中文题名: | 基于DHAV-1感染mRNA和microRNA表达谱分析山豆根抗DHAV-1主要成分及其作用、机制研究 |
姓名: | |
学号: | 2021207038 |
保密级别: | 公开 |
论文语种: | chi |
学科代码: | 090603 |
学科名称: | 农学 - 兽医学 - 临床兽医学 |
学生类型: | 博士 |
学位: | 农学博士 |
学校: | 南京农业大学 |
院系: | |
专业: | |
研究方向: | 中兽医学与中兽药学 |
第一导师姓名: | |
第一导师单位: | |
完成日期: | 2025-03-01 |
答辩日期: | 2025-05-29 |
外文题名: | Study on The Main Components of Sophorae Tonkinensis Radix et Rhizoma Against DHAV-1 and Their Mechanisms of Action Based on mRNA and microRNA Expression Profiles Analysis Following DHAV-1 Infection |
中文关键词: | |
外文关键词: | duck viral hepatitis ; Sophorae tonkinensis Radix et Rhizoma ; matrine ; mRNA and microRNA expression profiles ; RLR signaling pathway ; mitophagy |
中文摘要: |
鸭病毒性肝炎(Duck viral hepatitis,DVH)在鸭群中的感染和传播可导致雏鸭大规模死亡、成年鸭产蛋下降,严重危害养鸭业的经济发展。鸭甲型肝炎病毒1型(Duck hepatitis A virus,DHAV-1)是DVH分布最广、最常见的一种病原,可引起雏鸭的神经症状和急性肝炎,导致雏鸭快速死亡,卵黄抗体和疫苗接种是预防DVH的主要措施,但由于人工成本高等问题,部分养殖户不愿使用。因此,开发给药方便、成本低廉的抗病毒药物治疗DHAV-1感染尤为重要。 DVH雏鸭临床表现为里实热证,肝热生风,治则应清热解毒、息风止痉。山豆根(Sophorae tonkinensis Radix et Rhizoma,STR)具有清热解毒等功效,临床上常使用其总生物碱制剂治疗慢性肝炎和肝癌。实验室前期研究已经证实了山豆根多糖对DVH的治疗作用,但山豆根其他的主要成分是否可以抑制DHAV-1还需进一步研究。 病毒感染后宿主基因的变化有利于揭示病毒的致病机制和宿主的相互作用,寻找抗病毒的潜在通路和靶点,有利于推进抗病毒药物的研发。因此,本试验首先探究了DHAV-1感染后宿主mRNA和microRNA表达的变化,识别与DHAV-1感染相关的重要基因和信号通路,证实了DHAV-1感染可影响宿主RLR信号通路、引发线粒体自噬异常和炎症反应。基于筛选出的差异表达基因(Differentially expressed genes,DEGs)和差异表达miRNAs(Differentially expressed miRNAs,DEMs)的靶基因使用网络药理学和分子对接筛选出山豆根中潜在的抗DHAV-1中药成份:槲皮素、山奈酚和苦参碱,并在体外验证其抑制DHAV-1的作用,发现苦参碱具有较好的抗病毒效果。随后,雏鸭体内攻毒保护试验发现中剂量的苦参碱能有效提高DVH雏鸭存活率,减轻肝脏损伤和肝功能异常,缓解氧化应激,激活线粒体自噬,调控RLR信号通路并降低炎症反应。同时,在体外也探究了苦参碱对氧化应激、线粒体自噬、RLR信号通路和炎症反应的调控作用。接下来,使用自噬溶酶体降解抑制剂验证了苦参碱可通过激活线粒体自噬调控干扰素信号通路和炎症反应。试验分为以下五个部分: 试验I:基于mRNA和microRNA表达谱分析DHAV-1感染DEHs的作用机制 本试验旨在探究DHAV-1感染后鸭胚肝细胞(Duck embryonic hepatocytes,DEHs)mRNA和miRNA表达的变化。首先测定了DHAV-1感染DEHs的TCID50,随后使用RT-qPCR法检测不同时间点DHAV-1在DEHs中复制情况。为了阐明DHAV-1感染的潜在机制,本试验采用高通量测序的方法分析了DHAV-1感染后DEHs的mRNA和miRNA表达谱,并使用RT-qPCR法验证部分DEGs和DEMs的表达水平。结果发现DHAV-1的TCID50为10-4.48/0.1 mL,为了保证较高的细胞感染率并避免过度的CPE,我们选择在DHAV-1感染36 hpi时分析。发现了3410个DEGs和142个DEMs,这些DEGs和DEMs表达的靶基因主要与免疫反应、抗病毒信号通路和能量代谢相关。本试验检测了部分DEGs和DEMs在DEHs中的mRNA表达水平,结果与测序结果一致。 试验Ⅱ:基于mRNA和miRNA表达谱分析DHAV-1感染雏鸭的作用机制 本试验旨在探究DHAV-1感染后雏鸭肝脏mRNA和miRNA表达的变化,结合体外结果进行基因集合富集分析筛选关键信号通路。将雏鸭分为空白对照(Blank control,BC)组和病毒对照(Virus control,VC)组,VC组雏鸭以肌肉注射DHAV-1病毒液(50TCID50)的方式进行体内攻毒,BC组雏鸭肌肉注射等量的生理盐水,在相同环境下分开饲养。通过肝脏病理剖检和RT-qPCR筛选最佳时间点。随后使用高通量测序的方法分析DHAV-1感染后雏鸭肝组织mRNA和miRNA表达谱,并使用RT-qPCR法验证部分DEGs和DEMs的表达水平。采用Western blot法分析相关通路蛋白表达水平。结果发现了6818个DEGs和144个DEMs,这些DEGs和DEMs表达的靶基因主要与先天抗病毒免疫和炎症等信号通路相关,随后检测部分DEGs和DEMs的mRNA表达水平,结果与测序结果一致。对体内外基因集合富集分析发现DHAV-1主要影响RLR等信号通路。进一步的研究表明,DHAV-1激活宿主RLR信号通路,诱导ROS产生,破坏线粒体膜电位和线粒体自噬体降解,并诱导炎症反应。这些发现揭示了DHAV-1感染雏鸭肝脏的mRNA和miRNA的全面特征,有助于进一步了解DHAV-1感染的分子机制,为病毒与宿主的相互作用提供线索。 试验Ⅲ:基于DEGs和DEMs靶基因筛选山豆根抗DHAV-1的活性成分 本试验旨在挖掘潜在的抗DHAV-1的中药成分并进行体外试验验证其效果。本试验基于DHAV-1感染的DEGs和DEMs的靶基因通过网络药理学和分子对接方法探究山豆根中抗DHAV-1的主要活性成分。使用TCMSP数据库获得山豆根的主要活性成分。Cytoscape软件用于构建山豆根活性成分-靶基因相互作用网络。山豆根ING数据库和Cytoscape绘制了蛋白质-蛋白质相互作用(Protein-protein interaction,PPI)网络。通过分子对接探究山豆根的主要生物活性成分和关键靶点的结合能力。随后,采用MTT法检测槲皮素、山奈酚和苦参碱这三种山豆根的主要成分在DEHs上的最大安全浓度和抗DHAV-1的最佳浓度。使用RT-qPCR法检测几种中药成分对DHAV-1复制和关键基因IL-6的影响。构建DHAV-1 VP1蛋白多克隆抗体,使用免疫荧光法检测药物对DHAV-1的抑制作用。结果显示,山豆根-DHAV-1靶基因网络包括13种成分和34个靶基因。山豆根中主要活性成分是槲皮素、山奈酚和苦参碱,它们与关键靶基因IL-6具有较高的结合能力。鉴于苦参碱在山豆根和苦参中的质谱分析结果相似,仅含量有所不同,为了确保苦参碱的纯度和稳定性,本试验选择购买苦参碱标准品进行后续研究。苦参碱、山奈酚和槲皮素在DEHs上的最大安全浓度分别为156.25 µg/mL、500 µM和500 µM。槲皮素和山奈酚在安全浓度下无明显的抗DHAV-1作用,苦参碱在2.44 μg/mL和78.13 μg/mL之间具有较好的抗病毒效果。同时,苦参碱处理后可提高DEHs细胞的生存情况,并抑制DHAV-1在DEHs中复制,而槲皮素和山奈酚无明显的抑制作用。其次,不同浓度的苦参碱均可明显降低DHAV-1诱导的IL-6高表达,且可明显降低DHAV-1 VP1蛋白表达。以上结果表明,苦参碱有良好的抗DHAV-1的作用。 试验Ⅳ:苦参碱对雏鸭DVH的治疗作用及其调控机制 本试验旨在探究苦参碱对雏鸭DVH的治疗作用和调控机制。将雏鸭分为BC组、VC组、苦参碱低剂量(Matrine low dose group,ML)组、苦参碱中剂量(Matrine medium dose group,MM)组和苦参碱高剂量(Matrine high dose group,MH)组。除BC组外,其他各组雏鸭均肌肉注射DHAV-1病毒液(50TCID50),BC组雏鸭肌肉注射等量的生理盐水,在相同环境下分开饲养。攻毒1 h后,VC组雏鸭正常饮水,苦参碱各组按照给药剂量饮水给药,此后在攻毒后第24 h再次给药。记录雏鸭存活率,检测肝脏指数、血液生化和肝脏组织病理变化评价肝脏损伤情况;同时检测雏鸭肝脏中氧化应激水平,RT-qPCR法检测相关基因的mRNA表达水平,Western blot法分析相关蛋白的表达水平。结果发现苦参碱能有效提高DVH感染雏鸭存活率,减轻肝脏损伤,改善肝脏功能,其中MM的保护效果最佳。同时,苦参碱下调DHAV-1诱导的RLR信号通路相关基因和蛋白的表达水平,降低炎症相关蛋白表达,缓解氧化应激并激活线粒体自噬下游。 试验Ⅴ:苦参碱抑制DHAV-1感染DEHs的调控机制 本试验旨在探究在DHAV-1感染情况下,苦参碱处理对DEHs的氧化应激水平、线粒体自噬、RLR信号通路和炎症反应的调控机制。将DEHs分为细胞对照(Cell control,CC)组、VC组和不同浓度苦参碱组。除CC组外,其余各组使用DHAV-1病毒液处理2 h后,苦参碱各组加入不同浓度的苦参碱药液,CC组和VC组加入等量的培养基。首先使用试剂盒检测DEHs的氧化应激水平和线粒体膜电位水平,透射电子显微镜观察线粒体形态。使用Ad-mCherry-GFP-LC3B分析DEHs的自噬水平。使用RT-qPCR法分析RLR信号通路相关基因的表达水平,使用Western blot评价RLR信号通路、线粒体自噬和炎症等相关通路的蛋白表达水平。随后,添加自噬溶酶体降解抑制剂,再使用苦参碱处理,检测DEHs线粒体自噬水平、氧化应激水平、线粒体膜电位水平、RLR信号通路水平和炎症反应。结果发现苦参碱缓解DHAV-1诱导的氧化应激、线粒体形态和功能损伤、激活DHAV-1阻断的线粒体自噬流,缓解DHAV-1诱导的RLR信号通路紊乱和炎症反应。添加自噬溶酶体抑制剂后发现,苦参碱可通过激活线粒体自噬降低氧化应激、下调RLR信号通路下游和炎症反应。 综上所述,苦参碱在体内外均有抗DHAV-1的作用,并且通过激活线粒体自噬,降低氧化应激、下调RLR信号通路下游和炎症反应而表现出抗病毒作用。 |
外文摘要: |
The infection and spread of duck viral hepatitis (DVH) among ducks can lead to large-scale death of ducklings and a decrease in egg production of adult ducks, seriously jeopardizing the economic development of the duck industry. Duck hepatitis A virus type 1 (DHAV-1) is the most widely distributed and common pathogen of DVH. It can cause neurological symptoms and acute hepatitis in ducklings, leading to rapid death of ducklings. Yolk antibodies and vaccination is the main measure to prevent DVH, but some farmers are reluctant to use it due to high labor costs. Therefore, it is particularly important to develop antiviral drugs that are easy to administer and low-cost to treat DHAV-1 infection. The clinical manifestations of DVH ducklings are internal heat syndrome, liver heat and wind, and the treatment principles should be to clear away heat and detoxify, calm wind and stop spasm. Sophorae tonkinensis Radix et Rhizoma (STR) has heat-clearing, and detoxifying effects, and its total alkaloid preparations are often used clinically to treat chronic hepatitis and liver cancer. Preliminary laboratory studies have confirmed the therapeutic effect of polysaccharide from the STR on DVH, but whether other main components of STR can inhibit DHAV-1 requires further study. The changes in host genes after viral infection are helpful to reveal the pathogenic mechanism of the virus and host interactions, find potential antiviral pathways and targets, and promote the development of antiviral drugs. Therefore, this experiment first explored the changes in host mRNA and microRNA expression after DHAV-1 infection and identified important genes and signaling pathways related to DHAV-1 infection. This experiment confirmed that DHAV-1 infection can affect the host RLR signaling pathway, trigger abnormal mitophagy, and inflammatory responses. Based on the selected differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs), this experiment used network pharmacology and molecular docking to screen out the potential anti-DHAV-1 Chinese medicine ingredients in STR: quercetin, kaempferol, and matrine. Their inhibitory effect on DHAV-1 was verified in vitro and matrine was found to have a good antiviral effect. Subsequently, the antiviral effect of matrine was further verified through in vivo toxicity protection experiments of ducklings. It was found that a medium dose of matrine could effectively enhance the survival rate of DVH ducklings, alleviate liver damage and abnormal liver function, relieve oxidative stress, activate mitophagy, and regulate RLR signaling. pathways and reduce inflammatory responses. At the same time, the regulatory effect of matrine on oxidative stress, mitophagy, RLR signaling pathway and inflammatory response were also explored in vitro. Next, an autophagy-lysosomal degradation inhibitor was used to verify that matrine could regulate the interferon signaling pathway and inflammatory response by activating mitophagy. The test is divided into five parts: Experiment I: Analysis of the mechanism of DEHs infected with DHAV-1 based on mRNA and miRNA expression profiles This experiment aimed to explore the changes in mRNA and miRNA expression in duck embryonic hepatocytes (DEHs) after DHAV-1 infection. First, the TCID50 of DHAV-1 infected DEHs was determined, and then RT-qPCR method was used to detect the replication of DHAV-1 in DEHs at different time points. To elucidate the potential mechanism of DHAV-1 infection, this experiment used high-throughput sequencing to analyze the mRNA and miRNA expression profiles of DEHs after DHAV-1 infection and used RT-qPCR to verify the expression levels of some DEGs and DEMs. It was found that the TCID50 of DHAV-1 was 10-4.48/0.1 mL. To ensure a higher cell infection rate and avoid excessive CPE, we chose to analyze at 36 hpi of DHAV-1 infection. 3410 DEGs and 142 DEMs were discovered. The target genes expressed by these DEGs and DEMs are mainly related to immune response, antiviral signaling pathways and energy metabolism. This experiment detected the mRNA expression levels of some DEGs and DEMs in DEHs, and the results were consistent with the sequencing results. Experiment II: Analysis of the mechanism of ducklings infected with DHAV-1 based on mRNA and miRNA expression profiles The purpose of this experiment was to explore the changes in mRNA and miRNA expression in duck livers after DHAV-1 infection, and to conduct gene set enrichment analysis to screen key signaling pathways based on in vitro results. The ducklings were divided into a blank control (BC) group and a virus control (VC) group. The VC group ducklings underwent intramuscular injection with DHAV-1 virus solution for in vivo challenge (50TCID50), whereas the BC group ducklings received an intramuscular injection of an equal amount of saline. Both groups were raised separately in the same environment. The optimal time point was selected through liver pathological examination and RT-qPCR. High-throughput sequencing was then used to analyze the mRNA and miRNA expression profiles of duck liver tissue after DHAV-1 infection, and RT-qPCR was used to verify the expression levels of some DEGs and DEMs. Western blot method was used to analyze the expression levels of related pathway proteins. As a result, 6818 DEGs and 144 DEMs were found. The target genes expressed by these DEGs and DEMs were mainly related to signaling pathways such as innate antiviral immunity and inflammation. The mRNA expression levels of some DEGs and DEMs were subsequently detected, and the results were consistent with the sequencing results. Enrichment analysis of gene sets in vivo and in vitro found that DHAV-1 mainly affects signaling pathways such as RLR. Further studies showed that DHAV-1 activates the host RLR signaling pathway, induces ROS production, disrupts mitochondrial membrane potential and mitophagosome degradation, and induces inflammatory responses. These findings reveal the comprehensive characteristics of mRNA and miRNA in the liver of ducklings infected by DHAV-1, which will help to further understand the molecular mechanism of DHAV-1 infection and provide clues for the interaction between the virus and the host. Experiment III: Screening of active ingredients from Sophorae tonkinensis Radix et Rhizoma against DHAV-1 based on DEGs and DEMs target genes This experiment aims to explore potential anti-DHAV-1 traditional Chinese medicine ingredients and conduct in vitro experiments to verify their effects. This experiment uses network pharmacology and molecular docking methods to explore the main anti-DHAV-1 active ingredients in STR based on DHAV-1-infected DEGs and DEMs target genes. The main active components of STR were obtained using the TCMSP database. Cytoscape software was used to construct the STR active component-target gene interaction network. The STRING database and Cytoscape mapped the protein-protein interaction (PPI) network. Explore the binding ability of STR's main bioactive components and key targets through molecular docking. Subsequently, the MTT method was used to detect the maximum safe concentration of quercetin, kaempferol, and matrine, the primary components of STR, on DEHs, as well as the optimal concentration for anti-DHAV-1 efficacy. RT-qPCR method was used to detect the effects of several traditional Chinese medicine ingredients on DHAV-1 replication and the key gene IL-6. A polyclonal antibody against DHAV-1 VP1 protein was constructed, and the inhibitory effect of the drug on DHAV-1 was detected using immunofluorescence method. The results showed that the STR-DHAV-1 target gene network included 13 components and 34 target genes. The main active ingredients in STR are quercetin, kaempferol and matrine, which have high binding ability to the key target gene IL-6. Given that the mass spectrometry analysis of matrine in Sophorae tonkinensis Radix et Rhizoma and Sophorae Flavescentis Radix is similar, with only differences in content, this experiment opted to purchase a matrine standard to ensure the purity and stability of the compound for subsequent research. The maximum safe concentrations of matrine, kaempferol and quercetin on DEHs are 156.25 µg/mL, 500 µM and 500 µM respectively. Quercetin and kaempferol have no obvious anti-DHAV-1 effect at safe concentrations, while matrine has a good antiviral effect between 2.441406 μg/mL and 78.13 μg/mL. At the same time, matrine treatment can improve the survival of DEHs cells and inhibit the replication of DHAV-1 in DEHs, while quercetin and kaempferol have no obvious inhibitory effect. Secondly, different concentrations of MAT can significantly reduce the high expression of IL-6 induced by DHAV-1, and can significantly reduce the expression of DHAV-1 VP1 protein. The above results show that matrine has a good anti-DHAV-1 effect. Experiment IV: The therapeutic effect and regulatory mechanism of the matrine on DVH in ducklings This experiment aims to explore the therapeutic effect and regulatory mechanism of matrine on DVH ducklings. The ducklings were divided into BC group, VC group, matrine low-dose (ML) group, matrine medium-dose (MM) group and matrine high-dose (MH) group. Except for the BC group, all other groups of ducklings were intramuscularly injected with DHAV-1 virus solution (50TCID50). The BC group of ducklings were injected with an equal amount of saline and raised separately in the same environment. One hour after the challenge, the ducklings in the VC group were provided with normal drinking water, while the matrine groups received water in accordance with the specified dosage. Subsequently, another dose was administered 24 hours after the initial challenge. The survival rate of ducklings was recorded, liver index was detected, blood biochemical tests and liver tissue pathological changes were used to evaluate liver damage. The kit was used to detect the oxidative stress level in the liver of ducklings, the RT-qPCR method was used to detect the mRNA expression levels of related genes, and the Western blot method was used to analyze the expression levels of related proteins. The results showed that matrine could effectively improve the survival rate of DVH ducklings, reduce liver damage, and improve liver function, among which MM had the best protective effect. At the same time, matrine down-regulates the expression levels of genes and proteins related to the RLR signaling pathway induced by DHAV-1, reduces the expression of inflammation-related proteins, relieves oxidative stress and activates downstream mitophagy. Experiment V: The regulatory mechanism of matrine inhibiting DHAV-1 infection with DEHs This experiment aims to explore the oxidative stress level, mitophagy, RLR signaling pathway and inflammatory response of matrine treatment on DEHs under the condition of DHAV-1 infection. Divide DEHs into cell control (CC) group, VC group, and different concentrations of matrine group. Except for the CC group, all other groups were treated with DHAV-1 virus solution for 2 hours. Different concentrations of matrine solution were added to each group, and equal amounts of culture medium were added to the CC and VC groups. First, kits were used to detect the oxidative stress level and mitochondrial membrane potential level of DEHs, and the mitochondrial morphology was observed with a transmission electron microscope. The autophagy level of DEHs was analyzed using Ad-mCherry-GFP-LC3B. RT-qPCR was used to analyze the expression levels of genes related to the RLR signaling pathway, and Western blot was used to evaluate the protein expression levels of RLR signaling pathway, mitophagy, inflammation and other related pathways. Subsequently, autophagy lysosomal degradation inhibitors were added, and after matrine treatment, DEHs mitophagy levels, oxidative stress levels, mitochondrial membrane potential levels, RLR signaling pathway levels, and inflammatory responses were detected. The results showed that matrine alleviated DHAV-1-induced oxidative stress, mitochondrial morphological and functional damage, activated mitophagy flow blocked by DHAV-1, and alleviated DHAV-1-induced RLR signaling pathway disorder and inflammatory response. After adding autophagy lysosome inhibitor, it was found that matrine can reduce oxidative stress, downregulate RLR signaling pathway downstream and inflammatory response by activating mitophagy. In summary, matrine has anti-DHAV-1 effects in vivo and in vitro, and reduces oxidative stress by activating mitophagy, downregulating the downstream of the RLR signaling pathway and inflammatory response. |
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中图分类号: | S85 |
开放日期: | 2025-06-11 |