摘 要: 寄生蟲病流行范圍廣泛,嚴重威脅人類健康并影響畜牧業(yè)發(fā)展。miRNAs是一類長度約19~24 nt的高度保守的內(nèi)源性非編碼單鏈小分子RNAs,寄生蟲會表達大量的miRNAs介導(dǎo)其感染宿主,同時宿主miRNAs的表達譜也會發(fā)生改變,這些miRNAs將影響宿主的抗性或易感性,miRNAs已成為研究寄生蟲和宿主互作機制的熱點方向之一。本文綜述了不同種類寄生蟲表達的miRNAs在其感染宿主中的作用及宿主miRNAs對寄生蟲的調(diào)控,旨在為研發(fā)基于miRNAs的抗寄生蟲感染的治療措施提供參考。
關(guān)鍵詞: miRNAs;寄生蟲;感染機制;免疫應(yīng)答
中圖分類號:S852.7
文獻標(biāo)志碼:A
文章編號: 0366-6964(2024)09-3812-12
Research Advances in the Mechanism of Parasite-host Interaction Mediated by miRNAs
GAO" Yuxin" LIU" Qing2, CHEN" Jilan1, MA" Hui1*
(1.State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science,
Chinese Academy of Agricultural Sciences, Beijing 100193," China;
2.College of Animal Science, Shanxi Agricultural University, Taigu 030801," China)
Abstract:" Parasitic diseases are widespread and pose a serious threat to human health and animal husbandry. miRNAs are a class of highly conserved endogenous non-coding single-stranded small molecule RNAs with a length of approximately 19-24 nt. Parasite will express a large number of miRNAs to mediate its infection to the host, and the expression profiles of the host miRNAs will also change. These miRNAs will affect the host’s resistance or susceptibility, and miRNAs have become one of the hot areas to study the interaction mechanism between parasites and host. This article reviews the role of miRNAs expressed by different species of parasites in infecting the host and the regulatory effect of host miRNAs on parasites, aiming to provide therapeutic methods of anti-parasitic infection based on miRNAs.
Key words: miRNAs; parasites; infection mechanism; immune response
*Corresponding author:" MA Hui, E-mail: caumah@163.com
miRNAs是機體內(nèi)源性表達的長度為19~24個核苷酸的小分子非編碼RNA,其可與特定的mRNA結(jié)合并發(fā)揮作用,調(diào)節(jié)寄生蟲生長發(fā)育過程中基因轉(zhuǎn)錄后的表達[1]。1993年,Lee等[2]在秀麗隱桿線蟲中首次鑒定到miRNA即lin-4。Pasquinelli等[3]發(fā)現(xiàn)在秀麗隱桿線蟲和高等生物中存在高度保守的miRNA即let-7,說明miRNAs在物種中廣泛存在。隨著在植物、動物和微生物中鑒定出更多的miRNAs,且這些miRNAs是mRNA和蛋白質(zhì)的關(guān)鍵負調(diào)控因子,表明miRNAs在基因表達調(diào)控方面發(fā)揮著復(fù)雜的生物學(xué)功能[4-6]。因此,本文主要從寄生蟲miRNAs在侵染宿主中的作用和宿主miRNAs對寄生蟲的調(diào)控兩個方面綜述了miRNAs在寄生蟲感染中作用機制的研究進展,以期為寄生蟲感染后免疫調(diào)控機制研究及寄生蟲病的防治提供參考。
1 miRNAs概述
1.1 miRNAs調(diào)控基因表達的機制
在動物細胞質(zhì)內(nèi)進行DNA翻譯功能時,通常由RNA聚合酶Ⅱ參與轉(zhuǎn)錄miRNAs的編碼基因,經(jīng)5′m7G頭[7]和3′-poly (A)尾[8]等加工,形成起始miRNA(pri-miRNA)。大部分pri-miRNA也是由RNA聚合酶Ⅱ催化經(jīng)一系列的剪接及聚腺苷酸化[8],少部分由RNA聚合酶III轉(zhuǎn)錄[9]。隨后,在Drosha酶的參與下,pri-miRNA被加工成約70個核苷酸組成的莖環(huán)結(jié)構(gòu),即前體miRNA(pre-miRNA),Drosha的兩個RNase結(jié)構(gòu)可切割pri-miRNA的5′和3′末端,這決定了pre-miRNA的長度[10]。產(chǎn)生的pre-miRNA在Ran-GTP和核轉(zhuǎn)運受體蛋白(exportin-5)的作用下被轉(zhuǎn)運到細胞質(zhì)中,在Dicer酶和RNA結(jié)合蛋白的作用下被切割成成熟的miRNA雙鏈體,分別是成熟的miRNA引導(dǎo)鏈和miRNA隨從鏈[11];雙鏈分離后,miRNA引導(dǎo)鏈(5′端)與附著Argonaute(AGO)蛋白結(jié)合,形成RNA誘導(dǎo)的具有功能性的AGO-miRNA沉默復(fù)合物(RNA-induced silencing complex,RISC),RISC與靶基因的表達和調(diào)控有關(guān)[12-13]。隨后,由于miRNAs序列中部分序列的互補性,RISC會被誘導(dǎo)至靶mRNA[14];RISC復(fù)合物促進miRNAs和mRNA之間的堿基配對并產(chǎn)生相互作用,從而達到調(diào)控基因的目的。
miRNAs的作用是通過與靶基因的mRNA結(jié)合從而影響mRNA的存留時間或翻譯過程[12]。在miRNA序列中,和序列互補的RNA序列通常存在于mRNA的3′非翻譯區(qū)[5]。由miRNA-RISC復(fù)合物介導(dǎo)的基因抑制可能通過特異性位點切割,或通過增加mRNA的降解或翻譯抑制發(fā)生[15]。大部分真核生物中,miRNAs與mRNA的3′非翻譯區(qū)進行不完全互補配對,從而阻止靶mRNA的翻譯或致其降解[16]。然而,已有報道稱,miRNAs與其他區(qū)域也有相互作用,例如5′非翻譯區(qū)、編碼序列和基因啟動子等。此外,miRNAs對靶基因的調(diào)控不僅與miRNAs本身的含量有關(guān),還取決于靶基因的特征。
1.2 miRNAs在寄生蟲和宿主互作中的關(guān)系
在哺乳動物體內(nèi),寄生蟲產(chǎn)生的miRNAs可以借助存在于囊泡中的形式釋放至宿主體內(nèi)。外泌體是一類細胞分泌的囊泡,其存在于尿液、血液、羊水和唾液等體液中[17],并且也存在于體外培養(yǎng)的細胞和寄生蟲的上清液中[18]。與其他真核生物一致,寄生蟲能利用細胞外泌體將功能蛋白、代謝物和核酸轉(zhuǎn)運到受體細胞中,在細胞通訊中起重要作用[19]。而外泌體攜帶的核酸包含了mRNA和多種類型的miRNAs。通過對寄生蟲源外泌體miRNAs介導(dǎo)宿主免疫反應(yīng)機制的研究,可以針對miRNAs從分子水平阻斷寄生蟲的感染[20]。
寄生蟲miRNAs經(jīng)外泌體攜帶進入宿主內(nèi),由于其不具備免疫原性且可與宿主基因靶向結(jié)合,從而改變宿主基因的表達,破壞宿主免疫防御機制,并介導(dǎo)寄生蟲實現(xiàn)免疫逃逸和慢性感染,因此,蟲源miRNAs是寄生蟲感染宿主的有效途徑,也是研究寄生蟲感染機制,研發(fā)抗寄生蟲感染藥物的有效靶點。利什曼原蟲、陰道毛滴蟲、肝片吸蟲、棘口吸蟲、線蟲等寄生蟲都可以產(chǎn)生外泌體,外泌體可作為轉(zhuǎn)運小體將寄生蟲miRNAs及其他類型的小分子物質(zhì)從寄生蟲轉(zhuǎn)運到宿主細胞,使miRNAs發(fā)揮作用[21]。腸道寄生線蟲的分泌物中含有大量的miRNAs,分泌物被排到宿主體液中發(fā)揮作用,使宿主的生存環(huán)境發(fā)生改變,從而使寄生蟲實現(xiàn)免疫逃逸而存活[22]。另一方面,宿主miRNAs是宿主防御寄生蟲感染的重要組成部分,其功能可影響宿主對寄生蟲的抗性和易感性[5],宿主miRNAs失調(diào)可使免疫系統(tǒng)受到破壞,并加快病原體在宿主內(nèi)的定植[23]。miRNAs不僅有潛力作為診斷和預(yù)后工具,還是寄生蟲病化療和免疫療法的潛在靶點[24]。因此,在寄生蟲侵染宿主和宿主抗寄生蟲感染的過程中,miRNAs都發(fā)揮著重要的調(diào)節(jié)作用(表1)。
2 寄生蟲miRNAs在感染宿主中的作用
2.1 弓形蟲
Ferguson[46]對弓形蟲的發(fā)現(xiàn)史進行了總結(jié):
1908年Nicolle和Manceaux在北非嚙齒動物中首次發(fā)現(xiàn)了剛地弓形蟲,1909年Splendore在巴西的兔子體內(nèi)發(fā)現(xiàn)了弓形蟲。弓形蟲屬于頂復(fù)門的胞內(nèi)寄生病原體,可在所有哺乳動物或鳥類中感染和復(fù)制[47]。弓形蟲的形態(tài)有5種,即滋養(yǎng)體、包囊、裂殖體、配子體和卵囊,具有子孢子、速殖子和緩殖子三個感染階段,其在此三個階段中的形狀都為長4~8 μm、寬2~6 μm的新月形[48],并且其蟲體頂端有具備分泌功能的頂端復(fù)合體,該復(fù)合體參與弓形蟲感染宿主的過程。弓形蟲是首個被證實感染后可導(dǎo)致宿主內(nèi)源性miRNAs的表達發(fā)生改變的寄生蟲[49]。miRNAs在弓形蟲的不同生活史中具有保守性,結(jié)構(gòu)較穩(wěn)定,不易被核糖核酸酶(RNase)降解[50]。弓形蟲的外泌體核酸中含有大量的miRNAs,但是關(guān)于miRNAs的種類、數(shù)量、功能等尚待闡明[51]。研究表明,弓形蟲誘導(dǎo)感染后特異性表達的miRNAs可以影響宿主神經(jīng)元細胞的功能,從而影響弓形蟲感染的神經(jīng)病理學(xué)過程[25]。溫福利等[52]研究發(fā)現(xiàn),在被弓形蟲感染的小鼠模型中,弓形蟲miR-191表達量較對照組高,而在細菌、病毒感染的小鼠模型中未發(fā)現(xiàn)miR-191的表達,miR-191可作為生物靶標(biāo)應(yīng)用于寄生蟲的檢測和治療。研究表明,miR-17-92簇與腦癌相關(guān),因為它與原癌基因家族的高蛋白水平相關(guān)[53],c-Myc是miR-17-92的直接轉(zhuǎn)錄調(diào)節(jié)因子,弓形蟲感染期間c-Myc的表達量上調(diào)了2~3倍,表明弓形蟲在細胞內(nèi)生長期間通過miRNAs的轉(zhuǎn)錄調(diào)節(jié)因子參與誘導(dǎo)宿主細胞功能特異性改變的過程[54]。因此,弓形蟲依賴的miR-17-92簇的表達上調(diào)可能是這種寄生蟲促進腫瘤發(fā)生的機制之一;另外,弓形蟲很可能利用內(nèi)源性miRNAs抑制細胞凋亡,促進感染的發(fā)生,控制宿主的防御系統(tǒng)和部分支持其代謝所需的生物合成途徑[55]。
2.2 錐蟲
錐蟲病分為非洲錐蟲病和美洲錐蟲病,非洲錐蟲病又稱昏睡病,是由布氏錐蟲感染而引起的寄生蟲病,布氏錐蟲又分為布氏錐蟲羅德西和布氏錐蟲岡比亞兩個亞種[56];美洲錐蟲病的病原是克氏錐蟲病。錐蟲可以侵襲宿主的免疫系統(tǒng)并誘導(dǎo)宿主產(chǎn)生免疫反應(yīng)[57]。克氏錐蟲感染后,細胞中PI3K/Akt通路被激活[58-59],PI3K通過調(diào)節(jié)第二信使PIP3的生成而調(diào)控細胞代謝過程[60],而腫瘤抑制因子PTEN可將PIP3水解為PIP2,因此PTEN是PI3K信號轉(zhuǎn)導(dǎo)的負調(diào)控因子[61]??耸襄F蟲Berenice-62株感染心肌細胞后,寄生蟲產(chǎn)生的miR-190b能抑制PTEN蛋白的表達,從而促進克氏錐蟲在宿主細胞內(nèi)的存活[28]。Bayer-Santos等[62]對克氏錐蟲衍生的外泌體進行了深度測序和全基因組分析,結(jié)果表明,這些外泌體中包含了多種來源的miRNAs,包括tRNAs,并且這些miRNAs在不同的寄生蟲階段表達情況不同,所發(fā)揮的功能也不同。有學(xué)者在哺乳動物中共檢測到21個布氏錐蟲miRNAs,這些miRNAs中,只有tbr-miR-2491-3p在采采蠅中被發(fā)現(xiàn),但在人類基因組中未發(fā)現(xiàn),由于采采蠅是錐蟲的傳播媒介,因此推測該miRNA可能是參與布氏錐蟲感染宿主過程中的關(guān)鍵分子[63]。
2.3 血吸蟲
血吸蟲病是一種重要的人畜共患病,感染范圍極廣,可感染40余種動物,全球感染人數(shù)超2.5億[64],血吸蟲是一種寄生性蠕蟲,分為日本血吸蟲、曼氏血吸蟲、埃及血吸蟲、間插血吸蟲、湄公血吸蟲和馬來血吸蟲,其中以前3種血吸蟲較為常見[65]。雌雄異體是血吸蟲的特征,雌性沒有雄性就不會成熟[66];未配對的雌性發(fā)育比較遲緩,它們會吸收和攝取足夠的營養(yǎng)來維持基本功能,但不足以用于生長和成熟[67]。由于每對日本血吸蟲每日可產(chǎn)卵1 500~3 000個,大約是曼氏血吸蟲的5~10倍,因此日本血吸蟲的感染率、發(fā)病率和死亡率遠遠高于其他血吸蟲[66],所以對于血吸蟲在分化、成熟、產(chǎn)卵及感染宿主過程中分子機制的研究極為重要。日本血吸蟲能分泌大量miRNAs,包含保守和特異性miRNAs[10]。有學(xué)者對成熟和未成熟的日本血吸蟲miRNAs的差異表達譜分別進行了研究,并分析了miRNAs的靶基因,結(jié)果表明,配對的成熟雌性與未配對的未成熟雌性相比有更多的代謝途徑和基因miRNAs調(diào)節(jié)[68]。研究發(fā)現(xiàn),miR-277/4989能在曼氏血吸蟲幼蟲轉(zhuǎn)向成蟲的發(fā)育過程中的轉(zhuǎn)錄后調(diào)控中起主導(dǎo)作用,并在雌蟲的性發(fā)育過程中起重要作用[29]。寄生在肝組織中的蟲卵會分泌含有血吸蟲miRNAs的外泌體,且該miRNAs可以通過外泌體直接轉(zhuǎn)移到鄰近的宿主細胞[69]。日本血吸蟲miR-7-5p能轉(zhuǎn)移至受感染宿主的肝細胞中,通過靶向SKP2基因影響人和小鼠腫瘤細胞的生長和遷移,說明miR-7-5p會增強宿主對癌癥的抵抗力[30]。日本血吸蟲miR-3096通過靶向PIK3C2A基因抑制腫瘤細胞的生長和遷移,從而下調(diào)mTORC1信號通路的表達[31]。
2.4 多房棘球絳蟲
多房棘球絳蟲是引起人泡型包蟲病的一種寄生蟲,該病幾乎原發(fā)于肝,多房棘球絳蟲中間宿主為嚙齒類動物,主要是幼蟲寄生在中間宿主的肝[27],終末宿主為犬科動物,成蟲寄生在終末宿主的腸道中,大量的卵可隨糞便一起排到周圍環(huán)境中[70]。研究表明,NO是影響棘球絳蟲感染程度的關(guān)鍵因素之一,而多房棘球絳蟲miR-4989-3p可轉(zhuǎn)運至細胞外囊泡中,其在感染細胞后能抑制巨噬細胞產(chǎn)生NO,并調(diào)節(jié)細胞因子的表達和LPS/TLR4信號通路中主要成分的表達,說明miR-4989-3p可能在多房棘球絳蟲的發(fā)病機制中發(fā)揮調(diào)節(jié)作用[27]。郭寶平[27]對體外早期發(fā)育時的多房棘球絳蟲miRNAs進行了鑒定,發(fā)現(xiàn)miR-71是多房棘球絳蟲原代細胞培養(yǎng)物中表達量最高的miRNAs,甚至超過了miR-4989,并且miR-71在多房棘球蚴體外發(fā)育初期可調(diào)節(jié)相關(guān)靶點,揭示了miR-71在棘球蚴發(fā)育中的功能。Buck等[71]揭示miR-71是在寄生蟲中廣泛表達的保守miRNAs。有研究表明,線蟲外泌體產(chǎn)生的miR-71可被宿主細胞內(nèi)化,并作為先天調(diào)節(jié)劑,在寄生蟲-宿主相互作用中發(fā)揮重要作用[72]。
3 宿主miRNAs在寄生蟲免疫應(yīng)答中的作用
3.1 利什曼原蟲
機體在感染利什曼原蟲后,巨噬細胞在宿主抗感染的免疫調(diào)節(jié)中起雙重作用,其表達的miRNAs及分泌的細胞因子發(fā)揮重要作用,并且利什曼原蟲通過調(diào)控細胞因子而改變巨噬細胞miRNAs的表達,這些miRNAs會影響巨噬細胞分泌促炎因子和抗炎因子的能力,從而導(dǎo)致巨噬細胞對利什曼原蟲寄生功能和巨噬細胞的凋亡或存活產(chǎn)生影響,因此,被利什曼原蟲改變表達的這些宿主miRNAs間接決定了感染結(jié)果[73]。
在杜氏利什曼原蟲感染模型中,巨噬細胞可調(diào)控900多個miRNAs的表達,其中miR-6540可靶向作用于磷脂酰絲氨酸(phosphatidylserine, PS)并影響寄生蟲在巨噬細胞內(nèi)的感染,但是目前對PS和miR-6540的互作機制尚待闡明;另外,miR-3620和miR-6385在杜氏利什曼原蟲感染的巨噬細胞中的表達量顯著增加,并顯著下調(diào)缺氧誘導(dǎo)基因的表達,從而增強巨噬細胞對杜氏利什曼原蟲的清除作用;miR-3620可調(diào)控鐵穩(wěn)態(tài)相關(guān)基因的表達,使宿主細胞合成大量鐵,從而滿足利什曼原蟲對鐵的需求[35]。研究表明,利什曼原蟲感染宿主后,宿主BALB/c-BMDM中miR-294-3p和miR-721的表達上調(diào),而這兩種miRNAs與Nos2 3′UTR結(jié)合后會降低NOS2和NO產(chǎn)生的水平,并增加了利什曼原蟲對宿主的感染性[34]。此外,在感染期間miR-30e和miR-302d表達量失調(diào)會導(dǎo)致Nos2 mRNAs的表達和NO的產(chǎn)生受到影響,miR-294和miR-302d會調(diào)節(jié)Tnf 的mRNA水平,并且miR-294能改變Ccl2/Mcp-1的mRNA,以上都能表明這些miRNAs表達量的改變能控制利什曼原蟲對宿主的感染性[36]。
3.2 瘧原蟲
miRNAs在瘧疾檢測中也能起到一定的作用,瘧原蟲感染可以使宿主miRNAs的表達發(fā)生改變,且這些miRNAs能夠作為診斷瘧疾的生物標(biāo)志物[74]。研究者在缺乏細胞核和轉(zhuǎn)錄、翻譯機制的惡性瘧原蟲紅細胞中發(fā)現(xiàn)了約200個人類miRNAs[75],從而導(dǎo)致翻譯抑制。研究表明,瘧原蟲感染的人類紅細胞會分泌胞外囊泡,這些胞外囊泡中包含了人Argonaute2(hAgo2)-miRNA復(fù)合體,這個復(fù)合體包含了數(shù)百個miRNAs,而hAgo2-miRNA復(fù)合體會被轉(zhuǎn)運至瘧原蟲內(nèi),靶向調(diào)控miRNAs介導(dǎo)的基因[76]。其中l(wèi)et-7a和miR-15a分別靶向調(diào)控瘧原蟲的Rad54和脂質(zhì)/甾醇:H+同向轉(zhuǎn)運體[75],miR-451/140通過抑制瘧原蟲抗原PfEMP1的表達,而使其逃避先天免疫[76]。因此,可以針對這些miRNAs標(biāo)記物,進行瘧疾的靶向診斷和治療。
腦型瘧疾是由惡性瘧原蟲引起的瘧疾當(dāng)中最常見的神經(jīng)性疾病。在感染腦型瘧疾和非腦型瘧疾的小鼠大腦中檢測出miR-19b-3p、miR-19a-3p、miR-223-3p和miR142-3p等4種miRNAs的表達顯著失調(diào),這些miRNAs主要參與調(diào)控TGF-β和內(nèi)吞作用信號通路,通過下調(diào)通路中基因的表達而引發(fā)腦型瘧疾的神經(jīng)綜合征[37]。miR-146a、miR-27a和miR-155與腦型瘧疾發(fā)生后機體的炎癥和免疫反應(yīng)、神經(jīng)元細胞凋亡和細胞黏附有關(guān)[77-78];miR-27a通過阻礙微粒形成來負調(diào)控ABCA1基因,并能通過阻礙神經(jīng)元細胞凋亡來負調(diào)控APAF1基因,miR-146a通過下調(diào)NF-κB信號通路從而抑制TRAK1和TRAF6基因的表達,另外還通過阻礙參與IFNγ信號通路的信號轉(zhuǎn)導(dǎo)與轉(zhuǎn)錄激活因子(Stat1)來抑制免疫細胞的功能[39]。在非腦型瘧疾中,miR-451調(diào)節(jié)cAMP依賴蛋白激酶(PKA-R)的表達,使PKA的催化活性增加,進而促進了寄生蟲入侵、存活以及誘導(dǎo)配子體的生成[40]。
3.3 血吸蟲
有研究發(fā)現(xiàn),在感染血吸蟲的小鼠肝組織中,mmu-miR-146b、mmu-miR-155等鼠源miRNAs會在感染中期失調(diào),可能會參與肝組織炎癥的調(diào)節(jié)[79]。此外,mmu-miR-146b和mmu-miR-155的高表達可能反應(yīng)了B淋巴細胞和T淋巴細胞在蟲卵分泌的抗原刺激下向肝肉芽腫周圍的募集和激活;mmu-miR-146a/b、mmu-miR-223、mmu-miR-34c、mmu-miR-199、mmu-miR-155和mmu-miR-134等在血吸蟲感染后期表達呈峰值水平,預(yù)示血吸蟲所導(dǎo)致的肝疾病的發(fā)生[80]。miR-155已被認為是多種免疫細胞中的多效調(diào)節(jié)因子,在CD4+ T細胞中,miR-155抑制轉(zhuǎn)錄因子c-Maf的表達,從而減弱Th2細胞反應(yīng)[43]。因此,mmu-miR-155的表達量上調(diào)也能促進血吸蟲卵誘導(dǎo)免疫病理學(xué)過程中Th1/Th2的平衡。在感染血吸蟲的小鼠模型中,miR-223可以負調(diào)節(jié)祖細胞增殖和粒細胞分化,表明miR-223是粒細胞產(chǎn)生和炎癥反應(yīng)的調(diào)節(jié)因子[44],因此mmu-miR-223在日本血吸蟲感染晚期顯著上調(diào)可阻止粒細胞的過度分化,從而抑制免疫反應(yīng)。此外,宿主來源的miRNAs對血吸蟲感染后的免疫應(yīng)答起到重要作用,如宿主miR-96就可以通過轉(zhuǎn)化生長因子β1的表達從而抑制肝的纖維化[45]。
3.4 弓形蟲
弓形蟲通過RNA沉默途徑而重塑細胞環(huán)境的方式來干擾宿主的miRNAs表達[81]。弓形蟲感染人類成纖維細胞后,細胞內(nèi)miR-106b~25、miR-17~92及其來源的miRNAs的表達量提高了2~3倍,這些miRNAs在哺乳動物細胞調(diào)控中發(fā)揮重要作用,其過量表達可導(dǎo)致機體發(fā)生增生性疾?。?2]。研究發(fā)現(xiàn),miRNAs是宿主對頂復(fù)門寄生蟲感染的反應(yīng)調(diào)節(jié)因子[49]。研究者對剛地弓形蟲慢性感染階段和急性感染階段的小鼠肝中的miRNAs的表達進行了研究,其中mmu-miR-147-3p、mmu-miR-342-3p、mmu-miR-143-3p的表達均發(fā)生了變化,在急性感染期,前兩種小鼠miRNAs的表達分別上調(diào)了32.94倍和8.23倍,在慢性感染期,mmu-miR-147-3p表達下調(diào),mmu-miR-143-3p在感染的整個過程表達均發(fā)生了下調(diào),與剛地弓形蟲感染后小鼠肝的炎癥反應(yīng)有關(guān)[83]。此外,在弓形蟲感染的小鼠大腦中的miRNAs表達也發(fā)生改變,mmu-miR-155-5p是表達量上調(diào)最多的miRNAs,而mmu-miR-185-3p是表達量下調(diào)最多的miRNAs;mmu-miR-223-3p和mmu-miR-223-5p的表達均上調(diào),可能參與宿主對弓形蟲的防御[84]。Xiao等[47]對弓形蟲感染的神經(jīng)細胞進行了全基因組miRNAs表達譜分析,發(fā)現(xiàn)三種典型弓形蟲感染均會引起miR-132的表達量增加,深入研究發(fā)現(xiàn),miR-132與多巴胺受體通路的表達密切相關(guān),即弓形蟲的急性感染可誘導(dǎo)宿主miR-132的表達,并且是通過抑制相關(guān)蛋白表達而改變被感染小鼠的多巴胺通路的表達有關(guān)。Pope和Lsser[85]利用微陣列法分析了感染弓形蟲PRU株速殖子后的人包皮成纖維細胞所分泌的外泌體中的miRNAs,發(fā)現(xiàn)10個差異表達的miRNAs中miR-23b高度表達,且作為抗炎介質(zhì)抑制宿主細胞因子IL-17的表達,從而參與調(diào)控宿主細胞的免疫應(yīng)答反應(yīng)。
3.5 旋毛蟲
旋毛蟲病是由旋毛蟲感染后引起的一種重要的食源性人畜共患寄生蟲?。?6]。人類和其他哺乳動物是通過攝入被寄生蟲污染的未煮熟肉類而引起的旋毛蟲病,并且旋毛蟲的整個生命周期都可以在動物體內(nèi)完成[87]。馬小涵[88]對被毛蟲感染的小鼠miRNAs進行了鑒定,經(jīng)高通量測序結(jié)果發(fā)現(xiàn)在受感染小鼠血清中共有10個miRNAs發(fā)生了差異性表達,其中miR-467a-3P、miR-467d-3p、miR-292a-5p、miR-376b-3p、miR-664-3p等miRNAs表達上調(diào),對這些上調(diào)miRNAs進行GO功能富集分析發(fā)現(xiàn),這些miRNAs主要涉及細胞分化、蛋白質(zhì)的磷酸化、細胞-細胞黏附、轉(zhuǎn)錄、DNA模板化、多細胞生物發(fā)育等。這些差異表達miRNAs參與疾病的發(fā)生,如miR-376b可通過靶向作用于自噬相關(guān)基因Atg5而抑制慢性腎病小鼠巨噬細胞的自噬,從而防止腎間質(zhì)纖維化[89],miR-455-5p參與機體多種生物和病理過程,如癌細胞的增殖、凋亡、遷移和入侵,是潛在的腫瘤抑制因子[90]。
4 總結(jié)與展望
不論是寄生蟲源miRNAs還是宿主源miRNAs,在寄生蟲侵染宿主的過程中都發(fā)揮重要作用。部分寄生蟲源miRNAs可抑制抗炎因子的表達,破壞宿主的免疫應(yīng)答反應(yīng),從而使寄生蟲實現(xiàn)免疫逃逸;部分寄生蟲源miRNAs可通過調(diào)節(jié)宿主的受體細胞和信號通路,而影響宿主的生長發(fā)育。寄生蟲源miRNAs能夠幫助其在宿主體內(nèi)增殖,宿主源miRNAs能夠抵抗寄生蟲對自身的侵染。目前,治療寄生蟲病主要以藥物為主,部分寄生蟲病的治療效果不佳,而miRNAs靶向的特定基因位點可作為抗寄生蟲病藥物治療的靶標(biāo)位點,針對靶標(biāo)位點研發(fā)新的藥物可實現(xiàn)藥物治療的靶向性和抗生素替代,為寄生蟲病的防治提供了新的思路。數(shù)十年來,研究人員致力于確定疾病防治中新的生物標(biāo)志物,隨著miRNAs作為生物標(biāo)志物的研究和應(yīng)用不斷深入,其在寄生蟲病的診斷和治療中將發(fā)揮越來越重要的作用。
參考文獻(References):
[1] O’DONNELL K A,WENTZEL E A,ZELLER K I,et al.c-Myc-regulated microRNAs modulate E2F1 expression[J].Nature,2005,435(7043):839-843.
[2] LEE R C,F(xiàn)EINBAUM R L,AMBROS V.The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14[J].Cell,1993,75(5):843-854.
[3] PASQUINELLI A E,REINHART B J,SLACK F,et al.Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA[J].Nature,2000,408(6808):86-89.
[4] MANI V,ASSEFA A D,HAHN B S.Transcriptome analysis and miRNA target profiling at various stages of root-knot nematode Meloidogyne incognita development for identification of potential regulatory networks[J].Int J Mol Sci,2021,22(14):7442.
[5] 劉 可,黃海斌,楊桂連.miRNA在寄生蟲宿主免疫調(diào)控中的研究進展[J].中國寄生蟲學(xué)與寄生蟲病雜志,2018,36(4):405-408.
LIU K,HUANG H B,YANG G L.miRNA functions in parasite-related immune regulation in hosts[J].Chinese Journal of Parasitology and Parasitic Diseases,2018,36(4):405-408.(in Chinese)
[6] BAEK D,VILL N J,SHIN C,et al.The impact of microRNAs on protein output[J].Nature,2008,455(7209):64-71.
[7] XIE Z X,ALLEN E,F(xiàn)AHLGREN N,et al.Expression of Arabidopsis MIRNA genes[J].Plant Physiol,2005,138(4):2145-2154.
[8] JONES-RHOADES M W,BARTEL D P.Computational identification of plant microRNAs and their targets,including a stress-induced miRNA[J].Mol Cell,2004,14(6):787-799.
[9] FALLER M,GUO F.MicroRNA biogenesis:there’s more than one way to skin a cat[J].Biochim Biophys Acta,2008,1779(11):663-667.
[10] WANG Z X,XUE X Y,SUN J,et al.An \"in-depth\" description of the small non-coding RNA population of Schistosoma japonicum schistosomulum[J].PLoS Negl Trop Dis,2010,4(2):e596.
[11] RUBY J G,JAN C H,BARTEL D P.Intronic microRNA precursors that bypass Drosha processing[J].Nature,2007,448(7149):83-86.
[12] 郝大海,龔 明.miRNA作用機制研究進展[J].基因組學(xué)與應(yīng)用生物學(xué),2020,39(8):3647-3657.
HAO D H,GONG M.The progress of miRNA action mechanism[J].Genomics and Applied Biology,2020,39(8):3647-3657.(in Chinese)
[13] SONG X W,LI Y,CAO X F,et al.MicroRNAs and their regulatory roles in plant-environment interactions[J].Annu Rev Plant Biol,2019,70:489-525.
[14] CHEKULAEVA M,F(xiàn)ILIPOWICZ W.Mechanisms of miRNA-mediated post-transcriptional regulation in animal cells[J].Curr Opin Cell Biol,2009,21(3):452-460.
[15] CAI M,KOLLURU G K,AHMED A.Small molecule,big prospects:MicroRNA in pregnancy and its complications[J].J Pregnancy,2017,2017:6972732.
[16] 魏秀秀,吳志豪,黃 強.miRNA在寄生蟲與宿主協(xié)同進化中的作用[J].中國動物傳染病學(xué)報,2024,32(3):193-199.
WEI X X,WU Z H,HUANG Q.The role of miRNA during parasite and host co-evolution[J].Chinese Journal of Animal Infectious Diseases,2024,32(3):193-199.(in Chinese)
[17] VAN DER POL E,B ING A N,HARRISON P,et al.Classification,functions,and clinical relevance of extracellular vesicles[J].Pharmacol Rev,2012,64(3):676-705.
[18] KELLER S,SANDERSON M P,STOECK A,et al.Exosomes:from biogenesis and secretion to biological function[J].Immunol Lett,2006,107(2):102-108.
[19] VALADI H,EKSTR M K,BOSSIOS A,et al.Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells[J].Nat Cell Biol,2007,9(6):654-659.
[20] 倪愛心,麻 慧,陳繼蘭.寄生蟲來源的外泌體研究進展[J].畜牧獸醫(yī)學(xué)報,2019,50(5):909-917.
NI A X,MA H,CHEN J L.Research progress of parasite-derived Exosomes[J].Acta Veterinaria et Zootechnica Sinica,2019,50(5):909-917.(in Chinese)
[21] RASHIDI S,MANSOURI R,ALI-HASSANZADEH M,et al.miRNAs in the regulation of mTOR signaling and host immune responses:the case of Leishmania infections[J].Acta Trop,2022,231:106431.
[22] 黃 琳,葉昌林,生 燕,等.外泌體miRNA在寄生蟲中的進展[J].中國病原生物學(xué)雜志,2019,14(9):1115-1118.
HUANG L,YE C L,SHENG Y,et al.Advances in research on parasite exosomal miRNA[J].Journal of Pathogen Biology,2019,14(9):1115-1118.(in Chinese)
[23] ROJAS-PIRELA M,ANDRADE-ALVI REZ D,MEDINA L,et al.MicroRNAs:master regulators in host-parasitic protist interactions[J].Open Biol,2022,12(6):210395.
[24] BAYER-SANTOS E,MARINI M M,DA SILVEIRA J F.Non-coding RNAs in host-pathogen interactions:subversion of mammalian cell functions by protozoan parasites[J].Front Microbiol,2017,8:474.
[25] CRATER A K,MANNI E,ANANVORANICH S.Utilization of inherent miRNAs in functional analyses of Toxoplasma gondii genes[J].J Microbiol Methods,2015,108:92-102.
[26] P REZ M G,SPILIOTIS M,REGO N,et al.Deciphering the role of miR-71 in Echinococcus multilocularis early development in vitro[J].PLoS Negl Trop Dis,2019,13(12):e0007932.
[27] 郭寶平.多房棘球絳蟲致病差異與線粒體遺傳標(biāo)志相關(guān)性的研究[D].石河子:石河子大學(xué),2019.
GUO B P.Study on correlation between pathogenic differences and mitochondrial genetic markers in Echinococcus multilocularis[D].Shihezi:Shihezi University,2019.(in Chinese)
[28] MONTEIRO C J,MOTA S L A,DINIZ L D F,et al.Mir-190b negatively contributes to the Trypanosoma cruzi-infected cell survival by repressing PTEN protein expression[J].Mem Inst Oswaldo Cruz,2015,110(8):996-1002.
[29] PROTASIO A V,VAN DONGEN S,COLLINS J,et al.Correction:MiR-277/4989 regulate transcriptional landscape during juvenile to adult transition in the parasitic helminth Schistosoma mansoni[J].PLoS Negl Trop Dis,2022,16(6):e0010521.
[30] HU C,ZHU S L,WANG J,et al.Schistosoma japonicum MiRNA-7-5p inhibits the growth and migration of hepatoma cells via cross-species regulation of S-phase kinase-associated protein 2[J].Front Oncol,2019,9:175.
[31] LIN Y,ZHU S L,HU C,et al.Cross-species suppression of hepatoma cell growth and migration by a Schistosoma japonicum MicroRNA[J].Mol Ther Nucleic Acids,2019,18:400-412.
[32] MUXEL S M,ACU A S M,AOKI J I,et al.Toll-like receptor and miRNA-let-7e expression alter the inflammatory response in Leishmania amazonensis-infected macrophages[J].Front Immunol,2018,9:2792.
[33] DIOTALLEVI A,DE SANTI M,BUFFI G,et al.Leishmania infection induces MicroRNA hsa-miR-346 in human cell line-derived macrophages[J].Front Microbiol,2018,9:1019.
[34] MUXEL S M,LARANJEIRA-SILVA M F,ZAMPIERI R A,et al.Leishmania (Leishmania) amazonensis induces macrophage miR-294 and miR-721 expression and modulates infection by targeting NOS2 and L-arginine metabolism[J].Sci Rep,2017,7:44141.
[35] TIWARI N,KUMAR V,GEDDA M R,et al.Corrigendum:identification and characterization of miRNAs in response to Leishmania donovani infection:delineation of their roles in macrophage dysfunction[J].Front Microbiol,2017,8:1190.
[36] FERNANDES J C R,AOKI J I,MAIA ACU A S,et al.Melatonin and Leishmania amazonensis infection altered miR-294,miR-30e,and miR-302d Impacting on Tnf,Mcp-1,and Nos2 expression[J].Front Cell Infect Microbiol,2019,9:60.
[37] MARTIN-ALONSO A,COHEN A,QUISPE-RICALDE M A,et al.Differentially expressed microRNAs in experimental cerebral malaria and their involvement in endocytosis,adherens junctions,F(xiàn)oxO and TGF-β signalling pathways[J].Sci Rep,2018,8(1):11277.
[38] LI J J,HUANG M J,LI Z,et al.Identification of potential whole blood MicroRNA biomarkers for the blood stage of adult imported falciparum malaria through integrated mRNA and miRNA expression profiling[J].Biochem Biophys Res Commun,2018,506(3):471-477.
[39] PRABHU S R,WARE A P,SAADI A V.Erythrocyte miRNA regulators and malarial pathophysiology[J].Infect Genet Evol,2021,93:105000.
[40] WILDE M L,TRIGLIA T,MARAPANA D,et al.Protein kinase A is essential for invasion of Plasmodium falciparum into human erythrocytes[J].mBio,2019,10(5):e01972-19.
[41] GUESDON W,AURAY G,PEZIER T,et al.CCL20 displays antimicrobial activity against Cryptosporidium parvum,but its expression is reduced during infection in the intestine of neonatal mice[J].J Infect Dis,2015,212(8):1332-1340.
[42] HU G K,ZHOU R,LIU J,et al.MicroRNA-98 and let-7 regulate expression of suppressor of cytokine signaling 4 in biliary epithelial cells in response to Cryptosporidium parvum infection[J].J Infect Dis,2010,202(1):125-135.
[43] RODRIGUEZ A,VIGORITO E,CLARE S,et al.Requirement of bic/microRNA-155 for normal immune function[J].Science,2007,316(5824):608-611.
[44] JOHNNIDIS J B,HARRIS M H,WHEELER R T,et al.Regulation of progenitor cell proliferation and granulocyte function by microRNA-223[J].Nature,2008,451(7182):1125-1129.
[45] LUO X F,ZHANG D M,XIE J,et al.MicroRNA-96 promotes schistosomiasis hepatic fibrosis in mice by suppressing Smad7[J].Mol Ther Methods Clin Dev,2018,11:73-82.
[46] FERGUSON D J P.Toxoplasma gondii:1908-2008,homage to Nicolle,Manceaux and Splendore[J].Mem Inst Oswaldo Cruz,2009,104(2):133-148.
[47] XIAO J,LI Y,PRANDOVSZKY E,et al.MicroRNA-132 dysregulation in Toxoplasma gondii infection has implications for dopamine signaling pathway[J].Neuroscience,2014,268:128-138.
[48] DUBEY J P,LINDSAY D S,SPEER C A.Structures of Toxoplasma gondii tachyzoites,bradyzoites,and sporozoites and biology and development of tissue cysts[J].Clin Microbiol Rev,1998,11(2):267-299.
[49] CANNELLA D,BRENIER-PINCHART M P,BRAUN L,et al.miR-146a and miR-155 delineate a MicroRNA fingerprint associated with Toxoplasma persistence in the host brain[J].Cell Rep,2014,6(5):928-937.
[50] LAO K Q,XU N L,YEUNG V,et al.Multiplexing RT-PCR for the detection of multiple miRNA species in small samples[J].Biochem Biophys Res Commun,2006,343(1):85-89.
[51] SILVA V O,MAIA M M,TORRECILHAS A C,et al.Extracellular vesicles isolated from Toxoplasma gondii induce host immune response[J].Parasite Immunol,2018,40(9):e12571.
[52] 溫福利,鄭和平,黨 源,等.弓形蟲生物檢測靶標(biāo)miR-191的鑒定[J].實驗動物與比較醫(yī)學(xué),2018,38(5):350-355.
WEN F L,ZHENG H P,DANG Y,et al.Identification of the target miR-191 for the biological detection of Toxoplasma gondii[J].Laboratory Animal and Comparative Medicine,2018,38(5):350-355.(in Chinese)
[53] GRUSZKA R,ZAKRZEWSKA M.The oncogenic relevance of miR-17-92 cluster and its paralogous miR-106b-25 and miR-106a-363 clusters in brain tumors[J].Int J Mol Sci,2018,19(3):879.
[54] FRANCO M,SHASTRI A J,BOOTHROYD J C.Infection by Toxoplasma gondii specifically induces host c-Myc and the genes this pivotal transcription factor regulates[J].Eukaryot Cell,2014,13(4):483-493.
[55] CAI Y, CHEN H, MO X,et al. Toxoplasma gondii inhibits apoptosis via a novel STAT3-miR-17-92-Bim pathway in macrophages[J]. Cell Signal, 2014, 26(6): 1204-1212.
[56] WHO.Control and surveillance of African trypanosomiasis:report of a WHO expert committee[R].Geneva:WHO,1998.
[57] PONTE-SUCRE A.An overview of Trypanosoma brucei infections:an intense host-parasite interaction[J].Front Microbiol,2016,7:2126.
[58] CHUENKOVA M V,F(xiàn)URNARI F B,CAVENEE W K,et al.Trypanosoma cruzi trans-sialidase:a potent and specific survival factor for human Schwann cells by means of phosphatidylinositol 3-kinase/Akt signaling[J].Proc Natl Acad Sci U S A,2001,98(17):9936-9941.
[59] AOKI M P,GUI AZ N L,PELLEGRINI A V,et al.Cruzipain,a major Trypanosoma cruzi antigen,promotes arginase-2 expression and survival of neonatal mouse cardiomyocytes[J].Am J Physiol Cell Physiol,2004,286(2):C206-C212.
[60] MAEHAMA T,DIXON J E.The tumor suppressor,PTEN/MMAC1,dephosphorylates the lipid second messenger,phosphatidylinositol 3,4,5-trisphosphate[J].J Biol Chem,1998,273(22):13375-13378.
[61] OUDIT G Y,PENNINGER J M.Cardiac regulation by phosphoinositide 3-kinases and PTEN[J].Cardiovasc Res,2009,82(2):250-260.
[62] BAYER-SANTOS E,LIMA F M,RUIZ J C,et al.Characterization of the small RNA content of Trypanosoma cruzi extracellular vesicles[J].Mol Biochem Parasitol,2014,193(2):71-74.
[63] JACKSON A P,SANDERS M,BERRY A,et al.The genome sequence of Trypanosoma brucei gambiense,causative agent of chronic human african trypanosomiasis[J].PLoS Negl Trop Dis,2010,4(4):e658.
[64] YU J,YU Y,LI Q,et al.Comprehensive analysis of miRNA profiles reveals the role of Schistosoma japonicum miRNAs at different developmental stages[J].Vet Res,2019,50(1):23.
[65] 楊瑞冰,李云珍,蘇坤華,等.細胞外囊泡介導(dǎo)的血吸蟲-宿主相互作用研究進展[J].中國血吸蟲病防治雜志,2022,34(3):318-321.
YANG R B,LI Y Z,SU K H,et al.Advances in studies on schistosome-host interactions mediated by extracellular vesicles[J].Chinese Journal of Schistosomiasis Control,2022,34(3):318-321.(in Chinese)
[66] LU Z G,SESSLER F,HOLROYD N,et al.Schistosome sex matters:a deep view into gonad-specific and pairing-dependent transcriptomes reveals a complex gender interplay[J].Sci Rep,2016,6:31150.
[67] GUPTA B C,BASCH P F.The role of Schistosoma mansoni males in feeding and development of female worms[J].J Parasitol,1987,73(3):481-486.
[68] SUN J,WANG S W,LI C,et al.Novel expression profiles of microRNAs suggest that specific miRNAs regulate gene expression for the sexual maturation of female Schistosoma japonicum after pairing[J].Parasit Vectors,2014,7:177.
[69] ZHU S L,WANG S,LIN Y,et al.Release of extracellular vesicles containing small RNAs from the eggs of Schistosoma japonicum[J].Parasit Vectors,2016,9(1):574.
[70] DING J T,HE G T,WU J E,et al.miRNA-seq of Echinococcus multilocularis extracellular vesicles and immunomodulatory effects of miR-4989[J].Front Microbiol,2019,10:2707.
[71] BUCK A H,COAKLEY G,SIMBARI F,et al.Erratum:exosomes secreted by nematode parasites transfer small RNAs to mammalian cells and modulate innate immunity[J].Nat Commun,2015,6:8772.
[72] QUINTANA J F,MAKEPEACE B L,BABAYAN S A,et al.Extracellular Onchocerca-derived small RNAs in host nodules and blood[J].Parasit Vectors,2015,8:58.
[73] JAFARZADEH A,NEMATI M,AMINIZADEH N,et al.Bidirectional cytokine-microRNA control:a novel immunoregulatory framework in leishmaniasis[J].PLoS Pathog,2022,18(8):e1010696.
[74] KATARIA P,SURELA N,CHAUDHARY A,et al.MiRNA:biological regulator in host-parasite interaction during malaria infection[J].Int J Environ Res Public Health,2022,19(4):2395.
[75] DANDEWAD V,VINDU A,JOSEPH J,et al.Import of human miRNA-RISC complex into Plasmodium falciparum and regulation of the parasite gene expression[J].J Biosci,2019,44(2):50.
[76] WANG Z S,XI J M,HAO X,et al.Red blood cells release microparticles containing human argonaute 2 and miRNAs to target genes of Plasmodium falciparum[J].Emerg Microbes Infect,2017,6(8):e75.
[77] BARKER K R,LU Z Y,KIM H,et al.miR-155 modifies inflammation,endothelial activation and blood-brain barrier dysfunction in cerebral malaria[J].Mol Med,2017,23:24-33.
[78] EL-ASSAAD F,HEMPEL C,COMBES V,et al.Differential microRNA expression in experimental cerebral and noncerebral malaria[J].Infect Immun,2011,79(6):2379-2384.
[79] MORISHITA A,OURA K,TADOKORO T,et al.MicroRNA interference in hepatic host-pathogen interactions[J].Int J Mol Sci,2021,22(7):3554.
[80] CAI P F,PIAO X Y,LIU S,et al.MicroRNA-gene expression network in murine liver during Schistosoma japonicum infection[J].PLoS One,2013,8(6):e67037.
[81] HAKIMI M A,CANNELLA D.Apicomplexan parasites and subversion of the host cell microRNA pathway[J].Trends Parasitol,2011,27(11):481-486.
[82] ZEINER G M,NORMAN K L,THOMSON J M,et al.Toxoplasma gondii infection specifically increases the levels of key host microRNAs[J].PLoS One,2010,5(1):e8742.
[83] ZOU Y,MENG J X,WEI X Y,et al.CircRNA and miRNA expression analysis in livers of mice with Toxoplasma gondii infection[J].Front Cell Infect Microbiol,2022,12:1037586.
[84] ZHOU C X,AI K,HUANG C Q,et al.miRNA and circRNA expression patterns in mouse brain during toxoplasmosis development[J].BMC Genomics,2020,21(1):46.
[85] POPE S M,L SSER C.Toxoplasma gondii infection of fibroblasts causes the production of exosome-like vesicles containing a unique array of mRNA and miRNA transcripts compared to serum starvation[J].J Extracell Vesicles,2013,2(1):22484.
[86] DIAZ J H,WARREN R J,OSTER M J.The disease ecology,epidemiology,clinical manifestations,and management of trichinellosis linked to consumption of wild animal meat[J].Wilderness Environ Med,2020,31(2):235-244.
[87] LIU X L,SONG Y X,LU H J,et al.Transcriptome of small regulatory RNAs in the development of the zoonotic parasite Trichinella spiralis[J].PLoS One,2011,6(11):e26448.
[88] 馬小涵.旋毛蟲感染宿主血清中差異miRNA的功能及診斷價值研究[D].鄭州:鄭州大學(xué),2020.
MA X H.Research on the functions and diagnostic values of altered miRNA in the serum of hosts infected with Trichinella spiralis[D].Zhengzhou:Zhengzhou University,2020.(in Chinese)
[89] YANG S F,ABDULLA R,LU C,et al.Inhibition of microRNA-376b protects against renal interstitial fibrosis via inducing macrophage autophagy by upregulating Atg5 in mice with chronic kidney disease[J].Kidney Blood Press Res,2018,43(6):1749-1764.
[90] XING Q W,XIE H Y,ZHU B Y,et al.MiR-455-5p suppresses the progression of prostate cancer by targeting CCR5[J].BioMed Res Int,2019,2019:6394784.
(編輯 范子娟)