动物营养学报 >

2026 , Vol. 38 >Issue 4: 3029 - 3046

DOI: https://doi.org/10.12418/CJAN2026.243

研究论文

基于网络药理学与分子对接技术研究鬼针草属的抑菌作用

  • 曾令添 , 1, 2 ,
  • 陈志安 1, 2, 3, * ,
  • 黄欣欣 1, 2, 3 ,
  • 何敏嘉 1, 2, 3 ,
  • 陈美椿 1, 2 ,
  • 翁成桢 1, 2, 3 ,
  • 曹翀 1, 2 ,
  • 邱龙新 1, 2 ,
  • 陈洪博 , 1, 2, ** ,
  • 李晓冰 , 1, 2, **
展开
  • 1 龙岩学院生命科学学院, 龙岩 364000
  • 2 福建省预防兽医学与兽医生物技术重点实验室, 龙岩 364000
  • 3 福建农林大学动物科学学院, 福州 350002
**陈洪博,副教授,硕士生导师,E-mail: ;
李晓冰,讲师,硕士生导师,E-mail:

*同等贡献作者

曾令添(2003—),男,福建龙岩人,硕士研究生,从事中草药饲料开发与应用研究。E-mail:

Office editor: 武海龙

收稿日期: 2025-09-24

  网络出版日期: 2026-04-14

基金资助

新罗区产学研技术创新项目(2022XLXYZ007)

收起

Antibacterial Effects of Bidens Based on Network Pharmacology and Molecular Docking Technology

  • ZENG Lingtian , 1, 2 ,
  • CHEN Zhi’an 1, 2, 3 ,
  • HUANG Xinxin 1, 2, 3 ,
  • HE Minjia 1, 2, 3 ,
  • CHEN Meichun 1, 2 ,
  • WENG Chengzhen 1, 2, 3 ,
  • CAO Chong 1, 2 ,
  • QIU Longxin 1, 2 ,
  • CHEN Hongbo , 1, 2, ** ,
  • LI Xiaobing , 1, 2, **
Expand
  • 1 School of Life Sciences, Longyan University, Longyan 364000, China
  • 2 Fujian Provincial Key Laboratory of Preventive Veterinary Medicine and Veterinary Biotechnology, Longyan 364000, China
  • 3 College of Animal Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China
**CHEN Hongbo, associate professor, E-mail: ;
LI Xiaobing, lecturer, E-mail:

*Contributed equally

Received date: 2025-09-24

  Online published: 2026-04-14

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摘要

为筛选出具饲用潜力的鬼针草属(Bidens)抑菌添加剂,本研究基于网络药理学与分子对接技术探究鬼针草(Bidens pilosa L.)、狼杷草(Bidens tripartita L.)、婆婆针(Bidens bipinnata L.)、金盏银盘[Bidens biternata (Lour.) Merr. et Sherff]和小花鬼针草(Bidens parviflora Willd.)5种鬼针草属物种的抑菌效果及作用机制。通过TCMSP、PubChem、HERB等数据库筛选5种鬼针草属物种的有效活性成分及潜在靶点;利用GeneCards、OMIM数据库收集抑菌相关靶点,借助Venny网站获取活性成分与抑菌靶点的交集靶点并绘制韦恩图;通过STRING数据库构建蛋白质-蛋白质相互作用(PPI)网络,筛选关键靶点;采用DAVID数据库对交集靶点进行基因本体(GO)功能和京都基因与基因组百科全书(KEGG)通路富集分析,并通过微生信在线平台可视化;最后利用Autodock Tools1.5.7软件、PyMOL2.4软件及CB-DOCK2网站对5种鬼针草属物种相同靶点的结合的差异与活性成分进行分子对接及可视化分析。结果表明:1)5种鬼针草属物种有效活性成分的潜在靶点数量存在差异,鬼针草、狼杷草、婆婆针、金盏银盘和小花鬼针草的潜在靶点数量分别为149、211、175、140和127个,与抑菌相关靶点的交集数量分别为40、54、48、35和27个。2)PPI网络分析筛选出5种鬼针草属物种交集靶点均具有表皮生长因子受体(EGFR)和雌激素受体1(ESR1)交集靶点。与鬼针草、金盏银盘和小花鬼针草交集靶点相比,主要差异在狼杷草的交集靶点有基质金属蛋白酶2(MMP2)、蛋白激酶B1(AKT1)和前列腺素内过氧化物合酶2(PTGS2),婆婆针的交集靶点有肿瘤坏死因子(TNF)、B细胞淋巴瘤2(BCL2)和AKT1。3)GO功能富集分析表明,鬼针草、婆婆针、金盏银盘和小花鬼针草生物过程(BP)都主要富集于蛋白质磷酸化的正调控、对外源刺激响应等,涉及细胞信号转导、应激反应等相关过程;细胞组分(CC)主要富集于含蛋白质复合物、质膜等;分子功能(MF)主要富集于酶结合、蛋白质同源二聚化活性和ATP结合等。KEGG通路富集分析表明,狼杷草核心通路以内分泌抵抗、细胞凋亡为主,婆婆针核心通路以磷脂酰肌醇3-激酶-蛋白激酶B(PI3K-AKT)信号通路为主,其余3种鬼针草核心通路以癌症相关通路、内分泌抵抗和雌激素信号通路为主。4)EGFR和ESR1是5种鬼针草属物种均与抑菌有关的共同靶点。分子对接结果显示,5种鬼针草属物种有效活性成分与EGFR、ESR1的结合能均小于-5.0 kcal/mol(1 kcal/mol=4.184 kJ/mol),但狼杷草和婆婆针的平均结合能较高,有效活性成分与靶点结合更稳定。综上所述,通过交集靶点的数量和分子对接结合能,可得狼杷草和婆婆针更适合作为饲料添加剂。

关键词： 网络药理学; 鬼针草属; 抑菌; 分子对接

本文引用格式

曾令添 , 陈志安 , 黄欣欣 , 何敏嘉 , 陈美椿 , 翁成桢 , 曹翀 , 邱龙新 , 陈洪博 , 李晓冰 . 基于网络药理学与分子对接技术研究鬼针草属的抑菌作用[J]. 动物营养学报, 2026 , 38(4) : 3029 -3046 . DOI: 10.12418/CJAN2026.243

Abstract

In order to screen out the antibacterial additives of Bidens with feeding potential, this study explored the antibacterial effects and mechanisms of 5 Bidens species including Bidens pilosa L., Bidens tripartita L., Bidens bipinnata L., Bidens biternata (Lour.) Merr. et Sherff and Bidens parviflora Willd. based on network pharmacology and molecular docking technology. The effective active components and potential targets of 5 Bidens species were screened by TCMSP, PubChem, HERB and other databases. The GeneCards and OMIM databases were used to collect antibacterial related targets, and the Venny website was used to obtain the intersection targets of effective active components and antibacterial targets, and draw the Venn diagram. The protein-protein interaction (PPI) network was constructed through the STRING database to screen key targets. The DAVID database was used to perform gene ontology (GO) functional and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis on the intersection targets, and visualization was performed through the Weshengxin online platform. Finally, the Autodock Tools1.5.7 software, PyMOL 2.4 software and CB-DOCK2 website were used to perform molecular docking and visualization analysis on the differences in the binding of the same targets and effective active components of the 5 Bidens species. The results showed as follows: 1) there were differences in the number of potential targets of effective active components of 5 Bidens species, the numbers of potential targets of Bidens pilosa L., Bidens tripartita L., Bidens bipinnata L., Bidens biternata (Lour.) Merr. et Sherff and Bidens parviflora Willd. were 149, 211, 175, 140 and 127, respectively, and the numbers of intersections with antibacterial-related targets were 40, 54, 48, 35 and 27, respectively. 2) The PPI network analysis screened out the key targets of 5 Bidens species all had the intersection targets of epidermal growth factor receptor (EGFR) and estrogen receptor 1 (ESR1). Compared with the intersection targets of Bidens pilosa L. Bidens biternata (Lour.) Merr. et Sherff and Bidens parviflora Willd., the main differences showed that the intersection targets of Bidens tripartita L. were matrix metalloproteinase 2 (MMP2), protein kinase B1 (AKT1) and prostaglandin-endoperoxide synthase 2 (PTGS2), and the intersection targets of Bidens bipinnata L. were tumor necrosis factor (TNF), B cell lymphoma 2 (BCL2) and AKT1. 3) The GO functional enrichment analysis showed that the biological processes (BP) of Bidens pilosa L., Bidens bipinnata L., Bidens biternata (Lour.) Merr. et Sherff and Bidens parviflora Willd. were mainly enriched in positive regulation of protein phosphorylation and response to exogenous stimuli, involving cell signal transduction, stress response and other related processes; the cell components (CC) were mainly enriched in protein complexes, plasma membranes, etc; and the molecular function(MF) were mainly enriched in enzyme binding, protein homodimerization activity and ATP binding etc. The KEGG pathway enrichment analysis showed that the core pathways of Bidens tripartita L. were mainly endocrine resistance and cell apoptosis, the core pathways of Bidens bipinnata L. were mainly phosphatidylinositol 3-kinase protein kinase B (PI3K-AKT) signaling pathway, and the core pathways of other 3 Bidens species were mainly pathways in cancer, endocrine resistance and estrogen signaling pathway. 4) The EGFR and ESR1 were the common targets of 5 Bidens species and were related to bacteriostasis. The molecular docking results showed that the binding energy of the effective active components of 5 Bidens species to the key targets (EGFR and ESR1) was less than -5.0 kcal/mol (1 kcal/mol=4.184 kJ/mol), but the average binding energy of Bidens tripartita L. and Bidens bipinnata L. was higher, and the binding of effective active components to targets was more stable. In summary, through the number of intersection targets and molecular docking binding energy, it can be obtained that the Bidens tripartita L. and Bidens bipinnata L. are more suitable as feed additives.

Key words： network pharmacology; Bidens; antibacterial; molecular docking

在畜禽养殖业中,抗生素长期以来被广泛应用于饲料添加剂,其核心作用在于抑制或杀灭养殖环境中及畜禽体内的病原微生物,减少细菌性疾病的发生与传播,同时还能通过调节肠道菌群平衡、降低机体炎症反应等途径,在一定程度上促进畜禽生长发育、提高饲料利用率,在保障养殖业规模化、集约化发展方面发挥了重要作用[1-2]。但传统抗生素的泛滥及其不合理使用,促使病原耐药菌株不断涌现,导致诸多感染性疾病的治疗愈发艰难[3]。在这一背景下,开发能够替代抗生素的饲料添加剂成为研究热点[4]。
以中草药替代抗生素是缓解耐药性问题的安全高效策略[5]。中草药具有抗菌、抗炎和抗病毒等作用[6]。鬼针草属(Bidens)作为传统中药材,具有悠久的药用历史,具备清热解毒、祛风除湿、活血消肿等功效[7],现代药理学研究表明,鬼针草属具有抑菌、抗炎、抗氧化、抗肿瘤、降血糖、降血脂等多种生物学活性[8-9]。鬼针草属常见药物物种有鬼针草(Bidens pilosa L.)、狼杷草(Bidens tripartita L.)、婆婆针(Bidens bipinnata L.)、金盏银盘[Bidens biternata (Lour.) Merr. et Sherff]和小花鬼针草(Bidens parviflora Willd.),然而这5种鬼针草属物种在抑菌效果方面的研究还存在空白。网络药理学可有助于理解疾病的复杂机制和发现药物与疾病的相关靶点,加速新药的开发,用于预测功能活性物质对相关疾病治疗的潜在机制[10-11]。因此,本研究基于网络药理学方法,对鬼针草、狼杷草、婆婆针、金盏银盘和小花鬼针草的抑菌活性成分及其作用机制进行系统研究,筛选出抑菌效果最佳的鬼针草属物种。

1 材料与方法

1.1 5种鬼针草属物种有效活性成分和靶点筛选

通过TCMSP平台(https://old.temsp-e.com/tcmsp.php),以口服生物利用度(OB)≥30%、类药性(DL)≥0.18和药物半衰期(HL)≥4为筛选标准,通过PubChem平台(https://pubchem.ncbi.nlm.nih.gov)和HERB平台(http://herb.ac.cn/Contact)以高可信度蛋白进行搜索,筛选5种鬼针草属物种有效活性成分,并获取所筛选有效活性成分的潜在靶点。

1.2 5种鬼针草属物种有效活性成分-靶点网络图的构建

借助Uniprot平台(http://www.uniprot.org)将筛选到的潜在靶点转换为统一的基因名称,且将有效活性成分和潜在靶点导入Cytoscape 3.10.3软件中,绘制有效活性成分-靶点网络图。

1.3 抑菌相关靶点和交集靶点的获取

利用GeneCards数据库(https://www.genecards.org)、OMIM数据库(https://hwww.omim.org),以bacteriostasis为关键词,合并去重后与有效活性成分的潜在靶点取交集,并输出到Venny 2.1.0平台绘制韦恩图。

1.4 5种鬼针草属物种有效活性成分-靶点-抑菌网络图的构建

在1.2基础中,将5种鬼针草属物种的有效活性成分和其相对应的交集靶点导入Cytoscape 3.10.3软件中,绘制5种鬼针草属物种有效活性成分-靶点-抑菌网络图。

1.5 蛋白质-蛋白质相互作用(PPI)网络的构建和关键靶点的获取

将交集的靶点导入STRING数据库(https://string-db.org),进行PPI网络预测分析,将获得的PPI网络关系图导入Cytoscape 3.10.3软件,以度值作为筛选标准,从高到低排序,获取排名前6位的靶点作为关键靶点[12]。

1.6 GO功能和KEGG通路富集分析

使用DAVID数据库(https://davidbioinformatics.nih.gov/summary.jsp)对交集靶点进行GO功能和KEGG通路富集分析,调整筛选标准为P≤0.05[13],并通过微生信在线平台(https://www.bioinformatics.com.cn)对GO功能和KEGG通路富集分析排名前10的功能或通路进行可视化分析。

1.7 分子对接

将5种鬼针草属物种关键靶点汇总并筛选共用靶点后与有效活性成分进行分子对接操作。从PubChem平台获取活性成分3D结构文件。在PDB网站(https://www1.rcsb.org)下载关键核心靶点的3D晶体结构,借助PyMol2.4软件、Autodock Tools 1.5.7软件和CB-DOCK2网站(https://cadd.labshare.cn/cb-dock2/php/index.php)进行可视化分析。

2 结果与分析

2.1 5种鬼针草属物种有效活性成分

本研究筛选出的5种鬼针草属物种有效活性成分见表1。其中,鬼针草的有效活性成分包括:木犀草素(luteolin)、奥卡宁(okanin)、槲皮素(quercetin)、(R)-2-(3,4-二羟基苯基)-6,7-二羟基苯并呋喃-3(2H)-酮[(R)-2-(3,4-dihydroxyphenyl)-6,7-dihydroxybenzofuran-3(2H)-one]和(2E)-2-(3,4-二羟基亚苄基)-6,7-二羟基苯并呋喃-3-酮[(2E)-2-(3,4-dihydroxybenzylidene)-6,7-dihydroxy-benzofuran-3-one];狼杷草的有效活性成分包括:七叶内酯(aesculetin)、芹菜素(apigenin)、槲皮素、木犀草素和依色林(eseramine);婆婆针的有效活性成分包括:柚皮素(naringenin)、橙皮苷(hesperidin)、黄芪苷(astragalin)、山奈酚(kaempferol)和金丝桃苷(hyperoside);金盏银盘的有效活性成分包括:芦丁(rutin)、奥卡宁、色氨酸(tryptophane)、3-O-咖啡酰奎宁酸(3-O-caffeoylquinic aicd)和奥卡宁-O-葡萄糖苷(okanin-O-glucoside);小花鬼针草的有效活性成分包括:(1α,2α,3α,4α)-2,4-双(3,4-二羟基苯基)-1,3-环丁烷二甲酸二甲酯[dimethyl ester of(1α,2α,3α,4α)-2,4-bis(3,4-dihydroxyphenyl)-1,3-cyclobutanedicarboxylicacid]、(6-O-(E)-对香豆酰)-β-D-呋喃果糖基-(2→1)-α-D-吡喃葡萄糖苷[(6-O-(E)-p-coumaroyl)-β-D-fructofuranosyl-(2→1)-α-D-glucopyranoside]和鬼针草苷a1(bidensyneoside a1)。与鬼针草相比,除狼杷草中木犀草素和槲皮素以及金盏银盘中奥卡宁外,其余鬼针草属有效活性成分均不相同。
表1 5种鬼针草属物种有效活性成分

Table 1 Effective active components of 5 Bidens species

项目Items 分子名称Molecular names
鬼针草
Bidens pilosa L.		 luteolin okanin quercetin (2E)-2-(3,4-
dihydroxybenzylidene)-
6,7-dihydroxy-
benzofuran-
3-one		 (R)-2-(3,4-
dihydroxyphenyl)-
6,7-dihydroxybenzofuran-
3(2H)-one
狼杷草
Bidens tripartita L.		 aesculetin apigenin quercetin luteolin eseramine
婆婆针
Bidens bipinnata L.		 naringenin hesperidin astragalin kaempferol hyperoside
金盏银盘
Bidens biternata
(Lour.) Merr. et
Sherff		 rutin okanin tryptophane 3-O-caffeoylquinic
aicd		 okanin-O-glucoside
小花鬼针草
Bidens
parviflora
Willd.		 dimethyl ester of
(1α,2α,3α,4α)-2,
4-bis(3,4-dihydroxyp-
henyl)-1,3-cyclobu-
tanedicar-
boxylicacid		 (6-O-(E)-p-
coumaroyl)-
β-D-
fructofuranosyl-
(2→1)-α-
D-glucopyranoside		 bidensyneoside
a1

luteolin:木犀草素;okanin:奥卡宁;quercetin:槲皮素;(R)-2-(3,4-dihydroxyphenyl)-6,7-dihydroxybenzofuran-3(2H)-one:(R)-2-(3,4-二羟基苯基)-6,7-二羟基苯并呋喃-3(2H)-酮;(2E)-2-(3,4-dihydroxybenzylidene)-6,7-dihydroxy-benzofuran-3-one:(2E)-2-(3,4-二羟基亚苄基)-6,7-二羟基苯并呋喃-3-酮;aesculetin:七叶内酯;apigenin:芹菜素;eseramine:依色林;naringenin:柚皮素;hesperidin:橙皮苷;astragalin:黄芪苷;kaempferol:山奈酚;hyperoside:金丝桃苷;rutin:芦丁;tryptophane:色氨酸;3-O-caffeoylquinic aicd:3-O-咖啡酰奎宁酸;okanin-O-glucoside:奥卡宁-O-葡萄糖苷;dimethyl ester of(1α,2α,3α,4α)-2,4-bis(3,4-dihydroxyphenyl)-1,3-cyclobutanedicarboxylicacid:(1α,2α,3α,4α)-2,4-双(3,4-二羟基苯基)-1,3-环丁烷二甲酸二甲酯;(6-O-(E)-p-coumaroyl)-β-D-fructofuranosyl-(2→1)-α-D-glucopyranoside:(6-O-(E)-对香豆酰)-β-D-呋喃果糖基-(2→1)-α-D-吡喃葡萄糖苷;bidensyneoside a1:鬼针草苷a1。表3同 the same as Table 3。

2.2 5种鬼针草属物种有效活性成分-靶点网络图

由图1可见,合并去重后获得5种鬼针草属物种有效活性成分的潜在靶点,其中,鬼针草潜在靶点共149个,狼杷草的潜在靶点共211个,婆婆针的潜在靶点共175个,金盏银盘的潜在靶点共140个,小花鬼针草的潜在靶点共127个。
图1 5种鬼针草属物种有效活性成分-靶点网络图

仅列出后续相关靶点名称 list only subsequent related target names。MMP9:基质金属蛋白酶9 matrix metalloproteinase 9;MMP2:基质金属蛋白酶2 matrix metalloproteinase 2;PTGS2:前列腺素内过氧化物合酶2 prostaglandin-endoperoxide synthase 2;AKT1:蛋白激酶B1 protein kinase B1;BCL2:B细胞淋巴瘤2 B cell lymphoma 2;PPARG:过氧化物酶体增殖物激活受体γ peroxisome proliferator-activated receptor gamma;HSP90AA1:热休克蛋白90α家族A成员1 heat shock protein 90 alpha family class A member 1;SIRT1:沉默调节蛋白1 sirtuin 1;EGFR:表皮生长因子受体 epidermal growth factor receptor;ESR1:雌激素受体1 estrogen receptor 1;TNF:肿瘤坏死因子 tumor necrosis factor;a:(1α,2α,3α,4α)-2,4-双(3,4-二羟基苯基)-1,3-环丁烷二甲酸二甲酯 dimethyl ester of(1α,2α,3α,4α)-2,4-bis(3,4-dihydroxyphenyl)-1,3-cyclobutanedicarboxylicacid;b:(6-O-(E)-对香豆酰)-β-D-呋喃果糖基-(2→1)-α-D-吡喃葡萄糖苷 (6-O-(E)-p-coumaroyl)-β-D-fructofuranosyl-(2→1)-α-D-glucopyranoside。图3和图4同 the same as Fig.3 and Fig.4。

Fig.1 Effective active components-target network diagram of 5 Bidens species

2.3 抑菌相关靶点和交集靶点

由图2可见,合并去重后得到1 205个抑菌相关靶点,鬼针草、狼杷草、婆婆针、金盏银盘和小花鬼针草的潜在作用靶点与抑菌相关靶点取交集后分别得到40、54、48、35、27个交集靶点。
图2 5种鬼针草属物种抑菌靶点韦恩图

Fig.2 Venn diagram of antibacterial target of 5 Bidens species

2.4 5种鬼针草属物种有效活性成分-靶点-抑菌网络图

将上述获得的交集靶点与5种鬼针草属物种的有效活性成分分别导入Cytoscape 3.10.3软件绘制网络图,其节点的度值,即连接线的数目,被用作相互作用强度的衡量标准,度值越高,表明该成分作用的靶点越多[14]。由图3可见,鬼针草作用靶点较多的有效活性成分为木犀草素和槲皮素,狼杷草作用靶点较多的有效活性成分为七叶内酯、芹菜素、槲皮素和木犀草素,婆婆针作用靶点较多的有效活性成分为柚皮素、橙皮苷和山奈酚,金盏银盘作用靶点较多的有效活性成分为奥卡宁和色氨酸,小花鬼针草作用靶点较多的有效活性成分为(1α,2α,3α,4α)-2,4-双(3,4-二羟基苯基)-1,3-环丁烷二甲酸二甲酯。
图3 5种鬼针草属物种有效活性成分-靶点-抑菌网络图

仅列出后续相关有效活性成分名称 list only subsequent related effective active component names。Luteolin:木犀草素;Quercetin:槲皮素;Aesculetin:七叶内酯;Apigenin:芹菜素:Naringenin:柚皮素;Hesperidin:橙皮苷;Hyperoside:金丝桃苷;Kaempferol:山奈酚;Okanin:奥卡宁;Rutin:芦丁;Tryptophane:色氨酸;Eseramine:依色林;Dimethyl ester of(1α,2α,3α,4α)-2,4-bis(3,4-dihydroxyphenyl)-1,3-cyclobutanedicarboxylicacid:(1α,2α,3α,4α)-2,4-双(3,4-二羟基苯基)-1,3-环丁烷二甲酸二甲酯。图7至图10同。The same as Fig.7 to Fig.10。

Fig.3 Network diagram of effective active component-target-bacteriostasis of 5 Bidens species

2.5 PPI网络的构建和关键靶点

将上述交集靶点导入STRING数据库,构建PPI网络,并在构建过程中删除游离基因节点。将生成的PPI网络图导入Cytoscape 3.10.3软件开展拓扑分析,构建5种鬼针草属物种PPI网络图(图4)。最终根据度值情况,筛选出数值排名前6位的靶点,作为该研究中的关键靶点。由表2可见,5种鬼针草属物种都具有表皮生长因子受体(EGFR)和雌激素受体1(ESR1)交集靶点。与鬼针草、金盏银盘和小花鬼针草交集靶点相比,主要差异在狼杷草的交集靶点有基质金属蛋白酶2(MMP2)、蛋白激酶B1(AKT1)和前列腺素内过氧化物合酶2(PTGS2),婆婆针的交集靶点有肿瘤坏死因子(TNF)、B细胞淋巴瘤2(BCL2)和AKT1。
图4 5种鬼针草属物种PPI网络图

A:鬼针草 Bidens pilosa L.;B:狼杷草 Bidens tripartita L.;C:婆婆针 Bidens bipinnata L.;D:金盏银盘 Bidens biternata (Lour.) Merr. et Sherff;E:小花鬼针草 Bidens parviflora Willd.。

Fig.4 PPI network diagram of 5 Bidens species

表2 5种鬼针草属物种的关键靶点

Table 2 Key targets of 5 Bidens species

项目
Items		 鬼针草
Bidens pilosa
L.		 狼杷草
Bidens tripartita
L.		 婆婆针
Bidens bipinnata
L.		 金盏银盘
Bidens biternata
(Lour.) Merr.
et Sherff		 小花鬼针草
Bidens parviflora
Willd.
1 AKT1 AKT1 AKT1 TNF TNF
2 EGFR EGFR TNF PTGS2 ESR1
3 ESR1 ESR1 BCL2 MMP9 EGFR
4 PTGS2 MMP9 PTGS2 ESR1 BCL2
5 MMP9 PTGS2 EGFR EGFR PPARG
6 SIRT1 MMP2 ESR1 MMP2 HSP90A1

AKT1:蛋白激酶B1 protein kinase B1;TNF:肿瘤坏死因子 tumor necrosis factor;EGFR:表皮生长因子受体 epidermal growth factor receptor;PTGS2:前列腺素内过氧化物合酶2 prostaglandin-endoperoxide synthase 2;ESR1:雌激素受体1 estrogen receptor 1;BCL2:B细胞淋巴瘤2 B cell lymphoma 2;MMP9:基质金属蛋白酶9 matrix metalloproteinase 9;PPARG:过氧化物酶体增殖物激活受体γ peroxisome proliferator-activated receptor gamma;SIRT1:沉默调节蛋白1 sirtuin 1;MMP2:基质金属蛋白酶2 matrix metalloproteinase 2;HSP90AA1:热休克蛋白90α家族A成员1 heat shock protein 90 alpha family class A member 1。

2.6 GO功能和KEGG通路富集分析

将上述交集靶点导入DAVID数据库中,分别进行GO功能和KEGG通路富集分析,以P≤0.05为阈值进行筛选,选取排前10的功能或通路进行分析。由图5和图6可见,GO功能富集表明,狼杷草生物过程(BP)主要富集于胶原分解代谢过程、细胞凋亡过程的负调控等,涉及细胞代谢、增殖与凋亡调控等相关过程;细胞组分(CC)主要富集于细胞外区、质膜等;分子功能(MF)主要富集于酶结合、ATP结合等。其余4种鬼针草属物种生物过程都主要富集于蛋白质磷酸化的正调控、对外源刺激响应等,涉及细胞信号转导、应激反应等相关过程;细胞组分主要富集于含蛋白质复合物、质膜等;分子功能主要富集于酶结合、蛋白质同源二聚化活性和ATP结合等。
图5 5种鬼针草属物种的GO功能富集分析

Biological process:生物过程;positive regulation of protein phosphorylation:蛋白质磷酸化的正调控;response to xenobiotic stimulus:对外源物质刺激的应答;positive regulation of nitric oxide biosynthetic process:一氧化氮生物合成过程的正调控;response to oxidative stress:对氧化应激的应答;positive regulation of interleukin-8 production:白细胞介素-8产生的正调控;positive regulation of transcription by RNA polymerase Ⅱ:RNA聚合酶Ⅱ转录的正调控;ephrin receptor signaling pathway:肝配蛋白受体信号通路;positive regulation of apoptotic process:细胞凋亡过程的正调控;positive regulation of MAPK cascade:丝裂原活化蛋白激酶级联反应的正调控;positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction:磷脂酰肌醇3-激酶/蛋白激酶B信号转导的正调控;collagen catabolic process:胶原分解代谢过程;negative regulation of apoptotic process:细胞凋亡过程的负调控;rhythmic process:节律性过程;extracellular matrix disassembly:细胞外基质分解;positive regulation of cell population proliferation:细胞群体增殖的正调控;peptidyl-serine phosphorylation:肽基-丝氨酸磷酸化;positive regulation of cell growth:细胞生长的正调控;positive regulation of inflammatory response:炎症反应的正调控;cellular response to insulin stimulus:细胞对胰岛素刺激的应答;positive regulation of peptidyl-serine phosphorylation:肽基-丝氨酸磷酸化的正调控;response to lipopolysaccharide:对脂多糖的应答;response to hypoxia:对缺氧的应答;microglial cell activation:小胶质细胞活化;cellular response to estradiol stimulus:细胞对雌二醇刺激的应答;positive regulation of protein metabolic process:蛋白质代谢过程的正调控;negative regulation of miRNA transcription:微小RNA转录的负调控;positive;regulation of chemokine production:趋化因子产生的正调控;positive regulation of cholesterol transport:胆固醇转运的正调控;negative regulation of type Ⅱ interferon-mediated signaling pathway:Ⅱ型干扰素介导的信号通路的负调控;response to estrogen:对雌激素的应答。

Cellular Component:细胞组分;Protein-containing complex:含蛋白质复合物;Apical plasma membrane:顶质膜;Extracellular space:细胞外间隙;Collagen-containing extracellular matrix:含胶原细胞外基质;Plasma membrane:质膜;Cell surface:细胞表面;Extracellular region:细胞外区;Lysosome:溶酶体;Mitochondrion:线粒体;Nucleoplasm核质;Endolysosome lumen:内溶酶体腔;Ficolin-1-rich granule lumen:富含纤维胶凝蛋白-1-颗粒腔;Cytosol:细胞质基质;Perinuclear region of cytoplasm:细胞质核周区;Endoplasmic reticulum membrane:内质网膜;Intracellular membrane-bounded organelle:细胞内膜结合细胞器;Extracellular exosome:细胞外外泌体;Membrane raft:膜筏;Azurophil granule lumen:嗜天青颗粒腔;Receptor complex:受体复合物;Nucleus:细胞核;Endoplasmic reticulum:内质网;Cytoplasm:细胞质。

Molecular Function:分子功能;Enzyme binding:酶结合;Protein homodimerization activity:蛋白质同源二聚化活性;Chromatin binding:染色质结合;ATPase-coupled transmembrane transporter activity:ATP酶偶联跨膜转运蛋白活性;ABC-type transporter activity:ABC型转运蛋白活性;Identical protein binding:相同蛋白质结合;Nuclear receptor activity:核受体活性;Estrogen response element binding:雌激素反应元件结合:Flavin adenine dinucleotide binding:黄素腺嘌呤二核苷酸结合;Efflux transmembrane transporter activity:外排跨膜转运蛋白活性;ATP binding:ATP结合;Serine-type endopeptidase activity:丝氨酸型内肽酶活性;Proteoglycan binding:蛋白聚糖结合;Protein serine/threonine kinase activity:蛋白质丝氨酸/苏氨酸激酶活性;Protein kinase activity:蛋白激酶活性;Oxidoreductase activity:氧化还原酶活性;Collagen binding:胶原结合;Heme binding:血红素结合;Estrogen 2-hydroxylase activity:雌激素2-羟化酶活性;Integrin binding:整合素结合;Histone H2AXY142 kinase activity:组蛋白H2AXY142激酶活性;Histone H3Y41 kinase activity:组蛋白H3Y41激酶活性;Sequence-specific DNA binding:序列特异性DNA结合;Protein tyrosine kinase activity:蛋白质酪氨酸激酶活性;Protein serine kinase activity:蛋白质丝氨酸激酶活性。

A:鬼针草 Bidens pilosa L.;B:狼杷草 Bidens tripartita L.;C:婆婆针 Bidens bipinnata L.;D:金盏银盘 Bidens biternata (Lour.) Merr. et Sherff;E:小花鬼针草 Bidens parviflora Willd.。

Fig.5 GO functional enrichment analysis of 5 Bidens species

图6 5种鬼针草属物种的KEGG通路富集分析

Endocrine resistance:内分泌抵抗;Pathways in cancer:癌症相关通路;Estrogen signaling pathway:雌激素信号通路;ABC transporters:ABC转运蛋白;HIF-1 signaling pathway:缺氧诱导因子-1信号通路;Ovarian steroidogenesis:卵巢类固醇生成;Serotonergic synapse:血清素能突触;Proteoglycans in cancer:癌症中的蛋白聚糖;Chemical carcinogenesis-receptor activation:化学致癌作用-受体激活;Relaxin signaling pathway:松弛素信号通路;African trypanosomiasis:非洲锥虫病;Phenylalanine metabolism:苯丙氨酸代谢;Fluid shear stress and atherosclerosis:流体剪切应力与动脉粥样硬化;GnRH signaling pathway:促性腺激素释放激素信号通路;Bladder cancer:膀胱癌;Apoptosis:细胞凋亡;PD-L1 expression and PD-1 checkpoint pathway in cancer:癌症中PD-L1表达与PD-1检查点通路;Diabetic cardiomyopathy:糖尿病性心肌病;AGE-RAGE signaling pathway in diabetic complications:糖尿病并发症中的AGE-RAGE信号通路;NOD-like receptor signaling pathway:NOD样受体信号通路;Shigellosis:志贺菌病;Insulin resistance:胰岛素抵抗;Arachidonic acid metabolism:花生四烯酸代谢;Lipid and atherosclerosis:脂质与动脉粥样硬化;Small cell lung cancer:小细胞肺癌;Linoleic acid metabolism:亚油酸代谢;PI3K-AKT signaling pathway:磷脂酰肌醇3-激酶-蛋白激酶B信号通路。

A:鬼针草 Bidens pilosa L.;B:狼杷草 Bidens tripartita L.;C:婆婆针 Bidens bipinnata L.;D:金盏银盘 Bidens biternata (Lour.) Merr. et Sherff;E:小花鬼针草 Bidens parviflora Willd.。

Fig.6 KEGG pathway enrichment analysis of 5 Bidens species

KEGG通路富集分析表明,狼杷草核心通路以内分泌抵抗、细胞凋亡为主,婆婆针核心通路以磷脂酰肌醇3-激酶-蛋白激酶B(PI3K-AKT)信号通路为主,其余3种鬼针草核心通路以癌症相关通路、内分泌抵抗和雌激素信号通路为主。

2.7 分子对接

将上述的关键靶点进行汇总,去除重复项,可得到2个共同靶点(EGFR和ESR1),EGFR可以调控细胞免受细菌侵袭,ESR1具有对免疫系统的调控作用[15-16]。故用5种鬼针草属物种的有效活性成分将分别与其进行分子对接分析,其结合能均小于-5.0 kcal/mol(1 kcal/mol=4.184 kJ/mol)。由表3可见,狼杷草和婆婆针的平均结合能较高。狼杷草和婆婆针的蛋白质-小分子对接图见图7至图10。
表3 5种鬼针草属物种有效活性成分与疾病靶点分子对接结合能

Table 3 Effective active components and molecular docking binding energy with disease targets of 5 Bidens species

项目
Items		 有效活性成分
Effective active
components		 结合能Binding energy/(kcal/mol)
表皮生长因子受体
EGFR		 雌激素受体1
ESR1
鬼针草
Bidens pilosa L.		 luteolin -8.5 -7.0
okanin -6.7 -6.9
(2E)-2-(3,4-dihydroxybenzylidene)-6,7-
dihydroxy-benzofuran-3-one		 -7.0 -7.0
quercetin -8.3 -7.1
(R)-2-(3,4-dihydroxyphenyl)-6,7-
dihydroxybenzofuran-3(2H)-one		 -5.6 -6.5
狼杷草
Bidens tripartita L.		 aesculetin -6.3 -5.4
apigenin -8.1 -6.6
eseramine -8.5 -6.9
luteolin -8.5 -7.0
quercetin -8.3 -7.1
婆婆针
Bidens bipinnata L.		 naringenin -6.5 -6.7
hesperidin -10.4 -8.2
astragalin -7.6 -8.1
kaempferol -8.0 -6.9
hyperoside -7.2 -7.6
金盏银盘
Bidens biternata (Lour.) Merr. et Sherff		 3-O-caffeoylquinic aicd -8.7 -7.2
tryptophane -5.6 -5.7
okanin-O-glucoside -9.5 -7.3
rutin -7.6 -7.8
okanin -6.7 -6.9
小花鬼针草
Bidens parviflora Willd.		 bidensyneoside a1 -6.6 -5.4
dimethyl ester of(1α,2α,3α,4α)-2,4-bis(3,4-
dihydroxyphenyl)-1,3-cyclobutanedicarboxylicacid		 -8.4 -6.5
(6-O-(E)-p-coumaroyl)-β-D-
fructofuranosyl-(2→1)-α-D-glucopyranoside		 -9.7 -7.4
图7 EGFR与狼杷草有效活性成分分子对接3D图

EGFR:表皮生长因子受体 epidermal growth factor receptor;ESR1:雌激素受体1 estrogen receptor 1。下图同 the same as below。

Fig.7 Molecular docking 3D diagram of EGFR and effective active components of Bidens tripartita L.

图8 ESR1与狼杷草有效活性成分分子对接3D图

Fig.8 Molecular docking 3D diagram of ESR1 and effective active components of Bidens tripartita L.

图9 EGFR与婆婆针有效活性成分分子对接3D图

Fig.9 Molecular docking 3D diagram of EGFR and effective active components of Bidens bipinnata L.

图10 ESR1与婆婆针有效活性成分分子对接3D图

Fig.10 3D diagram of molecular docking between ESR1 and effective active components of Bidens bipinnata L.

3 讨论

饲料中添加抗生素可有效地促进动物生长发育、提高饲料利用率和对疾病的预防[17-18]。但在家畜养殖过程中,抗生素的滥用不仅导致了耐药菌的产生,也给环境带来了巨大压力[19]。目前,随着抗生素的广泛却不恰当使用,由超级细菌或病毒感染以及环境条件变化引起的炎症疾病或流感传染病给畜禽养殖业带来了巨大的经济损失,长期使用抗生素不仅会破坏动物机体原有免疫功能,而且会导致动物自身免疫能力下降,使动物疾病频繁发生[20-21]。网络药理学技术的发展和应用为药物研究提供了一个独特的视角。现代药理学研究表明,鬼针草属具有抗炎、抗菌等功能[22]。因此,本研究通过网络药理学方法,对5种鬼针草属物种的抑菌效果进行筛选。
通过5种鬼针草属物种有效活性成分来看,鬼针草中的木犀草素、槲皮素和狼杷草中的七叶内酯、芹菜素、木犀草素和槲皮素均具有良好的抗菌作用。七叶内酯具有降血糖、抗氧化、抗菌、抗炎、抗肿瘤等作用[23]。芹菜素可通过抑制细胞膜合成、核酸合成来抵抗细菌生长发育,如金黄色葡萄球菌、大肠杆菌和白色念珠菌等[24-25]。木犀草素对多种细菌具有良好的抑菌活性[26]。槲皮素对金黄色葡萄球菌、大肠杆菌有抑制作用[27],木犀草素和槲皮素都可通过破坏细菌细胞壁的完整性,从而起到抑菌的作用[28-29]。Zhang等[30]证明槲皮素通过调节信号通路和蛋白的表达水平对幽门螺杆菌起到抑制作用。婆婆针中的山奈酚、柚皮素和橙皮苷具备抑菌的作用。山奈酚可以通过ABC转运蛋白、鞭毛组装和脂肪酸代谢的作用,对幽门螺杆菌起到抑菌作用[31]。柚皮素可以通过对核因子(NF-κB)信号通路的抑制,减少炎症因子表达,对特定种类的致病菌显示出较好的抑菌活性[32-33]。橙皮苷可抑制细菌生物膜的生成起到抑菌作用[34]。金盏银盘中的芦丁有抑菌相关的作用,其通过抑制细胞质膜功能来抑制细菌细胞壁合成[35]。综上所述,本研究结果表明不同的鬼针草属物种均具有抑菌作用。
通过韦恩图和PPI网络分析结果表明,狼杷草和婆婆针的抑菌重叠度较高,而其余3种鬼针草属物种相对较低。与鬼针草、金盏银盘和小花鬼针草交集靶点相比,主要差异在狼杷草的交集靶点有MMP2、AKT1、PTGS2,婆婆针的交集靶点有TNF、BCL2、AKT1。TNF在炎症反应、免疫调节等具有重要作用,BCL2参与细胞凋亡的过程,MMP2在分解细胞外基质蛋白和细胞迁移黏附发挥重要作用[36-38]。AKT1是PI3K-AKT信号通路的核心因子,对细胞生长和存活至关重要[39-40]。AKT1可以通过调节AKT1/哺乳动物雷帕霉素靶蛋白(mTOR)信号通路抵抗病原菌的入侵[41]。EGFR是上皮生长因子细胞增殖和信号传导的受体,可通过提高胃黏膜再生能力来抵御幽门螺杆菌的感染[42]。PTGS2可在细菌感染期间激活巨噬细胞,发挥抑菌的作用[43]。
本研究中,通过GO功能和KEGG通路富集分析发现,鬼针草、金盏银盘和小花鬼针草的核心通路以癌症相关通路、内分泌抵抗和雌激素信号通路为主,与抑菌方面调控较为薄弱。狼杷草主要涉及胶原代谢、细胞增殖等生物学过程,这些过程主要在细胞外基质、细胞质等细胞组分,涉及激酶活性、胶原结合等分子功能,其交集靶点对内分泌抵抗、细胞凋亡等通路产生显著影响。婆婆针主要涉及外源刺激响应、细胞凋亡精细调控等生物学过程,这些过程主要在细胞膜、细胞外空间等细胞组分,涉及氧化还原酶、蛋白互作等分子功能,其交集靶点对花生四烯酸代谢、细胞凋亡和PI3K-AKT等信号通路产生显著影响,其中细胞凋亡通路可直接诱导细菌感染细胞死亡,PI3K-AKT信号通路则能增强宿主细胞的抗菌能力,通路间的协同作用为其强效抑菌提供保障[44]。花生四烯酸代谢途径能够起到抑制炎症细胞因子和介质的作用,从而减缓细菌感染所引起的炎症反应[45]。与细胞凋亡通路共同构成抑菌-抗炎双重调控机制。分子对接结果表明,结合能的数值越小,意味着活性成分与靶点之间的结合更为紧密且稳定[46],通过结合能这一指标来评估小分子与靶蛋白之间的相互作用强度,结合能小于零表示配体能够高效结合靶点,结合能越低则暗示了更高的结合亲和力和更稳定的构象[47],以发挥出抑菌效果。狼杷草和婆婆针的平均结合能在-7.5~-7.8 kcal/mol,其余3种鬼针草属平均结合能在-7.0~-7.4 kcal/mol。故从理论上说明狼杷草和婆婆针的活性成分与靶点结合效果更好。

4 结论

5种鬼针草属物种均具有抗炎和抑菌的作用,但狼杷草和婆婆针的有效抑菌活性成分更丰富,与抑菌靶点重叠度更高,对EGFR、ESR1的分子对接结合能更低,更适合作饲料添加剂。

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