基于网络药理学与分子对接探讨土家药复方竹节参片对肝损伤的作用机制.pdf

特产研究DOl:10.16720/ki.tcyj.2023.061Special Wild Economic Animal and Plant Research57基于网络药理学与分子对接探讨土家药复方竹节参片对肝损伤的作用机制宋添力1,2,3，孙永章2,3,李奇4,刘立安2,5，唐浪1,刘绪1,黄胜1（1.湖北民族大学医学部，湖北恩施4450 0 0;2.世界中医药学会联合会，北京10 0 10 1;3.中华中医药学会，北京10 0 0 2 9；4.北京京都儿童医院，北京10 2 2 0 8；5.北京中医药大学，北京10 0 0 2 9)摘要：应用网络药理学及分子对接技术，探讨土家药复方竹节参片治疗肝损伤（Liverinjury，LI)的物质基础及作用机制。从TCMSP数据库和中国知网数据库中提取复方竹节参片的化合物及靶点信息；Uniprot网站将靶点信息转换为Gene将中药-成分-Gene信息导入CytoscapeV3.8.2获得中药一成分-Gene网络；利用OMIM、G e n e Ca r d s 和DrugBank网站提取“Liverinjury”的疾病Gene，Excel绘制Venn图获得成分一疾病交集靶点，并构建交集靶点一成分网络图确定核心成分；利用STRING网站获得交集靶点的蛋白互作(PPI)网络及核心靶点，Matascape网站对核心靶点进行基因本体(GO)功能、京都基因和基因组数据库(KEGG)通路富集分析；用AutoDock工具进行核心成分与核心靶点的分子对接。复方竹节参片中共筛选出6 8 种有效活性成分，治疗LI的核心成分有皮素、山奈酚、-谷笛醇、木犀草素、（2 0 S)-原人参二醇和-胡萝卜素等；治疗LI的核心靶点15个，分别为STAT3、JU N、A K T 1、T P53、TNF、M A PK 1、I L6、R ELA、VEG FA、M A PK 8、M A PK 14、PI K 3CA、M YC、CT NNB1和FOS。靶点主要涉及调节与DNA结合的转录因子活性、蛋白激酶活性、细胞氧化应激及炎症反应、癌症相关蛋白的表达和血管生长等生物学过程；重要通路有乙型和丙型肝炎病毒途径、癌症及癌症中的蛋白多糖、流体剪切应力和动脉粥样硬化、糖尿病并发症中的AGE-RAGE、T NF、T o l l 样受体和MAPK等信号通路。分子对接结果显示，核心成分与关键靶点的结合活性良好。本研究表明，复方竹节参片可能通过作用于上述STAT3、JU N和AKT1等核心靶点，参与相关生物进程及通路的调节，进而发挥对LI的多成分一多靶点一多通路的治疗作用，本文为进一步研究复方竹节参片对LI的作用机制提供理论参考。关键词：复方竹节参片；肝损伤；网络药理学；分子对接；作用机制中图分类号：R285文献标识码：A文章编号：10 0 1-47 2 1(2 0 2 3)0 4-0 0 57-12Mechanism of Tujia Medicine of Fufang Panax japonicus Tablets AgainstLiver Injury:Based on Network Pharmacology and Molecular DockingSONG Tianli1.2.3,SUN Yongzhang23,LI Qi4,LIU Lian2.5,TANG Langl,LIU Xul,HUANG Shengl*(1.Department of Medicine,Hubei Minzu University,Enshi 445000,China;2.World Federation of Chinese Medicine Soci-eties,Beijing 100101,China;3.China Association of Chinese Medicine,Beijing 100029,China;4.Beijing Jingdu ChildrensHospital,Beijing 102208,China;5.Beijing Unversity of Chinese Medicine,Beijing 100029,China)Absrtact:The material basis and possible mechanism of compound Panax japonicus tablets in the treatment of Liver injury(LI)were stu-died by network pharmacology and molecular docking technique.The composition and target information of compound P.japonicus tabletswere extracted by TCSSP and CNKI databases.Using the Uniprot web site to convert target information into Gene.The information of herb-composition-gene was introduced into Cytoscape V3.8.2 to obtain its network.Using Omim,GeneCards and Druggbank to extract the dis-收稿日期：2 0 2 2-12-16基金项目：国家自然科学基金青年基金项目（32 16 0 141）；湖北省自然科学基金青年项目（2 0 19CFB358）作者简介：宋添力（1998-），男，山西孝义人，在读硕士研究生，从事中医学、民族医学研究。通讯作者：黄胜（198 7-），男，湖北利川人，博士，硕士研究生导师，从事民族药理学研究。58ease targets of Liver injury,Excl to draw Venn diagram to obtain the cross targets,and construct cross target-composition network to de-termine the core components.Use the STRING web site to obtain a cross-target protein-protein interaction(PPI)network to determine thecore targets.Gene ontology(GO)function and Genome Encyclopedia(KEGG)pathway enrichment analysis of the core targets were carriedout by Matascape.Molecular docking between core components and core targets using the AutoDock tool.A total of 68 active componentswere isolated from compound P.japonicus tablets,the core components are Quercetin,Kaempferol,-sitosterol,Luteolin,(2oS)-protopan-axadiol,Beta-carotene,and so on.The core therapeutic targets are STAT3,Jun,AKT1,TP53,TNF,MAPK1,IL6,Rela,Vegfa,Mapk8,MAPK14,PIK3CA,MYC,CTNNB1,FOS.The targets are mainly involved in the regulation of DNA-binding transcription factor activity,protein kinase activity,cell oxidative stress and inflammatory response,expression of cancer-related proteins,and vascular growth.Import-ant pathways are the B and Hepatitis C virus pathway,proteoglycan in cancer and cancer,fluid shear stress and arteriosclerosis,AGE-RAGEsignaling pathway in diabetic complications,TNF,Tollike receptors,MAPK,and so on.The results of molecular docking show that thecore components have good binding activity with the key target.Compound P.japonicus tablets may play a role in the treatment of LI byacting on STAT3,JUN,AKT1 and other core targets,and participating in the regulation of related biological processes and pathways,thisstudy laid a foundation for further study on the mechanism of compound P.japonicus tablets on LI.Keywords:Fufang Panax japonicus tablets;liver injury;network pharmacology;molecular docking;mechanism of action肝损伤是肝脏发生肝炎、肝纤维化、肝硬化及肝癌进程等在内的多种肝脏疾病的发病基础，肝脏疾病的发生发展伴随着不同程度的肝损伤进程。肝损伤的发病机制与氧化应激、炎症反应、细胞纤维化及细胞凋亡有关,其发生的主要致病原因有病毒感染、中毒、酒精、药物、免疫、血管障碍和代谢紊乱等 1。在中医之中并无“肝损伤”之说。根据其以往无慢性肝病史，骤然起病，临床症状如黄疽、胁部胀痛及胁下积块，甚则肝细胞大面积坏死、肝功能衰竭、出血和神经精神症状等 2 ,将其列为“黄疽”“胁痛”“斑疹”“厥症”及“温病”等范畴，中医学认为肝损伤病机为“湿”、“热”、“瘀”“毒”和“虚 3。结合现代研究认为，本病的病因病机多为湿热毒瘀、肝郁气滞、瘀血阻络、脾失健运及肝肾阴虚 4-6 ,多从解毒清热、利胆除湿、活血行气和扶正祛邪论治。中医药与民族医药在长期的生活实践中总结了对于肝损伤的特色治疗方法。本研究制剂“复方竹节参片”为我国土家族地区极具特色的中成药，以恩施州道地药材，土家珍稀名贵的“七”类药材之一一一竹节参（Pa n a x j a p o n i c u s）为主药，辅以三百棒（Toddaliaasiat-ica)、青风藤（Sinomenicaulis）、地蜂子（Poten-tllacry-ptotaeniae Maxim）、穿山龙（Rhizoma dioscoreae Nip-ponicae)、血当归（Radix rumicis Chalepensis)、白(Radix paeoniae Alba)和淫羊藿(Epimedium brevicor-nuMaxim)而成 7 。全方攻补兼施,具有补虚活血、败火解毒、通络除湿和消肿止痛之效，全方配伍较为符合治疗LI的病机原则。同时，现代研究也表明，复方竹节参片有较好的抗炎、抗氧化功效，可降低血清中炎症因特产研究子白介素-6(interleukin-6,IL-6)、IL-8 和肿瘤坏死因子-(tumor necrosis factor-,TNF-)的表达，表明其具有保护肝损伤的作用基础 8,9。而复方竹节参片对肝损伤(Liverinjury,LI)治疗的试验及临床研究较少，其分子作用机制尚未明确，故本研究通过网络药理学及分子对接，探讨复方竹节参片治疗LI的物质基础及作用机制,挖掘本方潜在的治疗靶点，为复方竹节参片治疗LI提供一定的理论参考。1方法1.1数据源TCMSP数据库(http:/tcmspW.com/index.php);中国知网(http:/);Uniprot 网站(https:/wwW.un-iprot.org/);OMIM 网站(https:/omim.org/);GeneCards网站（https:/www.genecards.org/)；D r u g Ba n k 网站(https:/ 网站(https:/string-db.org/);Matascape网站(https:/metascape.org/);PubChem 网 站(https:/pubchem.ncbi.nlm.nih.gov/);PDB 网站(http:/wwW.rcsb.org/)。1.2中药-成分-Gene网络构建利用TCMSP数据库及知网文献提取复方竹节参片的化合物成分和化合物靶点信息，限定参数口服生物利用度（OralBioavailability,OB）30%、类药性(Drug-like property,DL)0.18;其中知网文献得到相关中药成分的用化源网网站(https:/ PubChem 网站(https:/pubchem.ncbi.nlm.nih.gov/)进行CAS号检查比对后再用TCMSP数据库中CAS号检索功能查找得到对应的靶点信息；用Uniprot网站将靶点信息转换为Gene,将中药一成分-Gene相关2023年第45卷第4期第4期信息导入Cytoscape V3.8.2以构建中药一成分-Gene网络。1.3中药-疾病的Venn图构建及核心成分的确定以OMIM、G e n e Ca r d s 和DrugBank网站检索疾病“Liver injury的靶点基因,其中GeneCards 数据库得到的“疾病-Gene”信息以相关性分值（Relevancescore)连续取中位数至Relevance score10进行筛选，三者合并去重获得“疾病一Gene信息，以Excel绘制中药-疾病的Venn 图并得到交集靶点。构建交集靶点中药成分网络图，取Degree值前10 的中药成分确定为核心成分。1.4PPI网络及核心靶点的确定将交集靶点导入STRING网站，选择物种为人类(Homo sapiens),勾选 highist confidence 0.9,隐藏空白靶点，得到PPI网络图，并将TSV文件导入Cy-toscapeV3.8.2软件统计蛋白质PPI数，计算Degree值，以平均Degree值的两倍进行筛选，得到核心靶点。1.5GO功能分析和KEGG通路富集分析将核心交集靶点导入Matascape网站进行GO功能分析和KEGG通路富集分析，其中GO功能分析包含生物过程(Biologicalprocess,BP)、分子功能(Mol-ecular function,MF）和细胞组分（Cellular component,CC)3个内容，筛选排名靠前的基因功能及通路，应用宋添力，等：基于网络药理学与分子对接探讨土家药复方竹节参片对肝损伤的作用机制“中药一成分一Gene网络构建筛选得到复方竹节参片中含有6 8 种中药有效活性成分及353个对应的靶点Gene。构建得到中药-成分-Gene网络,见图1。2.2中药一疾病的Venn图构建及核心成分的确定获得“疾病-Gene”信息57 5个，用Excel绘制中药一疾病的Venn图，得到交集靶点95个，见图2。构建得到的95个交集靶点一成分网络图，见图3。计算Degree值，取Degree值前10 的中药成分为核心成分，得到11个核心成分，主要有皮素、山奈酚、-谷笛醇、木犀草素、（2 0 S)-原人参二醇、-胡萝卜素、人参皂苷Rh2、脱水淫羊藿素、去甲脱水淫羊藿素、异落新妇苷B和儿茶素等。59http:/ 次对接，导出对接能最低位置的pdbqt文件，采用PyMOL软件进行可视化分析。2结果2.1DF2CSSBB3B54SBB4BB1B1SBBSBB13ZS5B52XDG3FZDF22CSL1CSL2AHSA1CHRM5TACRRUNXZZS4QFT4ZZ53QFTDOFZ1OFTBAXCHUKYH1ZSZZ82XDG1Z5BCL2GABRA1H1YH51NCF1MAP2CHRNACOYCPOL6SYKGABRA6SLC5A4WKLF7TGS1EGFCHEKCSTEDNRHHMHTSEYHYH1DCAF5CA2GDD11GSTM2BB9SBBIA1A4D1PRKCABACEHRMADORA3RXRBJANR12SLC6ASMOTR1ECAPPDE2PPARCAPNCYP3A4HTR1IL10STATMAPTATERPMYRASABCHE1A2ADRA2ACNA130GEEGFMAOAST3GMAOEARPGRADORTGSNTGABRTNRFFOSCD14KR1CVSFAURKACTSDHRHRADHICDORA2MMP10CAGMCAMMP3PTKEYP19A1GGK3AHSPB1CATHIF1AYH7YHEB12CD2D3TH12YH1HYYHIO图1中药-成分-Gene网络Fig.1 Chinese herbal-component-gene network60药物Drug竹节参ZZS白芍BS穿山龙CSL地蜂子DFZ青风藤QFT三百棒SBB特表1药物成分信息Table 1Drug composition information简称分子编号AbbreviationMOLIDZZS1MOL006754ZZS2MOL005332ZZS3MOL005285ZZS4MOL005334ZZS5MOL005343ZZS6MOL005348ZZS7MOL012860D3MOL005344BS1MOL001918BS2MOL001919BS3MOL001924BS4MOL000211A1MOL000358A3MOL000359A4MOL000422A2MOL000492CSL1MOL000133CSL2MOL000139DFZ1MOL005190B2MOL004425A2MOL000492DFZ2MOL000096DFZ3MOL002773A1MOL000358B1MOL000263A1MOL000358QFT1MOL000621C1MOL000622QFT2MOL000623QFT3MOL000625QFT4MOL000627SBB1MOL000787SBB2MOL001461SBB3MOL002664SBB4MOL002663SBB5MOL013094SBB6MOL005103产Ginsenoside Rb3_qt(3R,5R,8R,9R,10R,12R,13R,14R,17S)-17-(2S)-2-hydroxy-6-methylhept-5-en-2-yll-4,4,8,10,14-pentamethyl-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1H-cyclo-pentalalphenanthrene-3,12-diol20(s)-protopanaxadiol(3S,5R,8R,9R,10R,12R,13R,14R,17S)-17-(2S)-2-hydroxy-6-methylhept-5-en-2-yl-4,4,8,10,14-pentamethyl-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1H-cyclo-pentalalphenanthrene-3,12-diolGinsenoside Rg3Ginsenoside-Rh4_qtVina-ginsenoside R2Ginsenoside Rh2Paeoniflorgenone(3S,5R,8R,9R,10S,14S)-3,17-dihydroxy-4,4,8,10,14-pentamethyl-2,3,5,6,7,9-hexahydro-1H-cyclopentalalphenanthrene-15,16-dionePaeoniflorinMairinBeta-sitosterolSitosterolKaempferol(+)-catechin7-EpitaxolSmitilbinEriodictyolIcarin(+)-catechin(-)-catechin-CaroteneBeta-SitosterolOleanic acidBeta-sitosterol16-epi-IsositsirikineMagnograndiolideMichelenolideSinomenineStepholidineFumarineDihydrochelerythrineFagarineSkimmianin8-(2R)-2,3-dihydroxy-3-methyl-butyll-5,7-dimethoxy-coumarin6-(2R)-2,3-dihydroxy-3-methyl-butyl-5,7-dimethoxy-coumarin研究分子名称Molecule name2023年第45卷第4期第4期续表1药物Drug三百棒SBB血当归XDG淫羊藿YYH宋添力，等：基于网络药理学与分子对接探讨土家药复方竹节参片对肝损伤的作用机制简称分子编号AbbreviationMOL IDSBB7MOL002644SBB8MOL001478SBB9MOL011746B1MOL000263SBB10MOL003588SBB11MOL003196A1MOL000358SBB12MOL008647SBB13MOL005105SBB14MOL013097SBB15MOL009998SBB16SBB17SBB18XDG1D1XDG2A1XDG3D3D2YYH1YYH2YYH3D1YYH4YYH5A3A4YYH6YYH7YYH8YYH9YYH10YYH11YYH12YYH13YYH14YYH15B2YYH16YYH17C1D261分子名称Molecule namePhellopterinToddalineIsopimpinellinOleanolic acidPrangenidinTryptophenolideBeta-SitosterolMoupinamideOxychelerythrineCoumurrayinToddaculin5-methoxyseselin一Braylin一LuvangetinMOL001494MandenolMOL001792DFVMOL002879DiopMOL000358Beta-sitosterolMOL000449StigmasterolMOL005344Ginsenoside Rh2MOL000098QuercetinMOL00151024-epicampesterolMOL001645Linoleyl acetateMOL001771Poriferast-5-en-3beta-olMOL001792DFVMOL003044ChryseriolMOL0035428-Isopentenyl-kaempferolMOL000359SitosterolMOL000422KaempferolMOL004367OlivilMOL004373AnhydroicaritinMOL004380C-homoerythrinan,1,6-didehydro-3,15,16-trimethoxy-,(3.beta.)-MOL004382Yinyanghuo AMOL004384YinyanghuoCMOL004386Yinyanghuo E6-hydroxy-11,12-dimethoxy-2,2-dimethyl-1,8-dioxo-2,3,4,8-tetrahydro-1H-iso-MOL004388chromeno3,4-hlisoquinolin-2-iumMOL0043918-(3-methylbut-2-enyl)-2-phenyl-chromoneMOL004394Anhydroicaritin-3-O-alpha-L-rhamnosideMOL0043961,2-bis(4-hydroxy-3-methoxypheny)propan-1,3-diolMOL004425IcarinMOL004427Icariside A7MOL000006luteolinMOL000622MagnograndiolideMOL000098Quercetin62Fig.2 Venn diagram of Chinese herbal medicine-liver injurySBB15CSL2XDG3SOPAHERELINSRA4ZZS2DFZDFZXDG1A1SBB14SBB93SBB8YYH4SBB13ZZS3YYH9SBB7SDB12CSL1图3肝损伤95个交集靶点一成分网络图Fig.3 Network diagram of 95 intersectingtargets-components of liver injury2.3PPI网络及核心靶点的确定得到的PPI网络图，见图4。计算Degree值，以平均Degree值(10.6 2)的2 倍(2 0)进行核心靶点的筛选后，最终得到15个核心靶点：STAT3、JU N、A K T 1、T表2核心靶点Table 2Core targets核心靶点中文名Core targetChinese nameSTAT3信号传导与转录激活因子3JUN转录因子AP-1AKT1丝氨酸/苏氨酸蛋白激酶1TP53肿瘤蛋白p53TNF肿瘤坏死因子MAPK1丝裂原活化蛋白激酶1IL6白介素-6RELA核转录因子p65VEGFA血管内皮生长因子AMAPK8丝裂原活化蛋白激酶8MAPK14丝裂原活化蛋白激酶14PIK3CA磷脂酰肌醇-3-激酶p110a亚基MYC髓细胞瘤原癌基因蛋白CTNNB1-连环蛋白FOS原癌基因蛋白c-fos特产研P53、T NF、M A PK 1、I L6、R ELA、V EG FA、M A PK 8、MAPK14、PI K 3CA、M YC、CT NNB1和FOS,见图5和表2。35395腹方竹节参片图2 中药-肝损伤Venn图DFZ2QFT3YYH11YYH12YYHBYYH10QFTMOM2K3HMGCR究575MECXCL8CYPAAZCAL肝损伤(LI)IL1MAPTSTAT3PPARGRCLABB2D2SBB1SBB4FNC2ZS4BS3L1AAMFBR3S3ERPINSTAT2023年第45卷第4期CYP3A4IGFBICAMMYCIENGCLSBB5￥YH 13ZZS5NNPMAPK8FRBB2CAABCBP￥YH 17CFAYYH15YYH7SBB11YYH2SBB6YYH16YYH8CRPPARAIL6MAP2K1KN1AAKTXRABAX图4PPI网络图Fig.4PPI network diagram核心靶点DegreeFOS20SPPSBB10JUNAAPKCTNNB1MYCPIK3CAMAPK14MAPK8VEGFARELAIL6MAPK1TNFTP53AKT1JUNSTAT3图5核心靶点条形图Fig.5 Core target bar graph英文名English nameSignal transducer and activator of transcription 3Transcription factor AP-1Serine/threonine-protein kinase 1Tumor protein p53Tumor necrosis factorMotigen-activated protein kinase 1Interleukin-6Nuclear transcription factor kappa B p65Vascular endothelial growth factor ASerine/threonine-protein kinase 8Serine/threonine-proteinkinase 14Phosphatidylino-sitol 3-kinase-pl10-alpha subunitMyelocytomatosis proto-oncogene protein-cateninProto oncogene protein c fosGYP2C19IL1DSFESR1202122232324252527283131343810APK40LMAPKETNF2LABCB1RBCNLNO93GSK3BPRKGUTAT1HIMOX1MP1S2FOSNR1H4YP2C9VFGFATNNB1TP53TEN第4期2.4核心靶点的基因功能(GO)分析筛选排名前10 的基因功能，见表3和图6。其中Table 3(Gene ontology(GO)function analysis of core targets基因本体编号GOID0051090003249600708480062197BP1902893003459900346140002521000156800514030090575000566700359760005819CC00059110000791001989800355250034774006020501402970008134003361300199020061629MF00010460019900000470700012280004712核心靶点可能通过作用于上述细胞组分进而影响相应的分子功能，最终影响调节与DNA结合的转录宋添力，等：基于网络药理学与分子对接探讨土家药复方竹节参片对肝损伤的作用机制表3核心分子的基因本体(GO)功能分析功能描述注译DescriptionNotesRegulation of DNA-binding transcription调节与DNA结合的转录因子活性factor activityResponse to lipopolysaccharideResponse to growth factorCellular response to chemical stressRegulation of pri-miRNA transcription byRNA polymerase IICellular response to oxidative stressCellular response to reactive oxygen species 细胞对活性氧的反应Leukocyte differentiationBlood vessel developmentStress-activated MAPK cascadeRNA polymerase II transcription regulatorcomplexTranscription regulator complexTranscription factor AP-1 complexSpindleCell-cell junctionEuchromatinExtrinsic component of membraneNF-kappaB p50/p65 complexSecretory granule lumenCytoplasmic vesicle lumenDNA-binding transcription factor bindingTranscription factor bindingActivating transcription factor bindingPhosphatase bindingRNA polymerase II-specific DNA-bindingtranscription factor bindingCore promoter sequence-specific DNA bin-dingKinase bindingMAPkinase activityDNA-binding transcription activator activity，D NA 结合转录激活因子活性，RNA聚RNA polymerase II-specificProtein serine/threonine/tyrosine kinase ac-tivity63生物过程(BP)得到6 0 0 条，细胞组分（CC)分析得到31条，分子功能(MF)分析得到33条。数量-LogPCount19.052 046 3812对脂多糖的反应13.802 971 53对生长因子的反应14.348 765 25细胞对化学应激的反应13.535 221 69RNA聚合酶II 调控pri-miRNA转录12.837 744 25细胞对氧化应激的反应12.028 781 2212.003 598 41白细胞分化11.931 437 11血管的发展10.529 137 46应激激活MAPK级联10.461 791 55RNA聚合酶I转录调节因子复合物7.665 387 877转录调节复合物7.392.210 126转录因子AP-1复合物5.799 208 383纺锤体4.397 924 276细胞-细胞连接3.991 399 164常染色质3.782.295 992膜外成分3.288 439 733Nf-kB p50/p65复合体3.273 572 235分泌颗粒腔3.215 756 059胞质囊腔3.200 177 464DNA结合转录因子结合11.254 898 86转录因子结合11.205 547 49激活转录因子结合9.376 307 784磷酸酶结合9.341 387 097RNA聚合酶II特异性DNA结合转录8.4563 749 67因子结合核心启动子序列特异性DNA结合激酶结合MAPK酶活性合酶II特异性蛋白丝氨酸/苏氨酸/酪氨酸激酶活性因子活性、生长因子和脂多糖的反应、化学应激和氧化应激的反应以及血管的发展等生物过程。91196879975624423133895668.282 760 9147.346 475 71777.353 20735537.186 984 05665.796 455 175564(eneAd)3of-特产研19.0517.515.012.510.07.55.02.50.0究13.8014.3513.54.12.8412.0312.0011.932023年第45卷第4期BPCCMF11.2511.2110.5310.469.38.9.348.46 8.287.677.395.804.403.99 3.783.29 3.27 3.22 3.207.35 7.35 7.195.809:895100080200忆026142900200093.BiologicalprocessCellularcomponent图6GO分析Fig.6GO AnalysisKEGG Pathwayshsa05200:Pathways incancerhsa05161:Hepatitis B-ko05418:Fluid shear stress and atherosclerosisko04933:AGE-RAGE signaling pathway in diabetic complicationshsa05205:Proteoglycans incancerhsa05169:Epstein-Barrvirusinfectionhsa05166:HTLV-1infectionhsa05160:Hepatitis