Systematic elucidation of the mechanism of Jingyin granule in the treatment of Novel Coronavirus (COVID-19) Pneumonia via Network Pharmacology

Background: Jingyin granule is one of the widely used traditional Chinese medicine mixture composed of multiple herbs in the treatment of respiratory system diseases. The mechanism of its therapeutic effects has still been obscure. The aim of this study is to use the network pharmacology approach for identification of the main active ingredients of Jingyin granule against COVID-19 targets and to explore their therapeutic mechanism.Material and Method: In this study, the ingredients of Jingyin granule were evaluated by the usage of Traditional Chinese Medicine Systems Pharmacology Database and Traditional Chinese Medicine Integrated Database, and the interactions between potential gene targets and ingredients were identified using the SwissTargetPrediction database. Meanwhile the possible efficient targets COVID-19 acts on were identified via Online Mendelian Inheritance in Man database, DisGeNET database and GeneCards database. In addition, functions, components and pathways were identified by Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Protein interaction, ingredients-targets network was established.Results: Our findings showed that numerous ingredients of Jingyin granule could act on COVID-19 with 88 target genes. GO enrichment analysis, KEGG pathway analysis, and protein-protein interaction network revealed that these targets were interrelated with regulation of immune function, directly targeting disease genes.Conclusions: Jingyin granule could be utilized to exert systematic pharmacological effects. Jingyin granule could directly target the major genes, and also regulate the immune system, acting as oblique disease treatment.     

基于网络药理学和分子对接探讨蠲痹汤治疗骨关节炎的机制

目的采用网络药理学和分子对接探讨蠲痹汤治疗骨关节炎的机制。方法应用TCMSP数据库获取蠲痹汤的活性成分和对应靶点,检索GeneCards数据库、OMIM数据库、PharmGkb数据库和TTD数据库获得骨关节炎的治疗靶点。运用R语言软件(版本4.0.2)获得蠲痹汤治疗骨关节炎的交集靶点,使用Cytoscape软件(版本3.8.0)构建“活性成分—治疗靶点”网络并将关键成分进行排序,同时通过蛋白质相互作用(PPI)网络筛选出其核心靶点。运用R语言软件对蠲痹汤治疗骨关节炎的作用靶点进行基因本体(GO)富集分析和京都基因与基因组百科全书(KEGG)富集分析。运用AutoDockVina(版本1.1.2)等软件对上述核心靶点及关键成分进行分子对接验证。结果应用TCMSP数据库共得到蠲痹汤活性成分165个及对应靶点2529个,药物药效靶点与骨关节炎治疗靶点取交集得到115个靶点,关键成分有槲皮素、山柰酚、柚皮素等,核心靶点有STAT3、TNF、MAPK14等。GO富集分析得到2306个生物过程条目,144个分子功能条目,69个细胞组成条目;KEGG富集分析得到TNF信号通路、IL-17信号通路、PI3K-AKT信号通路等相关通路。分子对接结果显示,蠲痹汤治疗骨关节炎的关键成分槲皮素、山柰酚、柚皮素、甘草酮A、刺芒柄花素与其对应的核心靶点有较好的结合性。结论蠲痹汤可能通过多成分、多靶点、多通路的相互作用发挥对骨关节炎的治疗作用。     

基于网络药理学研究寒湿痹颗粒治疗强直性脊柱炎的机制

文题释义： 寒湿痹颗粒：由附子、制川乌、黄芪、桂枝、麻黄、白术、当归、白芍、威灵仙、木瓜、细辛、甘草等10多味中药组成,具有温肾散寒、祛风、益气活血、止痛等功效,可用于治疗强直性脊柱炎、风湿性关节炎、骨关节炎等病。 网络药理学：基于系统生物学的理论,对生物系统网络进行分析,从成分-靶点-通路进行整体预测及阐明药物在体内作用机制。 背景：寒湿痹颗粒已被临床中用于治疗强直性脊柱炎,但其药理作用机制不明确。 目的：基于网络药理学的方法,对寒湿痹颗粒的主要化学成分进行筛选,并收集其化合物对应的靶点,并构建化合物-靶点网络,对其治疗强直性脊柱炎的药理作用机制进行系统阐述。 方法：寒湿痹颗粒化合物及与药物靶点的收集主要基于TCMSP数据库及文献报道,强直性脊柱炎疾病靶点来源于DRUGBANK、GeneCards、Home-OMIM-NCBI、PALM-IST数据库。所获得药物基因和疾病基因经过Uniprot数据库校正后使用Draw Venn Diagrams分析工具获得交集基因。结合STRING数据库与Cytoscape3.6.1对交集基因进行PPI分析。通过使用Cytoscape3.6.1插件ClueGO对交集基因进行GO富集分析及KEGG通路富集分析。 结果与结论：①从TCMSP获得69个活性成分,142个药物靶点,利用DRUGBANK、GeneCards、Home-OMIM-NCBI、PALM-IST数据库获得595个强直性脊柱炎疾病靶点;②使用Draw Venn Diagrams工具分析获得交集基因39个,通过PPI分析,肿瘤坏死因子、白细胞介素6、前列腺素内过氧化物合酶2在PPI网络中连接度较高;③通过GO富集分析发现,其主要涉及活性氧代谢调节、脂肪酸代谢、急性炎症反应、神经递质的生物过程、花生四烯酸的代谢等生物功能;④通过KEGG通路富集分析发现,其主要涉及AGE-RAGE信号通路、流体剪切应力和动脉粥样硬化、白细胞介素17信号通路、核因子κB信号通路、肿瘤坏死因子信号通路、Toll样受体信号通路等;⑤研究初步预测寒湿痹颗粒治疗强直性脊柱炎的药理作用机制,为老药新用及实验研究提供新思路。 ORCID: 0000-0001-9827-9537(王卓) 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

基于生物信息学的息痛散治疗痛风性关节炎的作用机制

目的:挖掘中药复方息痛散的有效成分、预测其潜在功能靶标,通过网络药理学和实验验证的方法探讨息痛散治疗痛风性关节炎的作用机制。方法:利用TCMSP、TCMID数据库筛选出息痛散的活性成分及靶标;通过NCBI、GeneCards数据库筛选痛风性关节炎的疾病靶点;将两者靶点通过Cytoscape软件构建蛋白互作网络图并进行拓扑学分析;筛选出核心靶点;通过R软件进行KEGG和GO富集分析;最后分子对接及Western Blot实验验证网络药理学富集分析结果。结果:共筛选出146个活性成分以及158个关键靶点,涉及PI3K-Akt信号通路、TNF信号通路和MAPK信号通路等,实验验证显示通路关键节点蛋白存在差异性表达。结论:本研究系统揭示息痛散通过多成分-多靶点-多途径共同调控痛风性关节炎的物质基础和作用机制,为中药复方息痛散的临床应用提供理论基础和科学依据。     

基于网络药理学的黄连治疗糖尿病的作用机制研究

目的 利用网络药理学手段研究黄连治疗糖尿病的作用机制。方法 从TCMSP数据库获取黄连的有效成分以及作用靶点,与GeneCards数据库中糖尿病的作用靶点取交集获取黄连治疗糖尿病的预测靶点,利用Cytoscape软件构建中药化合物-靶点网络及STRING数据库构建PPI网络,利用 DAVID在线工具进行GO功能分析及KEGG通路富集分析。结果 黄连的活性成分有14个,关键有效成分有11个,治疗糖尿病靶点137个。黄连主要活性成分作用的核心靶点为JUN、MAPK1、IL-6等靶基因,参与调控Insulin resistance,Regulation of lipolysis in adipocytes等多个信号通路。结论 黄连能发挥多靶点、多通路的协同治疗糖尿病作用。     

Network-based pharmacology to predict the mechanism of Ginger and Forsythia combined treatment of viral pneumonia

Background: Viral pneumonia (VP) is a common inflammatory disease caused by a virus in the upper respiratory tract. However, current treatment options for pneumonia are limited because of the strong infectivity and lack of research. Method: Based on various databases, the mechanisms of Ginger and Forsythia were predicted by network pharmacology. The possible active ingredients of Ginger and Forsythia were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and screened by pharmacokinetic parameters. Their possible targets were predicted by the TCMSP database. The VP-related targets were collected from the GeneCards and OMIM databases. The compound-target-disease network was visualized by Cytoscape 3.7.1. In addition, the protein functional annotation and identification of signalling pathways of possible targets were performed with Gene Ontology (GO) and KEGG enrichment analysis. Molecular docking was finally employed for in silico simulation matching between representative Ginger and Forsythia compounds and their core genes. Results: Twenty-eight active ingredients of Ginger and Forsythia were found and 30 common targets for the combined treatment of VP were obtained. The enrichment analysis of GO functions and KEGG pathways included 186 GO function entries and 56 KEGG pathways. Molecular docking showed that the main ingredients can closely bind three targets (CASP3, JUN, and ESR1). Thus, Ginger and Forsythia play significant roles in the prevention and treatment of VP, and this study showed their mechanism was “multicomponent, multitarget, and multipathway” for the prevention and treatment of VP. Conclusion: We successfully predicted the active components and targets of Ginger and Forsythia for prevention and treatment of VP. This may systematically clarify its mechanism of action and provide a direction for future research.     

Using network pharmacology approaches to identify treatment mechanisms for codonopsis in esophageal cancer

Objective: We explored codonopsis mechanisms for the treatment of esophageal cancer using a network pharmacology approach. Materials and methods: Using the Laboratory of Systems Pharmacology website, codonopsis compounds and targets were gathered. After identifying esophageal cancer target intersections from the GeneCards website, possible codonopsis targets for esophageal cancer were screened. A protein-protein interaction (PPI) network diagram of protein targets was then constructed using the STRING database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analyses were performed in R 3.6.0 software. A network diagram of “disease-drug-component-target-pathways” was also constructed using Cytoscape 3.7.1. Results: We screened 21 codonopsis compounds as possible esophageal cancer treatments and 31 drug-disease intersecting targets. GO enrichment analysis identified 778 biological process (BP) components, 15 cellular component (CC) components, and 50 molecular function (MF) components, and KEGG analyses identified 90 signaling pathways. Our analyses showed that p53 and PI3K-Akt signaling pathways (among others) were significant pathways in these processes. Conclusions: Codonopsis may be used to treat esophageal cancer by multiple components, targets, and pathways.     

去分化脂肪肉瘤潜在核心基因的生物信息学预测及分析

目的 探讨去分化脂肪肉瘤的潜在核心基因在其恶性生物学行为中的作用.方法 获取基因表达数据库(gene expres-sion omnibus,GEO)数据库中GSE21122和GSE52390的芯片数据,通过GEO2R筛选差异表达基因,对差异表达基因进行GO功能、KEGG通路富集分析和蛋白互作分析,并用Cytoscap...     

基于网络药理学探究络石藤-牛膝药治疗关节炎的作用机制

目的 基于网络药理学分析“络石藤-牛膝”药对治疗关节炎（Arthritis）的潜在作用机制。 方法 通过检索中草药系统药理学数据库平台（TCMSP）进行药对“络石藤-牛膝”有效成分及靶基因筛选;以“Arthritis”为关键词,在GeneCards数据库、NCBI基因数据库以及OMIM数据库进行人类基因检索并获得关节炎相关基因;将筛选出的药对靶点与疾病靶点输入韦恩图制作软件Venny2.1,获得共有靶点;运用STRING数据库进行PPI网络构建,Cystoscape构建“药物-成分-靶点-疾病”网络;运用R语言软件对关键靶基因进行基因本体论（GO）功能富集分析及与基因组百科全书（KEGG）通路的集分析。 结果 从TCMSP中筛选获得络石藤9种化合物成分,94个靶点;牛膝获得21种化合物成分,205个靶点。Venny映射得到128个共有靶点,STRING数据库筛选出5个基因簇和4个核心基因构建PPI网络。GO功能富集分析显示,“络石藤-牛膝”药对涉及2329条生物过程,150项分子功能相关,60项细胞组成相关。通过KEGG通路富集分析,“络石藤-牛膝”药对治疗关节炎富集到154条信号通路。 结论 基于网络药理学,从有效成分、基因靶点、信号通路等方面初步验证了“络石藤-牛膝”药对治疗关节炎的作用机制。     

Janus kinase signaling as risk factor and therapeutic target for severe SARS-CoV-2 infection

Cytokine signaling, especially interferon (IFN) signaling is closely linked to several aspects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. During initial SARS-CoV-2 infection, symptomatic patients present with impaired type I/III IFN-mediated antiviral responses. Interestingly, IFNs regulate the cellular entry receptor for SARS-CoV-2 on epithelial and endothelial cells. As reported recently, critically ill COVID-19 patients show genetic polymorphisms in one IFN receptor gene (IFNRA2) and in a gene locus near the Janus kinase (JAK) TYK2, which is key for IFN, interleukin (IL)-12 and IL-23 signaling, and T helper (Th) 1/Th17 cell-mediated antiviral immune responses. In the advanced stage of the disease, critically ill COVID-19 patients develop a cytokine storm where many inflammatory mediators using the JAK/STAT signaling pathway such as IL-6, IFN-γ, the granulocyte colony-stimulating factor (G-CSF) or IL-2, and chemokines result in an influx of macrophages and neutrophils damaging the lung tissue. The knowledge on the cytokine and JAK/STAT signaling pathways in severe COVID-19 disease explains the promising first results with JAK inhibitors like baricitinib, which not only dampen the inflammation but in the case of baricitinib also affect virus replication and endocytosis in target cells. Here, we summarize the current immunological associations of SARS-CoV-2 infection with cytokine signaling, the JAK/STAT pathway, and the current clinical stage of JAK inhibitors for improving severe COVID-19 disease.     

利什曼原虫感染树突状细胞早期基因表达差异分析及关键基因筛选

目的:分析利什曼原虫感染树突状细胞(DCs)早期的基因表达与信号通路变化,探究DCs感染后应答,寻找利什曼原虫感染后基于DCs的免疫治疗方法。方法:GEO数据库下载利什曼原虫感染前后DCs基因芯片数据,RStudio软件筛选差异表达基因(DEGs),STRING构建DEGs蛋白质相互作用网络(PPI),Cytoscape筛选差异表达蛋白质的核心模块,RStudio软件对DEGs进行GO和KEGG富集分析。结果:共筛选出DEGs 129个,其中IL12B与CXCL10差异最为显著,GO分析共富集23个过程,主要涉及病毒感染过程相关细胞反应及Ⅰ-IFN相关免疫反应;KEGG分析共富集3条信号通路,分别为甲型流感、麻疹及DNA复制信号通路。结论:利什曼原虫感染DCs前后Ⅰ-IFN信号通路和TLR4/NF-κB信号通路激活,影响IL12表达,提示Ⅰ-IFN/IL12信号通路与TLR4/NF-κB/IL12信号通路可作为利什曼原虫感染治疗的靶点,CXCL10也有望成为潜在的治疗靶点;利什曼原虫感染后,出现类似病毒感染现象,推测抗病毒免疫疗法可能在对抗利什曼原虫感染中具有一定疗效。     

基于网络药理学和蛋白模块分析淫羊藿治疗骨关节炎的作用与机制

文题释义：网络药理学：是基于系统生物学的理论,对生物系统的网络分析、选取特定信号节点进行多靶点药物分子设计的新学科。网络药理学强调对信号通路的多途径调节,提高药物的治疗效果,降低毒副作用,从而提高新药临床试验的成功率,节省药物的研发费用。 淫羊藿：为小檗科多年生草本植物,其性温,味辛,归肝经、肾经,传统中医药理论认为淫羊藿具有补肾壮阳、强筋健骨、祛除风湿痹痛等功效,临床上广泛将其应用于骨关节炎疾病的治疗。淫羊藿参与调控骨关节炎的信号通路主要有白细胞介素受体通路、肿瘤坏死因子信号通路、Toll样受体信号通路、T细胞受体信号通路、NF-κB信号通路、破骨细胞分化通路(RANK/RANKL/OPG)。 背景：现代中药药理学研究表明淫羊藿苷在骨关节炎方面有着非常积极的作用。由于淫羊藿所含化学成分较为复杂,且在分子水平上治疗骨关节炎的机制尚不明确,因此利用网络药理学从分子水平来解释淫羊藿治疗骨关节炎的潜在化学成分及作用机制,可为后期药物研发及疾病治疗提供一定理论依据。 目的：采用网络药理学方法探讨淫羊藿治疗骨关节炎的分子机制。 方法：通过TCMSP数据库筛选淫羊藿的药效成分,通过TCMSP、Swiss Target Prediction和STITCH数据库预测淫羊藿药效成分的调控靶点,通过OMIM、GeneCards和TTD数据库预测治疗骨关节炎的靶点,将淫羊藿药效靶点与骨关节炎治疗靶点取交集,得到淫羊藿治疗骨关节炎的靶点,并构建“药物-成分-靶点-疾病”网络。通过STRING数据库分析蛋白互作关系,运用DAVID数据库分析蛋白模块的相关信号通路和功能。 结果与结论：①筛选得到23个淫羊藿药效成分,共预测得到230个淫羊藿药效靶点和1 221个骨关节炎的治疗靶点,取交集后得到95个淫羊藿治疗骨关节炎的靶点,蛋白互作分析提示JUN、AKT1、RELA、MAPK1、IL6、CXCL8、MAPK8、MAPK14、FOS、IL1B为蛋白互作网络中的核心靶点;②关键蛋白模块主要涉及白细胞介素受体通路、肿瘤坏死因子信号通路、Toll样受体信号通路、T细胞受体信号通路、NF-κB信号通路和破骨细胞分化通路,可能通过调控细胞增殖与凋亡、免疫细胞及免疫反应、炎症因子及炎症反应、脂多糖的细胞反应等多种生物过程发挥治疗骨关节炎的作用。 ORCID: 0000-0002-2572-0229(章晓云) 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

唾液腺腺样囊性癌中相关微小RNAs及其靶基因的生物信息学分析

目的 探讨唾液腺腺样囊性癌(SACC)潜在的微小RNAs(miRNAs)分子标志物,构建miRNA-mRNA调控网络,并阐明其潜在的分子机制.方法 从Gene Expression Omnibus(GEO)数据库下载2个SACC的微阵列芯片数据,通过R语言进行分析差异的miRNAs与mRNA.应用FunRich 3.1...     

肌层浸润性膀胱癌亚型的生物信息学分析

目的通过生物信息学分析研究两种膀胱癌亚型(基底样膀胱癌和管腔型膀胱癌)之间不同的分子调控机制和分子特性,为更准确地区分膀胱癌亚型和探索潜在的治疗靶点提供帮助。方法利用稳健的多芯片平均算法将由22个基底样膀胱癌和132管腔型膀胱癌样本组成的数据集进行标准化,并选择其中前1000个具有最高标准差的基因进行两种亚型的差异表达基因分析。将得到的差异表达基因进行GO功能注释和KEGG通路富集分析。此外,选择前100个差异表达基因构建蛋白质互作网络。结果得到基底样和管腔型膀胱癌差异表达基因共742,其中基底样亚型上调的基因405个,下调的基因337个。GO富集分析显示差异表达基因显著富集在细胞外区基质、趋化性、炎症等功能上,KEGG通路富集显示差异表达基因显著富集在细胞外基质受体相互作用的通路上。构建的蛋白质互作网络显示重要的hub蛋白质为LNX1、MSN和PPARG。结论本研究得到的基底样和管腔型膀胱癌亚型分子机制的区别主要体现在细胞外区域的分子作用机制、细胞趋化性和炎症反应等,基因LNX1、MSN和PPARG为区别两种膀胱癌亚型的特征基因。     

PI3K/Akt/mTOR pathway: a potential target for anti-SARS-CoV-2 therapy

Coronavirus disease 2019 (COVID-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A single-stranded RNA virus from a β-Coronaviridae family causes acute clinical manifestations. Its high death rate and severe clinical symptoms have turned it into the most significant challenge worldwide. Up until now, several effective COVID-19 vaccines have been designed and marketed, but our data on specialized therapeutic drugs for the treatment of COVID-19 is still limited. In order to synthesis virus particles, SARS-CoV-2 uses host metabolic pathways such as phosphoinositide3-kinase (PI3K)/protein kinase B (PKB, also known as AKT)/mammalian target of rapamycin (mTOR). mTOR is involved in multiple biological processes. Over-activation of the mTOR pathway improves viral replication, which makes it a possible target in COVID-19 therapy. Clinical data shows the hyperactivation of the mTOR pathway in lung tissues during respiratory viral infections. However, the exact impact of mTOR pathway inhibitors on the COVID-19 severity and death rate is yet to be thoroughly investigated. There are several mTOR pathway inhibitors. Rapamycin is the most famous inhibitor of mTORC1 among all. Studies on other respiratory viruses suggest that the therapeutic inhibitors of the mTOR pathway, especially rapamycin, can be a potential approach to anti-SARS-CoV-2 therapy. Using therapeutic methods that inhibit harmful immune responses can open a new chapter in treating severe COVID-19 disease. We highlighted the potential contribution of PI3K/Akt/mTOR inhibitors in the treatment of COVID-19.

     

基于网络药理学探讨白藜芦醇抗衰老的作用机制

目的:运用网络药理学方法探寻白藜芦醇抗衰老的关键靶点及分子作用机制。方法:通过PharmMapper数据库查找白藜芦醇的作用靶点;采用GeneCards数据库搜索衰老的相关蛋白。将白藜芦醇作用靶点和疾病靶点取交集,即为白藜芦醇抗衰老潜在靶点。采用STRING数据库找出靶点的作用关系,以DAVID数据库分析结果,Cytoscape3.8.0软件构建药物-疾病-靶点-通路网络。结果:从PharmMapper得到的91个白藜芦醇(Resveratrol,Res)作用靶点,GeneCards数据库得到的474个衰老相关靶点,两者取交集后共得到22个白藜芦醇抗衰老的作用靶点。在蛋白相互作用网络中IGF1、ESR1、MAPK1和EGFR处于核心位置。在GO富集分析和KEGG通路分析中,EGFR、MAPK1和IGFR均存在于PI3K-Akt通路、FoxO通路和HIF-1通路中。在药物-疾病-靶点-通路网络中,EGFR和MAPK1处于核心位置。结论:Res通过EGFR、MAPK1、IGFR调节PI3K-Akt和FoxO通路抗衰老。