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Article(id=1193632559629304395, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1193558470239678932, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2024-0759, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1722873600000, receivedDateStr=2024-08-06, revisedDate=1728835200000, revisedDateStr=2024-10-14, acceptedDate=null, acceptedDateStr=null, onlineDate=1762513778836, onlineDateStr=2025-11-07, pubDate=1736611200000, pubDateStr=2025-01-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1762513778836, onlineIssueDateStr=2025-11-07, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1762513778836, creator=13701087609, updateTime=1762513778836, updator=13701087609, issue=Issue{id=1193558470239678932, tenantId=1146029695717560320, journalId=1189982191388893191, year='2025', volume='60', issue='1', pageStart='1', pageEnd='244', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1762496114549, creator=13701087609, updateTime=1764224942173, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200809698921402865, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1193558470239678932, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200809698921402866, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1193558470239678932, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=117, endPage=129, ext={EN=ArticleExt(id=1193632559906128460, articleId=1193632559629304395, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Exploring mechanism of Porana racemosa Roxb. in treating rheumatoid arthritis based on integration of network pharmacology and molecular docking combined with experimental validation, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Through network pharmacology and molecular docking technology, combined with in vitro experiment verification, we explored the mechanism of action of Porana racemosa Roxb. (PRA) in the treatment of rheumatoid arthritis (RA), and provided a modern pharmacological basis for the treatment of RA by PRA. The potential target of chemical components in the analyzed moth rattan was predicted by Swiss Target Prediction database; OMIM, GeneCards, TTD and Disgenet databases were used to search the disease targets of RA; the protein interaction (PPI) network and medicine-composition-target network were constructed using STRING database and Cytoscape software; GO (gene ontology) functional enrichment and KEGG (kyoto encyclopedia of genes and genomes) pathway analysis were carried out using DAVID database, and molecular docking software was used to dock the potentially active ingredients of PRA and core targets; finally, MH7A cells were selected for cell viability, scratch healing and mRNA expression level analysis of key genes to explore the effects of PRA and their potentially active ingredients on the proliferation, migration and apoptosis of MH7A cells. In this study, a total of 628 potentially active ingredient targets, 1 890 RA targets and 235 intersection targets were identified. It was screened that the potentially active ingredients of RA treatment by PRA were ethylcaffeate, N-p-coumaroyltyramine, 9, 12, 15-octadecatrienoic acid, methyl ester and so on, and the core targets involved tumor necrosis factor (TNF), matrix metalloproteinase 9 (MMP9), prostaglandin-endoperoxide synthase 2 (PTGS2) and so on. 1 200 GO entries and 166 KEGG pathway entries were obtained from the enrichment analysis; molecular docking results showed that N-p-coumaroyltyramine and ethylcaffeate had good binding activity with TNF, MMP9, cysteine-aspartate protease 3 (CASP3), PTGS2, B-cell lymphoma 2 (BCL2) proteins. In vitro experiments showed that PRA, ethylcaffeate and N-p-coumaroyltyramine could inhibit the proliferation, migration and invasion of MH7A cells, up-regulate the expression of apoptosis-related gene CASP3 mRNA, and down-regulate the expression of MMP9, PTGS2 and BCL2 mRNA, and it can also down-regulate the expression of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) mRNA and PI3K and p-AKT proteins. This study preliminarily revealed that the treatment of RA by PRA may be related to proliferation, migration, invasion, apoptosis and regulation of PI3K/AKT signaling pathway.

, correspAuthors=Zhi-yong CHEN, Hui REN, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2025 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Chen-yu YE, Ning LI, Yin-zi CHEN, Tong QU, Jing HU, Zhi-yong CHEN, Hui REN), CN=ArticleExt(id=1193633183230034896, articleId=1193632559629304395, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=网络药理学、分子对接结合实验验证探讨飞蛾藤治疗类风湿关节炎的作用机制, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

通过网络药理学和分子对接技术, 结合体外实验验证探究飞蛾藤(Porana racemosa Roxb., PRA) 治疗类风湿关节炎(rheumatoid arthritis, RA) 的作用机制, 为飞蛾藤治疗RA提供现代药理学依据。通过Swiss Target Prediction数据库预测已解析飞蛾藤中化学成分的潜在靶点; 采用OMIM、GeneCards、TTD、Disgenet数据库检索RA的疾病靶点; 利用STRING数据库和Cytoscape软件构建蛋白相互作用(PPI) 网络和药材-成分-靶点网络; 使用DAVID数据库进行GO (gene ontology) 功能富集和KEGG (kyoto encyclopedia of genes and genomes) 通路分析, 并利用分子对接软件对飞蛾藤潜在活性成分与核心靶点进行对接; 最后选取MH7A细胞进行细胞活力、划痕愈合、关键基因mRNA表达水平分析等实验, 以探索飞蛾藤及其潜在活性成分对MH7A细胞增殖、迁移、凋亡的影响。该研究共筛选出飞蛾藤潜在活性成分靶点628个, RA靶点1 890个, 交集靶点235个, 筛选出飞蛾藤治疗RA的主要潜在活性成分是咖啡酸乙酯、N-对反式香豆酰酪胺、亚麻酸甲酯等, 核心靶点涉及肿瘤坏死因子(TNF)、基质金属蛋白酶9 (MMP9)、前列腺素内过氧化物合酶2 (PTGS2) 等, 富集分析确定了1 200个GO功能富集条目和166条信号通路; 分子对接结果显示, N-对反式香豆酰酪胺和咖啡酸乙酯与TNF、MMP9、半胱氨酸天冬氨酸蛋白酶3 (CASP3)、PTGS2、B淋巴细胞瘤2 (BCL2) 均具有较好的结合活性; 体外实验显示, 飞蛾藤、咖啡酸乙酯和N-对反式香豆酰酪胺均可抑制MH7A细胞增殖、迁移和侵袭能力, 上调凋亡相关基因CASP3 mRNA的表达, 下调MMP9、PTGS2、BCL2 mRNA的表达, 还能下调磷脂酰肌醇3-激酶(PI3K)、蛋白激酶B (AKT) mRNA和PI3K、p-AKT蛋白的表达。该研究初步揭示了飞蛾藤治疗RA可能与抑制MH7A细胞增殖、迁移和侵袭, 诱导细胞凋亡, 调控PI3K/AKT信号通路等有关。

, correspAuthors=陈志永, 任慧, authorNote=null, correspAuthorsNote=
*陈志永, E-mail:
任慧, E-mail:
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Shaanxi Academy of Traditional Chinese Medicine, Xi'an 710003, China), AuthorCompanyExt(id=1194708582911419158, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, companyId=1194708582894641940, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.陕西省中医药研究院, 陕西 西安 710003)])], figs=[ArticleFig(id=1194708586451411783, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=EN, label=null, caption=null, figureFileSmall=fivcks5WnrZg3bh8fI0AyQ==, figureFileBig=CZKfzekqsLvZRjLFVP/Wow==, tableContent=null), ArticleFig(id=1194708586522714952, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=CN, label=Figure 1, caption= Network diagram of six potentially active ingredients-target. The purple ovals represent six potential active ingredients, and the orange hexagon represents six potential active ingredients for the treatment of rheumatoid arthritis (RA) , figureFileSmall=fivcks5WnrZg3bh8fI0AyQ==, figureFileBig=CZKfzekqsLvZRjLFVP/Wow==, tableContent=null), ArticleFig(id=1194708586623378249, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=EN, label=null, caption=null, figureFileSmall=Mc1VHyV/2cVlPGcMD5bz+Q==, figureFileBig=mKp2UkHsnihD6R6ZVHeQVg==, tableContent=null), ArticleFig(id=1194708586677904202, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=CN, label=Figure 2, caption= GO functional enrichment analysis , figureFileSmall=Mc1VHyV/2cVlPGcMD5bz+Q==, figureFileBig=mKp2UkHsnihD6R6ZVHeQVg==, tableContent=null), ArticleFig(id=1194708586736624459, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=EN, label=null, caption=null, figureFileSmall=0MUgZwt79mBka8OZYAonZg==, figureFileBig=2t2dEMY7OGih7wsHO58n1Q==, tableContent=null), ArticleFig(id=1194708586795344716, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=CN, label=Figure 3, caption= KEGG pathway enrichment analysis , figureFileSmall=0MUgZwt79mBka8OZYAonZg==, figureFileBig=2t2dEMY7OGih7wsHO58n1Q==, tableContent=null), ArticleFig(id=1194708586849870669, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=EN, label=null, caption=null, figureFileSmall=yfEIX6m06qTtWvXJtlE6jw==, figureFileBig=Y4f09wPfr8brTNaNV2v/aw==, tableContent=null), ArticleFig(id=1194708586912785230, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=CN, label=Figure 4, caption= Heat map of molecular docking binding energy , figureFileSmall=yfEIX6m06qTtWvXJtlE6jw==, figureFileBig=Y4f09wPfr8brTNaNV2v/aw==, tableContent=null), ArticleFig(id=1194708586975699791, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=EN, label=null, caption=null, figureFileSmall=qAGcg/R2wHrScl9dhAP0dg==, figureFileBig=vl5ABGR7s0X5yePLO1qZOA==, tableContent=null), ArticleFig(id=1194708587042808656, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=CN, label=Figure 5, caption= Effects of PRA and its potentially active ingredients on the proliferation of MH7A cells , figureFileSmall=qAGcg/R2wHrScl9dhAP0dg==, figureFileBig=vl5ABGR7s0X5yePLO1qZOA==, tableContent=null), ArticleFig(id=1194708587109917521, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=EN, label=null, caption=null, figureFileSmall=+ra46uxe3Do9yZDkO96L1g==, figureFileBig=M85ilVPHLyks72N9eGibHw==, tableContent=null), ArticleFig(id=1194708587177026386, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=CN, label=Figure 6, caption= Effects of PRA and its potentially active ingredients on migration ability of MH7A cells. Scale bar: 200 μm. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 <i>vs</i> blank group , figureFileSmall=+ra46uxe3Do9yZDkO96L1g==, figureFileBig=M85ilVPHLyks72N9eGibHw==, tableContent=null), ArticleFig(id=1194708587239940948, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=EN, label=null, caption=null, figureFileSmall=Pl6UewE80irEjP/hb2z4jw==, figureFileBig=qqMLnFKHJEWCcMcTzMVkwg==, tableContent=null), ArticleFig(id=1194708587311244117, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=CN, label=Figure 7, caption= Effects of PRA and its potentially active ingredients on MH7A cell invasion. Scale bar: 200 μm. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001, <sup>****</sup><i>P</i> < 0.000 1 <i>vs</i> blank group , figureFileSmall=Pl6UewE80irEjP/hb2z4jw==, figureFileBig=qqMLnFKHJEWCcMcTzMVkwg==, tableContent=null), ArticleFig(id=1194708587420296022, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=EN, label=null, caption=null, figureFileSmall=unKQKDvOxyq4bRPpzxoRsw==, figureFileBig=mH1JjL1hGzBDweIyiCtLWA==, tableContent=null), ArticleFig(id=1194708587495793495, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=CN, label=Figure 8, caption= Effects of PRA and its potentially active ingredients on tumor necrosis factor <i>α</i> (TNF-<i>α</i>) levels in MH7A cell supernatant. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 <i>vs</i> blank group , figureFileSmall=unKQKDvOxyq4bRPpzxoRsw==, figureFileBig=mH1JjL1hGzBDweIyiCtLWA==, tableContent=null), ArticleFig(id=1194708587567096664, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=EN, label=null, caption=null, figureFileSmall=crCNTJA81/XQ3HIw1z1neg==, figureFileBig=fY/qzEt7VNQ3HlrSryDqtQ==, tableContent=null), ArticleFig(id=1194708587630011225, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=CN, label=Figure 9, caption= Effects of PRA and its potentially active ingredients on expression of cysteine-aspartate protease 3 (CASP3), matrix metalloproteinase 9 (MMP9), prostaglandin-endoperoxide synthase 2 (PTGS2) and B-cell lymphoma 2 (BCL2) mRNA in MH7A cells. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001, <sup>****</sup><i>P</i> < 0.000 1 <i>vs</i> blank group , figureFileSmall=crCNTJA81/XQ3HIw1z1neg==, figureFileBig=fY/qzEt7VNQ3HlrSryDqtQ==, tableContent=null), ArticleFig(id=1194708587701314394, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=EN, label=null, caption=null, figureFileSmall=69rii04rJxXdAWpGXR+3Yg==, figureFileBig=hIVfp/J7aDh9r+IFTkcZPw==, tableContent=null), ArticleFig(id=1194708587772617563, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=CN, label=Figure 10, caption= Effects of PRA and its potentially active ingredients on the expression of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) mRNA in MH7A cells. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001, <sup>****</sup><i>P</i> < 0.000 1 <i>vs</i> blank group , figureFileSmall=69rii04rJxXdAWpGXR+3Yg==, figureFileBig=hIVfp/J7aDh9r+IFTkcZPw==, tableContent=null), ArticleFig(id=1194708587852309340, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=EN, label=null, caption=null, figureFileSmall=C2s4FukWJHprqueYk9apSw==, figureFileBig=Bn7zqbXQUU3yp0loyyzNkA==, tableContent=null), ArticleFig(id=1194708587936195421, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=CN, label=Figure 11, caption= Effects of PRA and its potentially active ingredients on proteins associated with PI3K/AKT signaling pathway in MH7A cells. A: Blank; B: MTX: C: PRA-0.125 mg·mL<sup>-1</sup>; D: PRA-0.0625 mg·mL<sup>-1</sup>; E: <i>N</i>-<i>p</i>-Coumaroyltyramine-40 μg·mL<sup>-1</sup>; F: <i>N</i>-<i>p</i>-Coumaroyltyramine-20 μg·mL<sup>-1</sup>; G: Ethylcaffeate-40 μg·mL<sup>-1</sup>; H: Ethylcaffeate-20 μg·mL<sup>-1</sup>. <sup>**</sup><i>P</i> < 0.01, <sup>****</sup><i>P</i> < 0.000 1 <i>vs</i> blank group , figureFileSmall=C2s4FukWJHprqueYk9apSw==, figureFileBig=Bn7zqbXQUU3yp0loyyzNkA==, tableContent=null), ArticleFig(id=1194708588007498590, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Gene name Forward primer (5'-3') Reverse primer (5'-3')
GAPDH CACTCACGGCAAATTCAACGGCAC GACTCCACGACATACTCAGCA
MMP9 TCCCTGGAGACCTGAGAACC GCCACCCGAGTGTAACCAT
CASP3 GCTATTGTGAGGCGGTTGT TGTTTCCCTGAGGTTTGC
PTGS2 CGAGGTGTATGTATGAGTGT AGTGGGTAAGTATGTAGTGC
BCL2 ACGACCTTTAGATTCCAG ACAGATGTCCCTACCAAC
PI3K GCTGTATAATGCTTGGGAGG CTGTGGAAATGCGTCTGG
AKT TGAGCGACGTGGCTATTGT CAGTCTGGATGGCGGTTG
), ArticleFig(id=1194708588078801759, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=CN, label=Table 1, caption=

Primer sequences of RT-qPCR. GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; MMP9: Matrix metalloproteinase 9; CASP3: Cysteine aspartate-specific protease 3; PTGS2: Prostaglandin-endoperoxide synthase 2; BCL2: B-cell lymphoma 2; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B

, figureFileSmall=null, figureFileBig=null, tableContent=
Gene name Forward primer (5'-3') Reverse primer (5'-3')
GAPDH CACTCACGGCAAATTCAACGGCAC GACTCCACGACATACTCAGCA
MMP9 TCCCTGGAGACCTGAGAACC GCCACCCGAGTGTAACCAT
CASP3 GCTATTGTGAGGCGGTTGT TGTTTCCCTGAGGTTTGC
PTGS2 CGAGGTGTATGTATGAGTGT AGTGGGTAAGTATGTAGTGC
BCL2 ACGACCTTTAGATTCCAG ACAGATGTCCCTACCAAC
PI3K GCTGTATAATGCTTGGGAGG CTGTGGAAATGCGTCTGG
AKT TGAGCGACGTGGCTATTGT CAGTCTGGATGGCGGTTG
), ArticleFig(id=1194708588150104928, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No. Name Formula CAS number
1 Serine C3H7NO3 56-45-1
2 Threonine C4H9NO3 7013-32-3
3 L(+)-Arginine C6H14N4O2 74-79-3
4 L-Valine C5H11NO2 72-18-4
5 Tartaric acid C4H6O6 526-83-0
6 L(+)-Ascorbic acid C6H8O6 50-81-7
7 Oxalic acid C2H2O4 144-62-7
8 Sucrose C12H22O11 57-50-1
9 Erycibelline C7H13NO2 107633-95-4
10 Hygrine C8H15NO 496-49-1
11 3-Hydroxy-2-methyl-4-pyrone C6H6O3 118-71-8
12 Malic acid C4H6O5 6915-15-7
13 9, 12, 15-Octadecatrienoic acid, methyl ester C19H32O2 14202-25-6
14 Nicotinic acid C6H5NO2 59-67-6
15 Citric acid C6H8O7 77-92-9
16 Succinic acid C4H6O4 110-15-6
17 Uridine C9H12N2O6 58-96-8
18 Uracil C4H4N2O2 66-22-8
19 p-Coumaric acid C9H8O3 501-98-4
20 L-Tyrosine C9H11NO3 60-18-4
21 Phenylacetaldehyde C8H8O 122-78-1
22 L-Leucine C6H13NO2 61-90-5
23 Tachioside C13H18O8 109194-60-7
24 L-Phenylalanine C9H11NO2 63-91-2
25 Vanillic acid C8H8O4 121-34-6
26 Neochlorogenic acid C16H18O9 906-33-2
27 (E)-p-Ethyl coumarate C11H12O3 7362-39-2
28 Glucosyringic acid C15H20O10 33228-65-8
29 Syringate C9H10O5 24697-74-3
30 Esculetin C9H6O4 305-01-1
31 Chlorogenic acid C16H18O9 327-97-9
32 Isoscopoletin C10H8O4 776-86-3
33 Osmanthuside H C19H28O11 149155-70-4
34 Cryptochlorogenic acid C16H18O9 905-99-7
35 Dihydrophaseic acid C15H22O5 41756-77-8
36 Roseoside C19H30O8 54835-70-0
37 2, 4-Dihydroxy-6-methoxyacetophenone C9H10O4 3602-54-8
38 Umbelliferone C9H6O3 93-35-6
39 Scopoletin C10H8O4 92-61-5
40 Quercetin-3-O-β-D-galactose-7-O-β-D-glucoside C27H30O17 /
41 Ethylcaffeate C11H12O4 102-37-4
42 Caffeic acid C9H8O4 331-39-5
43 Caffeic acid methyl ester C10H10O4 67667-67-8
44 Kaempferitrin C27H30O14 482-38-2
45 N-p-Coumaroyltyramine C17H17NO3 36417-86-4
46 Bornyl acetate C12H20O2 76-49-3
47 Cafestol C20H28O3 469-83-0
48 3, 12-Dihydroxy palmitic acid C16H32O4 66675-73-8
49 Cinnamic acid C9H8O2 140-10-3
50 13-Hydroxy-9Z, 11E-octadecadienoic acid C18H32O3 18104-45-5
51 Lasiodiplodin C17H24O4 32885-81-7
52 Anethole C10H12O 4180-23-8
), ArticleFig(id=1194708588263351137, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=CN, label=Table 2, caption=

Potentially active ingredients information of PRA. PRA: Porana racemosa Roxb.

, figureFileSmall=null, figureFileBig=null, tableContent=
No. Name Formula CAS number
1 Serine C3H7NO3 56-45-1
2 Threonine C4H9NO3 7013-32-3
3 L(+)-Arginine C6H14N4O2 74-79-3
4 L-Valine C5H11NO2 72-18-4
5 Tartaric acid C4H6O6 526-83-0
6 L(+)-Ascorbic acid C6H8O6 50-81-7
7 Oxalic acid C2H2O4 144-62-7
8 Sucrose C12H22O11 57-50-1
9 Erycibelline C7H13NO2 107633-95-4
10 Hygrine C8H15NO 496-49-1
11 3-Hydroxy-2-methyl-4-pyrone C6H6O3 118-71-8
12 Malic acid C4H6O5 6915-15-7
13 9, 12, 15-Octadecatrienoic acid, methyl ester C19H32O2 14202-25-6
14 Nicotinic acid C6H5NO2 59-67-6
15 Citric acid C6H8O7 77-92-9
16 Succinic acid C4H6O4 110-15-6
17 Uridine C9H12N2O6 58-96-8
18 Uracil C4H4N2O2 66-22-8
19 p-Coumaric acid C9H8O3 501-98-4
20 L-Tyrosine C9H11NO3 60-18-4
21 Phenylacetaldehyde C8H8O 122-78-1
22 L-Leucine C6H13NO2 61-90-5
23 Tachioside C13H18O8 109194-60-7
24 L-Phenylalanine C9H11NO2 63-91-2
25 Vanillic acid C8H8O4 121-34-6
26 Neochlorogenic acid C16H18O9 906-33-2
27 (E)-p-Ethyl coumarate C11H12O3 7362-39-2
28 Glucosyringic acid C15H20O10 33228-65-8
29 Syringate C9H10O5 24697-74-3
30 Esculetin C9H6O4 305-01-1
31 Chlorogenic acid C16H18O9 327-97-9
32 Isoscopoletin C10H8O4 776-86-3
33 Osmanthuside H C19H28O11 149155-70-4
34 Cryptochlorogenic acid C16H18O9 905-99-7
35 Dihydrophaseic acid C15H22O5 41756-77-8
36 Roseoside C19H30O8 54835-70-0
37 2, 4-Dihydroxy-6-methoxyacetophenone C9H10O4 3602-54-8
38 Umbelliferone C9H6O3 93-35-6
39 Scopoletin C10H8O4 92-61-5
40 Quercetin-3-O-β-D-galactose-7-O-β-D-glucoside C27H30O17 /
41 Ethylcaffeate C11H12O4 102-37-4
42 Caffeic acid C9H8O4 331-39-5
43 Caffeic acid methyl ester C10H10O4 67667-67-8
44 Kaempferitrin C27H30O14 482-38-2
45 N-p-Coumaroyltyramine C17H17NO3 36417-86-4
46 Bornyl acetate C12H20O2 76-49-3
47 Cafestol C20H28O3 469-83-0
48 3, 12-Dihydroxy palmitic acid C16H32O4 66675-73-8
49 Cinnamic acid C9H8O2 140-10-3
50 13-Hydroxy-9Z, 11E-octadecadienoic acid C18H32O3 18104-45-5
51 Lasiodiplodin C17H24O4 32885-81-7
52 Anethole C10H12O 4180-23-8
), ArticleFig(id=1194708588359820130, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Uniport ID Target Closeness Betweenness Degree
P01375 TNF 0.003 247 4 490.975 0 159
P31749 AKT1 0.003 096 2 502.927 0 144
P00533 EGFR 0.002 924 1 732.596 4 128
P04637 TP53 0.002 924 1 337.305 7 127
P12931 SRC 0.002 933 4 932.844 9 127
P40763 STAT3 0.002 899 1 444.778 8 124
P14780 MMP9 0.002 825 1 359.148 9 117
P42574 CASP3 0.002 825 800.193 8 115
P35354 PTGS2 0.002 825 2 104.462 4 115
P10415 BCL2 0.002 817 1 140.609 5 115
), ArticleFig(id=1194708588481454947, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193632559629304395, language=CN, label=Table 3, caption=

Core targets (top 10 by degree). TNF: Tumor necrosis factor; AKT1: Akt serine/threonine kinase 1; EGFR: Epidermal growth factor receptor; TP53: Tumor protein P53; SRC: Proto-oncogene tyrosine-protein kinase Src; STAT3: Signal transducer and activator of transcription 3

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Uniport ID Target Closeness Betweenness Degree
P01375 TNF 0.003 247 4 490.975 0 159
P31749 AKT1 0.003 096 2 502.927 0 144
P00533 EGFR 0.002 924 1 732.596 4 128
P04637 TP53 0.002 924 1 337.305 7 127
P12931 SRC 0.002 933 4 932.844 9 127
P40763 STAT3 0.002 899 1 444.778 8 124
P14780 MMP9 0.002 825 1 359.148 9 117
P42574 CASP3 0.002 825 800.193 8 115
P35354 PTGS2 0.002 825 2 104.462 4 115
P10415 BCL2 0.002 817 1 140.609 5 115
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No. Name Closeness Betweenness Degree
1 3, 12-Dihydroxy palmitic acid 0.001 416 11 416.587 9 48
2 9, 12, 15-Octadecatrienoic acid, methyl ester 0.001 416 11 548.173 5 48
3 13-Hydroxy-9Z, 11E-octadecadienoic acid 0.001 408 11 619.291 4 46
4 (E)-p-Ethyl coumarate 0.001 385 7 680.060 7 40
5 N-p-Coumaroyltyramine 0.001 385 8 793.678 9 40
6 Ethylcaffeate 0.001 366 4 698.334 4 35
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PRA ranked the top six potentially active ingredients network node characteristic parameters

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No. Name Closeness Betweenness Degree
1 3, 12-Dihydroxy palmitic acid 0.001 416 11 416.587 9 48
2 9, 12, 15-Octadecatrienoic acid, methyl ester 0.001 416 11 548.173 5 48
3 13-Hydroxy-9Z, 11E-octadecadienoic acid 0.001 408 11 619.291 4 46
4 (E)-p-Ethyl coumarate 0.001 385 7 680.060 7 40
5 N-p-Coumaroyltyramine 0.001 385 8 793.678 9 40
6 Ethylcaffeate 0.001 366 4 698.334 4 35
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网络药理学、分子对接结合实验验证探讨飞蛾藤治疗类风湿关节炎的作用机制
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叶晨昱 1 , 李宁 2 , 陈音孜 1 , 曲彤 2 , 胡静 2 , 陈志永 2, * , 任慧 2, *
药学学报 | 研究论文 2025,60(1): 117-129
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药学学报 | 研究论文 2025, 60(1): 117-129
网络药理学、分子对接结合实验验证探讨飞蛾藤治疗类风湿关节炎的作用机制
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叶晨昱1, 李宁2, 陈音孜1, 曲彤2, 胡静2, 陈志永2, * , 任慧2, *
作者信息
  • 1.西北大学生命科学学院, 陕西 西安 710069
  • 2.陕西省中医药研究院, 陕西 西安 710003

通讯作者:

*陈志永, E-mail:
任慧, E-mail:
Exploring mechanism of Porana racemosa Roxb. in treating rheumatoid arthritis based on integration of network pharmacology and molecular docking combined with experimental validation
Chen-yu YE1, Ning LI2, Yin-zi CHEN1, Tong QU2, Jing HU2, Zhi-yong CHEN2, * , Hui REN2, *
Affiliations
  • 1. School of Life Sciences, Northwest University, Xi'an 710069, China
  • 2. Shaanxi Academy of Traditional Chinese Medicine, Xi'an 710003, China
出版时间: 2025-01-12 doi: 10.16438/j.0513-4870.2024-0759
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通过网络药理学和分子对接技术, 结合体外实验验证探究飞蛾藤(Porana racemosa Roxb., PRA) 治疗类风湿关节炎(rheumatoid arthritis, RA) 的作用机制, 为飞蛾藤治疗RA提供现代药理学依据。通过Swiss Target Prediction数据库预测已解析飞蛾藤中化学成分的潜在靶点; 采用OMIM、GeneCards、TTD、Disgenet数据库检索RA的疾病靶点; 利用STRING数据库和Cytoscape软件构建蛋白相互作用(PPI) 网络和药材-成分-靶点网络; 使用DAVID数据库进行GO (gene ontology) 功能富集和KEGG (kyoto encyclopedia of genes and genomes) 通路分析, 并利用分子对接软件对飞蛾藤潜在活性成分与核心靶点进行对接; 最后选取MH7A细胞进行细胞活力、划痕愈合、关键基因mRNA表达水平分析等实验, 以探索飞蛾藤及其潜在活性成分对MH7A细胞增殖、迁移、凋亡的影响。该研究共筛选出飞蛾藤潜在活性成分靶点628个, RA靶点1 890个, 交集靶点235个, 筛选出飞蛾藤治疗RA的主要潜在活性成分是咖啡酸乙酯、N-对反式香豆酰酪胺、亚麻酸甲酯等, 核心靶点涉及肿瘤坏死因子(TNF)、基质金属蛋白酶9 (MMP9)、前列腺素内过氧化物合酶2 (PTGS2) 等, 富集分析确定了1 200个GO功能富集条目和166条信号通路; 分子对接结果显示, N-对反式香豆酰酪胺和咖啡酸乙酯与TNF、MMP9、半胱氨酸天冬氨酸蛋白酶3 (CASP3)、PTGS2、B淋巴细胞瘤2 (BCL2) 均具有较好的结合活性; 体外实验显示, 飞蛾藤、咖啡酸乙酯和N-对反式香豆酰酪胺均可抑制MH7A细胞增殖、迁移和侵袭能力, 上调凋亡相关基因CASP3 mRNA的表达, 下调MMP9、PTGS2、BCL2 mRNA的表达, 还能下调磷脂酰肌醇3-激酶(PI3K)、蛋白激酶B (AKT) mRNA和PI3K、p-AKT蛋白的表达。该研究初步揭示了飞蛾藤治疗RA可能与抑制MH7A细胞增殖、迁移和侵袭, 诱导细胞凋亡, 调控PI3K/AKT信号通路等有关。

类风湿关节炎  /  飞蛾藤  /  网络药理学  /  分子对接  /  凋亡  /  MH7A细胞

Through network pharmacology and molecular docking technology, combined with in vitro experiment verification, we explored the mechanism of action of Porana racemosa Roxb. (PRA) in the treatment of rheumatoid arthritis (RA), and provided a modern pharmacological basis for the treatment of RA by PRA. The potential target of chemical components in the analyzed moth rattan was predicted by Swiss Target Prediction database; OMIM, GeneCards, TTD and Disgenet databases were used to search the disease targets of RA; the protein interaction (PPI) network and medicine-composition-target network were constructed using STRING database and Cytoscape software; GO (gene ontology) functional enrichment and KEGG (kyoto encyclopedia of genes and genomes) pathway analysis were carried out using DAVID database, and molecular docking software was used to dock the potentially active ingredients of PRA and core targets; finally, MH7A cells were selected for cell viability, scratch healing and mRNA expression level analysis of key genes to explore the effects of PRA and their potentially active ingredients on the proliferation, migration and apoptosis of MH7A cells. In this study, a total of 628 potentially active ingredient targets, 1 890 RA targets and 235 intersection targets were identified. It was screened that the potentially active ingredients of RA treatment by PRA were ethylcaffeate, N-p-coumaroyltyramine, 9, 12, 15-octadecatrienoic acid, methyl ester and so on, and the core targets involved tumor necrosis factor (TNF), matrix metalloproteinase 9 (MMP9), prostaglandin-endoperoxide synthase 2 (PTGS2) and so on. 1 200 GO entries and 166 KEGG pathway entries were obtained from the enrichment analysis; molecular docking results showed that N-p-coumaroyltyramine and ethylcaffeate had good binding activity with TNF, MMP9, cysteine-aspartate protease 3 (CASP3), PTGS2, B-cell lymphoma 2 (BCL2) proteins. In vitro experiments showed that PRA, ethylcaffeate and N-p-coumaroyltyramine could inhibit the proliferation, migration and invasion of MH7A cells, up-regulate the expression of apoptosis-related gene CASP3 mRNA, and down-regulate the expression of MMP9, PTGS2 and BCL2 mRNA, and it can also down-regulate the expression of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) mRNA and PI3K and p-AKT proteins. This study preliminarily revealed that the treatment of RA by PRA may be related to proliferation, migration, invasion, apoptosis and regulation of PI3K/AKT signaling pathway.

rheumatoid arthritis  /  Porana racemosa Roxb.  /  network pharmacology  /  molecular docking  /  apoptosis  /  MH7A cell
叶晨昱, 李宁, 陈音孜, 曲彤, 胡静, 陈志永, 任慧. 网络药理学、分子对接结合实验验证探讨飞蛾藤治疗类风湿关节炎的作用机制. 药学学报, 2025 , 60 (1) : 117 -129 . DOI: 10.16438/j.0513-4870.2024-0759
Chen-yu YE, Ning LI, Yin-zi CHEN, Tong QU, Jing HU, Zhi-yong CHEN, Hui REN. Exploring mechanism of Porana racemosa Roxb. in treating rheumatoid arthritis based on integration of network pharmacology and molecular docking combined with experimental validation[J]. Acta Pharmaceutica Sinica, 2025 , 60 (1) : 117 -129 . DOI: 10.16438/j.0513-4870.2024-0759
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类风湿关节炎(rheumatoid arthritis, RA) 是一种以侵蚀性关节炎为主要特征的自身免疫性疾病, 其病理基础为持续性滑膜炎症、滑膜细胞增殖、炎性细胞浸润、软骨和骨组织侵蚀等[1-3]。目前RA的治疗策略是以控制滑膜炎症和防止关节损伤为目标, 临床上非甾体类抗炎药和抗风湿药等药物因可缓解关节疼痛和肿胀、减少关节畸形被广泛用于治疗RA, 但由于药物的不良反应以及个体差异性, 长期用药的安全性和有效性仍然存在争议, 如甲氨蝶呤(MTX) 有肝、肾毒性[4, 5]。Grönroos等[6]研究发现MTX可通过激活Na+-H+逆向转运体诱导钠离子内流和质子外流增加, 导致肾小管细胞肿胀和死亡。中医药具有辨证施治、整体调节之优势, 在发病早期可迅速改善症状缓解病程, 且无耐药性, 长期应用还可减轻西药不良反应, 能从根本上调节身体免疫功能, 在治疗RA方面发挥重要作用[7, 8]。
旋花科飞蛾藤属植物飞蛾藤(Porana racemosa Roxb.), 又名马郎花、小元宝, 常以全草入药, 主要分布于我国长江以南各省以及陕西、甘肃等地, 多生于灌丛或路旁荒坡[9]。飞蛾藤在《中药大辞典》中被记载全草可治疗伤风感冒、食积不消等, 其茎及根在湖南民间用于治疗风湿病[10]; 现代药理研究显示飞蛾藤中所含成分如东莨菪素、咖啡酸乙酯、β-谷甾醇等具有强心、抗凝血、抗风湿、抗炎镇痛、抑制血管生成等作用[9]。然而, 飞蛾藤及主要潜在活性成分治疗RA的作用机制尚不清楚。网络药理学结合实验验证的方法是探索和解析中药治疗疾病复杂作用机制的有效方法。本课题组前期已采用UPLC-Q-Exactive Focus-MS/MS技术从飞蛾藤中鉴定出77个化学成分, 包括有机酸及其酯类、苯丙素类、黄酮类等[11], 在此基础上, 本研究通过网络药理学手段筛选飞蛾藤治疗RA主要潜在活性成分、关键靶点及通路, 并采用分子对接研究潜在活性成分与关键靶点之间的结合活性, 同时借助体外细胞实验进行初步验证, 为后续飞蛾藤治疗RA的临床应用及深入研究提供科学依据。
材料与方法
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细胞株  人类风湿关节炎成纤维样滑膜细胞系(MH7A) 购自武汉普诺赛生命科技有限公司, 培养基为不含丙酮酸钠的DMEM完全培养基(含10%胎牛血清, 1%青-链霉素), 37 ℃、5% CO2培养箱培养。
药材制备  飞蛾藤药材采自云南文山, 经陕西省中医药研究院陈志永副研究员鉴定并保存于陕西省中医药研究院中药所; 取200 g飞蛾藤药材粗粉用1.6 L 80%乙醇通过加热回流法提取, 合并3次滤液并浓缩, 得提取液粉末, 4 ℃保存。
试剂和仪器  咖啡酸乙酯(批号: CHB240111)、N-对反式香豆酰酪胺(批号: CH8240229) 购自成都克洛玛生物科技有限公司, 对照品质量分数均≥98%; 甲氨蝶呤片(上海信宜药业有限公司, 规格每片2.5 mg, 国药准字H31020644), 不含丙酮酸钠DMEM培养基(美国Gibco公司, 批号: C11965500BT)、PBS缓冲液(Labshark公司, 批号: 130114001); 胎牛血清(上海逍鹏生物科技有限公司, 批号: 2343386); 青-链霉素溶液(武汉普诺赛生命科技有限公司, 批号: WHAB24X081); 0.1%结晶紫染色液(北京索莱宝科技有限公司, 批号: 240001001); 4%多聚甲醛通用型组织固定液(美国Biosharp公司, 批号: 23355142); First-strand cDNA Synthesis Mix反转录试剂盒(批号: F0202-100T)、2× Realab Green PCR Fast mixture通用型荧光定量试剂盒(批号: R0202-02)(兰博利德生物技术有限公司); CO2细胞培养箱、酶标仪(美国赛默飞世尔科技公司); 荧光定量PCR仪(美国Bio-rad公司); CJ-ID超净工作台(天津泰斯特仪器有限公司); 倒置荧光显微镜(日本Olympus公司)。
网络药理学分析数据库及网站  PubChem (https://pubchem.ncbi.nlm.nih.gov/); Swiss Target Prediction (http://swisstargetprediction.ch/); OMIM (https://omim.org/); TTD (http://db.idrblab.net/ttd/); GeneCards (https://www.genecards.org); DisGeNET (https://www.disgenet.org/); Venny 2.1.0 (https://bioinfogp.cnb.csic.es/tools/venny); STRING数据库(https://string-db.org/); DAVID 6.8在线数据库(https://david.ncifcrf.gov/); 微生信(http://www.bioinformatics.com.cn/); RSCB PDB数据库(https://www.rcsb.org/)。
飞蛾藤化学成分及RA潜在靶点的获取  本课题组在前期研究中采用UPLC-Q-Exactive Focus-MS/MS技术从飞蛾藤中共鉴定出77个化学成分。将鉴定出的化学成分在PubChem数据库中搜索并下载相应的SMILES号或2D结构图, 导入Swiss Target Prediction数据库, 物种设置为“Homo sapiens”, 下载对应靶点, 归纳筛选结果剔除probability值为0的作用靶点, 并剔除重复项, 获得飞蛾藤潜在活性成分对应的靶点合集。在OMIM、TTD、GeneCards、DisGeNET数据库中以“rheumatoid arthritis”为关键词进行疾病靶点检索, 将筛选结果整合并去重得RA疾病靶点。
成分-疾病交集靶点的获取与蛋白相互作用(PPI) 分析  将RA靶点与飞蛾藤成分靶点在Venny 2.1.0平台上取交集获得交集靶点。将以上交集靶点导入STRING数据库, 物种限定为“Homo sapiens”, 获得靶点间相互作用关系文件并导入Cytoscape3.9.1软件进行PPI网络图构建及分析, 以度值(degree)、介数中心性(betweenness)、接近中心性(closeness) 均大于其平均值进行筛选, 取前10个定义为飞蛾藤治疗RA的关键靶点。
“药材-成分-靶点”网络构建  将飞蛾藤潜在活性成分、成分-疾病交集靶点导入Cytoscape3.9.1软件绘制飞蛾藤治疗RA的“药材-成分-靶点”网络图, 并进行相关拓扑学分析, 以度值、介数中心性、接近中心性均大于其平均值进行筛选, 取度值排名靠前的成分作为核心潜在活性成分。
交集靶点GO功能及KEGG通路富集分析  将筛选出的交集靶点导入DAVID 6.8在线数据库, 选择“Homo sapiens”、“OFFICIAL_GENE_SYMBOL”和“Gene List”, 提交列表后进行GO功能: 包括生物过程(BP)、细胞组成(CC)和分子功能(MF) 以及KEGG信号通路富集分析, 导入微生信平台绘制GO三合一柱状图和KEGG富集气泡图。KEGG图中气泡大小代表该信号通路富集的基因数量, 颜色越红代表该通路富集显著性越高, 说明该条信号通路的重要性越高。
分子对接  运用RSCB PDB数据库下载大分子蛋白肿瘤坏死因子(TNF, PDB ID: 5UUI)、基质金属蛋白酶9 (MMP9, PDB ID: 6ESM)、半胱氨酸天冬氨酸蛋白酶3 (CASP3, PDB ID: 2DKO)、前列腺素内过氧化物合酶2 (PTGS2, PDB ID: 3NT1)、B淋巴细胞瘤2 (BCL2, PDB ID: 6O0K) 的PDB Format文件; PubChem数据库下载潜在活性成分的SDF格式文件, 并将其转化为mol2格式文件。利用PyMOL2.4.0软件对大分子蛋白进行去水、去配体等处理, 然后通过AutoDock Tools 1.5.6软件对大分子蛋白和小分子配体进行分子对接, 并得到结合能值, 通常数值越小则结合力越强。最后将对接结果PDBQT结构转化为PDB结构, 再运用PyMOL2.4.0软件进行可视化绘图分析。
MTT法检测细胞活力  将培养至对数生长期的MH7A细胞以1.2×104个/孔接种于96孔板中, 每孔200 μL, 种板24 h后弃上清, 分别设置空白组与给药组, 空白组加入200 μL空白培养基, 给药组分别加入不同浓度(0.031 25、0.062 5、0.125、0.25、0.5、0.75、1 mg·mL-1) 的飞蛾藤提取液及不同浓度(1.25、2.5、5、10、20、40、60、80、100 μg·mL-1) 咖啡酸乙酯和N-对反式香豆酰酪胺200 μL, 每组设置6个复孔, 37 ℃培养箱中继续培养24 h, 加入20 μL噻唑蓝(MTT, 5 mg·mL-1), 4 h后弃掉上清液, 每孔加入150 μL DMSO, 于摇床上震荡10 min至紫色结晶物完全溶解, 用酶标仪检测490 nm处每孔的吸光度值。
划痕实验检测细胞迁移能力  将培养至对数生长期的MH7A细胞以5×105个/孔接种于预先画好标尺的6孔板中, 待细胞贴壁并长满时, 吸出原培养基, 用200 μL的枪头在孔内划线, 贴壁加入PBS洗去漂浮的细胞。给药组分别加入2 mL不同浓度的飞蛾藤、咖啡酸乙酯和N-对反式香豆酰酪胺溶液进行培养, 阳性对照组加入2 mL 0.25 μmol·L-1 MTX药液, 于0、24 h置于显微镜下拍照并观察细胞迁移情况, 用Image J软件计算细胞融合面积。
Transwell实验检测细胞侵袭能力  将培养至对数生长期的MH7A细胞以2×105个/孔接种于6孔板中, 培养24 h后, 同“划痕实验检测细胞迁移能力”给药24 h。实验开始前, 先将Matrigel基质胶(按1∶8稀释) 铺在小室, 并于37 ℃孵育3 h。上室加入200 μL各组细胞悬液, 下室加入500 μL含10% FBS的培养基, 培养箱孵育24 h。取出小室, 弃去室内培养液, PBS清洗2次后, 用4%多聚甲醛固定细胞30 min, PBS稍洗; 随后用0.1%结晶紫染色30 min, 轻轻用PBS清洗小室数次, 用湿棉棒小心擦去小室膜上表面尚未穿过的细胞; 底面朝上稍晾干, 倒置显微镜下观察, 用Image J软件对穿过底膜的细胞进行计数。
酶联免疫吸附(ELISA) 测定炎症因子TNF-α水平  将培养至对数生长期的MH7A细胞以1.2×104个/孔接种于96孔板中, 培养24 h后, 给药组分别加入200 μL不同浓度的飞蛾藤、咖啡酸乙酯、N-对反式香豆酰酪胺和MTX溶液继续培养24 h后, 按照ELISA试剂盒说明书进行操作, 于450 nm处测定吸光度值, 绘制标准曲线并计算细胞培养上清液中TNF-α水平。
RT-qPCR检测相关基因表达水平  将培养至对数生长期的MH7A细胞以3×105个/孔接种于6孔板中, 待细胞贴壁后, 弃掉培养基, 阳性对照组加入MTX药液, 给药组分别加入不同浓度的飞蛾藤、咖啡酸乙酯和N-对反式香豆酰酪胺溶液给药24 h后, TRIzol法提取细胞总RNA并测定浓度, 反转录为cDNA后使用RT-qPCR试剂盒扩增, 以GADPH作为内参, 采用2-ΔΔCT方法进行分析, MMP9、CASP3、PTGS2、BCL2、PI3K、AKT引物序列见表 1。反应条件为: 95 ℃、30 s预变性, 95 ℃、10 s变性, 60 ℃、10 s退火, 72 ℃、30 s延伸, 反应循环40次。
Western blot检测PI3K/AKT信号通路蛋白表达水平  种板及给药操作同“RT-qPCR检测相关基因表达水平”, 给药24 h后收集细胞, 加入适量RIPA裂解液提取细胞总蛋白, 采用BCA法测定蛋白浓度, 配置SDS-PAGE凝胶、电泳, 转至PVDF膜, 5%脱脂牛奶室温封闭30 min; 加PI3K、AKT、p-AKT和β-actin一抗(1∶1 000) 于4 ℃孵育过夜, 加HRP-山羊抗兔二抗(1∶3 000) 室温孵育30 min, TBST洗膜3次。显影后用Image J软件分析条带灰度值, 以β-actin为内参计算蛋白相对表达量。
统计学分析  使用GraphPad Prism 9.0.0软件对实验数据进行统计学分析, 数据以$\bar{x} \pm s$表示, 多组间数据比较采用单因素方差分析, P < 0.05表示差异有统计学意义。
结果
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1 网络药理学
1.1 飞蛾藤化学成分及靶点筛选
将本课题组前期从飞蛾藤中鉴定得到的77个化学成分分别导入Swiss Target Prediction数据库, 共获得52个具有作用靶点的潜在活性成分(表 2)。所有靶点经筛选并去重, 得到628个成分靶点。
1.2 飞蛾藤作用于RA疾病的相关靶点
在OMIM等多个数据库中分别获得RA疾病靶点, 整合去重后共得到1 890个疾病靶点。通过Venny 2.1.0平台交集后获得飞蛾藤潜在活性成分-疾病交集靶点235个。
1.3 PPI网络构建
将交集靶点通过String 11.5数据库和Cytoscape3.9.1软件进行PPI网络分析, 该网络由235个节点、4 259条边组成。以betweenness > 238.974 4, closeness > 0.002 2, degree > 36.401 7进行筛选得出48个核心靶点。其中, 度值排名靠前的TNF、丝氨酸苏氨酸蛋白激酶1 (AKT1)、表皮生长因子受体(EGFR)、肿瘤蛋白p53 (TP53)、酪氨酸蛋白激酶(SRC)、信号转导和转录激活因子3 (STAT3)、MMP9、CASP3、PTGS2、BCL2可能为飞蛾藤治疗RA的核心靶点, 发挥着重要作用(表 3)。潜在靶点中大部分与细胞凋亡有关, 结合RA中滑膜细胞过度增殖的病理特征, 后续选取TNF、MMP9、CASP3、PTGS2、BCL2等凋亡相关靶点作为关键靶点进行实验验证。
1.4 “药材-成分-靶点”相互作用网络和拓扑分析
将235个交集靶点及对应的成分导入Cytoscape3.9.1软件绘制“药材-成分-靶点”网络, 该网络图共有节点284个、边789条。利用软件内置插件“Centiscape2.2”对网络进行拓扑分析, 该网络中化学成分的betweenness平均值为643.464 8, closeness的平均值为0.001 1, degree的平均值为5.556 3, 以化学成分的3个网络拓扑参数同时大于相应的平均值进行潜在活性成分的筛选, 最后选取潜在活性成分中degree排名前6的成分作为核心成分, 包括3, 12-dihydroxy palmitic acid、亚麻酸甲酯、13-hydroxy-9Z, 11E-octadecadienoic acid、对香豆酸乙酯、N-对反式香豆酰酪胺、咖啡酸乙酯, 具体节点特征参数见表 4。6个潜在活性成分-靶点网络图见图 1, 该网络图共有节点162个、边252条。
1.5 GO与KEGG通路分析
235个交集靶点导入DAVID 6.8在线数据库后, 共筛选得到1 200个条目, 其中BP条目893个, 主要涉及信号转导(signal transduction)、细胞增殖的正调控(positive regulation of cell proliferation)、凋亡过程的负调控(negative regulation of apoptotic process) 等; CC条目107个, 主要涉及细胞质膜(plasma membrane)、细胞质(cytoplasm)、细胞溶质(cytosol)、细胞核(nucleus) 等; MF条目200个, 主要涉及蛋白结合(protein binding)、相同蛋白结合(identical protein binding)、ATP结合(ATP binding)、蛋白丝氨酸/苏氨酸/酪氨酸激酶活性(protein serine/threonine/tyrosine kinase activity) 等。根据富集基因数量降序排序, 选取每个类别P值最小的前10个条目通过微生信进行可视化分析(图 2)[12]。KEGG通路富集分析得到166条通路, 筛选排除如“癌症”、“脂质和动脉粥样硬化”等不相关的通路, 按P值从小到大的顺序选取富集靶点最多的前15条通路绘制气泡图(图 3)。KEGG富集分析表明, 飞蛾藤治疗RA与炎症相关通路关系密切, 主要涉及PI3K/AKT信号通路、丝裂原活化蛋白激酶(MAPK) 信号通路、Ras信号通路、Rap1信号通路等, 其中PI3K/AKT信号通路是富集基因数最多且显著性最高的通路。
2 分子对接
从PPI网络degree值排名前十的核心靶点中选取TNF、MMP9、CASP3、PTGS2、BCL2与核心成分3, 12-dihydroxy palmitic acid、亚麻酸甲酯、13-hydroxy-9Z, 11E-octadecadienoic acid、对香豆酸乙酯、N-对反式香豆酰酪胺、咖啡酸乙酯进行30次分子对接。具体对接结合能结果见图 4, 颜色越深代表结合能越小, 表明核心成分与核心靶点结合稳定, 生物亲和力高, 具有较高的药效活性。由图 4可知, 所有对接结合能均为负值, 其中N-对反式香豆酰酪胺与MMP9结合能最低, 其次是对香豆酸乙酯、咖啡酸乙酯与MMP9, N-对反式香豆酰酪胺、对香豆酸乙酯与BCL2、TNF、PTGS2。将后续进行细胞实验验证的咖啡酸乙酯、N-对反式香豆酰酪胺与5个核心靶点对接结果进行可视化, 其中N-对反式香豆酰酪胺的一端含有疏水链, 其能与氨基酸(ASP-111、GLN-118) 的质子形成很强的氢键相互作用, 氢键距离较短, 结合能力强, 并且其疏水链和疏水性氨基酸(LEU-119) 形成了很强的疏水作用, 可稳定小分子。
3 细胞实验验证
3.1 飞蛾藤及潜在活性成分对MH7A细胞增殖的影响
结果如图 5所示, 与空白组相比, 飞蛾藤在0.031 25~1 mg·mL-1浓度范围可抑制MH7A细胞增殖; 咖啡酸乙酯在1.25~100 μg·mL-1浓度范围可抑制MH7A细胞增殖, 呈浓度依赖性; N-对反式香豆酰酪胺在浓度小于40 μg·mL-1时呈浓度依赖性, 而在40~100 μg·mL-1浓度范围时, 并未随浓度变化, 且均在50%抑制率以上。选择药物抑制率在60%~80%区间的浓度开展后续实验, 飞蛾藤浓度设置为0.031 25、0.062 5、0.125 mg·mL-1, 咖啡酸乙酯和N-对反式香豆酰酪胺浓度设置为10、20、40 μg·mL-1 [13, 14]。
3.2 飞蛾藤及潜在活性成分对MH7A细胞迁移的影响
结果如图 6所示, 与空白组比较, 各给药组的细胞迁移运动能力减弱, 细胞融合面积明显减少, 呈浓度依赖性。提示飞蛾藤、咖啡酸乙酯、N-对反式香豆酰酪胺和MTX均可以抑制MH7A细胞的迁移能力。
3.3 飞蛾藤及潜在活性成分对MH7A细胞侵袭的影响
结果如图 7所示, 与空白组相比, 随着各给药组药物浓度的增加, 细胞侵袭能力明显减弱, 穿过小室的细胞个数显著减少, 呈浓度依赖性。提示飞蛾藤、咖啡酸乙酯、N-对反式香豆酰酪胺和MTX均能减弱MH7A细胞的侵袭能力。
3.4 飞蛾藤及潜在活性成分对MH7A细胞上清液中TNF-α水平的影响
结果如图 8所示, 与空白组相比, MTX组、给药组细胞上清中炎症因子TNF-α水平降低, 呈浓度依赖性。
3.5 飞蛾藤及潜在活性成分对MH7A细胞中凋亡相关基因表达的影响
成纤维样滑膜细胞(FLSs) 的侵袭性增殖和凋亡抵抗表型会直接导致RA滑膜的炎症增生、释放大量炎症因子, 进一步导致关节破坏。因此, 抑制RA-FLS的异常增殖并诱导其凋亡可能是治疗RA的有效策略之一[15]。为确定飞蛾藤及潜在活性成分能否诱导RA-FLS细胞凋亡, 通过RT-qPCR检测了凋亡相关基因, 结果如图 9所示, 与空白组相比, MTX组、给药组CASP3 mRNA表达水平显著升高, MMP9、PTGS2、BCL2 mRNA表达水平显著降低。
3.6 飞蛾藤及潜在活性成分对MH7A细胞PI3K/AKT信号通路的影响
PI3K/AKT信号通路是KEGG通路富集分析中发现的显著性最高且富集基因数最多的通路, 在RA的发病机制中起重要作用, 也是重要的细胞内信号转导途径[16]。Xu等[17]通过Western blot实验初步证实加味黄芪桂枝五味汤可能通过下调PI3K、p-AKT蛋白表达水平发挥抗RA作用; Jiang等[18]研究发现别欧前胡素通过抑制PI3K/AKT信号通路发挥对MH7A细胞的调控作用。为探究飞蛾藤、咖啡酸乙酯和N-对反式香豆酰酪胺对PI3K/AKT信号通路产生的影响, 采用RT-qPCR和Western blot检测PI3K、AKT mRNA和蛋白的相对表达水平。结果如图 10、11所示, 与空白对照组相比, MTX组、给药组PI3K、AKT mRNA和PI3K、p-AKT蛋白的表达水平显著下降, 推测飞蛾藤、咖啡酸乙酯和N-对反式香豆酰酪胺可能是通过影响PI3K/AKT信号通路发挥抗RA的作用。
讨论
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本研究采用网络药理学和体外细胞实验相结合的方法, 对飞蛾藤抗RA的潜在活性成分和作用机制进行了系统的研究。首先通过数据库查询获得了52个具有靶点的潜在活性成分、628个成分靶点, 以及1 890个RA相关靶点, 其中飞蛾藤可作用于RA的靶点有235个, GO分析这些共有靶点共涉及893个生物过程、107类细胞组分和200种分子功能。根据“药材-成分-靶点”网络图, 发现飞蛾藤抗RA的主要潜在活性成分为3, 12-dihydroxy palmitic acid、亚麻酸甲酯、13-hydroxy-9Z, 11E-octadecadienoic acid、对香豆酸乙酯、N-对反式香豆酰酪胺、咖啡酸乙酯。根据PPI网络分析发现飞蛾藤治疗RA的核心靶点主要为与细胞凋亡和炎症相关的靶点, 如TNF、AKT1、EGFR、TP53、SRC、STAT3、MMP9、CASP3、PTGS2、BCL2等。这些靶点参与了RA炎症的发展, 介导了关节炎破骨细胞生长、增殖分化等生物学过程, 并且与滑膜细胞的增殖和血管增生关系密切[19-24]。
FLSs是参与RA发生和发展的关键细胞, 其在正常生理状态下可以维持关节稳态, 但RA的发生会导致FLSs的过度迁移和增殖, 进而导致关节破坏。并且据报道, RA的发生会引起FLSs细胞凋亡失衡, BCL2等部分抗凋亡因子水平持续升高, 同时伴随肿瘤坏死因子相关凋亡诱导配体(TRAIL)、CASP3等促凋亡介质下调。因此, 抑制RA-FLSs的增殖并诱导其凋亡成为改善RA的有效策略之一[25]。本实验采用MH7A成纤维滑膜细胞初步评价飞蛾藤的药理作用, 发现其与潜在活性成分咖啡酸乙酯和N-对反式香豆酰酪胺均对MH7A细胞有明显的抑制作用。同时对飞蛾藤及其潜在活性成分作用滑膜细胞后的凋亡相关基因进行检测发现, 滑膜细胞中的炎症因子TNF-α和PTGS2、抗凋亡基因BCL2均明显被下调, 而促凋亡基因CASP3的表达则上升, 这说明飞蛾藤可能调节RA中FLSs细胞凋亡失衡。由于在RA病程中, 滑膜转变为增生的侵袭性组织, 活化的FLSs向骨和软骨的迁移和侵袭导致关节破坏, FLSs的这种肿瘤样特性在RA的骨破坏和软骨退化中起着关键作用, 因此抑制其迁移和侵袭是阻止RA破坏性进展的有效途径[26]。所以本实验利用细胞划痕实验和Transwell实验探索飞蛾藤及其潜在活性成分对滑膜细胞的迁移和侵袭作用。结果显示, 飞蛾藤及其潜在活性成分给药后, 不仅降低了细胞融合的速度, 也减少了细胞透过基质胶的数量, 并且明显减少了细胞中MMP9的表达。MMPs是一类蛋白水解酶, 能够促进炎症细胞向关节滑膜募集, 从而促进血管翳的形成。过表达的MMPs可导致RA大鼠的细胞外基质降解和关节软骨破坏。其中MMP9是MMPs家族中的重要一员, 在RA患者滑膜组织中检测到MMP9的高表达, 可见FLSs过度增生和凋亡不足, 使FLS分泌更多MMPs导致更严重的组织破坏[27, 28]。因此, 飞蛾藤及其潜在活性成分不仅能够抑制滑膜细胞增殖及炎症因子的表达, 还能通过调节滑膜细胞的凋亡失衡, 抑制其迁移能力, 阻止其向其他组织侵袭。
为进一步探索飞蛾藤对RA的作用机制, 实验前期将飞蛾藤作用于RA的靶点进行KEGG分析, 发现飞蛾藤治疗RA主要涉及PI3K/AKT、MAPK、Ras等多条信号通路, 其中, 富集基因数量最多的PI3K/AKT信号通路是细胞中一个经典的信号通路, 其与RA的发生发展密切相关, 不仅参与滑膜细胞的异常增殖和滑膜炎症, 还影响破骨细胞的分化与生成[26]。Li等[29]研究发现白虎加桂枝汤可通过抑制P13K/AKT信号通路减轻RA热证滑膜血管增生。PI3K的激活诱导AKT的磷酸化, 作为下游效应物, 它可以通过调节MMPs的转录水平参与FLSs的侵袭。近年来, 大量研究表明中药通过调节PI3K/AKT通路抑制RA-FLSs增殖、迁移, 促进凋亡, 减少血管新生, 抑制炎症反应, 从而抗RA作用。而RT-qPCR和Western blot结果也显示, 飞蛾藤及其潜在活性成分能够抑制MH7A细胞中PI3K和AKT基因的表达, 表明飞蛾藤及其潜在活性成分可能也通过调节PI3K/AKT信号通路抑制滑膜细胞增殖, 加速细胞凋亡和自噬, 从而发挥抗炎作用, 缓解RA的症状。
综上所述, 本研究采用网络药理学方法结合体外实验验证, 较为全面分析了飞蛾藤治疗RA的主要潜在活性成分、靶点和通路。实验证明飞蛾藤及其潜在活性成分可以抑制MH7A细胞的增殖、迁移和侵袭, 并进一步抑制了炎症反应的发生, 其潜在机制可能与调控PI3K/AKT信号通路并诱导其凋亡有关。本研究为飞蛾藤在防治RA的临床应用提供了理论依据。
作者贡献: 叶晨昱负责完成网络药理学分析、分子对接、细胞实验、数据分析与论文撰写; 李宁协助实验开展并参与文章修改; 陈音孜、曲彤、胡静负责数据收集并参与文章修改; 陈志永、任慧指导研究思路、设计研究方法并修改文章。
利益冲突: 全体作者声明本研究内容无任何利益冲突。
基金
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  • 国家重点研发计划(2023YFC3504900)
  • 国家自然科学基金面上项目(81973419)
  • 陕西省中医药管理局“双链融合”中青年科研创新团队(2022-SLRH-YQ-003)
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doi: 10.16438/j.0513-4870.2024-0759
  • 接收时间：2024-08-06
  • 首发时间：2025-11-07
  • 出版时间：2025-01-12
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  • 收稿日期：2024-08-06
  • 修回日期：2024-10-14
基金
国家重点研发计划(2023YFC3504900)
国家自然科学基金面上项目(81973419)
陕西省中医药管理局“双链融合”中青年科研创新团队(2022-SLRH-YQ-003)
作者信息
    1.西北大学生命科学学院, 陕西 西安 710069
    2.陕西省中医药研究院, 陕西 西安 710003

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species		 占总种数比例
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total species (%)		 属
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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