahlobo ea t ea Seithuti. *P < 0,05 было получено с помощью t-критерия Стьюдента. *P <0.05 e fumanoe ho sebelisoa tlhahlobo ea t ea Seithuti. *P <0.05 通过学生t 检验获得. *P <0.05 * P <0,05, полученный с помощью t-критерия Стьюдента. * P <0.05 e fumanoe ho sebelisoa tlhahlobo ea t ea Seithuti.
Li-exosomes tse tsoang liseleng tsa BV2 tse tšoaelitsoeng ke RH li ile tsa lebisa ho holeng ha li-glioma ka vivo le in vitro (setšoantšo sa 2, 3).Ho bona li-mRNA tse amehang, re ile ra hlahloba maemo a mRNA a liphatsa tsa lefutso tsa antitumor, lebokose la forkhead O1 (FoxO1), PTEN, le "cell death 4" (PDCD4) e hlophisitsoeng ka liseleng tsa U87 tse tšoaelitsoeng ke li-exosomes tse tsoang ho BV2 kapa RH BV2.Tlhahlobo ea Bioinformatics e bonts'itse hore liphatsa tsa lefutso tse 'maloa tse amanang le tumor, ho kenyeletsoa liphatsa tsa lefutso tsa FoxO1, PTEN, le PDCD4, li na le libaka tse tlamang tsa miR-2121,22.Litekanyetso tsa mRNA tsa liphatsa tsa lefutso tsa antitumor li ile tsa fokotsoa ho li-exosomes tse entsoeng ka RH tse nang le tšoaetso ea BV2 ha li bapisoa le li-exosomes tse tsoang ho BV2 (Fig. 5A).FoxO1 e bonts'itse maemo a fokotsehileng a protheine ho li-exosomes tse tsoang ho RH-infected BV2 ha li bapisoa le li-exosomes tse tsoang ho BV2 (Setšoantšo sa 5B).Ho latela liphetho tsena, re ka netefatsa hore li-exosomes tse tsoang ho BV2 e tšoaelitsoeng ke RH li theola liphatsa tsa lefutso tsa anti-oncogenic, li boloka karolo ea tsona kholong ea hlahala.
Li-exosomes tse entsoeng ka BV2 tse nang le tšoaetso ea toxoplasma RH li etsa hore ho be le khatello ea liphatsa tsa lefutso tsa antitumor liseleng tsa glioma tsa U87 ka li-exosomes tse entsoeng ke Toxoplasma RH-infected BV2.(A) PCR ea nako ea sebele ea FoxO1, PTEN le PDCD4 polelo ea li-exosomes tse tsoang ho T. gondii RH-infected BV2 bapisoa le PBS exosomes.β-actin mRNA e ne e sebelisoa e le taolo.(B) Polelo ea FoxO1 e khethiloe ke ho phunya Bophirimela le data ea densitometry e ile ea hlahlojoa ka lipalo ho sebelisa lenaneo la ImageJ. *P <0.05 e fumanoe ka tlhahlobo ea t ea Seithuti. *P <0.05 e fumanoe ka tlhahlobo ea t ea Seithuti. *P < 0,05 было получено с помощью t-критерия Стьюдента. *P <0.05 e fumanoe ho sebelisoa tlhahlobo ea t ea Seithuti. *P <0.05 通过学生t 检验获得. *P <0.05 * P <0,05, полученный с помощью t-критерия Стьюдента. * P <0.05 e fumanoe ho sebelisoa tlhahlobo ea t ea Seithuti.
Ho utloisisa phello ea miP-21 ho li-exosomes taolong ea liphatsa tsa lefutso tse amanang le tumor, lisele tsa U87 li ile tsa fetisoa ka inhibitor ea miP-21 ho sebelisoa Lipofectamine 2000 mme lisele li ile tsa kotuloa lihora tse 24 kamora phetisetso.FoxO1 le p27 maemo a polelo ka liseleng tse fetisitsoeng ka miR-21 inhibitors li ne li bapisoa le lisele tse tšoaroang ka li-exosome tse tsoang ho BV2 tse sebelisang qRT-PCR (Fig. 6A, B).Phetisetso ea inhibitor ea miR-21 ho lisele tsa U87 e fokolitse haholo FoxO1 le polelo ea p27 (FIG. 6).
RH-infected exosomal BV2-derived miP-21 e fetotse polelo ea FoxO1/p27 liseleng tsa U87 tsa glioma.Lisele tsa U87 li ile tsa fetisoa ka miP-21 inhibitor ho sebelisa Lipofectamine 2000 'me lisele li ile tsa kotuloa lihora tse 24 ka mor'a phetisetso.FoxO1 le p27 maemo a polelo ka liseleng tse fetisitsoeng ka miR-21 inhibitors li ne li bapisoa le maemo a lisele tse tšoaroang ka li-exosome tse tsoang ho BV2 tse sebelisang qRT-PCR (A, B).
E le hore e balehe karabelo ea 'mele ea 'mele ea ho itšireletsa mafung, kokoana-hloko ea Toxoplasma e fetoha cyst ea lisele.Li tšoaetsa lisele tse fapa-fapaneng, ho kopanyelletsa le boko, pelo le mesifa ea lerapo, bophelo bohle ba motho ea amohelang 'mele le ho laola tsela eo masole a 'mele a sebetsang ka eona.Ho phaella moo, ba ka laola potoloho ea lisele le apoptosis ea lisele tse amohelang, ho khothalletsa ho ata ha tsona14,24.Toxoplasma gondii e tšoaetsa haholo lisele tsa dendritic tse amohelang, li-neutrophils, le leloko la monocyte/macrophage, ho kenyeletsoa le microglia ea boko.Toxoplasma gondii e etsa hore ho be le phapang ea macrophages ea phenotype ea M2, e ama pholiso ea maqeba ka mor'a tšoaetso ea kokoana-hloko, hape e amahanngoa le hypervascularization le granulomatous fibrosis.Pathogenesis ena ea boitšoaro ea tšoaetso ea Toxoplasma e kanna ea amana le matšoao a amanang le nts'etsopele ea hlahala.Tikoloho e tletseng bora e laoloang ke Toxoplasma e ka tšoana le mofetše o tšoanang.Ka hona, ho ka nahanoa hore tšoaetso ea Toxoplasma e lokela ho kenya letsoho ho nts'etsopele ea lihlahala tsa boko.Ebile, litekanyetso tse phahameng tsa tšoaetso ea Toxoplasma li tlalehiloe serum ea bakuli ba nang le lihlahala tse fapaneng tsa boko.Ho phaella moo, Toxoplasma gondii e ka 'na ea e-ba phello e' ngoe ea kankere 'me e sebetsa ka mokhoa o ts'oanang ho thusa likokoana-hloko tse ling tse tšoaetsanoang ho hlahisa lihlahala tsa boko.Tabeng ena, ke habohlokoa ho hlokomela hore kokoana-hloko ea P. falciparum le Epstein-Barr ka synergistically e kenya letsoho ho thehoeng ha lymphoma ea Burkitt.
Karolo ea li-exosomes joalo ka balaoli lefapheng la lipatlisiso tsa mofets'e e se e batlisisitsoe haholo.Leha ho le joalo, karolo ea li-exosomes lipakeng tsa likokoana-hloko le batho ba tšoaelitsoeng e ntse e sa utloisisoe hantle.Ho fihlela joale, balaoli ba fapa-fapaneng, ho kenyelletsa le liprotheine tse patiloeng, ba hlalositse mekhoa ea likokoana-hloko eo likokoana-hloko tsa protozoan li hanelang ho hlaseloa ke batho ba bangata le ho tsoela pele ho tšoaetsoa.Haufinyane tjena, ho bile le mohopolo o ntseng o hola oa hore li-microvesicles tse amanang le protozoan le li-microRNA tsa tsona li sebelisana le lisele tse amohelang ho theha tikoloho e ntle bakeng sa ho phela ha tsona.Ka hona, lithuto tse ling lia hlokahala ho fumana kamano lipakeng tsa li-exosomal miRNA tse fetotsoeng le ho ata ha lisele tsa glioma.MicroRNA alteration (cluster gene miR-30c-1, miR-125b-2, miR-23b-27b-24-1 le miR-17-92) e tlama ho mothetsi oa STAT3 ho li-macrophages tsa batho tse tšoaelitsoeng ke toxoplasma, li laoloa le ho susumetsa anti -apoptosis ka lebaka la tšoaetso ea Toxoplasma gondii 29.Tšoaetso ea toxoplasma e eketsa polelo ea miR-17-5p le miR-106b-5p, e amanang le mafu a 'maloa a hyperproliferative 30.Lintlha tsena li fana ka maikutlo a hore li-miRNAs tse laoloang ke tšoaetso ea Toxoplasma ke limolek'hule tsa bohlokoa bakeng sa ho phela ha likokoana-hloko le likokoana-hloko boitšoarong ba likokoana-hloko.
Li-miRNA tse fetotsoeng li ka ama mefuta e fapaneng ea boits'oaro nakong ea ho qala le ho tsoela pele ha lisele tse kotsi, ho kenyelletsa le li-gliomas: ho ikemela ha matšoao a kholo, ho hloka kutlo ho mats'oao a thibelang kholo, ho baleha ha apoptosis, bokhoni bo sa lekanyetsoang ba ho ikatisa, angiogenesis, tlhaselo le metastasis, le ho ruruha.Ho glioma, li-miRNA tse fetotsoeng li fumanoe lithutong tse 'maloa tsa profiling ea polelo.
Thutong ea hona joale, re netefalitse maemo a phahameng a polelo ea miRNA-21 liseleng tse amohelang tšoaetso ea toxoplasma.miR-21 e khethiloe e le e 'ngoe ea li-microRNA tse atisang ho hlahisoa hangata ka har'a lihlahala tse tiileng, ho kenyeletsoa li-gliomas, 33 mme polelo ea eona e hokahane le boemo ba glioma.Bopaki bo bokelletsoeng bo fana ka maikutlo a hore miR-21 ke buka ea oncogene e sebetsang e le ntho e khahlanong le apoptotic kholong ea glioma mme e pepeseha haholo ka har'a lisele le plasma ea boko ba motho.Ho khahlisang, ho se sebetse ha miR-21 liseleng tsa glioma le liseleng ho baka thibelo ea ho ata ha lisele ka lebaka la apoptosis e itšetlehileng ka caspase.Tlhahlobo ea bioinformatic ea lipheo tse boletsoeng esale pele tsa miR-21 e senotse mefuta e mengata ea lihlahala tse hatellang li-tumor tse amanang le litsela tsa apoptosis, ho kenyeletsoa le "programmed cell death 4 (PDCD4), tropomyosin (TPM1), PTEN, le forkhead box O1 (FoxO1), le sebaka se tlamang sa miR-2121..22.38.
FoxO1, joalo ka e 'ngoe ea lintlha tse ngotsoeng (FoxO), e ameha ho nts'etsopele ea mefuta e fapaneng ea mofets'e oa motho mme e khona ho laola polelo ea liphatsa tsa lefutso tsa tumor suppressor tse kang p21, p27, Bim, le FasL40.FoxO1 e ka tlama le ho kenya tšebetsong li-cell cycle inhibitors joalo ka p27 ho hatella kholo ea lisele.Ho feta moo, FoxO1 ke sehlahisoa sa bohlokoa sa pontšo ea PI3K/Akt mme e laola lits'ebetso tse ngata tsa bioloji joalo ka tsoelo-pele ea potoloho ea lisele le phapang ea lisele ka ho kenya tšebetsong mongolo oa p2742.
Qetellong, re lumela hore exosomal miR-21 e tsoang ho microglia e tšoaelitsoeng ke Toxoplasma e ka 'na ea phetha karolo ea bohlokoa e le molaoli oa kholo ea lisele tsa glioma (setšoantšo sa 7).Leha ho le joalo, lithuto tse ling lia hlokahala ho fumana kamano e tobileng pakeng tsa exosomal miR-21, tšoaetso e fetotsoeng ea Toxoplasma, le kholo ea glioma.Liphetho tsena li lebelletsoe ho fana ka qalo ea ho ithuta kamano lipakeng tsa ts'oaetso ea Toxoplasma le ketsahalo ea glioma.
Sets'oants'o sa moralo oa mochini oa glioma (boko) carcinogenesis se hlahisoa thutong ena.Sengoli se hula PowerPoint 2019 (Microsoft, Redmond, WA).
Melao eohle ea liteko thutong ena, ho kenyeletsa le tšebeliso ea liphoofolo, e ne e lumellana le Seoul National University Animal Care and User Committee Standard Ethical Guidelines 'me e ile ea amoheloa ke Boto ea Tlhahlobo ea Setheo ea Seoul National University School of Medicine (Nomoro ea IRB SNU- 150715).-2).Mekhoa eohle ea liteko e entsoe ho latela likhothaletso tsa ARRIVE.
BV2 mouse microglia le U87 human glioma cell li ile tsa hlahisoa ho Dulbecco's Modified Eagle's Medium (DMEM; Welgene, Seoul, Korea) le Roswell Park Memorial Institute's Medium (RPMI; Welgene), ka ho latellana, e 'ngoe le e 'ngoe e na le 10% fetal bovine serum, 4 mM l- glutamine, 0.2 mM penicillin le 0.05 mM streptomycin.Lisele li ile tsa hlahisoa ka har'a incubator e nang le 5% CO2 ho 37°C.E 'ngoe ea lisele tsa glioma, U118, e sebelisitsoe ho bapisa le lisele tsa U87.
Ho arola li-exosomes tse tsoang ho T. gondii-infected RH le ME49 strains, T. gondii tachyzoites (RH strain) e ile ea kotuloa ho tloha ka mpeng ea litoeba tsa 6-beke tsa BALB / c tse entsoeng matsatsi a 3-4 pele ho moo.Li-tachyzoite li ne li hlatsuoa ka makhetlo a mararo ka PBS 'me li hloekisoa ka centrifugation ka 40% Percoll (Sigma-Aldrich, St. Louis, MO, USA)43.Ho fumana li-tachyzoites tsa khatello ea ME49, litoeba tsa BALB / c li ne li kenngoa ka intraperitoneally ka li-cysts tsa 20 tsa li-tissue le phetoho ea tachyzoite ho li-cysts e ile ea bokelloa ka ho hlatsoa sekoti sa mpa ka letsatsi la 6-8 ka mor'a tšoaetso (PI).Litoeba tse tšoaelitsoeng ke PBS.ME49 tachyzoites e ne e jetsoe ka liseleng tse tlatsitsoeng ka 100 μg/ml penicillin (Gibco/BRL, Grand Island, NY, USA), 100 μg/ml streptomycin (Gibco/BRL), le 5% ea serum ea fetal bovine (Lonza, Walkersville, MD) .., USA) ho 37 °C le 5% carbon dioxide.Kamora ho lengoa liseleng tsa Vero, li-tachyzoite tsa ME49 li ile tsa fetisoa habeli ka nale ea 25 gauge ebe ka filthara ea 5 µm ho tlosa litšila le lisele.Kamora ho hlatsuoa, li-tachyzoite li ile tsa emisoa hape ho PBS44.Li-tissue cysts tsa Toxoplasma gondii strain ME49 li ne li bolokiloe ka ente ea intraperitoneal ea li-cysts tse arohaneng le boko ba C57BL / 6 litoeba tse nang le tšoaetso (Orient Bio Animal Center, Seongnam, Korea).Boko ba litoeba tse nang le tšoaetso ea ME49 bo ile ba kotuloa ka mor'a likhoeli tsa 3 tsa PI 'me tsa cheka ka tlas'a microscope ho arola li-cysts.Litoeba tse tšoaelitsoeng li ne li bolokoa tlas'a maemo a khethehileng a se nang pathogen (SPF) Sekolong sa Bongaka sa Seoul National University.
Kakaretso ea RNA e ntšitsoe ho li-exosomes tse nkiloeng ho BV2, lisele tsa BV2 le lisele tse sebelisang miRNeasy Mini Kit (Qiagen, Hilden, Germany) ho ea ka litaelo tsa moetsi, ho kenyelletsa le nako ea ho incubation bakeng sa mohato oa elution.Khatiso ea RNA e ile ea khethoa ho NanoDrop 2000 spectrophotometer.Boleng ba li-microarrays tsa RNA bo ile ba hlahlojoa ho sebelisoa Agilent 2100 bioanalyzer (Agilent Technologies, Amstelveen, Netherlands).
DMEM e nang le 10% exosome-foor FBS e ile ea lokisoa ke ultracentrifugation ho 100,000g bakeng sa lihora tse 16 ho 4°C le ho tlhotloa ka sefene sa 0.22 µm (Nalgene, Rochester, NY, USA).Lisele tsa BV2, 5 × 105, li ne li lengoa ka DMEM e nang le 10% exosome-depleted FBS le 1% lithibela-mafu ho 37 ° C le 5% CO2.Ka mor'a lihora tse 24 tsa incubation, tachyzoites of strain RH kapa ME49 (MOI = 10) e ile ea kenngoa liseleng 'me likokoana-hloko tse sa hlaseleng li ile tsa tlosoa ka mor'a hora' me tsa tlatsoa hape ka DMEM.Li-exosomes tse tsoang liseleng tsa BV2 li ne li khethiloe ke centrifugation e fetotsoeng, mokhoa o sebelisoang ka ho fetisisa.Khutlisetsa pellet ea exosome ho 300 µl PBS bakeng sa RNA kapa tlhahlobo ea protheine.Khatello ea li-exosomes tse ka thoko e ile ea khethoa ho sebelisoa sesebelisoa sa tlhahlobo ea protheine ea BCA (Pierce, Rockford, IL, USA) le NanoDrop 2000 spectrophotometer.
Li-precipitates tse tsoang liseleng tsa BV2 kapa li-exosomes tse nkiloeng ho BV2 li ile tsa tšeloa ka har'a protheine ea PRO-PREP™ (iNtRon Biotechnology, Seongnam, Korea) 'me liprotheine li ile tsa kenngoa holim'a li-gels tsa Coomassie tse boputsoa bo botala bo khanyang 10% SDS polyacrylamide.Ho feta moo, liprotheine li ile tsa fetisetsoa ho membrane ea PVDF ka lihora tse peli.Li-blots tsa Bophirimela li netefalitsoe ho sebelisoa antibody ea Alix (Cell Signaling Technology, Beverly, MA, USA) joalo ka lesupa la exosomal.HRP-conjugated pōli anti-mouse IgG (H + L) (Bethyl Laboratories, Montgomery, TX, USA) le LAS-1000 plus luminescent image analyzer (Fuji Photographic Film, Tokyo, Japan) li ne li sebelisoa e le antibody ea bobeli..Microscopy ea elektrone ea phetiso e ile ea etsoa ho ithuta boholo le morphology ea li-exosomes.Li-exosomes tse arohaneng le lisele tsa BV2 (6.40 µg/µl) li ne li lokiselitsoe ka meshes e koahetsoeng ka carbon 'me e silafalitsoe hampe ka 2% ea uranyl acetate bakeng sa 1 min.Mehlala e lokisitsoeng e ile ea hlokomeloa ka motlakase o potlakileng oa 80 kV ho sebelisoa JEOL 1200-EX II (Tokyo, Japan) e nang le khamera ea ES1000W Erlangshen CCD (Gatan, Pleasanton, CA, USA).
Li-exosomes tse entsoeng ka BV2 li ne li silafatsoa ka ho sebelisa PKH26 Red Fluorescent Linker Kit (Sigma-Aldrich, St. Louis, MO, USA) bakeng sa metsotso ea 15 mocheso oa kamore.Lisele tsa U87, 2 × 105, tse nang le li-exosomes tse ngotsoeng ka PKH26 (tse khubelu) kapa tse se nang li-exosomes e le taolo e mpe, li ne li kenngoa ka 37 ° C ka lihora tse 24 ka 5% CO2 incubator.Li-nuclei tsa lisele tsa U87 li ne li silafalitsoe ka DAPI (e putsoa), lisele tsa U87 li ne li behiloe ka 4% paraformaldehyde bakeng sa 15 min ho 4 ° C ebe e hlahlojoa ka Leica TCS SP8 STED CW confocal microscope system (Leica Microsystems, Mannheim, Jeremane).hlokomelehang.
cDNA e entsoe ho tloha ho siRNA ho sebelisoa Mir-X siRNA ea pele ea strand synthesis le SYBR qRT-PCR kit (Takara Bio Inc., Shiga, Japan).PCR ea nako ea sebele e ile ea etsoa ho sebelisoa mokhoa oa ho lemoha oa PCR oa iQ5 oa nako ea sebele (Bio-Rad, Hercules, CA, USA) ho sebelisoa li-primers le li-template tse tsoakiloeng le SYBR Premix.DNA e ile ea phahamisoa bakeng sa 40 cycles of denaturation ho 95°C bakeng sa 15 s le annealing ho 60°C bakeng sa 60 s.Lintlha tse tsoang karabelong e 'ngoe le e' ngoe ea PCR li ile tsa hlahlojoa ho sebelisoa module ea tlhahlobo ea data ea iQ™5 optical system software (Bio-Rad).Liphetoho tse amanang le liphatsa tsa lefutso pakeng tsa liphatsa tsa lefutso tse khethiloeng le β-actin/siRNA (le U6) li ile tsa baloa ho sebelisoa mokhoa o tloaelehileng oa curve.Litaelo tsa pele tse sebelisitsoeng li bontšitsoe ho Lethathamo la 1.
Lisele tsa glioma tse 3 x 104 U87 li ile tsa jaloa ka lipoleiti tsa seliba tse 96 'me tsa tsoakoa le li-exosomes tse nang le tšoaetso ea Toxoplasma tse nkiloeng ho BV2 (50 μg / mL) kapa li-nonpulse exosomes tse nkiloeng ho BV2 (50 μg / mL) e le taolo ho 12, lihora tsa 18 le 36 .Sekhahla sa ho ata ha lisele se ile sa khethoa ho sebelisoa Cell Counting Kit-8 (Dojindo, Kumamoto, Japan) (Lipalo tse Tlatsetsang S1-S3) 46.
Litoeba tsa basali tse nang le libeke tse 5 tsa BALB/c tse hlobotseng li ile tsa rekoa ho tsoa Orient Bio (Seongnam-si, Korea Boroa) 'me tsa bolokoa ka bonngoe ka har'a masaka a sa hloekang mocheso oa kamore (22±2°C) le mongobo (45±15°C).%) mocheso oa kamore (22±2°C) le mongobo (45±15%).Potoloho ea leseli la lihora tsa 12 le potoloho ea lefifi ea lihora tsa 12 e ile ea etsoa tlas'a SPF (Seoul National University School of Medicine Animal Center).Litoeba li ne li arotsoe ka lihlopha tse tharo tsa litoeba tsa 5 e 'ngoe le e' ngoe 'me lihlopha tsohle li ne li kenngoa ka tlas'a 400 ml ea PBS e nang le lisele tsa glioma tsa 1 x 107 U87 le ntlha ea ho hōla e fokotsehile BD Matrigel™ (BD Science, Miami, FL, USA).Matsatsi a ts'eletseng ka mor'a ente ea tumor, 200 mg ea li-exosomes tse nkiloeng ho lisele tsa BV2 (tse nang le / ntle le tšoaetso ea Toxoplasma) li ile tsa kenngoa sebakeng sa hlahala.Matsatsi a mashome a mabeli a metso e 'meli ka mor'a tšoaetso ea hlahala, boholo ba hlahala ba litoeba sehlopheng ka seng bo ne bo lekantsoe ka caliper ka makhetlo a mararo ka beke,' me molumo oa hlahala o ne o baloa ka mokhoa o latelang: 0.5 × (bophara) × 2 × bolelele.
Tlhahlobo ea polelo ea MicroRNA e sebelisa miRCURYTM LNA miRNA array, moloko oa 7 o na le, mmu le rno arrays (EXIQON, Vedbaek, Denmark) e koahelang litoeba tse 1119 tse nang le mekhoa e metle har'a li-probe tsa 3100 tsa batho, mouse le rat miRNA.Nakong ea ts'ebetso ena, 250 ho 1000 ng ea kakaretso ea RNA e ile ea tlosoa ho 5'-phosphate ka ho phekoloa ka namane ea mala a alkaline phosphatase e lateloang ke ho ngola ka dae ea Hy3 e tala ea fluorescent.Ka mor'a moo, lisampole tse ngotsoeng li ile tsa kopanngoa ka ho kenya li-slide tse nyenyane ka ho sebelisa mochine oa hybridization chamber (Agilent Technologies, Santa Clara, CA, USA) le lisebelisoa tsa li-slide tse nyalisitsoeng (Agilent Technologies).Hybridization e ile ea etsoa lihora tse 16 ho 56 ° C, joale li-microarrays li ne li hlatsuoa ho latela litlhahiso tsa moetsi.Li-slide tsa microarray tse sebetsitsoeng li ile tsa hlahlojoa ka mokhoa oa Agilent G2565CA microarray scanner system (Agilent Technologies).Litšoantšo tse hlahlobiloeng li ile tsa romelloa ka ntle ho sebelisoa mofuta oa Agilent Feature Extraction software version 10.7.3.1 (Agilent Technologies) 'me matla a fluorescence a setšoantšo ka seng a ile a lekanyetsoa ho sebelisoa faele ea GAL e tsamaellanang ea protocol e fetotsoeng ea Exiqon.Lintlha tsa Microarray tsa thuto ea hajoale li kentsoe polokelong ea GEO tlasa nomoro ea phihlello ea GPL32397.
Litlaleho tsa maikutlo tsa li-exosomal miRNA tse hōlileng ka har'a microglia ea RH kapa ME49 mefuta e tšoaelitsoeng ke Toxoplasma e ile ea hlahlojoa ho sebelisoa lisebelisoa tse fapaneng tsa marang-rang.Li-miRNA tse amanang le nts'etsopele ea hlahala li ile tsa khetholloa ho sebelisoa miRWalk2.0 (http://mirwalk.umm.uni-heidelberg.de) 'me tsa tlhotloa ka matla a tloaelehileng a tloaelehileng (log2) a fetang 8.0.Har'a li-miRNA, li-miRNA tse hlalositsoeng ka mokhoa o fapaneng li fumanoe li feta 1.5-folded by filter analysis of miRNAs e fetotsoeng ke mefuta ea RH kapa ME49 e tšoaelitsoeng ke T. gondii.
Lisele li ne li kenngoa ka lipoleiti tse tšeletseng tsa seliba (3 x 105 lisele / seliba) ho opti-MEM (Gibco, Carlsbad, CA, USA) ho sebelisoa Lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA).Lisele tse fetisitsoeng li ile tsa ntlafatsoa ka lihora tse 6 'me ka mor'a moo li fetoloa ho ba seaplane se hloekileng.Lisele li ile tsa kotuloa lihora tse 24 ka mor'a hore li fetisetsoe.
Tlhahlobo ea lipalo-palo e ne e etsoa haholo-holo ho sebelisoa tlhahlobo ea t ea Seithuti ka software ea Excel (Microsoft, Washington, DC, USA).Bakeng sa tlhahlobo ea liteko ea liphoofolo, ANOVA ea litsela tse peli e ile ea etsoa ho sebelisoa software ea Prism 3.0 (GraphPad Software, La Jolla, CA, USA). Litekanyetso tsa P <0.05 li ne li nkoa e le tsa bohlokoa ka lipalo. Litekanyetso tsa P <0.05 li ne li nkuoa li le bohlokoa ho latela lipalo. Значения P <0,05 считались статистически значимыми. Litekanyetso tsa P <0.05 li ne li nkuoa e le tsa bohlokoa ka lipalo. P 值< 0.05 被认为具有统计学意义。 P <0.05 Значения P <0,05 считались статистически значимыми. Litekanyetso tsa P <0.05 li ne li nkuoa e le tsa bohlokoa ka lipalo.
Melao eohle ea liteko e sebelisitsoeng thutong ena e ile ea amoheloa ke Boto ea Tlhahlobo ea Setsi sa Seoul National University School of Medicine (nomoro ea IRB SNU-150715-2).
The data used in this study are available upon reasonable request from the first author (BK Jung; mulddang@snu.ac.kr). And the microarray data for the current study is deposited in the GEO database under registration number GPL32397.
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