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I-Toxoplasma gondii iyi-parasite ye-intracellular protozoan ehlela imvelo encane yomsingathi onegciwane futhi yaziwa ukuthi ihlotshaniswa nesigameko sokukhula kwesimila ebuchosheni.Kulolu cwaningo, sicabanga ukuthi i-exosomal miRNA-21 evela ekuthelelekeni kwe-Toxoplasma ikhuthaza ukukhula kwesimila ebuchosheni.Ama-exosomes avela ku-Toxoplasma-infected BV2 microglia abonakaliswe futhi ukufakwa ngaphakathi kwamaseli e-glioma e-U87 kwaqinisekiswa.Amaphrofayili e-Exosomal microRNA expression ahlaziywa kusetshenziswa amalungu afanayo e-microRNA kanye ne-microRNA-21A-5p ehlotshaniswa ne-Toxoplasma gondii nokuhlungwa kwesimila.Siphinde saphenya amazinga e-mRNA ezakhi zofuzo ezihambisana nesimila kumaseli e-glioma e-U87 ngokushintsha amazinga e-miR-21 kuma-exosomes kanye nomthelela wama-exosomes ekwandeni kwamaseli e-glioma e-U87.Kuma-exosomes amaseli e-glioma e-U87 atheleleke nge-Toxoplasma gondii, ukuvezwa kwe-microRNA-21 kuyanda futhi umsebenzi wezakhi zofuzo ze-antitumor (FoxO1, PTEN, ne-PDCD4) uyancipha.Ama-exosome asuselwa ku-BV2 atheleleke nge-Toxoplasma adala ukwanda kwamaseli e-glioma e-U87.Ama-Exosomes adala ukukhula kwamaseli e-U87 kumodeli yesimila segundane.Siphakamisa ukuthi ukukhuphuka kwe-exosomal miR-21 ku-Toxoplasma-infected BV2 microglia kungase kudlale indima ebalulekile njengomgqugquzeli wokukhula kwamaseli kumaseli e-glioma e-U87 ngokunciphisa ufuzo lwe-antitumor.
Kulinganiselwa ukuthi zingaphezu kwezigidi eziyi-18.1 izehlakalo zomdlavuza othuthukisiwe emhlabeni wonke ngo-2018, kanti cishe zingu-297,000 izimila zesistimu yezinzwa ezitholakala minyaka yonke (1.6% yazo zonke izimila)1.Ucwaningo lwangaphambilini lubonise ukuthi izici eziyingozi zokuthuthukisa izimila zobuchopho bomuntu zihlanganisa imikhiqizo ehlukene yamakhemikhali, umlando womndeni, kanye nemisebe ye-ionizing evela emishini yokwelapha ekhanda kanye nokuxilonga.Nokho, imbangela yangempela yalezi zinkinga ayaziwa.Cishe u-20% wawo wonke umdlavuza emhlabeni wonke ubangelwa amagciwane, amagciwane, amagciwane kanye nezimuncagazi3,4.Amagciwane athathelwanayo aphazamisa izinqubo zofuzo zeseli eliphethe, njengokulungisa i-DNA kanye nomjikelezo wamaseli, futhi kungaholela ekuvuvukeni okungapheli kanye nokulimala kwamasosha omzimba5.
Izifo ezithathelwanayo ezihambisana nomdlavuza womuntu zingamagciwane avame kakhulu egciwane, okuhlanganisa ama-human papillomavirus kanye namagciwane e-hepatitis B no-C.Izimuncagazi zingadlala indima engaba khona ekukhuleni komdlavuza womuntu.Izinhlobo eziningana ze-parasite, okuyi-Schistosoma, i-Opishorchis viverrini, i-O. felineus, i-Clonorchis sinensis kanye ne-Hymenolepis nana, ziye zathinteka ezinhlotsheni ezihlukahlukene zomdlavuza womuntu 6,7,8.
I-Toxoplasma gondii iyi-protozoan ye-intracellular elawula i-microenvironment yamangqamuzana aphethwe yigciwane.Lesi silwanyana silinganiselwa ukuthi singathelela cishe amaphesenti angama-30 abantu emhlabeni, okubeka sonke isibalo sabantu engozini9,10.I-Toxoplasma gondii ingathelela izitho ezibalulekile, okuhlanganisa nesimiso sezinzwa esimaphakathi (CNS), futhi ibangele izifo ezingathi sína ezifana ne-meningitis ebulalayo kanye ne-encephalitis, ikakhulukazi ezigulini ezingenawo amandla omzimba9.Kodwa-ke, i-Toxoplasma gondii ingaphinde iguqule indawo ezungezile yesiguli esinegciwane ngokushintsha ukukhula kwamangqamuzana kanye nezimpendulo zokuzivikela komzimba kubantu abangenawo amandla omzimba, okuholela ekugcinweni kokutheleleka okungapheli okungabonakali9,11.Kuyathakazelisa ukuthi uma kubhekwa ukuhlobana phakathi kokuvama kwe-T. gondii kanye nokwenzeka kwesimila ebuchosheni, eminye imibiko iphakamisa ukuthi ku-vivo ibamba izinguquko zemvelo ngenxa yokutheleleka okungapheli kwe-T. gondii kufana ne-tumor microenvironment.
Ama-Exosomes aziwa ngokuthi ama-intercellular communicators aletha okuqukethwe kwezinto eziphilayo, okuhlanganisa amaprotheni nama-nucleic acid, kusuka kumaseli angomakhelwane16,17.Ama-exosomes angathonya izinqubo zebhayoloji ezihlobene nesimila ezifana ne-anti-apoptosis, i-angiogenesis, kanye ne-metastasis ku-microenvironment yesimila.Ikakhulukazi, ama-miRNAs (miRNAs), ama-RNA amancane angafaki ikhodi cishe angama-nucleotide angama-22 ubude, abalulekile alawula izakhi zofuzo zangemva kokubhala ezilawula ngaphezu kuka-30% we-mRNA yomuntu ngokusebenzisa inkimbinkimbi yokuthulisa eyenziwe yi-miRNA (miRISC).I-Toxoplasma gondii ingaphazamisa izinqubo zebhayoloji ngokulawula isisho se-miRNA kubabungazi abathelelekile.Ama-miRNA asokhaya aqukethe amasiginali abalulekile okulawula izinqubo zebhayoloji yomsingathi ukuze kuzuzwe isu lokusinda le-parasite.Ngakho, ukutadisha izinguquko kuphrofayela yomsingathi we-miRNA ekuthelelekeni nge-T. gondii kungasisiza siqonde ukusebenzisana phakathi komsingathi kanye no-T. gondii ngokucacile.Ngempela, Thirugnanam et al.15 uphakamise ukuthi u-T. gondii uthuthukisa umdlavuza wobuchopho ngokushintsha indlela okhuluma ngayo kuma-miRNA athile ahlobene nokukhula kwesimila futhi wathola ukuthi i-T. gondii ingabangela ama-glioma ezilwaneni zokuhlola.
Lolu cwaningo lugxile ekuguqulweni kwe-exosomal miR-21 ku-host microglia etheleleke nge-Toxoplasma BV2.Sibone indima engaba khona ye-exosomal miR-21 eguquliwe ekukhuleni kwamaseli e-glioma e-U87 ngenxa yokugcinwa ku-nucleus ye-FoxO1/p27, okuyimpokophelo ye-miR-21 evezwe ngokweqile.
Ama-Exosomes atholakala ku-BV2 atholwe kusetshenziswa i-centrifugation ehlukile futhi aqinisekiswa ngezindlela ezihlukahlukene ukuvimbela ukungcola ngezingxenye zamaselula noma amanye ama-vesicle.I-SDS-polyacrylamide gel electrophoresis (SDS-PAGE) ibonise amaphethini ahlukene phakathi kwamaprotheni akhishwe kumaseli e-BV2 nama-exosomes (Umfanekiso 1A), futhi amasampula ahlolwe ukuba khona kwe-Alix, eyahlaziywa ngokucinywa kwaseNtshonalanga komaka amaprotheni e-exosomal ku-.Ukulebula kwe-Alix kutholwe kumaprotheni e-exosome kodwa hhayi ku-BV2 cell lysate proteins (Fig. 1B).Ngaphezu kwalokho, i-RNA ehlanzekile evela kuma-exosomes athathwe ku-BV2 yahlaziywa kusetshenziswa i-bioanalyzer.I-18S kanye ne-28S subunits ye-ribosomal yayingavamile ukubonwa kuphethini ye-exosomal RNA yokufuduka, ebonisa ukuhlanzeka okuthembekile (Umfanekiso 1C).Ekugcineni, i-electron microscopy yokudlulisela yabonisa ukuthi ama-exosomes abonwa ayengaba ngu-60-150 nm ngobukhulu futhi anesakhiwo esifana nenkomishi ejwayelekile ye-exosome morphology (Fig. 1D).
Ukubonakala kwama-exosomes atholakala kumaseli e-BV2.(A) Ikhasi leshidi ledatha yokuphepha.Amaprotheni ayehlukanisiwe kumaseli e-BV2 noma ama-exosomes athathwe ku-BV2.Amaphethini amaprotheni ayahluka phakathi kwamaseli nama-exosomes.(B) Ukuhlaziywa kwebala laseNtshonalanga lomaka we-exosomal (Alix).(C) Ukuhlolwa kwe-RNA ehlanzekile evela kumaseli e-BV2 kanye nama-exosome atholakala e-BV2 kusetshenziswa i-bioanalyzer.Ngakho-ke, ama-18S kanye ne-28S ama-ribosomal subunits kumaseli e-BV2 ayengavamile ukutholakala ku-exosomal RNA.(D) I-microscopy ye-electron yokudlulisela ibonise ukuthi ama-exosomes ahlukanisiwe kumaseli e-BV2 ayengcoliswe kabi nge-uranyl acetate engu-2%.Ama-Exosomes acishe abe ngu-60-150 nm ngobukhulu futhi amise okwenkomishi (Ingoma neJung, idatha engashicilelwe).
Ukufakwa ngaphakathi kweselula kwama-exosome asuselwa ku-BV2 kumaseli e-glioma e-U87 womuntu kwabonwa kusetshenziswa i-confocal microscopy.Ama-exosome anelebula e-PKH26 atholakala ku-cytoplasm yamaseli angu-U87.I-Nuclei yayingcoliswe nge-DAPI (Fig. 2A), ebonisa ukuthi ama-exosomes atholakala ku-BV2 angafakwa ngaphakathi ngamaseli abamba futhi athonye imvelo yamaseli abamukeli.
Ukufakwa ngaphakathi kwama-exosome asuselwa ku-BV2 kumaseli e-glioma e-U87 kanye nama-exosome asuselwa ku-BV2 atheleleke nge-Toxoplasma RH kwenze ukwanda kwamaseli e-glioma e-U87.(A) Ama-exosome ambozwe amaseli angu-U87 akalwa nge-confocal microscopy.Amaseli e-glioma e-U87 afakwe ama-exosome abhalwe ukuthi PKH26 (obomvu) noma ngaphandle kokulawula amahora angu-24.Ama-nuclei ayengcoliswe nge-DAPI (eluhlaza okwesibhakabhaka) bese ebhekwa ngaphansi kwe-confocal microscope (ibha yesikali: 10 μm, x 3000).(B) Ukwanda kweseli ye-glioma ye-U87 kwanqunywa ukuhlolwa kokwanda kwamaseli.Amaseli e-glioma e-U87 aphathwe ngama-exosomes ngesikhathi esibonisiwe. *P <0.05 itholwe ukuhlolwa koMfundi. *P <0.05 itholwe ukuhlolwa koMfundi. *P < 0,05 получено по t-критерию Стьюдента. *P <0.05 ngokuhlolwa kuka-t koMfundi. *P <0.05 通过学生t 检验获得. *P <0.05 * P < 0,05, полученный с помощью t-критерия Стьюдента. * U-P <0.05 utholwe kusetshenziswa i-t-test Yomfundi.
Ngemva kokuqinisekisa ukufakwa ngaphakathi kwama-exosome asuselwa ku-BV2 kumaseli e-glioma e-U87, senze ukuhlolwa kokwanda kwamaseli ukuze siphenye indima yama-exosome asuselwa ku-BV2 asuselwa ku-Toxoplasma ekuthuthukisweni kwamaseli e-glioma yomuntu.Ukwelashwa kwamaseli e-U87 anama-exosomes avela ku-T. gondii-infected BV2 cells kubonise ukuthi i-T. gondii-infected BV2-derived exosomes ibangele ukwanda okukhulu kwamaseli e-U87 uma kuqhathaniswa nokulawula (Fig. 2B).
Ukwengeza, ukukhula kwamaseli e-U118 kube nemiphumela efanayo ne-U87, njengoba i-Toxoplasma ivuselela ama-exosomes yabangela amazinga aphezulu okusabalala (idatha engaboniswa).Ngokusekelwe kule datha, singabonisa ukuthi ama-exosomes asuselwe ku-BV2 atholakala ku-Toxoplasma adlala indima ebalulekile ekwandeni kwamaseli e-glioma.
Ukuphenya umthelela wama-exosome asuselwa ku-BV2 athathelwe yi-Toxoplasma ekuthuthukisweni kwesimila, sifake amaseli e-glioma e-U87 kumagundane anqunu emodeli ye-xenograft futhi sajova ama-exosome asuselwa ku-BV2 noma ama-exosome asuselwa ku-RH asuselwe ku-BV2.Ngemva kokuba izimila zibonakale ngemva kwesonto le-1, iqembu ngalinye lokuhlola lamagundane angu-5 lahlukaniswa ngokosayizi wesimila ukuze kutholwe indawo yokuqala efanayo, futhi usayizi wesimila walinganiswa izinsuku ezingu-22.
Kumagundane anemodeli ye-U87 ye-xenograft, usayizi we-tumor okhudlwana kakhulu nesisindo kwabonwa ku-BV2-derived RH-infected exosome group ngosuku lwe-22 (Fig. 3A, B).Ngakolunye uhlangothi, kwakungekho mehluko obalulekile kusayizi wesimila phakathi kweqembu le-exosome elisuselwa ku-BV2 kanye neqembu lokulawula ngemuva kokwelashwa kwe-exosome.Ngaphezu kwalokho, amagundane ajovwe ngamaseli e-glioma kanye nama-exosomes abonisa ngokubonakalayo umthamo omkhulu wesimila eqenjini lama-exosome asuselwa ku-RH asuselwe ku-BV2 (Fig. 3C).Le miphumela ibonisa ukuthi ama-exosomes asuselwe ku-BV2 asuselwa ku-Toxoplasma adala ukukhula kwe-glioma kumodeli yesimila segundane.
I-Oncogenesis (AC) yama-exosome asuselwa ku-BV2 kumodeli yegundane ye-xenograft ye-U87.Usayizi wesimila (A) nesisindo (B) kwandiswe kakhulu kumagundane anqunu e-BALB/c aphathwe ngama-exosome anegciwane le-RH asuselwa ku-BV2.I-BALB/c amagundane anqunu (C) ajovwe ngaphansi kwesikhumba namaseli angu-1 x 107 U87 amisiwe kungxube ye-Matrigel.Ezinsukwini eziyisithupha ngemuva komjovo, i-100 μg yama-exosome asuselwa ku-BV2 alashwa kumagundane.Ubukhulu besimila nesisindo kukalwa ngezinsuku ezikhonjisiwe nangemva komhlatshelo, ngokulandelana. *P <0.05. *P <0.05. *Р <0,05. *P <0.05. *P <0.05. *P <0.05. *Р <0,05. *P <0.05.
Idatha ibonise ukuthi i-37 miRNAs (i-16 overexpressed kanye ne-21 downexpressed) ehlotshaniswa nokuzivikela komzimba noma ukuthuthukiswa kwesimila kwashintshwa kakhulu ku-microglia ngemva kokutheleleka nge-Toxoplasma RH strain (Fig. 4A).Amazinga wokukhuluma ahlobene we-miR-21 phakathi kwama-miRNA ashintshiwe aqinisekiswa i-RT-PCR yesikhathi sangempela kuma-exosomes athathwe ku-BV2, ama-exosomes aphathwa nge-BV2 kanye namaseli e-U87.Ukuvezwa kwe-miR-21 kubonise ukwanda okukhulu kwama-exosomes avela kumaseli e-BV2 atheleleke nge-Toxoplasma gondii (RH strain) (Fig. 4B).Amazinga wokukhuluma ahlobene we-miR-21 kumaseli e-BV2 nama-U87 anda ngemva kokuthathwa kwama-exosomes aguquliwe (Fig. 4B).Amazinga ahlobene wenkulumo ye-miR-21 ezicutshini zobuchopho zeziguli zesimila kanye namagundane atheleleke nge-Toxoplasma gondii (uhlobo lwe-ME49) ayephakeme kunokulawula, ngokulandelana (Fig. 4C).Le miphumela ihlotshaniswa nomehluko phakathi kwamazinga wokuvezwa kwama-microRNA abikezelwe naqinisekisiwe ku-vitro kanye ne-vivo.
Izinguquko ekuvezweni kwe-exosomal miP-21a-5p ku-microglia etheleleke nge-Toxoplasma gondii (RH).(A) Ibonisa izinguquko eziphawulekayo ku-siRNA ezihambisana nokuvikeleka noma ukukhula kwesimila kulandela ukutheleleka kwe-T. gondii RH.(B) Amazinga we-miR-21 ahlobene atholwe yi-RT-PCR yesikhathi sangempela kuma-exosome asuselwa ku-BV2, ama-exosome aphethwe i-BV2, namaseli e-U87.(C) Amazinga we-miR-21 ahlobene atholwe ezicutshini zobuchopho zeziguli zesimila (N=3) namagundane atheleleke nge-Toxoplasma gondii (uhlobo lwe-ME49) (N=3). *P <0.05 itholwe ukuhlolwa koMfundi. *P <0.05 itholwe ukuhlolwa koMfundi. *P < 0,05 было получено с помощью t-критерия Стьюдента. *P <0.05 itholwe kusetshenziswa i-t-test Yomfundi. *P <0.05 通过学生t 检验获得. *P <0.05 * P <0,05, полученный с помощью t-критерия Стьюдента. * U-P <0.05 utholwe kusetshenziswa i-t-test Yomfundi.
Ama-exosomes avela kumaseli e-BV2 angenwe yi-RH aholele ekukhuleni kwama-gliomas ku-vivo kanye ne-in vitro (Fig. 2, 3).Ukuze sithole ama-mRNA afanelekile, sihlole amazinga e-mRNA ezakhi zofuzo eziqondiswe e-antitumor, ibhokisi lemfologo O1 (FoxO1), PTEN, kanye ne-programmed cell death 4 (PDCD4) kumaseli e-U87 angenwe ama-exosomes atholakala ku-BV2 noma ku-RH BV2.Ukuhlaziywa kwe-Bioinformatics kubonise ukuthi izakhi zofuzo ezimbalwa ezihlotshaniswa nesimila, okuhlanganisa uhlobo lwe-FoxO1, PTEN, kanye ne-PDCD4, zinezindawo ezibophayo ze-miR-2121,22.Amazinga we-mRNA wezakhi zofuzo ezihlosiwe ze-antitumor ancishisiwe kuma-exosomes atholakala ku-RH atholakala ku-BV2 uma kuqhathaniswa nama-exosomes atholakala e-BV2 (Fig. 5A).I-FoxO1 ibonise amazinga amaprotheni ancishisiwe kuma-exosomes atholakala ku-RH atholakala ku-BV2 uma kuqhathaniswa nama-exosomes atholakala e-BV2 (Umfanekiso 5B).Ngokusekelwe kule miphumela, singaqinisekisa ukuthi ama-exosomes atholakala ku-RH-infected BV2 ehlisa izakhi zofuzo ezilwa ne-oncogenic, agcine indima yawo ekukhuleni kwesimila.
Ama-exosomes asuselwa ku-BV2 ane-toxoplasma ethelelekile e-RH enza ukucindezelwa kwezakhi zofuzo ze-antitumor kumaseli e-glioma e-U87 ngama-exosomes asuselwa ku-BV2 angenwe yi-Toxoplasma RH.(A) I-PCR yesikhathi sangempela ye-FoxO1, PTEN kanye ne-PDCD4 expression in exosomes esuselwe ku-T. gondii RH-infected BV2 uma kuqhathaniswa nama-PBS exosomes.I-β-actin mRNA isetshenziswe njengokulawula.(B) Isisho se-FoxO1 sanqunywa ukucishwa kwaseNtshonalanga kanye nedatha ye-densitometry yahlolwa ngokwezibalo kusetshenziswa uhlelo lwe-ImageJ. *P <0.05 itholwe ukuhlolwa koMfundi. *P <0.05 itholwe ukuhlolwa koMfundi. *P < 0,05 было получено с помощью t-критерия Стьюдента. *P <0.05 itholwe kusetshenziswa i-t-test Yomfundi. *P <0.05 通过学生t 检验获得. *P <0.05 * P <0,05, полученный с помощью t-критерия Стьюдента. * U-P <0.05 utholwe kusetshenziswa i-t-test Yomfundi.
Ukuze uqonde umphumela we-miP-21 kuma-exosomes ekulawuleni izakhi zofuzo ezihambisana nesimila, amaseli e-U87 adluliselwa nge-inhibitor ye-miP-21 kusetshenziswa i-Lipofectamine 2000 futhi amaseli avunwa amahora angu-24 ngemva kokudluliselwa.I-FoxO1 kanye namazinga we-p27 wenkulumo kumaseli adluliselwe nge-miR-21 inhibitors aqhathaniswe namaseli aphathwe ngama-exosome asuselwa ku-BV2 kusetshenziswa i-qRT-PCR (Fig. 6A,B).Ukudluliswa kwe-miR-21 inhibitor kumaseli e-U87 kwehlisa ngokuphawulekayo i-FoxO1 nenkulumo ye-p27 (FIG. 6).
I-exosomal BV2-derived miP-21 ethathwe yi-RH eguqule isisho se-FoxO1/p27 kumaseli e-glioma e-U87.Amaseli e-U87 adluliselwa nge-miP-21 inhibitor esebenzisa i-Lipofectamine 2000 futhi amaseli avunwa amahora angu-24 ngemva kokudluliselwa.I-FoxO1 kanye namazinga we-p27 wenkulumo kumaseli adluliselwe nge-miR-21 inhibitors aqhathaniswe namazinga kumaseli aphathwa ngama-exosome asuselwa ku-BV2 kusetshenziswa i-qRT-PCR (A, B).
Ukuze ubalekele ukusabela kwamasosha omzimba, i-Toxoplasma parasite ishintsha ibe i-cyst yezicubu.Baqeda izicubu ezihlukahlukene, okuhlanganisa ubuchopho, inhliziyo, nemisipha yohlaka lwamathambo, kukho konke ukuphila komsingathi futhi balungise ukusabela kokuzivikela komzimba komsingathi.Ngaphezu kwalokho, bangakwazi ukulawula umjikelezo weseli kanye ne-apoptosis yamaseli abamba, okukhuthaza ukwanda kwawo14,24.I-Toxoplasma gondii ihlasela kakhulu amaseli e-dendritic, ama-neutrophils, kanye nohlu lozalo lwe-monocyte/macrophage, okuhlanganisa ne-microglia yobuchopho.I-Toxoplasma gondii idala ukuhlukaniswa kwama-macrophages we-phenotype ye-M2, ithinta ukuphulukiswa kwesilonda ngemva kokutheleleka kwe-pathogen, futhi ihlotshaniswa ne-hypervascularization kanye ne-granulomatous fibrosis.Le pathogenesis yokuziphatha yokutheleleka kwe-Toxoplasma ingase ihlotshaniswe nezimpawu ezihlobene nokuthuthukiswa kwesimila.Imvelo enobutha elawulwa yi-Toxoplasma ingase ifane ne-precancer ehambisanayo.Ngakho-ke, kungacatshangwa ukuthi ukutheleleka kwe-Toxoplasma kufanele kube nomthelela ekuthuthukiseni izimila zobuchopho.Eqinisweni, amazinga aphezulu okutheleleka kwe-Toxoplasma kuye kwabikwa ku-serum yeziguli ezinezimila ezihlukahlukene zobuchopho.Ngaphezu kwalokho, i-Toxoplasma gondii ingase ibe omunye umphumela we-carcinogenic futhi isebenze ngokubambisana ukuze isize amanye ama-carcinogens athathelwanayo athuthukise izimila zobuchopho.Mayelana nalokhu, kufanele kuqashelwe ukuthi igciwane le-P. falciparum ne-Epstein-Barr lifaka isandla ekwakhekeni kwe-Burkitt's lymphoma.
Iqhaza lama-exosomes njengabalawuli emkhakheni wocwaningo lomdlavuza seliphenywe kabanzi.Kodwa-ke, indima yama-exosomes phakathi kwama-parasites kanye ne-host hosts ayikaqondwa kahle.Kuze kube manje, abalawuli abahlukahlukene, okuhlanganisa amaprotheni afihliwe, baye bachaza izinqubo zebhayoloji lapho ama-protozoan parasites amelana nokuhlasela kwebutho futhi aqhubekisele phambili ukutheleleka.Muva nje, kube nomqondo okhulayo wokuthi ama-microvesicles ahlobene ne-protozoan kanye nama-microRNAs awo asebenzisana namaseli abamba ukuze adale indawo ekahle yokuphila kwawo.Ngakho-ke, ucwaningo olwengeziwe luyadingeka ukuze kutholwe ubudlelwano phakathi kwe-exosomal miRNAs eshintshiwe kanye nokwanda kwamaseli e-glioma.Ukuguqulwa kwe-MicroRNA (izakhi zofuzo ze-cluster miR-30c-1, miR-125b-2, miR-23b-27b-24-1 kanye ne-miR-17-92) zibophezela kumgqugquzeli we-STAT3 kuma-macrophages abantu abane-toxoplasma, kuyalawulwa futhi kubangele ukulwa -i-apoptosis ekuphenduleni ukutheleleka kwe-Toxoplasma gondii 29.Ukutheleleka kwe-Toxoplasma kwandisa ukubonakaliswa kwe-miR-17-5p ne-miR-106b-5p, ehlotshaniswa nezifo eziningana ze-hyperproliferative 30.Le datha iphakamisa ukuthi ama-miRNA asokhaya alawulwa ukutheleleka kwe-Toxoplasma angama-molecule abalulekile okusinda kwe-parasite kanye ne-pathogenesis ekuziphatheni kwe-biological host.
Ama-miRNA ashintshile angaba nomthelela ezinhlotsheni ezahlukahlukene zokuziphatha ngesikhathi sokuqala nokuqhubekela phambili kwamangqamuzana ayingozi, okuhlanganisa ama-gliomas: ukuzenelisa amasignali okukhula, ukungazweli kumasiginali okuvimbela ukukhula, ukubalekela i-apoptosis, amandla okuphindaphinda angenamkhawulo, i-angiogenesis, ukuhlasela kanye ne-metastasis, nokuvuvukala.Ku-glioma, ama-miRNA ashintshiwe akhonjwe ezifundweni ezimbalwa zokuchaza iphrofayili.
Ocwaningweni lwamanje, siqinisekise amazinga aphezulu wenkulumo ye-miRNA-21 kumaseli aphethe atheleleke nge-toxoplasma.I-miR-21 ikhonjwe njengenye yama-microRNA avame ukuvezwa ngokweqile kumathumba aqinile, okuhlanganisa ama-gliomas, ama-33 kanye nokusho kwawo kuhlobana nebanga le-glioma.Ubufakazi obunqwabelanayo buphakamisa ukuthi i-miR-21 iyinoveli ye-oncogene esebenza njenge-anti-apoptotic factor ekukhuleni kwe-glioma futhi igcizelelwe kakhulu ezicutshini naku-plasma yobuchopho bomuntu.Kuyathakazelisa ukuthi ukungasebenzi kwe-miR-21 kumaseli e-glioma nezicubu kubangela ukuvinjelwa kokwanda kwamaseli ngenxa ye-apoptosis encike ku-caspase.Ukuhlaziywa kwe-Bioinformatic kokuhlosiwe okubikezelwe kwe-miR-21 kwembule izakhi zofuzo eziningi zokucindezela isimila ezihambisana nezindlela ze-apoptosis, okuhlanganisa ukufa kweseli ehleliwe 4 (PDCD4), i-tropomyosin (TPM1), PTEN, kanye nebhokisi lemfologo O1 (FoxO1), elinendawo ebophayo ye-miR-2121..22.38.
I-FoxO1, njengenye yezinto ezibhalwe phansi (FoxO), ibandakanyeka ekwakhiweni kwezinhlobo ezahlukene zomdlavuza womuntu futhi ingalawula ukuvezwa kwezakhi zofuzo zokucindezela isimila ezifana ne-p21, p27, Bim, ne-FasL40.I-FoxO1 ingabopha futhi yenze kusebenze ama-cell cycle inhibitors njenge-p27 ukucindezela ukukhula kwamaseli.Ngaphezu kwalokho, i-FoxO1 ingumthelela oyinhloko wokusayinda i-PI3K/Akt futhi ilawula izinqubo eziningi zebhayoloji njengokuqhubeka komjikelezo weseli nokuhlukaniswa kwamaseli ngokwenza kusebenze ukuloba kwe-p2742.
Ekuphetheni, sikholelwa ukuthi i-exosomal miR-21 etholakala ku-Toxoplasma-infected microglia ingase idlale indima ebalulekile njengokulawula ukukhula kwamaseli e-glioma (Fig. 7).Kodwa-ke, ucwaningo olwengeziwe luyadingeka ukuze kutholwe ukuxhumana okuqondile phakathi kwe-exosomal miR-21, ukutheleleka kwe-Toxoplasma okushintshiwe, nokukhula kwe-glioma.Le miphumela kulindeleke ukuthi inikeze isiqalo sokutadisha ubudlelwane phakathi kokutheleleka kwe-Toxoplasma kanye nesigameko se-glioma.
Kuhlongozwa umdwebo wohlelo lwe-glioma (ubuchopho) carcinogenesis kulolu cwaningo.Umbhali udweba ku-PowerPoint 2019 (Microsoft, Redmond, WA).
Zonke izimiso zokuhlola zokuhlola kulolu cwaningo, okuhlanganisa nokusetshenziswa kwezilwane, bezihambisana ne-Seoul National University Animal Care kanye Neziqondiso Ezijwayelekile Zekomidi Labasebenzisi futhi zagunyazwa Ibhodi Lokubuyekeza Lesikhungo Se-Seoul National University School of Medicine (inombolo ye-IRB SNU- 150715).-2).Zonke izinqubo zokuhlola zenziwe ngokuhambisana nezincomo ze-ARRIVE.
I-BV2 mouse microglia kanye ne-U87 human glioma cell akhuliswe ku-Dulbecco's Modified Eagle's Medium (DMEM; Welgene, Seoul, Korea) kanye ne-Roswell Park Memorial Institute's Medium (RPMI; Welgene), ngokulandelana, ngalinye liqukethe u-10% we-fetus serum, 4 mM l- glutamine, 0.2 mM penicillin kanye 0.05 mM streptomycin.Amaseli akhuliswe ku-incubator ene-5% CO2 ku-37°C.Omunye umugqa wamaseli we-glioma, i-U118, wasetshenziselwa ukuqhathanisa namaseli e-U87.
Ukuze kuhlukaniswe ama-exosomes kusukela ku-T. gondii-infected RH kanye nezinhlobo ze-ME49, i-T. gondii tachyzoites (uhlobo lwe-RH) yavunwa emgodini wesisu wamagundane anamasonto angu-6 e-BALB/c ajovwe ezinsukwini ezingu-3-4 ngaphambili.Ama-Tachyzoite ahlanjululwe kathathu nge-PBS futhi ahlanzwa nge-centrifugation ku-40% Percoll (Sigma-Aldrich, St. Louis, MO, USA)43.Ukuze uthole ama-tachyzoites ohlobo lwe-ME49, amagundane e-BALB/c ajovwe nge-intraperitoneally nama-cysts ezicubu ze-20 kanye nokuguqulwa kwe-tachyzoite kuma-cysts kwaqoqwa ngokugeza i-cavity yesisu ngosuku lwe-6-8th ngemva kokutheleleka (PI).Amagundane angenwe yi-PBS.I-ME49 tachyzoites yakhuliswa kumaseli engezwe nge-penicillin engu-100 μg/ml (Gibco/BRL, Grand Island, NY, USA), 100 μg/ml streptomycin (Gibco/BRL), kanye ne-5% ye-fetus serum (Lonza, Walkersville, MD) .., USA) ku-37 °C no-5% we-carbon dioxide.Ngemva kokutshalwa kumaseli e-Vero, ama-tachyzoites e-ME49 adluliswa kabili ngenaliti yegeji engu-25 kwase kuba ngesihlungi esingu-5 µm ukuze kukhishwe udoti namaseli.Ngemva kokugeza, ama-tachyzoite aphinde amiswa ku-PBS44.Ama-tissue cysts of Toxoplasma gondii strain ME49 ayenakekelwa ngomjovo we-intraperitoneal wama-cysts ahlukanisiwe nobuchopho bamagundane angenwe yi-C57BL/6 (i-Orient Bio Animal Center, i-Seongnam, Korea).Ubuchopho bamagundane anegciwane le-ME49 buvunwe ngemva kwezinyanga ezi-3 ze-PI futhi bagaywa ngaphansi kwesibonakhulu ukuze kuhlukaniswe ama-cysts.Amagundane anegciwane agcinwa ngaphansi kwezimo ezikhethekile ezingenayo i-pathogen (SPF) eSeoul National University School of Medicine.
Isamba se-RNA sikhishwe kuma-exosome asuselwa ku-BV2, amaseli e-BV2 namathishu kusetshenziswa i-miRNeasy Mini Kit (Qiagen, Hilden, Germany) ngokwemiyalo yomkhiqizi, okuhlanganisa nesikhathi sokufukamela sesinyathelo se-lution.Ukugxiliswa kwe-RNA kwanqunywa ku-spectrophotometer ye-NanoDrop 2000.Izinga le-RNA microarrays lihlolwe kusetshenziswa i-Agilent 2100 bioanalyzer (Agilent Technologies, Amstelveen, Netherlands).
I-DMEM ene-10% exosome-poor FBS yalungiswa nge-ultracentrifugation ku-100,000g amahora angu-16 ku-4°C futhi yahlungwa ngesihlungi esingu-0.22 µm (Nalgene, Rochester, NY, USA).Amaseli e-BV2, i-5 × 105, akhuliswe ku-DMEM equkethe i-10% ye-FBS ekhishwe i-exosome kanye nama-antibiotic angu-1% ku-37°C naku-5% CO2.Ngemva kwamahora angu-24 okufukamela, ama-tachyzoite ohlobo lwe-RH noma i-ME49 (MOI = 10) afakwa kumaseli futhi izimuncagazi ezingahlaseli zakhishwa phakathi nehora futhi zagcwaliswa kabusha nge-DMEM.Ama-Exosomes asuka kumaseli e-BV2 ahlukaniswa nge-modified differential centrifugation, indlela esetshenziswa kakhulu.Misa kabusha i-exosome pellet ku-300 µl PBS ye-RNA noma ukuhlaziya amaprotheni.Ukugxiliswa kwama-exosome ahlukanisiwe kwanqunywa kusetshenziswa ikhithi yokuhlola amaprotheni e-BCA (Pierce, Rockford, IL, USA) kanye ne-NanoDrop 2000 spectrophotometer.
Imvula esuka kumaseli e-BV2 noma ama-exosome athathwe ku-BV2 afakwe kusixazululo se-PRO-PREP™ sokukhipha amaprotheni (iNtRon Biotechnology, Seongnam, Korea) futhi amaprotheni alayishwa kumajeli e-Coomassie aluhlaza okwesibhakabhaka anemibala engu-10% ye-SDS polyacrylamide.Ngaphezu kwalokho, amaprotheni adluliselwa kulwelwesi lwe-PVDF amahora ama-2.Amachashazi aseNtshonalanga aqinisekiswa kusetshenziswa i-Alix antibody (Cell Signaling Technology, Beverly, MA, USA) njengomaka exosomal.I-HRP-conjugated goat anti-mouse IgG (H + L) (Bethyl Laboratories, Montgomery, TX, USA) kanye ne-LAS-1000 plus luminescent image analyzer (Fuji Photographic Film, Tokyo, Japan) zisetshenziswe njenge-antibody yesibili..I-Transmission electron microscopy yenziwa ukuze kufundwe usayizi nokuma kwe-exosomes.Ama-exosomes ahlukanisiwe kumaseli e-BV2 (6.40 µg/µl) alungiswa kumameshi ambozwe ngekhabhoni futhi angcoliswa kabi nge-uranyl acetate engu-2% iminithi elingu-1.Amasampula alungisiwe abonwe kumandla kagesi asheshisayo angu-80 kV kusetshenziswa i-JEOL 1200-EX II (Tokyo, Japan) efakwe ikhamera ye-ES1000W Erlangshen CCD (Gatan, Pleasanton, CA, USA).
Ama-exosome asuselwa ku-BV2 aye angcoliswa kusetshenziswa i-PKH26 Red Fluorescent Linker Kit (Sigma-Aldrich, St. Louis, MO, USA) imizuzu engu-15 ekamelweni lokushisa.Amaseli e-U87, 2×105, anama-exosome anelebuli ye-PKH26 (abomvu) noma awekho ama-exosomes njengokulawula okungekuhle, afakwa ku-37°C amahora angu-24 ku-5% CO2 incubator.I-U87 cell nuclei yayine-DAPI (eluhlaza okwesibhakabhaka), amaseli e-U87 afakwe ku-4% paraformaldehyde imizuzu engu-15 ku-4 ° C bese ahlaziywa ohlelweni lwe-Leica TCS SP8 STED CW confocal microscope (Leica Microsystems, Mannheim, Germany).ebonakalayo.
I-cDNA yahlanganiswa kusuka ku-siRNA kusetshenziswa i-Mir-X siRNA yokuqala ye-strand synthesis kanye nekhithi ye-SYBR qRT-PCR (Takara Bio Inc., Shiga, Japan).I-PCR yobuningi besikhathi sangempela yenziwa kusetshenziswa isistimu yokuthola i-PCR ye-iQ5 yesikhathi sangempela (Bio-Rad, Hercules, CA, USA) kusetshenziswa iziqalo nezifanekiso ezixutshwe ne-SYBR Premix.I-DNA ikhuliselwe imijikelezo engama-40 yokushintshashintsha kwe-denaturation ku-95°C ngamasekhondi ayi-15 kanye nokudonsa ku-60°C ngamasekhondi angama-60.Idatha evela ekuphenduleni ngakunye kwe-PCR yahlaziywa kusetshenziswa imojula yokuhlaziya idatha yesofthiwe ye-iQ™5 optical system (Bio-Rad).Izinguquko ezihlobene ekubonakalisweni kofuzo phakathi kwezakhi zofuzo ezikhethiwe kanye ne-β-actin/siRNA (kanye ne-U6) zibalwe kusetshenziswa indlela yejika evamile.Ukulandelana kokuqala okusetshenzisiwe kukhonjisiwe kuThebula 1.
Amaseli e-glioma angu-3 x 104 U87 afakwe ezitsheni zemithombo engu-96 futhi axutshwa nama-exosome anegciwane le-Toxoplasma atholakala ku-BV2 (50 μg/mL) noma ama-nonpulse exosomes atholakala ku-BV2 (50 μg/mL) njengezilawuli ku-12, amahora angu-18 no-36. .Izinga lokusabalala kwamaseli lanqunywa kusetshenziswa i-Cell Counting Kit-8 (Dojindo, Kumamoto, Japan) (Izibalo Ezingeziwe S1-S3) 46.
Amagundane esifazane anamaviki angu-5 ubudala e-BALB/c athengwe ku-Orient Bio (Seongnam-si, South Korea) futhi agcinwa ngamanye kumakheji angenalutho ekamelweni lokushisa (22±2°C) kanye nomswakama (45±15°C).%) ekamelweni lokushisa (22±2°C) kanye nomswakama (45±15%).Umjikelezo wokukhanya wamahora angu-12 kanye nomjikelezo omnyama wamahora angu-12 wenziwa ngaphansi kwe-SPF (Seoul National University School of Medicine Animal Center).Amagundane ahlukaniswa ngokungahleliwe aba amaqembu amathathu amagundane angu-5 ngalinye futhi wonke amaqembu ajovwe ngaphansi kwesikhumba nge-400 ml ye-PBS equkethe amaseli e-glioma angu-1 x 107 U87 kanye nesici sokukhula sinciphise i-BD Matrigel™ (BD Science, Miami, FL, USA).Ezinsukwini eziyisithupha ngemva kokujova isimila, u-200 mg wama-exosomes athathwe kumaseli e-BV2 (ane/ngaphandle kokutheleleka kwe-Toxoplasma) ajovwa endaweni yesimila.Ezinsukwini ezingamashumi amabili nambili ngemva kokutheleleka kwesimila, usayizi wesimila wamagundane eqenjini ngalinye walinganiswa nge-caliper kathathu ngesonto, futhi umthamo we-tumor ubalwa ngefomula: 0.5 × (ububanzi) × 2 × ubude.
Ukuhlaziywa kwenkulumo ye-MicroRNA kusetshenziswa i-miRCURYTM LNA miRNA array, isizukulwane sesi-7 sine, i-mmu kanye ne-rno arrays (EXIQON, Vedbaek, Denmark) emboza amagundane anezimpawu ezinhle ezingu-1119 phakathi kwama-3100 abantu, igundane kanye ne-rat miRNA probes.Phakathi nale nqubo, u-250 kuya ku-1000 ng wesamba se-RNA sakhishwa ku-5'-phosphate ngokwelashwa ngenkonyane i-alkaline phosphatase yamathumbu okulandelwa ukulebula ngodayi we-Hy3 oluhlaza okotshani we-fluorescent.Amasampula anelebuli abe esehlanganiswa ngokulayisha amaslayidi amancane kusetshenziswa ikhithi yegumbi lokuhlanganisa (Agilent Technologies, Santa Clara, CA, USA) kanye nekhithi yesilayidi yokuhlanganisa (Agilent Technologies).I-Hybridization yenziwa amahora angu-16 ku-56 ° C, khona-ke ama-microarrays ahlanzwa ngokuhambisana nezincomo zomkhiqizi.Amaslayidi e-microarray acutshunguliwe abe eseskenwa kusetshenziswa i-Agilent G2565CA microarray scanner system (Agilent Technologies).Izithombe eziskeniwe zingeniswe kusetshenziswa isoftware ye-Agilent Feature Extraction engu-10.7.3.1 (Agilent Technologies) futhi ubukhulu be-fluorescence besithombe ngasinye bulinganiswa kusetshenziswa ifayela elihambisanayo le-GAL lephrothokholi ye-Exiqon elungisiwe.Idatha ye-Microarray yocwaningo lwamanje ifakwe kusizindalwazi se-GEO ngaphansi kwenombolo yokungena ethi GPL32397.
Amaphrofayili okuveza ama-exosomal miRNA avuthiwe ku-microglia ye-RH noma i-ME49 strains etheleleke nge-Toxoplasma ahlaziywa kusetshenziswa amathuluzi enethiwekhi ahlukahlukene.Ama-miRNA ahlotshaniswa nokuthuthukiswa kwesimila ahlonzwe kusetshenziswa i-miRWalk2.0 (http://mirwalk.umm.uni-heidelberg.de) futhi ahlungwa ngokuqina kwesignali evamile (log2) okukhulu kuno-8.0.Phakathi kwama-miRNA, ama-miRNA avezwa ngokuhlukile atholwe engaphezu kuka-1.5 ashintshwe ngokuhlaziywa kwesihlungi sama-miRNA ashintshwe yi-RH noma i-ME49 strains etheleleke nge-T. gondii.
Amaseli afakwe ezitsheni zemithombo eyisithupha (3 x 105 amaseli/umthombo) ku-opti-MEM (Gibco, Carlsbad, CA, USA) kusetshenziswa i-Lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA).Amaseli athathelwanayo akhuliswa amahora angu-6 futhi okuphakathi kwashintshwa kwaba into entsha ephelele.Amaseli avunwa emahoreni angama-24 ngemuva kokudluliselwa.
Ukuhlaziywa kwezibalo kwenziwa ikakhulukazi kusetshenziswa i-t-test yoMfundi ngesoftware ye-Excel (Microsoft, Washington, DC, USA).Ukuhlaziya izilwane zokuhlola, i-ANOVA yezindlela ezimbili yenziwe kusetshenziswa isofthiwe ye-Prism 3.0 (I-GraphPad Software, La Jolla, CA, USA). Amanani we-P <0.05 athathwe njengabalulekile ngokwezibalo. Amanani we-P <0.05 athathwe njengabalulekile ngokwezibalo. Значения P <0,05 считались статистически значимыми. Amanani we-P <0.05 athathwe njengebalulekile ngokwezibalo. P 值< 0.05 被认为具有统计学意义。 P <0.05 Значения P <0,05 считались статистически значимыми. Amanani we-P <0.05 athathwe njengebalulekile ngokwezibalo.
Zonke izivumelwano zokuhlola ezisetshenziswe kulolu cwaningo zigunyazwe Ibhodi Lokubuyekeza Isikhungo se-Seoul National University School of Medicine (inombolo ye-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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