2. 中国农业大学动物医学院, 北京 100193;
3. 内蒙古自治区农牧业科学研究院, 呼和浩特 010031
2. College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
3. Inner Mongolia Academy of Agricultural & Animal Husbandry Sciences, Hohhot 010031, China
我国畜牧业集约化养殖模式不断趋于成熟并广而用之，近十年来，猪、牛、羊年存栏量分别稳定在4亿头、9 000万头和3亿只左右。但随着集约化饲养模式的推广、饲养空间的高密度利用以及早期断奶技术的实施，各种应激源成为了制约行业发展的要点所在[1]。大量研究表明，热应激、冷应激、断奶应激、运输应激、氧化应激等均会导致动物机体免疫功能紊乱，诱发炎症反应，降低对疾病的抵抗力[2-4]。肠道作为哺乳动物最大的消化与免疫器官，在应激刺激下极易受损。应激会导致肠黏膜屏障损伤，造成肠道微生态失衡，细菌毒素等病原体更易侵入，引发肠道甚至全身的剧烈炎性反应，从而抑制动物的生长发育，大幅降低其生产性能[5-6]。对于免疫系统还未完全建立的幼畜来说，应激会导致直肠升温，腹泻率增加，且肠道损伤的影响会持续到其成年阶段，制约产业发展[6-7]。
miRNA是在转录水平上调控相应蛋白表达的一类内源性的可通过RNAi作用于靶mRNA的非编码RNA，长度约为22 nt。miRNA广泛参与细胞发育、增殖、组织分化及胚胎凋亡等生理过程，且与疾病的发生、发展息息相关[8-9]。miRNA与肠黏膜屏障功能密切相关[10-12]，其参与免疫细胞增殖、肠道菌群定植、机体内环境稳态维持，是潜在的免疫与炎症调节因子[13]，且有研究证实miRNA参与应激引起的肠黏膜屏障功能调控[14]。本文综述了应激导致肠黏膜各屏障功能受损情况、miRNA介导应激状态下幼畜肠黏膜屏障功能调控机制及miRNA在营养素靶向调控幼畜肠黏膜屏障功能中的作用。
1 miRNA的生物合成及生物学功能miRNA是一类可调控基因表达的内源性非编码单链小分子RNA，是最为丰富的基因家族之一，几乎影响着机体内部所有的信号通路。多数miRNA的生物发生起始于细胞核，DNA在RNA聚合酶Ⅱ的作用下转录形成具有发夹结构的由33~35 bp组成的pri-miRNA，再经过核糖核酸酶Ⅲ (RNase Ⅲ)-Drosha作用后转变成长度约为70 nt的pre-miRNA，与转运蛋白5(Exportin5)结合到Ran-GTP形成转运复合物出核转运至细胞质。在胞质内，复合物解体释放出的pre-miRNA被RNase Ⅲ-Dicer识别并修剪成长度约22 nt的双链RNA，其中一条链与AGO1蛋白结合，形成RNA诱导沉默复合体(RNA-induced silencing complex, RISC)，即为成熟的miRNA(图 1)[15-16]。自2005年起，猪[17]、羊[18]、鸡[19]、牛[20]的miRNA不断被发现，揭开了miRNA在家畜领域的神秘面纱。哺乳动物miRNA通过在转录后水平上抑制特定的靶基因表达，对机体的各项生物学功能发挥至关重要的作用[8]。目前，已有大量研究证实miRNA在家畜的肌肉发育[21-23]、脂肪沉积[23-24]、生殖调控[25-26]和疾病发生[27-29]等多项生理病理过程中发挥重要作用。
miRNA在哺乳动物肠道中广泛存在，种类繁多、数量丰富。2007年，Coutinho等[20]在犊牛中鉴定得到187个小肠组织中特异表达的miRNAs；2008年，Sharbati-Tehrani等[29]在猪肠道组织中鉴定得到7种miRNAs；随着研究的不断深入，已经鉴定出多种动物肠道组织中的miRNA表达谱(表 1)[30]。多项研究表明，miRNA介导肠黏膜屏障功能，在维持肠道形态结构和内环境稳态方面发挥重要作用。研究miRNA对肠黏膜屏障的调节作用，能够为深入了解幼畜应激状态下肠损伤机制、添加外源营养素靶向缓解肠损伤提供有力支撑。
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表 1 家畜肠道组织高表达miRNAs Table 1 High expression miRNAs in intestine of farm animals |
肠黏膜是动物体内与体外接触的最大界面，主要扮演着“守卫”的角色，能够允许营养物质通过，而禁止细菌、病毒等致病性物质流通。肠黏膜屏障是肠黏膜阻止肠道内有毒有害物质入侵的立体防御系统，由内到外主要是由微生物屏障、化学屏障、物理屏障和免疫屏障四部分构成[31]。正常状态下，四类肠黏膜屏障为维持肠道结构与功能稳定协同互作，共同抵御外来病原体侵害，保持菌群平衡，调节免疫功能，维持肠道内环境稳态。
应激通常是指机体在应对各种内外非常刺激时所产生的非特异性应答反应的总和。在畜牧生产过程中，畜禽往往会遭受到各类应激源的刺激，当刺激程度超出机体所能承受的范围时，就会诱发应激反应，主要表现为：生理、心理状态不佳；生长发育缓慢；种畜繁殖利用率下降；严重时甚至死亡。由于肠道是哺乳动物最大的消化与免疫器官，当机体遭受外界刺激产生应激反应时，肠道是最早也是最易受损的部位，且最后也最难恢复，极易导致幼畜肠道屏障受损、免疫功能紊乱，因此发生肠易激综合征等病症，降低其生产性能及存活率[7, 21]。应激会打破肠道内环境稳态，损害肠黏膜屏障功能(表 2)，导致机体血液循环不畅、胆汁分泌减少、肠道菌群功能紊乱、肠黏膜通透性增强。这使得肠上皮细胞内线粒体无法维持正常的呼吸作用，产生大量的有毒代谢物，快速穿过肠黏膜进入机体并诱发全身性的炎症反应。对于组织器官尚未发育完全的幼畜来说，免疫水平远不及成年动物，如何调控其肠黏膜屏障功能，保护肠道组织对其发育和存活至关重要。
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表 2 应激破坏肠道黏膜屏障功能 Table 2 Stress disrupted intestinal barrier functions |
2.1.1 微生物屏障功能 肠道是哺乳动物体内最大的细菌库，其内定植有大量的微生物，有益菌与致病菌之间形成微妙的平衡，这就构成了微生物屏障。目前，微生物屏障功能主要表现在益生菌与宿主之间互利共生，既能够分泌细菌素杀菌、阻止致病菌附着、抑制致病菌生长以提高机体免疫力，又能够为机体提供营养物质，还能够保护黏膜、调节机体内环境稳态，保障肠道健康[32-33]。
2.1.2 应激导致微生物屏障功能受损 肠黏膜微生物屏障与物理屏障和免疫屏障之间有较强的协同作用。应激会导致肠黏膜物理屏障功能受损，使肠黏膜上皮通透性增高，致病菌更易黏附、穿透肠黏膜进入肠道组织，打破肠道菌群间的平衡，导致革兰阴性菌过度繁殖、对黏膜的黏附性和侵袭力增加，从而产生大量的内毒素等有毒有害物质，进入机体后诱发更严重的肠黏膜屏障损伤及免疫与炎症反应[33, 43]。正常状态下，肠道内有益菌占绝对优势，而一旦发生应激反应则有可能引起细菌易位，肠道内致病菌蓄积。霍乱弧菌[44]、产气荚膜梭菌[45]、黄曲霉毒素B1[34]等致病菌，可通过破坏细胞间紧密连接、产生内毒素和蛋白酶，导致细胞凋亡，肠上皮渗透性增加、抵御病原体能力降低等，甚至会增加白细胞介素8(interleukin-8, IL-8)、肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)等促炎性细胞因子表达水平，诱发肠道炎症反应，使幼畜出现腹泻、水肿等病理状态[34]。
2.1.3 miRNA介导微生物屏障损伤调控 Singh等[46]通过对比无菌与正常饲养小鼠肠道miRNA表达谱，鉴定出16种差异表达miRNAs，提示miRNA与肠黏膜微生物屏障功能相关。miRNA在维持肠道菌群稳态和促进肠道菌群定植过程中发挥关键作用，肠道微生物同样可通过调节宿主miRNA表达影响机体健康[47]。在断奶应激条件下，miR-136、miR-196b、miR-4995p和miR-218-3p与仔猪抵抗E. coli F18入侵的能力相关[48]；miR-146a可通过激活Toll样受体(Toll like receptor，TLR)/NF-κB信号通路，缓解致病菌诱导的肠黏膜损伤[49]。粪肠球菌可促进仔猪肠道免疫细胞中miR-423-5p的表达，进而参与免疫调控[50]；miR-21-3p、miR-26b、miR-27a、miR-134-5p、miR-542-5p和miR-671在羊肠道组织对E. granulosus的反应中发挥重要作用[51]；miR-29d-3p、miR-211、miR-378b、miR-2284d、miR-2284j和miR-2887家族在牛肠道E. coli O157的脱落中具备潜在的调节作用[52]；Bacillus licheniformis H2可通过上调miR-200a-3p、miR-215-5p和miR-34a-5p的表达，激活Notch和丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)等免疫与炎症相关的信号通路缓解亚临床坏死性肠炎[53]。综上，应激状态下，miRNA可介导TLR/NF-κB、MAPK、Notch等信号通路调控肠道菌群稳态。
2.2 miRNA与化学屏障2.2.1 化学屏障功能 化学屏障是指胃肠道分泌的胃酸、胆汁、各种消化酶、糖蛋白、糖脂等化学物质，通过抑制致病菌黏附与定植、裂解致病菌、黏附破坏抗原、降解内毒素分子，起到杀菌、消炎、清除内毒素和自由基等作用，将肠道组织与菌群隔离开，保护机体不被病菌入侵的同时防止肠道组织被降解[31, 54]。
2.2.2 应激导致化学屏障功能受损 应激状态下机体肠黏膜化学屏障损伤，主要是由于机体采食量下降，肠道上皮受食物磨损减少、消化道激素刺激减弱，肠黏膜更新修复缓慢；同时胃酸、胆汁、溶菌酶和黏多糖等分泌减少，且肠道内压力较低，更易流失上述物质，故肠道消化液的化学杀菌能力减弱[55-56]。应激还会导致肠黏膜化学屏障的骨架成分黏蛋白2分泌与表达异常、O型寡糖链的糖基化程度增强，从而丧失对肠上皮细胞的保护作用，诱发肠道炎症反应[35, 57]。此外，应激会导致免疫屏障中杯状细胞受损，糖蛋白表达减少，使致病菌及其代谢产物更易破坏化学屏障[35]。
2.2.3 miRNA介导化学屏障损伤调控 有关于miRNA直接调控化学屏障功能的研究相对较少，主要集中于调控黏蛋白表达及其糖基化程度，参与细菌黏附与定植过程，Goto等[58]发现miRNA参与调控小肠上皮杯状细胞分化，调控黏蛋白表达；miR-124-3p[59]、miR-1-3p[60]通过直接靶向O-糖基化的限速酶T-合成酶调控O-糖基化，破坏肠黏膜化学屏障，诱发肠道炎症。此外，Liao等[22]发现断奶应激条件下，羔羊体内调控胆汁分泌过程的miRNA表达异常；miR-195作为一种肠上皮特异性miRNA，可减少溶菌酶含量，破坏肠黏膜屏障，使其对病菌易感性增强[36]。
2.3 miRNA与物理屏障2.3.1 物理屏障功能 物理屏障则主要由肠黏膜表面的黏液层(杯状细胞分泌)、肠上皮细胞及细胞间的紧密连接构成，既能够抵御外界有毒有害物质入侵，又可以阻止肠道内容物渗出，起到选择性透过作用，也有促进肠道蠕动的功能[6, 54]。细胞间连接主要包括有紧密连接、缝隙连接、黏附连接及桥粒连接等，其中紧密连接是由咬合蛋白(occludin)、闭锁小带蛋白(zonula occludens, ZO)、闭合蛋白(claudin)和连接黏附因子(junctional adhesion molecule, JAM)组成，是发挥肠黏膜屏障功能的结构基础[54]。
2.3.2 应激导致物理屏障功能受损 应激会导致羔羊[37]、仔猪[38]、雏鸭[61]、犊牛[39]肠道黏膜隐窝增生、肠绒毛高度萎缩甚至糜烂出血；还会导致仔猪[40]、小鼠[62]、犊牛[39]肠道上皮细胞紧密连接蛋白ZO-1、Occludin等表达量下降，肠道通透性异常增加。其诱发肠黏膜机械屏障功能损伤的机制主要为：应激导致机体血液循环不畅，流经肠道的血流量减少，肠黏膜缺氧缺血，导致肠道上皮水肿、细胞坏死、凋亡，紧密连接功能丧失，肠道通透性增强，进而诱发细菌易位，活性氧自由基、炎性细胞因子等进一步破坏肠黏膜物理屏障，导致疾病发生[5-7]。
2.3.3 miRNA介导物理屏障损伤调控 miRNA通过调控肠上皮细胞增殖与凋亡、杯状细胞分化和紧密连接蛋白表达水平，参与肠黏膜物理屏障调控。Zhang等[61]发现，miR-217-5p可能通过调节雏鸭肠道CHRDL1表达，以缓解应激状态下肠绒毛高度降低，隐窝深度增加的现象；Liu等[63]通过敲除小鼠肠上皮细胞Dicer1基因，诱导let-7b缺失，发现细胞凋亡增多，细胞迁移加速，炎性因子分泌上升，而肠黏膜中ZO-1、occludin、claudin表达减少，肠黏膜物理屏障受损，肠道通透性增强。多项研究表明，miR-101、miR-17和miR-27a介导蛋白质丝氨酸酪氨酸激酶(protein kinase B, AKT)、核因子2相关因子2(the nuclear factor-E2-related factor 2, Nrf2)、MAPK信号通路参与细胞的增殖、迁移、侵袭及凋亡过程以调控氧化应激诱导的细胞坏死和凋亡[32]；miR-21-5p、miR-99a-5p、miR-146b、miR-145、miR-2285t、miR-133a和miR-29c通过靶向Wnt、转化生长因子-β(transforming growth factor-β, TGF-β)、MAPK、Notch和酪氨酸蛋白激酶/信号传导与转录激活因子(Janus kinase/signal transducers and activators of transcription，JAK/STAT)相关信号通路调控热应激状态下细胞损伤与凋亡过程[64-65]；miR-17-5p[66]和miR-210[67]介导JAK1/STAT通路分别在应激状态下发挥抗糜烂、抗凋亡作用；miR-191a通过促进TNF-α表达，激活NF-κB信号通路，调控ZO-1的表达水平[68]；miR-200c-3p通过激活磷脂酰肌醇-3-激酶(phosphatidylinositol-3-kinase, PI3K)/AKT信号通路，增强ZO-1和occludin的表达水平，缓解应激条件下的肠黏膜物理屏障损伤[56]；然而，miR-124a[69]、miR-21[70]过表达，会降低紧密连接蛋白occludin和ZO-1的表达水平，增加肠上皮通透性，诱发肠道炎症反应。综上，应激状态下，miRNA可介导JAK/STAT、MAPK、TGF-β、Nrf2、PI3K/AKT、Wnt、Notch、NF-κB等信号通路调控肠黏膜物理屏障功能。
2.4 miRNA与免疫屏障2.4.1 免疫屏障功能 由于肠道内细胞群长期暴露在富含有大量的微生物、病原菌、内毒素等代谢产物的环境中，肠黏膜为适应环境逐渐形成了由淋巴滤泡和黏膜固有层中的弥散淋巴组织组成的独特的免疫系统，即免疫屏障[71]。作为免疫反应的起始点，淋巴滤泡主要由Peyer结(Peyer’s patches，PPs)、M细胞(Microfold cells，MCs)和树突状细胞(Dendritic cells，DCs)构成[6, 71]，主要作用就是捕捉、处理并呈递抗原；到达效应部位后，则是由肠黏膜固有层中的淋巴组织分泌特应性抗体(IgA、IgM、IgE)并分化成熟的免疫细胞发挥作用[72-73]，具体参与肠黏膜免疫屏障的细胞类型及其作用方式如图 2所示。
2.4.2 应激导致免疫屏障功能受损 应激会导致幼畜肠道内积累大量的活性氧(reactive oxygen species，ROS)、脂多糖(Lipopolysaccharide, LPS)等有毒代谢物，诱发肠黏膜损伤，并通过损害杯状细胞以减少sIgA分泌、延缓黏液流动、影响炎性细胞因子分泌、改变机体内激素水平等方式限制机体自身免疫系统发挥功能，导致肠黏膜屏障功能受损，诱发肠道炎症反应。应激状态下，机体血液循环不畅，营养供给不足，肠黏膜中B淋巴细胞分化受阻，浆细胞数量下降，导致分泌型免疫球蛋白A(seceretory immunoglobulin A, sIgA)分泌减少，对有害菌的消除能力减弱，T淋巴细胞功效大打折扣，肠黏膜抗感染能力削弱[5-6, 74]。由于应激会破坏肠黏膜化学屏障功能，使机体内胆汁分泌减少，sIgA借由胆汁分泌进入肠腔的量也随之减少[22]。同时，应激会导致肠黏膜中杯状细胞受损，黏蛋白分泌减少，延缓肠黏膜表面黏液流动，难以阻止细菌对肠黏膜的黏附[35]。另外，大量研究证实，应激可能通过改变机体内激素水平，影响肠黏膜免疫功能发挥，这一过程与转录反应具有一定的关联性[41]。Biolatti等[75]在2010年揭示了氧化应激具有增加糖皮质激素含量的作用，且糖皮质激素对于犊牛胸腺萎缩具有诱导作用、对免疫应答具有抑制作用；Zhang等[42]发现，断奶应激也会导致犊牛血浆内皮质醇激素含量升高，并通过交感-肾上腺轴刺激免疫细胞分泌促炎细胞因子。而且应激会导致犊牛血液中IL-1、TNF-α等促炎细胞因子增多，而嗜中性粒细胞数与淋巴细胞数减少[42]；仔猪血浆IFN-γ、IL-1β、TNF-α等基因表达水平显著升高，诱发肠道炎症反应[3]。
2.4.3 miRNA介导免疫屏障损伤调控 目前已经发现miRNA参与氧化应激引起的肠黏膜免疫屏障功能调控[14]，并参与猪[27]、牛[28]、羊[29]免疫与炎症反应过程。Han等[37]基于RNA-seq和iTRAQ技术联合分析了断奶羔羊肠道组织在转录和翻译水平的变化情况，推测miRNA可能通过转录后调控参与免疫和活性氧应答调节。Do等[76]发现，miR-15b通过靶向IKBKB调控断奶应激条件下犊牛免疫功能；miR-146b靶向TLR4介导仔猪肠上皮细胞凋亡与免疫应答[27]，还可通过负反馈调节介导白细胞介素1受体相关激酶(interleukin 1 receptor-associated kinase, IRAK1)和TGF-β信号通路参与肠黏膜免疫调控[64]。miRNA还可调控肠道固有免疫系统和特异性免疫系统，如miRNA参与调控小肠上皮杯状细胞分化并促进Th2的免疫与抗炎反应[58]；miR-195[36]抑制小肠上皮中潘氏细胞的功能；miR-155[77]、miR-21-5p[78]分别介导树突状细胞、巨噬细胞凋亡与增殖调控；miR-200a-3p[79]、miR-21[80]、miR-221和miR-222[81]、miR-155[77]分别调控Th1、Th2细胞分化、肠道Th17细胞应答及肠道Treg细胞增殖。近年来，多项研究结果发现，miR-19b、miR-20a、miR-29a、miR-182、miR-223等miRNAs的表达可以调控激活PI3K/AKT信号通路，从而增强应激条件下细胞的生物学功能[82]；let-7f、miR-9、miR-27a/b、miR-28-5p、miR-96、miR-145和miR-486-5p等可通过靶向叉头转录因子(forkhead transcription factor 1, FOXO1)调控免疫细胞下游靶基因的表达，而若miRNA缺失，FOXO1的磷酸化及降解都会受阻[83-84]。此外，miR-146a可以与TLR转导所必须的多种分子结合，并对NF-κB敏感且参与调节应激引起的细胞炎症反应[58, 85]；miR-34a和miR-181a介导NF-κB信号通路参与应激反应调控[86]；miR-21、miR-125、miR-146a、miR-155等能够负向调控TLR/NF-κB信号通路介导的免疫炎症反应[87-88]。而miR-17-5p可介导JAK1/STAT3通路发挥抗炎作用[66]；miR-146a可介导JAK/STAT通路改善炎症反应，减缓应激损伤[66]。综上，应激状态下，miRNA可介导TGF-β、PI3K/AKT/FOXO1(图 3)、TLR/NF-κB、JAK/STAT等信号通路调控肠黏膜免疫应答过程。
|
图 3 PI3K/AKT/FOXO1参与肠道黏膜免疫应答调控[83] Fig. 3 PI3K/AKT/FOXO1 involved in the regulation of intestinal mucosal immune response[83] |
发掘更优质、更高效的外源添加剂，以缓解幼畜培育过程中肠黏膜屏障功能损伤，已经成为行业研究热点。近年来，已有大量研究发现，添加外源性添加剂能够通过miRNA介导的肠黏膜屏障功能调控作用，缓解肠黏膜损伤。阿魏酸通过上调miR-200c-3p的表达水平，激活PI3K/AKT信号通路，增加ZO-1和occludin蛋白表达，缓解内毒素诱导的肠上皮屏障功能损伤[56]；柚皮素可通过上调miR-22水平，抑制核苷酸结合寡聚化结构域样受体蛋白3(nucleotide-binding oligomerization domain-like receptor protein 3, NLRP3)炎症小体活化，缓解DSS诱导的大鼠小肠组织黏膜结构破坏、炎症细胞浸润、ZO-1、occludin和claudin-1蛋白表达水平下调等肠黏膜屏障功能受损情况[89]；大黄素可通过下调miR-218a-5p介导过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptor, PPAR)、内皮型一氧化氮合酶(endothelial nitric oxide synthase, eNOs)、JAK/STAT通路活性，增强肠道组织蠕动，抑制炎性因子释放，调控凋亡基因Bcl-2和Bax表达水平，清除活性氧自由基，缓解应激诱发的肠上皮细胞损伤，维护肠黏膜屏障完整性[55, 90]；参苓白术散通过调控miR-21、miR-150和miR-200b的表达水平，改变Claudin-1蛋白表达，同样对肠上道皮损伤具有明显改善的作用[91]。王莉[68]发现黄岑苷通过抑制乏氧诱导因子-1(hypoxia-inducible factor-1，HIF-1)与乏氧反应元件(hypoxia response element，HRE)结合，从而下调miR-191a的转录水平，抑制TNF-α等促炎因子表达，保护紧密连接蛋白ZO-1，而TNF-α是介导NF-κB信号通路诱导肠上皮通透性增加的，推测黄岑苷可介导NF-κB信号通路缓解应激导致的肠黏膜免疫损伤。综上，发掘能够调控miRNA表达水平，介导幼畜肠黏膜屏障功能的外源添加剂，并深入探讨其作用机制，已经成为时下研究的关键所在。
4 小结在现代养殖模式下，应激是制约畜牧业集约化发展的突出问题之一，多种应激源均可导致幼畜肠道损伤。miRNA可通过PI3K/AKT/FOXO1、TLR/NF-κB、JAK/STAT、MAPK或Notch等通路调控肠上皮细胞增殖与凋亡、免疫和活性氧应答等生理过程，介导应激诱发的幼畜肠道损伤。另外，研究已经表明miRNA在外源物质改善肠黏膜屏障损伤过程中发挥重要作用，但miRNA介导幼畜肠黏膜损伤的作用机制还有待进一步研究。同时，miRNA在多种外源添加剂中的作用及如何利用这一机制开发新的外源添加剂，仍需大量研究进行探索完善。本文通过揭示miRNA调控应激状态下肠道损伤的具体机制，为通过营养干预降低应激引起的幼畜肠黏膜屏障损伤提供理论支撑，同时为在饲料全面禁抗背景下，寻求经济效益更高、使用效果更好的营养素提供了新的探索方向。
| [1] |
CHAUHAN S S, RASHAMOL V P, BAGATH M, et al. Impacts of heat stress on immune responses and oxidative stress in farm animals and nutritional strategies for amelioration[J]. Int J Biometeorol, 2021, 65(7): 1231-1244. DOI:10.1007/s00484-021-02083-3 |
| [2] |
BAGATH M, KRISHNAN G, DEVARAJ C, et al. The impact of heat stress on the immune system in dairy cattle: A review[J]. Res Vet Sci, 2019, 126: 94-102. DOI:10.1016/j.rvsc.2019.08.011 |
| [3] |
NOVAIS A K, DESCHÊNE K, MARTEL-KENNES Y, et al. Weaning differentially affects mitochondrial function, oxidative stress, inflammation and apoptosis in normal and low birth weight piglets[J]. PLoS One, 2021, 16(2): e0247188. DOI:10.1371/journal.pone.0247188 |
| [4] |
GE J, LI H, SUN F, et al. Transport stress-induced cerebrum oxidative stress is not mitigated by activating the Nrf2 antioxidant defense response in newly hatched chicks[J]. J Anim Sci, 2017, 95(7): 2871-2878. |
| [5] |
KOCH F, THOM U, ALBRECHT E, et al. Heat stress directly impairs gut integrity and recruits distinct immune cell populations into the bovine intestine[J]. Proc Natl Acad Sci U S A, 2019, 116(21): 10333-10338. DOI:10.1073/pnas.1820130116 |
| [6] |
MOESER A J, POHL C S, RAJPUT M. Weaning stress and gastrointestinal barrier development: implications for lifelong gut health in pigs[J]. Anim Nutr, 2017, 3(4): 313-321. DOI:10.1016/j.aninu.2017.06.003 |
| [7] |
POHL C S, MEDLAND J E, MACKEY E, et al. Early weaning stress induces chronic functional diarrhea, intestinal barrier defects, and increased mast cell activity in a porcine model of early life adversity[J]. Neurogastroenterol Motil, 2017, 29(11): e13118. DOI:10.1111/nmo.13118 |
| [8] |
BARTEL D P. Metazoan microRNAs[J]. Cell, 2018, 173(1): 20-51. DOI:10.1016/j.cell.2018.03.006 |
| [9] |
CHEN L, HEIKKINEN L, WANG C L, et al. Trends in the development of miRNA bioinformatics tools[J]. Brief Bioinform, 2019, 20(5): 1836-1852. DOI:10.1093/bib/bby054 |
| [10] |
EARLEY H, LENNON G, BALFE Á, et al. The abundance of Akkermansia muciniphila and its relationship with sulphated colonic mucins in health and ulcerative colitis[J]. Sci Rep, 2019, 9(1): 15683. DOI:10.1038/s41598-019-51878-3 |
| [11] |
SCHÖNAUEN K, LE N, VON ARNIM U, et al. Circulating and fecal microRNAs as biomarkers for inflammatory bowel diseases[J]. Inflamm Bowel Dis, 2018, 24(7): 1547-1557. DOI:10.1093/ibd/izy046 |
| [12] |
MAHURKAR-JOSHI S, RANKIN C R, VIDELOCK E J, et al. The colonic mucosal microRNAs, microRNA-219a-5p, and microRNA-338-3p are downregulated in irritable bowel syndrome and are associated with barrier function and MAPK signaling[J]. Gastroenterology, 2021, 160(7): 2409-2422. DOI:10.1053/j.gastro.2021.02.040 |
| [13] |
MOMEN-HERAVI F, BALA S. miRNA regulation of innate immunity[J]. J Leukoc Biol, 2018, 103(6): 1205-1217. DOI:10.1002/JLB.3MIR1117-459R |
| [14] |
ENGEDAL N, ŽEROVNIK E, RUDOV A, et al. From oxidative stress damage to pathways, networks, and autophagy via microRNAs[J]. Oxid Med Cell Longev, 2018, 2018: 4968321. |
| [15] |
RANI V, SENGAR R S. Biogenesis and mechanisms of microRNA-mediated gene regulation[J]. Biotechnol Bioeng, 2022, 119(3): 685-692. DOI:10.1002/bit.28029 |
| [16] |
KHVOROVA A, REYNOLDS A, JAYASENA S D. Functional siRNAs and miRNAs exhibit strand bias[J]. Cell, 2003, 115(2): 209-216. DOI:10.1016/S0092-8674(03)00801-8 |
| [17] |
SAWERA M, GORODKIN J, CIRERA S, et al. Mapping and expression studies of the mir17-92 cluster on pig chromosome 11[J]. Mamm Genome, 2005, 16(8): 594-598. DOI:10.1007/s00335-005-0013-3 |
| [18] |
DAVIS E, CAIMENT F, TORDOIR X, et al. RNAi-mediated allelic trans-interaction at the imprinted Rtl1/Peg11 locus[J]. Curr Biol, 2005, 15(8): 743-749. DOI:10.1016/j.cub.2005.02.060 |
| [19] |
XU H T, WANG X B, DU Z L, et al. Identification of microRNAs from different tissues of chicken embryo and adult chicken[J]. FEBS Lett, 2006, 580(15): 3610-3616. DOI:10.1016/j.febslet.2006.05.044 |
| [20] |
COUTINHO L L, MATUKUMALLI L K, SONSTEGARD T S, et al. Discovery and profiling of bovine microRNAs from immune-related and embryonic tissues[J]. Physiol Genomics, 2007, 29(1): 35-43. DOI:10.1152/physiolgenomics.00081.2006 |
| [21] |
TONG H L, JIANG R Y, LIU T T, et al. bta-miR-378 promote the differentiation of bovine skeletal muscle-derived satellite cells[J]. Gene, 2018, 668: 246-251. DOI:10.1016/j.gene.2018.03.102 |
| [22] |
LIAO R R, LV Y H, ZHU L H, et al. Altered expression of miRNAs and mRNAs reveals the potential regulatory role of miRNAs in the developmental process of early weaned goats[J]. PLoS One, 2019, 14(8): e0220907. DOI:10.1371/journal.pone.0220907 |
| [23] |
IQBAL A, PING J, ALI S, et al. Role of microRNAs in myogenesis and their effects on meat quality in pig-A review[J]. Asian-Australas J Anim Sci, 2020, 33(12): 1873-1884. DOI:10.5713/ajas.20.0324 |
| [24] |
WANG X G, YU J F, ZHANG Y, et al. Identification and characterization of microRNA from chicken adipose tissue and skeletal muscle[J]. Poult Sci, 2012, 91(1): 139-149. DOI:10.3382/ps.2011-01656 |
| [25] |
HONG L J, LIU R Z, QIAO X W, et al. Differential microRNA expression in porcine endometrium involved in remodeling and angiogenesis that contributes to embryonic implantation[J]. Front Genet, 2019, 10: 661. DOI:10.3389/fgene.2019.00661 |
| [26] |
DONADEU F X, SANCHEZ J M, MOHAMMED B T, et al. Relationships between size, steroidogenesis and miRNA expression of the bovine corpus luteum[J]. Theriogenology, 2020, 145: 226-230. DOI:10.1016/j.theriogenology.2019.10.033 |
| [27] |
TAO X, LIU S J, MEN X, et al. Over-expression of miR-146b and its regulatory role in intestinal epithelial cell viability, proliferation, and apoptosis in piglets[J]. Biol Direct, 2017, 12(1): 27. DOI:10.1186/s13062-017-0199-9 |
| [28] |
QI X F, LI Z, LI H, et al. MicroRNA-1 negatively regulates peripheral NK cell function via Tumor Necrosis Factor-like Weak Inducer of Apoptosis (TWEAK) signaling pathways during PPRV infection[J]. Front Immunol, 2020, 10: 3066. DOI:10.3389/fimmu.2019.03066 |
| [29] |
SHARBATI-TEHRANI S, KUTZ-LOHROFF B, BERGBAUER R, et al. miR-Q: A novel quantitative RT-PCR approach for the expression profiling of small RNA molecules such as miRNAs in a complex sample[J]. BMC Mol Biol, 2008, 9: 34. DOI:10.1186/1471-2199-9-34 |
| [30] |
HOU L, JI Z B, WANG G Z, et al. Identification and characterization of microRNAs in the intestinal tissues of sheep (Ovis aries)[J]. PLoS One, 2018, 13(2): e0193371. DOI:10.1371/journal.pone.0193371 |
| [31] |
LIAN P Q, BRABER S, VARASTEH S, et al. Hypoxia and heat stress affect epithelial integrity in a Caco-2/HT-29 co-culture[J]. Sci Rep, 2021, 11(1): 13186. DOI:10.1038/s41598-021-92574-5 |
| [32] |
LAM S, BAI X W, SHKOPOROV A N, et al. Roles of the gut virome and mycobiome in faecal microbiota transplantation[J]. Lancet Gastroenterol Hepatol, 2022, 7(5): 472-484. DOI:10.1016/S2468-1253(21)00303-4 |
| [33] |
HARRIS L A, BAFFY N. Modulation of the gut microbiota: A focus on treatments for irritable bowel syndrome[J]. Postgrad Med, 2017, 129(8): 872-888. DOI:10.1080/00325481.2017.1383819 |
| [34] |
CAO Q Q, LIN L X, XU T T, et al. Aflatoxin B1 alters meat quality associated with oxidative stress, inflammation, and gut-microbiota in sheep[J]. Ecotoxicol Environ Saf, 2021, 225: 112754. DOI:10.1016/j.ecoenv.2021.112754 |
| [35] |
JOHANSSON M E V, HANSSON G C. Immunological aspects of intestinal mucus and mucins[J]. Nat Rev Immunol, 2016, 16(10): 639-649. DOI:10.1038/nri.2016.88 |
| [36] |
KWON M S, CHUNG H K, XIAO L, et al. MicroRNA-195 regulates Tuft cell function in the intestinal epithelium by altering translation of DCLK1[J]. Am J Physiol Cell Physiol, 2021, 320(6): C1042-C1054. DOI:10.1152/ajpcell.00597.2020 |
| [37] |
HAN L L, TAO H, KANG L Y, et al. Transcriptome and iTRAQ-Based proteome reveal the molecular mechanism of intestinal injury induced by weaning Ewe's milk in lambs[J]. Front Vet Sci, 2022, 9: 809188. DOI:10.3389/fvets.2022.809188 |
| [38] |
LIU L, WU C M, CHEN D W, et al. Selenium-enriched yeast alleviates oxidative stress-induced intestinal mucosa disruption in weaned pigs[J]. Oxid Med Cell Longev, 2020, 2020: 5490743. |
| [39] |
王亚芳. 黄芪甲苷对犊牛抗氧化功能的影响及其作用机制的研究[D]. 济南: 山东师范大学, 2020. WANG Y F. Research about the effect of Astragaloside Ⅳ on antioxidant function and correlative action mechanism of calves[D]. Jinan: Shandong Normal University, 2020. (in Chinese) |
| [40] |
CAO S T, WANG C C, WU H, et al. Weaning disrupts intestinal antioxidant status, impairs intestinal barrier and mitochondrial function, and triggers mitophagy in piglets[J]. J Anim Sci, 2018, 96(3): 1073-1083. DOI:10.1093/jas/skx062 |
| [41] |
FRANCO L M, GADKARI M, HOWE K N, et al. Immune regulation by glucocorticoids can be linked to cell type-dependent transcriptional responses[J]. J Exp Med, 2019, 216(2): 384-406. DOI:10.1084/jem.20180595 |
| [42] |
ZHANG Q, LI C, NIU X L, et al. An intensive milk replacer feeding program benefits immune response and intestinal microbiota of lambs during weaning[J]. BMC Vet Res, 2018, 14(1): 366. DOI:10.1186/s12917-018-1691-x |
| [43] |
BHATTACHARYYA A, CHATTOPADHYAY R, MITRA S, et al. Oxidative stress: An essential factor in the pathogenesis of gastrointestinal mucosal diseases[J]. Physiol Rev, 2014, 94(2): 329-354. DOI:10.1152/physrev.00040.2012 |
| [44] |
PÉREZ-REYTOR D, JAÑA V, PAVEZ L, et al. Accessory toxins of Vibrio pathogens and their role in epithelial disruption during infection[J]. Front Microbiol, 2018, 9: 2248. DOI:10.3389/fmicb.2018.02248 |
| [45] |
VECCHIO A J, STROUD R M. Claudin-9 structures reveal mechanism for toxin-induced gut barrier breakdown[J]. Proc Natl Acad Sci U S A, 2019, 116(36): 17817-17824. DOI:10.1073/pnas.1908929116 |
| [46] |
SINGH N, SHIRDEL E A, WALDRON L, et al. The murine caecal microRNA signature depends on the presence of the endogenous microbiota[J]. Int J Biol Sci, 2012, 8(2): 171-186. DOI:10.7150/ijbs.8.171 |
| [47] |
LI M H, CHEN W D, WANG Y D. The roles of the gut microbiota-miRNA interaction in the host pathophysiology[J]. Mol Med, 2020, 26(1): 101. DOI:10.1186/s10020-020-00234-7 |
| [48] |
WU Z C, QIN W Y, WU S, et al. Identification of microRNAs regulating Escherichia coli F18 infection in Meishan weaned piglets[J]. Biol Direct, 2016, 11(1): 59. DOI:10.1186/s13062-016-0160-3 |
| [49] |
SABHARWAL H, CICHON C, ÖLSCHLÄGER T A, et al. Interleukin-8, CXCL1, and MicroRNA miR-146a responses to probiotic Escherichia coli Nissle 1917 and Enteropathogenic E.coli in human intestinal epithelial T84 and Monocytic THP-1 cells after apical or Basolateral infection[J]. Infect Immun, 20106, 84(9): 2482-2492. |
| [50] |
KREUZER-REDMER S, BEKURTZ J C, ARENDS D, et al. Feeding of Enterococcus faecium NCIMB 10415 leads to intestinal miRNA-423-5p-Induced regulation of immune-relevant genes[J]. Appl Environ Microbiol, 2016, 82(8): 2263-2269. DOI:10.1128/AEM.04044-15 |
| [51] |
JIANG S, LI X, WANG X H, et al. MicroRNA profiling of the intestinal tissue of Kazakh sheep after experimental Echinococcus granulosus infection, using a high-throughput approach[J]. Parasite, 2016, 23: 23. DOI:10.1051/parasite/2016023 |
| [52] |
WANG O, ZHOU M, CHEN Y H, et al. MicroRNAomes of cattle intestinal tissues revealed possible miRNA regulated mechanisms involved in Escherichia coli O157 fecal shedding[J]. Front Cell Infect Microbiol, 2021, 11: 634505. DOI:10.3389/fcimb.2021.634505 |
| [53] |
ZHAO Y, ZENG D, WANG H S, et al. Analysis of miRNA expression in the ileum of broiler chickens during Bacillus licheniformis H2 supplementation against subclinical necrotic enteritis[J]. Probiotics Antimicro Prot, 2021, 13(2): 356-366. DOI:10.1007/s12602-020-09709-9 |
| [54] |
OSHIMA T, MIWA H. Gastrointestinal mucosal barrier function and diseases[J]. J Gastroenterol, 2016, 51(8): 768-778. DOI:10.1007/s00535-016-1207-z |
| [55] |
石凯歌, 段志军. 大黄素修复肠屏障的研究进展[J]. 中华中医药学刊, 2021, 39(9): 130-133. SHI K G, DUAN Z J. Research progress of Emodin in repair of intestinal barriers[J]. Chinese Archives of Traditional Chinese Medicine, 2021, 39(9): 130-133. (in Chinese) |
| [56] |
HE S S, GUO Y H, ZHAO J X, et al. Ferulic acid ameliorates lipopolysaccharide-induced barrier dysfunction via microRNA-200c-3p-mediated activation of PI3K/AKT pathway in Caco-2 Cells[J]. Front Pharmacol, 2020, 11: 376. DOI:10.3389/fphar.2020.00376 |
| [57] |
YAO D B, DAI W L, DONG M, et al. MUC2 and related bacterial factors: Therapeutic targets for ulcerative colitis[J]. eBioMedicine, 2021, 74: 103751. DOI:10.1016/j.ebiom.2021.103751 |
| [58] |
GOTO Y, KIYONO H. Epithelial cell microRNAs in gut immunity[J]. Nat Immunol, 2011, 12(3): 195-197. DOI:10.1038/ni0311-195 |
| [59] |
HUANG L, SUN T Y, HU L J, et al. Elevated miR-124-3p in the aging colon disrupts mucus barrier and increases susceptibility to colitis by targeting T-synthase[J]. Aging Cell, 2020, 19(11): : e13252. |
| [60] |
SUN T Y, LI Y Q, ZHAO F Q, et al. miR-1-3p and miR-124-3p synergistically damage the intestinal barrier in the ageing colon[J]. J Crohns Colitis, 2022, 16(4): 656-667. DOI:10.1093/ecco-jcc/jjab179 |
| [61] |
ZHANG H, CHEN F, LIANG Z H, et al. Analysis of miRNAs and their target genes associated with mucosal damage caused by transport stress in the mallard duck intestine[J]. PLoS One, 2020, 15(8): e0237699. DOI:10.1371/journal.pone.0237699 |
| [62] |
WU S, PAN L J, LIAO H F, et al. High-fat diet increased NADPH-oxidase-related oxidative stress and aggravated LPS-induced intestine injury[J]. Life Sci, 2020, 253: 117539. DOI:10.1016/j.lfs.2020.117539 |
| [63] |
LIU Z, TIAN Y, JIANG Y, et al. Protective effects of let-7b on the expression of occludin by targeting P38 MAPK in preventing intestinal barrier dysfunction[J]. Cell Physiol Biochem, 2018, 45(1): 343-355. DOI:10.1159/000486815 |
| [64] |
TAO X, XU Z W. MicroRNA transcriptome in swine small intestine during weaning stress[J]. PLoS One, 2013, 8(11): e79343. DOI:10.1371/journal.pone.0079343 |
| [65] |
LI Q L, YANG C H, DU J, et al. Characterization of miRNA profiles in the mammary tissue of dairy cattle in response to heat stress[J]. BMC Genomics, 2018, 19(1): 975. DOI:10.1186/s12864-018-5298-1 |
| [66] |
NAJM A, MASSON F M, PREUSS P, et al. MicroRNA-17-5p reduces inflammation and bone erosions in mice with Collagen-induced arthritis and directly targets the JAK/STAT pathway in rheumatoid arthritis Fibroblast-like synoviocytes[J]. Arthritis Rheumatol, 2020, 72(12): 2030-2039. DOI:10.1002/art.41441 |
| [67] |
YUE J N, LI W M, HONG W Z, et al. miR-210 inhibits apoptosis of vascular endothelial cells via JAK-STAT in arteriosclerosis obliterans[J]. Eur Rev Med Pharmacol Sci, 2019, 23(3 Suppl): 319-326. |
| [68] |
王莉. 黄芩苷通过microRNA对TNF-α诱导的肠上皮细胞通透性的保护机制[D]. 广州: 广州中医药大学, 2017. WANG L. Baicalin protects against TNF-α-induced injury by regulating microRNA in IEC-6 cells[D]. Guangzhou: Guangzhou University of Chinese Medicine, 2017. (in Chinese) |
| [69] |
ZHAO X J, LI J J, MA J J, et al. miR-124a mediates the impairment of intestinal epithelial integrity by targeting aryl hydrocarbon receptor in Crohn's disease[J]. Inflammation, 2020, 43(5): 1862-1875. DOI:10.1007/s10753-020-01259-0 |
| [70] |
LIU Z H, LI C, CHEN S H, et al. MicroRNA-21 increases the expression level of occludin through regulating ROCK1 in prevention of intestinal barrier dysfunction[J]. J Cell Biochem, 2019, 120(3): 4545-4554. DOI:10.1002/jcb.27742 |
| [71] |
PAN F, TANG W, ZHOU Z, et al. Intestinal macrophages in mucosal immunity and their role in systemic lupus erythematosus disease[J]. Lupus, 2018, 27(12): 1898-1902. DOI:10.1177/0961203318797417 |
| [72] |
MICHAUD E, MASTRANDREA C, ROCHEREAU N, et al. Human secretory IgM: an elusive player in mucosal immunity[J]. Trends Immunol, 2020, 41(2): 141-156. DOI:10.1016/j.it.2019.12.005 |
| [73] |
SHACKLETT B L. Mucosal immunity in HIV/SIV infection: T Cells, B cells and beyond[J]. Curr Immunol Rev, 2019, 15(1): 63-75. DOI:10.2174/1573395514666180528081204 |
| [74] |
CHANG C S, KAO C Y. Current understanding of the gut microbiota shaping mechanisms[J]. J Biomed Sci, 2019, 26(1): 59. DOI:10.1186/s12929-019-0554-5 |
| [75] |
BIOLATTI B, BOLLO E, CANNIZZO F T, et al. Effects of low-dose dexamethasone on thymus morphology and immunological parameters in veal calves[J]. J Vet Med A Physiol Pathol Clin Med, 2005, 52(4): 202-208. DOI:10.1111/j.1439-0442.2005.00714.x |
| [76] |
DO D N, DUDEMAINE P L, FOMENKY B E, et al. Integration of miRNA and mRNA co-expression reveals potential regulatory roles of miRNAs in developmental and immunological processes in calf ileum during early growth[J]. Cells, 2018, 7(9): 134. DOI:10.3390/cells7090134 |
| [77] |
CHEN L, GAO D, SHAO Z Z, et al. miR-155 indicates the fate of CD4+ T cells[J]. Immunol Lett, 2020, 224: 40-49. DOI:10.1016/j.imlet.2020.05.003 |
| [78] |
GAO X L, HUANG X Y, YANG Q L, et al. MicroRNA-21-5p targets PDCD4 to modulate apoptosis and inflammatory response to Clostridium perfringens beta2 toxin infection in IPEC-J2 cells[J]. Dev Comp Immunol, 2021, 114: 103849. DOI:10.1016/j.dci.2020.103849 |
| [79] |
PHAM T T, BAN J, HONG Y, et al. MicroRNA gga-miR-200a-3p modulates immune response via MAPK signaling pathway in chicken afflicted with necrotic enteritis[J]. Vet Res, 2020, 51(1): 8. DOI:10.1186/s13567-020-0736-x |
| [80] |
SAWANT D V, WU H, KAPLAN M H, et al. The Bcl6 target gene microRNA-21 promotes Th2 differentiation by a T cell intrinsic pathway[J]. Mol Immunol, 2013, 54(3-4): 435-442. DOI:10.1016/j.molimm.2013.01.006 |
| [81] |
MIKAMI Y, PHILIPS R L, SCIUMÈ G, et al. MicroRNA-221 and -222 modulate intestinal inflammatory Th17 cell response as negative feedback regulators downstream of interleukin-23[J]. Immunity, 2021, 54(3): 514-525. DOI:10.1016/j.immuni.2021.02.015 |
| [82] |
YAO L, YAN H. MiR-182 inhibits oxidative stress and epithelial cell apoptosis in lens of cataract rats through PI3K/Akt signaling pathway[J]. Eur Rev Med Pharmacol Sci, 2020, 24(23): 12001-12008. |
| [83] |
GRAVES D T, MILOVANOVA T N. Mucosal immunity and the FOXO1 transcription factors[J]. Front Immunol, 2019, 10: 2530. DOI:10.3389/fimmu.2019.02530 |
| [84] |
COFFRE M, BENHAMOU D, RIEß D, et al. miRNAs are essential for the regulation of the PI3K/AKT/FOXO pathway and receptor editing during B cell maturation[J]. Cell Rep, 2016, 17(9): 2271-2285. DOI:10.1016/j.celrep.2016.11.006 |
| [85] |
WILLIAMS D L, HA T Z, LI C F, et al. Modulation of tissue Toll-like receptor 2 and 4 during the early phases of polymicrobial sepsis correlates with mortality[J]. Crit Care Med, 2003, 31(6): 1808-1818. DOI:10.1097/01.CCM.0000069343.27691.F3 |
| [86] |
CHELESCHI S, TENTI S, MONDANELLI N, et al. MicroRNA-34a and microRNA-181a mediate Visfatin-induced apoptosis and oxidative stress via NF-κB pathway in human osteoarthritic chondrocytes[J]. Cells, 2019, 8(8): 874. DOI:10.3390/cells8080874 |
| [87] |
LV Z C, CAO X Y, GUO Y X, et al. Effects of MiR-146a on repair and inflammation in rats with spinal cord injury through the TLR/NF-κB signaling pathway[J]. Eur Rev Med Pharmacol Sci, 2019, 23(11): 4558-4563. |
| [88] |
CAO Y X, GUO Y K, ZONG R K, et al. Drug-containing serum of Xinfeng capsules protect against H9C2 from death by enhancing miRNA-21 and inhibiting toll-like receptor 4/phosphorylated p-38(p-p38)/p-p65 signaling pathway and proinflammatory cytokines expression[J]. J Tradit Chin Med, 2018, 38(3): 359-365. DOI:10.1016/S0254-6272(18)30626-5 |
| [89] |
谢春燕, 谢刚, 季语竹. 柚皮素通过miR-22抑制NLRP3炎症小体并减轻溃疡性结肠炎大鼠模型肠屏障损伤[J]. 中国病理生理杂志, 2021, 37(9): 1573-1581. XIE C Y, XIE G, JI Y Z. Naringenin inhibits NLRP3 inflammasome through miR-22 and reduces intestinal barrier damage in a rat model of ulcerative colitis[J]. Chinese Journal of Pathophysiology, 2021, 37(9): 1573-1581. DOI:10.3969/j.issn.1000-4718.2021.09.005 (in Chinese) |
| [90] |
TAN Y, ZHANG W, WU H Y, et al. Effects of emodin on intestinal mucosal barrier by the upregulation of miR-218a-5p expression in rats with acute necrotizing pancreatitis[J]. Int J Immunopathol Pharmacol, 2020, 34: 2058738420941765. |
| [91] |
张志谦, 赵斌, 肖秋平, 等. 基于miR-21、miR-150和miR-200b研究参苓白术散对克罗恩病大鼠肠黏膜屏障的干预机制[J]. 中医临床研究, 2021, 13(25): 8-13. ZHANG Z Q, ZHAO B, XIAO Q P, et al. The intervention mechanism of Shenling Baizhu San on miR-21, miR-150 and miR-200b in intestinal mucosal barrier of rats with Crohn's disease[J]. Clinical Journal of Chinese Medicine, 2021, 13(25): 8-13. DOI:10.3969/j.issn.1674-7860.2021.25.002 (in Chinese) |
(编辑 范子娟)