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Article(id=1201124481847750782, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201124478286786612, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2023-0750, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1686844800000, receivedDateStr=2023-06-16, revisedDate=1694707200000, revisedDateStr=2023-09-15, acceptedDate=null, acceptedDateStr=null, onlineDate=1764299992286, onlineDateStr=2025-11-28, pubDate=1710172800000, pubDateStr=2024-03-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764299992286, onlineIssueDateStr=2025-11-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764299992286, creator=13701087609, updateTime=1764299992286, updator=13701087609, issue=Issue{id=1201124478286786612, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='3', pageStart='493', pageEnd='788', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764299991434, creator=13701087609, updateTime=1764300490467, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1201126571420639892, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201124478286786612, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1201126571420639893, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201124478286786612, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=693, endPage=703, ext={EN=ArticleExt(id=1201124483110236312, articleId=1201124481847750782, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Exploration of potential active ingredients and mechanism of action of Xihuang pill-medicated serum against glioma based on HPLC-Q-TOF-MS/MS, network pharmacology and experimental verification, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Qualitative analysis of the ingredients absorbed into blood and their metabolites of Xihuang pill (XHP) were conducted using high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS/MS) technology. Network pharmacology was used to explore the potential anticancer mechanisms of the ingredients against glioma, and their specific mechanisms were validated through molecular docking and experimental verification. SD rats were intragastrically administered with XHP, and rat serum samples were collected. Ingredients absorbed into blood and their metabolites were identified based on the retention time of chromatographic peaks, accurate molecular mass, characteristic fragment ions, and comparisons with reference substances and literature data. PharmMapper and SwissTarget Prediction databases were used to obtain the targets of the XHP-medicated serum, while GeneCards, OMIM, PharmGKB, TTD, and DrugBank databases were used to obtain glioma disease targets. The "component-target" network relationship diagram was constructed using Cytoscape 3.9.1 software. The protein-protein interaction (PPI) network diagram was constructed using the STRING database, and the targets were analyzed using GO and KEGG analyses. Molecular docking was used to verify the binding ability of core targets with their corresponding compounds in XHP-medicated serum. The potential mechanism of the anti-glioma effect of 11-keto-β-boswellic acid (KBA), a representative component of XHP-medicated serum, was verified using CCK-8 and Western blot assays. A total of 40 compounds were identified in the XHP-medicated serum, including 28 prototype components and 12 metabolites. The network pharmacology results showed that elemonic acid, 3-acetyl-β-boswellic acid, KBA, α-boswellic acid, and other 5 compounds might be the active ingredients of XHP-medicated serum in the treatment of glioma. Glutathione reductase (GSR), glucose-6-phosphate dehydrogenase (G6PD), ATP-citrate lyase (ACLY), aldo-keto reductase family 1 member B1 (AKR1B1) and glutaredoxin (GLRX) were identified as key targets, involving pathways such as glutathione metabolism and the pentose phosphate pathway. Further cell experiments showed that KBA significantly inhibited the proliferation of T98G cells with an IC50 of 30.96 μmol·L-1, and KBA (30 μmol·L-1) significantly downregulated the protein expression levels of GSR in T98G cells. In summary, XHP-medicated serum may exert its anti-glioma effect by regulating GSR and G6PD-targeted pathways involved in glutathione metabolism. These results provide valuable evidence for further investigating the mechanism of XHP in treating glioma. The animal welfare and experimental procedures were approved by the Ethical Committee of Laboratory Animals at Nanjing University of Chinese Medicine (approval No. ACU221001).

, correspAuthors=Wei-feng YAO, Hong-bin XU, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 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=Jing PAN, Qi-hai ZHANG, Hao-wen FAN, Xia WANG, Wei-feng YAO, Hong-bin XU), CN=ArticleExt(id=1201124485190611238, articleId=1201124481847750782, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=基于HPLC-Q-TOF-MS/MS、网络药理学及实验验证探讨西黄丸含药血清抗脑胶质瘤的潜在活性成分及作用机制, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

基于高效液相色谱-四极杆飞行时间串联质谱(HPLC-Q-TOF-MS/MS) 技术对西黄丸的入血成分进行定性分析, 采用网络药理学对入血成分抗脑胶质瘤的潜在作用机制进行探究, 并通过分子对接和实验验证其具体机制。大鼠灌胃给予西黄丸后收集血清, 根据色谱峰保留时间、精确分子质量、特征碎片离子, 结合对照品及文献数据, 鉴定西黄丸含药血清的化学成分; 通过PharmMapper数据库和SwissTarget Prediction数据库获得成分靶点, 通过GeneCards、OMIM、PharmGKB、TTD、DrugBank数据库获得脑胶质瘤疾病靶点, 利用Cytoscape3.9.1软件构建“成分-靶点”网络关系图; 以STRING数据库构建蛋白质互作(PPI) 网络关系图并对靶点进行GO分析和KEGG分析; 利用分子对接验证核心靶点与相对应的入血成分的结合能力; CCK-8、Western blot验证西黄丸含药血清中代表性成分11-羰基-β-乳香酸(KBA) 抗脑胶质瘤的潜在作用机制。结果共鉴定出入血成分40个(原型成分28个, 代谢产物12个)。网络药理学结果显示, β-榄香酮酸、3-乙酰基-β-乳香酸、KBA、α-乳香酸等9个成分可能是西黄丸含药血清抗脑胶质瘤的活性成分, 其中谷胱甘肽还原酶(glutathione reductase, GSR)、葡萄糖-6-磷酸脱氢酶(glucose-6-phosphate dehydrogenase, G6PD)、ATP柠檬酸裂解酶(ATP-citrate lyase, ACLY)、醛酮还原酶1成员B1 (AKR1B1)、谷氧还蛋白(glutaredoxin, GLRX) 为关键靶点, 涉及谷胱甘肽代谢(glutathione metabolism) 通路、磷酸戊糖途径(pentose phosphate pathway) 等。进一步细胞实验结果表明, KBA显著抑制T98G细胞增殖(IC50为30.96 μmol·L-1), KBA (30 μmol·L-1) 显著下调T98G细胞中GSR蛋白表达水平。综上所述, 西黄丸含药血清可能通过调控谷胱甘肽代谢通路相关靶点GSR和G6PD抗脑胶质瘤。研究结果可进一步为西黄丸抗脑胶质瘤的作用机制研究提供一个有价值的依据。动物福利和实验过程获得南京中医药大学实验动物伦理委员会标准(批准号: ACU221001)。

, correspAuthors=姚卫峰, 徐宏彬, authorNote=null, correspAuthorsNote=
*姚卫峰, Tel: 86-25-85811524, E-mail: ;
徐宏彬, Tel: 86-25-87089123, E-mail:
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Front Oncol, 2020, 10: 593017., articleTitle=null, refAbstract=null), Reference(id=1201124500629844135, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[31], rfOrder=30, authorNames=null, journalName=null, refType=null, unstructuredReference=Icard P, Wu Z, Fournel L, et al. ATP citrate lyase: a central metabolic enzyme in cancer [J]. Cancer Lett, 2020, 471: 125-134., articleTitle=null, refAbstract=null), Reference(id=1201124500734701736, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[32], rfOrder=31, authorNames=null, journalName=null, refType=null, unstructuredReference=Ogata FT, Branco V, Vale FF, et al. Glutaredoxin: discovery, redox defense and much more [J]. Redox Biol, 2021, 43: 101975., articleTitle=null, refAbstract=null), Reference(id=1201124500826976430, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[33], rfOrder=32, authorNames=null, journalName=null, refType=null, unstructuredReference=Ghergurovich JM, García-Cañaveras JC, Wang J, et al. A small molecule G6PD inhibitor reveals immune dependence on pentose phosphate pathway [J]. Nat Chem Biol, 2020, 16: 731-739., articleTitle=null, refAbstract=null)], funds=[Fund(id=1201124494741042132, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, awardId=ZD2021031, language=CN, fundingSource=江苏省卫健委医学科研重点项目(ZD2021031), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1201124485681344832, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, xref=null, ext=[AuthorCompanyExt(id=1201124485702316356, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, companyId=1201124485681344832, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1. The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210017, China), AuthorCompanyExt(id=1201124485723287877, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, companyId=1201124485681344832, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.南京中医药大学第二附属医院, 江苏 南京 210017)]), AuthorCompany(id=1201124485853311318, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, xref=null, ext=[AuthorCompanyExt(id=1201124485874282837, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, companyId=1201124485853311318, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2. Northern Jiangsu People's Hospital, Yangzhou 225001, China), AuthorCompanyExt(id=1201124485882671447, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, companyId=1201124485853311318, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.江苏省苏北人民医院, 江苏 扬州 225001)]), AuthorCompany(id=1201124486008500580, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, xref=null, ext=[AuthorCompanyExt(id=1201124486025277798, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, companyId=1201124486008500580, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3. The Second Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Second Chinese Medicine Hospital), Nanjing 210017, China), AuthorCompanyExt(id=1201124486037860712, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, companyId=1201124486008500580, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3.南京中医药大学第二附属医院 (江苏省第二中医院), 江苏 南京 210017)]), AuthorCompany(id=1201124487191294332, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, xref=null, ext=[AuthorCompanyExt(id=1201124487203877245, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, companyId=1201124487191294332, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=4. School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China), AuthorCompanyExt(id=1201124487262597503, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, companyId=1201124487191294332, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=4.南京中医药大学药学院, 江苏 南京 210023)]), AuthorCompany(id=1201124487405203853, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, xref=null, ext=[AuthorCompanyExt(id=1201124487413592462, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, companyId=1201124487405203853, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=5. Department of Pharmacy, The First Affiliated Hospital of Ningbo University, Ningbo 315010, China), AuthorCompanyExt(id=1201124487421981072, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, companyId=1201124487405203853, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=5.宁波大学附属第一医院药学部, 浙江 宁波 315010)])], figs=[ArticleFig(id=1201124492132184871, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, language=EN, label=null, caption=null, figureFileSmall=avN406TKsWmBfvVgFkVZDw==, figureFileBig=XdX06epZUYYx33I9nXY0Bw==, tableContent=null), ArticleFig(id=1201124492278985518, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, language=CN, label=Figure 1, caption= Proposed fragmentation pathways of prototype ingredients in XHP-medicated serum. A: 11-Carbonyl-<i>β</i>-boswellic acid (KBA); B: Arachic acid; C: Glycohyodeoxycholic acid; D: Taurine , figureFileSmall=avN406TKsWmBfvVgFkVZDw==, figureFileBig=XdX06epZUYYx33I9nXY0Bw==, tableContent=null), ArticleFig(id=1201124492522255174, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, language=EN, label=null, caption=null, figureFileSmall=wBgoBoAn8kuFOZCaM+A3Fg==, figureFileBig=fcunE5odvi0Jho3zM5fpDw==, tableContent=null), ArticleFig(id=1201124492664861516, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, language=CN, label=Figure 2, caption= Ingredients-targets network of XHP-medicated serum. Pink rectangle: Active components; Blue rectangle: Disease-related targets , figureFileSmall=wBgoBoAn8kuFOZCaM+A3Fg==, figureFileBig=fcunE5odvi0Jho3zM5fpDw==, tableContent=null), ArticleFig(id=1201124492811662167, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, language=EN, label=null, caption=null, figureFileSmall=DhjM76a258gXCo3JJaYcEw==, figureFileBig=qbU78gkp+vJSRPkNoSJEew==, tableContent=null), ArticleFig(id=1201124492929102687, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, language=CN, label=Figure 3, caption= Glioma-related PPI network regulated by XHP-medicated serum based on string database. Red circle: Core targets. Degree of glutathione reductase (GSR) and glucose-6-phosphate dehydrogenase (G6PD): 8; Degree of glutaredoxin (GLRX), aldo-keto reductase family 1 member B1 (AKR1B1) and ATP-citrate lyase (ACLY): 6 , figureFileSmall=DhjM76a258gXCo3JJaYcEw==, figureFileBig=qbU78gkp+vJSRPkNoSJEew==, tableContent=null), ArticleFig(id=1201124493101069164, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, language=EN, label=null, caption=null, figureFileSmall=rPU02qUBi+UUln/ILlbHGg==, figureFileBig=ilAJGiLSzJogXCO9+G+12g==, tableContent=null), ArticleFig(id=1201124493222703988, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, language=CN, label=Figure 4, caption= Pathway enrichment analysis (A) and GO enrichment analysis (B) , figureFileSmall=rPU02qUBi+UUln/ILlbHGg==, figureFileBig=ilAJGiLSzJogXCO9+G+12g==, tableContent=null), ArticleFig(id=1201124493356921718, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, language=EN, label=null, caption=null, figureFileSmall=fADvWLjh4ZLhXQJqeNv9AA==, figureFileBig=nbMaPAeFRrfcWuFqjnEYOw==, tableContent=null), ArticleFig(id=1201124493524693889, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, language=CN, label=Figure 5, caption= Molecular docking of active ingredients to GSR and G6PD. Green marked with "letter-number": Amino acid residues; Wheat-colored structure: Molecules; Dashed line: Forces; Green: Hydrogen bonds; Purple: Hydrophobic action; Orange: Electrostatic action , figureFileSmall=fADvWLjh4ZLhXQJqeNv9AA==, figureFileBig=nbMaPAeFRrfcWuFqjnEYOw==, tableContent=null), ArticleFig(id=1201124493671494540, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, language=EN, label=null, caption=null, figureFileSmall=h9oHzRxDcPFLsaJqGgUwlg==, figureFileBig=SytnZmBTZgkSzCRpiylJqw==, tableContent=null), ArticleFig(id=1201124493797323670, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, language=CN, label=Figure 6, caption= Effects of KBA of different concentrations on the protein expression of GSR (A, B) and G6PD (A, C) in T98G cells. <i>n</i> = 3, <span class="mag-xml-inline-formula"><tex-math id="M2">$ \overline{x} $</tex-math></span> ± <i>s</i>. <sup>**</sup><i>P</i> < 0.01 <i>vs</i> control group , figureFileSmall=h9oHzRxDcPFLsaJqGgUwlg==, figureFileBig=SytnZmBTZgkSzCRpiylJqw==, tableContent=null), ArticleFig(id=1201124493902181281, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No.Rt /minNameFormulaAdductMeasured massCalculated massError /ppmMS/MSSource
P140.7316-Hydroperoxymansumbin-13(17)-en-3-oneC22H34O3-H345.243 7345.243 50.6345.243 7MY
P248.19Lanosta-8, 24-dien-21-oic acid, 3, 7-dioxo-, (13α, 14β, 17α, 20S)C30H44O4-H467.317 0467.316 70.7467.317 0RX
P349.8311-Carbonyl-β-boswellic acidC30H46O4-H469.332 3469.332 32.9376.276 2, 407.330 0, 391.299 1, 451.321 4, 469.330 2RX
P456.11(2α, 3α, 4β)-2, 3-Dihydroxyurs-12-en-23-oic acidC30H48O4-H471.347 5471.348 00.4427.359 1, 441.327 2, 453.311 5, 471.348 2RX
P5*56.3911-Carbonyl-β-acetyl-boswellic acidC32H48O5-H511.342 7511.342 9-0.2511.342 7RX
P657.28Urs-12-en-23-oic acid, 3-(acetyloxy)-11-hydroxy-, (3α, 4β)C32H50O5-H513.358 6513.358 64.0453.339 6, 495.347 7, 513.360 6RX
P7*57.58Ursolic acidC30H48O3-H455.353 1455.353 13.6455.353 1NH
P8*61.36Elemonic acidC30H46O3-H453.337 4453.337 4-0.4453.337 4RX
P962.73Methyl 3-[(3aR, 5aR, 6S, 7S, 9aR, 9bR)-9a, 9b-dimethyl-7-prop-1-en-2-yl-3a, 4, 5, 5a, 6, 7, 8, 9-octahydro-1H-cyclopenta[a]naphthalen-6-yl]propanoateC22H34O2-H329.249 0329.248 61.5231.212 0, 285.258 7, 329.249 1MY
P1064.76IncensoleC20H34O2-H305.249 9305.248 61.3287.238 9, 305.248 2RX
P1166.14Lanosta-8, 24-dien-21-oic acid, 23-hydroxy-3-oxo-, γ-lactone, (13α, 14β, 20S)C30H44O3-H451.321 8451.321 83.5451.323 4RX
P1266.569, 11-Dehydro-β-boswellic acidC30H46O3-H453.337 8453.337 43.8435.331 3, 453.339 1RX
P1367.44α-Boswellic acidC30H48O3-H455.353 4455.353 13.3455.354 6RX
P1469.52Boscartol BC20H32O2-H303.233 0303.233 02.9303.233 8RX
P1571.993-Acetyl-β-boswellic acidC32H50O4-H497.364 8497.363 65.059.013 9, 437.338 1, 497.365 1RX
P1672.23Bomyl acetateC12H20O2-H195.132 8195.139 10.4195.139 1RX
P1773.70Mansumbin-13(17)-en-3, 16-dioneC22H32O2+H329.242 3329.247 50.9329.247 8MY
P1865.0212-Hexadecenoic acid, methyl esterC17H32O2-H267.233 0267.233 02.6267.232 6RX
P1971.07Methyl palmitateC17H34O2-H269.249 5269.248 62.7269.249 2MY
P2074.85Stearic acidC18H36O2-H283.264 2283.264 31.9283.264 8RX
P2175.96Arachic acidC20H40O2-H311.295 6311.295 62.6183.013 7, 311.296 3RX
P2267.82Asclepic acidC18H34O2-H281.248 6281.248 60.6281.248 4SX
P2318.58Glycohyodeoxycholic acidC26H43NO5-H448.307 5448.306 98.974.025 3, 448.309 9NH
P2419.12Cholic acidC24H40O5-H407.280 3407.280 34.0343.265 3, 345.280 6, 407.281 9NH
P2570.35Cholanic acidC24H40O2-H359.295 6359.295 60.1359.296 5NH
P262.81TaurineC2H7NO3S-H124.007 4124.007 44.379.957 5, 124.006 9NH
P27*22.89QuercetinC15H10O7-H301.035 2301.035 4-0.5301.035 2MY
P2864.01Guggulsterol-IVC27H44O3-H415.322 4415.321 83.1347.219 3, 415.323 1MY
), ArticleFig(id=1201124494040593317, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, language=CN, label=Table 1, caption=

Identification analysis results of prototype ingredients in Xihuang pill (XHP)-medicated serum. *Compounds validated by reference substances. MY: Myrrh; RX: Frankincense; NH: Bovis Calculus; SX: Moschus

, figureFileSmall=null, figureFileBig=null, tableContent=
No.Rt /minNameFormulaAdductMeasured massCalculated massError /ppmMS/MSSource
P140.7316-Hydroperoxymansumbin-13(17)-en-3-oneC22H34O3-H345.243 7345.243 50.6345.243 7MY
P248.19Lanosta-8, 24-dien-21-oic acid, 3, 7-dioxo-, (13α, 14β, 17α, 20S)C30H44O4-H467.317 0467.316 70.7467.317 0RX
P349.8311-Carbonyl-β-boswellic acidC30H46O4-H469.332 3469.332 32.9376.276 2, 407.330 0, 391.299 1, 451.321 4, 469.330 2RX
P456.11(2α, 3α, 4β)-2, 3-Dihydroxyurs-12-en-23-oic acidC30H48O4-H471.347 5471.348 00.4427.359 1, 441.327 2, 453.311 5, 471.348 2RX
P5*56.3911-Carbonyl-β-acetyl-boswellic acidC32H48O5-H511.342 7511.342 9-0.2511.342 7RX
P657.28Urs-12-en-23-oic acid, 3-(acetyloxy)-11-hydroxy-, (3α, 4β)C32H50O5-H513.358 6513.358 64.0453.339 6, 495.347 7, 513.360 6RX
P7*57.58Ursolic acidC30H48O3-H455.353 1455.353 13.6455.353 1NH
P8*61.36Elemonic acidC30H46O3-H453.337 4453.337 4-0.4453.337 4RX
P962.73Methyl 3-[(3aR, 5aR, 6S, 7S, 9aR, 9bR)-9a, 9b-dimethyl-7-prop-1-en-2-yl-3a, 4, 5, 5a, 6, 7, 8, 9-octahydro-1H-cyclopenta[a]naphthalen-6-yl]propanoateC22H34O2-H329.249 0329.248 61.5231.212 0, 285.258 7, 329.249 1MY
P1064.76IncensoleC20H34O2-H305.249 9305.248 61.3287.238 9, 305.248 2RX
P1166.14Lanosta-8, 24-dien-21-oic acid, 23-hydroxy-3-oxo-, γ-lactone, (13α, 14β, 20S)C30H44O3-H451.321 8451.321 83.5451.323 4RX
P1266.569, 11-Dehydro-β-boswellic acidC30H46O3-H453.337 8453.337 43.8435.331 3, 453.339 1RX
P1367.44α-Boswellic acidC30H48O3-H455.353 4455.353 13.3455.354 6RX
P1469.52Boscartol BC20H32O2-H303.233 0303.233 02.9303.233 8RX
P1571.993-Acetyl-β-boswellic acidC32H50O4-H497.364 8497.363 65.059.013 9, 437.338 1, 497.365 1RX
P1672.23Bomyl acetateC12H20O2-H195.132 8195.139 10.4195.139 1RX
P1773.70Mansumbin-13(17)-en-3, 16-dioneC22H32O2+H329.242 3329.247 50.9329.247 8MY
P1865.0212-Hexadecenoic acid, methyl esterC17H32O2-H267.233 0267.233 02.6267.232 6RX
P1971.07Methyl palmitateC17H34O2-H269.249 5269.248 62.7269.249 2MY
P2074.85Stearic acidC18H36O2-H283.264 2283.264 31.9283.264 8RX
P2175.96Arachic acidC20H40O2-H311.295 6311.295 62.6183.013 7, 311.296 3RX
P2267.82Asclepic acidC18H34O2-H281.248 6281.248 60.6281.248 4SX
P2318.58Glycohyodeoxycholic acidC26H43NO5-H448.307 5448.306 98.974.025 3, 448.309 9NH
P2419.12Cholic acidC24H40O5-H407.280 3407.280 34.0343.265 3, 345.280 6, 407.281 9NH
P2570.35Cholanic acidC24H40O2-H359.295 6359.295 60.1359.296 5NH
P262.81TaurineC2H7NO3S-H124.007 4124.007 44.379.957 5, 124.006 9NH
P27*22.89QuercetinC15H10O7-H301.035 2301.035 4-0.5301.035 2MY
P2864.01Guggulsterol-IVC27H44O3-H415.322 4415.321 83.1347.219 3, 415.323 1MY
), ArticleFig(id=1201124494162228139, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No.Rt/minPathwayFormulaMeasured massCalculated massError /ppmMS/MSSource
M145.87GlucuronidationC36H54O10645.368 8645.364 4-9.759.017 3, 469.336 1, 583.313 2, 601.383 0RX
M246.53HydroxylationC30H46O5485.328 3485.327 30.9423.329 6, 485.330 4RX
M345.51Dehydrogenation of lactoneC32H46O6525.323 4525.322 20.1465.298 9, 481.298 9, 525.324 8RX
M449.66DeacetylationC30H46O5485.326 4485.327 30.9467.315 5, 485.328 7RX
M558.18ReductionC20H30O2301.217 9301.217 30.6257.227 6, 283.207 5, 301.217 9MY
M654.00Reduction+HydroxylationC20H30O3317.216 6317.212 20.8273.221 1, 299.201 6, 317.216 1MY
M749.78HydroxylationC32H48O6527.338 9527.337 80.659.015 0, 423.328 2, 527.340 8RX
M854.97Hydroxylation+GlucuronidationC38H58O11689.399 7689.390 6-8.4513.358 1RX
M955.16GlucuronidationC36H56O9631.388 5631.385 21.0455.356 9RX
M1061.01GlucuronidationC36H54O9629.368 1629.369 53.7453.336 2RX
M1112.64GlucuronidationC21H18O13447.093 8477.067 5-9.1151.002 9, 271.060 6MY
M1217.96AcetylationC26H42O5433.293 7433.296 00.0387.249 2, 433.297 9NH
), ArticleFig(id=1201124494288057270, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, language=CN, label=Table 2, caption=

Identification analysis results of metabolites in XHP-medicated serum. M1, M2: Metabolites of P3; M3, M4: Metabolites of lanost-8-en-21-oic acid, 3-(acetyloxy)-24, 25-dihydroxy-7-oxo-, δ-lactone, (3α, 13α, 14β, 17α, 20S, 24R); M5, M6: Metabolites of dehydroabietic acid; M7: Metabolite of P5; M8: Metabolite of P15; M9: Metabolite of P13; M10: Metabolite of P12; M11: Metabolite of naringenin; M12: Metabolite of deoxycholic acid

, figureFileSmall=null, figureFileBig=null, tableContent=
No.Rt/minPathwayFormulaMeasured massCalculated massError /ppmMS/MSSource
M145.87GlucuronidationC36H54O10645.368 8645.364 4-9.759.017 3, 469.336 1, 583.313 2, 601.383 0RX
M246.53HydroxylationC30H46O5485.328 3485.327 30.9423.329 6, 485.330 4RX
M345.51Dehydrogenation of lactoneC32H46O6525.323 4525.322 20.1465.298 9, 481.298 9, 525.324 8RX
M449.66DeacetylationC30H46O5485.326 4485.327 30.9467.315 5, 485.328 7RX
M558.18ReductionC20H30O2301.217 9301.217 30.6257.227 6, 283.207 5, 301.217 9MY
M654.00Reduction+HydroxylationC20H30O3317.216 6317.212 20.8273.221 1, 299.201 6, 317.216 1MY
M749.78HydroxylationC32H48O6527.338 9527.337 80.659.015 0, 423.328 2, 527.340 8RX
M854.97Hydroxylation+GlucuronidationC38H58O11689.399 7689.390 6-8.4513.358 1RX
M955.16GlucuronidationC36H56O9631.388 5631.385 21.0455.356 9RX
M1061.01GlucuronidationC36H54O9629.368 1629.369 53.7453.336 2RX
M1112.64GlucuronidationC21H18O13447.093 8477.067 5-9.1151.002 9, 271.060 6MY
M1217.96AcetylationC26H42O5433.293 7433.296 00.0387.249 2, 433.297 9NH
), ArticleFig(id=1201124494405497789, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124481847750782, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
IngredientTarget
Affininty / kcal·mol-1
GSRG6PD
P4-11.4-8.5
M3-9.9-10.2
M7-10.3-8.6
P12-10.9-8.5
P18-5.0-4.4
P24-8.4-8.4
P2-9.9-9.7
P9-8.2-6.4
P7-11.2-8.9
Control-10.0-9.4
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Molecular docking results for components and potential active targets

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IngredientTarget
Affininty / kcal·mol-1
GSRG6PD
P4-11.4-8.5
M3-9.9-10.2
M7-10.3-8.6
P12-10.9-8.5
P18-5.0-4.4
P24-8.4-8.4
P2-9.9-9.7
P9-8.2-6.4
P7-11.2-8.9
Control-10.0-9.4
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基于HPLC-Q-TOF-MS/MS、网络药理学及实验验证探讨西黄丸含药血清抗脑胶质瘤的潜在活性成分及作用机制
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潘晶 1 , 张其海 1, 2 , 樊昊雯 1 , 王霞 3 , 姚卫峰 4, * , 徐宏彬 1, 5, *
药学学报 | 研究论文 2024,59(3): 693-703
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药学学报 | 研究论文 2024, 59(3): 693-703
基于HPLC-Q-TOF-MS/MS、网络药理学及实验验证探讨西黄丸含药血清抗脑胶质瘤的潜在活性成分及作用机制
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潘晶1, 张其海1, 2, 樊昊雯1, 王霞3, 姚卫峰4, * , 徐宏彬1, 5, *
作者信息
  • 1.南京中医药大学第二附属医院, 江苏 南京 210017
  • 2.江苏省苏北人民医院, 江苏 扬州 225001
  • 3.南京中医药大学第二附属医院 (江苏省第二中医院), 江苏 南京 210017
  • 4.南京中医药大学药学院, 江苏 南京 210023
  • 5.宁波大学附属第一医院药学部, 浙江 宁波 315010

通讯作者:

*姚卫峰, Tel: 86-25-85811524, E-mail: ;
徐宏彬, Tel: 86-25-87089123, E-mail:
Exploration of potential active ingredients and mechanism of action of Xihuang pill-medicated serum against glioma based on HPLC-Q-TOF-MS/MS, network pharmacology and experimental verification
Jing PAN1, Qi-hai ZHANG1, 2, Hao-wen FAN1, Xia WANG3, Wei-feng YAO4, * , Hong-bin XU1, 5, *
Affiliations
  • 1. The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210017, China
  • 2. Northern Jiangsu People's Hospital, Yangzhou 225001, China
  • 3. The Second Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Second Chinese Medicine Hospital), Nanjing 210017, China
  • 4. School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
  • 5. Department of Pharmacy, The First Affiliated Hospital of Ningbo University, Ningbo 315010, China
出版时间: 2024-03-12 doi: 10.16438/j.0513-4870.2023-0750
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基于高效液相色谱-四极杆飞行时间串联质谱(HPLC-Q-TOF-MS/MS) 技术对西黄丸的入血成分进行定性分析, 采用网络药理学对入血成分抗脑胶质瘤的潜在作用机制进行探究, 并通过分子对接和实验验证其具体机制。大鼠灌胃给予西黄丸后收集血清, 根据色谱峰保留时间、精确分子质量、特征碎片离子, 结合对照品及文献数据, 鉴定西黄丸含药血清的化学成分; 通过PharmMapper数据库和SwissTarget Prediction数据库获得成分靶点, 通过GeneCards、OMIM、PharmGKB、TTD、DrugBank数据库获得脑胶质瘤疾病靶点, 利用Cytoscape3.9.1软件构建“成分-靶点”网络关系图; 以STRING数据库构建蛋白质互作(PPI) 网络关系图并对靶点进行GO分析和KEGG分析; 利用分子对接验证核心靶点与相对应的入血成分的结合能力; CCK-8、Western blot验证西黄丸含药血清中代表性成分11-羰基-β-乳香酸(KBA) 抗脑胶质瘤的潜在作用机制。结果共鉴定出入血成分40个(原型成分28个, 代谢产物12个)。网络药理学结果显示, β-榄香酮酸、3-乙酰基-β-乳香酸、KBA、α-乳香酸等9个成分可能是西黄丸含药血清抗脑胶质瘤的活性成分, 其中谷胱甘肽还原酶(glutathione reductase, GSR)、葡萄糖-6-磷酸脱氢酶(glucose-6-phosphate dehydrogenase, G6PD)、ATP柠檬酸裂解酶(ATP-citrate lyase, ACLY)、醛酮还原酶1成员B1 (AKR1B1)、谷氧还蛋白(glutaredoxin, GLRX) 为关键靶点, 涉及谷胱甘肽代谢(glutathione metabolism) 通路、磷酸戊糖途径(pentose phosphate pathway) 等。进一步细胞实验结果表明, KBA显著抑制T98G细胞增殖(IC50为30.96 μmol·L-1), KBA (30 μmol·L-1) 显著下调T98G细胞中GSR蛋白表达水平。综上所述, 西黄丸含药血清可能通过调控谷胱甘肽代谢通路相关靶点GSR和G6PD抗脑胶质瘤。研究结果可进一步为西黄丸抗脑胶质瘤的作用机制研究提供一个有价值的依据。动物福利和实验过程获得南京中医药大学实验动物伦理委员会标准(批准号: ACU221001)。

西黄丸  /  含药血清  /  高效液相色谱-四极杆-飞行时间串联质谱  /  入血成分  /  脑胶质瘤

Qualitative analysis of the ingredients absorbed into blood and their metabolites of Xihuang pill (XHP) were conducted using high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS/MS) technology. Network pharmacology was used to explore the potential anticancer mechanisms of the ingredients against glioma, and their specific mechanisms were validated through molecular docking and experimental verification. SD rats were intragastrically administered with XHP, and rat serum samples were collected. Ingredients absorbed into blood and their metabolites were identified based on the retention time of chromatographic peaks, accurate molecular mass, characteristic fragment ions, and comparisons with reference substances and literature data. PharmMapper and SwissTarget Prediction databases were used to obtain the targets of the XHP-medicated serum, while GeneCards, OMIM, PharmGKB, TTD, and DrugBank databases were used to obtain glioma disease targets. The "component-target" network relationship diagram was constructed using Cytoscape 3.9.1 software. The protein-protein interaction (PPI) network diagram was constructed using the STRING database, and the targets were analyzed using GO and KEGG analyses. Molecular docking was used to verify the binding ability of core targets with their corresponding compounds in XHP-medicated serum. The potential mechanism of the anti-glioma effect of 11-keto-β-boswellic acid (KBA), a representative component of XHP-medicated serum, was verified using CCK-8 and Western blot assays. A total of 40 compounds were identified in the XHP-medicated serum, including 28 prototype components and 12 metabolites. The network pharmacology results showed that elemonic acid, 3-acetyl-β-boswellic acid, KBA, α-boswellic acid, and other 5 compounds might be the active ingredients of XHP-medicated serum in the treatment of glioma. Glutathione reductase (GSR), glucose-6-phosphate dehydrogenase (G6PD), ATP-citrate lyase (ACLY), aldo-keto reductase family 1 member B1 (AKR1B1) and glutaredoxin (GLRX) were identified as key targets, involving pathways such as glutathione metabolism and the pentose phosphate pathway. Further cell experiments showed that KBA significantly inhibited the proliferation of T98G cells with an IC50 of 30.96 μmol·L-1, and KBA (30 μmol·L-1) significantly downregulated the protein expression levels of GSR in T98G cells. In summary, XHP-medicated serum may exert its anti-glioma effect by regulating GSR and G6PD-targeted pathways involved in glutathione metabolism. These results provide valuable evidence for further investigating the mechanism of XHP in treating glioma. The animal welfare and experimental procedures were approved by the Ethical Committee of Laboratory Animals at Nanjing University of Chinese Medicine (approval No. ACU221001).

Xihuang pill  /  medicated serum  /  HPLC-Q-TOF-MS/MS  /  ingredient absorbed into blood  /  glioma
潘晶, 张其海, 樊昊雯, 王霞, 姚卫峰, 徐宏彬. 基于HPLC-Q-TOF-MS/MS、网络药理学及实验验证探讨西黄丸含药血清抗脑胶质瘤的潜在活性成分及作用机制. 药学学报, 2024 , 59 (3) : 693 -703 . DOI: 10.16438/j.0513-4870.2023-0750
Jing PAN, Qi-hai ZHANG, Hao-wen FAN, Xia WANG, Wei-feng YAO, Hong-bin XU. Exploration of potential active ingredients and mechanism of action of Xihuang pill-medicated serum against glioma based on HPLC-Q-TOF-MS/MS, network pharmacology and experimental verification[J]. Acta Pharmaceutica Sinica, 2024 , 59 (3) : 693 -703 . DOI: 10.16438/j.0513-4870.2023-0750
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西黄丸又称犀黄丸, 早在18世纪便由王洪绪记载于《外科证治全生集》。全方由牛黄、麝香、乳香和没药共四味中药组成[1]。西黄丸整方清消并用, 瘀毒兼散, 药效简宏, 有清热解毒、消肿散结及活血化瘀之功效, 现常用于恶性肿瘤的辅助治疗, 能够在提高放化疗疗效, 降低不良反应的同时, 改善患者的生存质量[2]。
西黄丸通过抑制肿瘤细胞和肿瘤干细胞增殖、抑制组织肿瘤侵袭转移、调节免疫功能和肿瘤免疫微环境、逆转肿瘤多药耐药、抑制肿瘤血管生成多种途径发挥抗肿瘤作用[3-8], 用于治疗乳腺癌、宫颈癌、非霍奇金淋巴瘤、肺癌、肝癌和结直肠癌等多种癌症[9]。前期研究发现西黄丸可显著诱导人脑胶质瘤U251和U87细胞凋亡, 抑制裸鼠异位移植瘤生长, 协同增强替莫唑胺的抗脑胶质瘤作用[10]; 通过下调HIF-1α/VEGFA/VEGFR2信号通路, 抑制U251细胞血管生成拟态(vasculogenic mimicry, VM) 形成[8], 发挥抗血管生成的作用。目前研究以药理机制探索和有效成分鉴定居多, 但对药物入血后的成分转化研究尚浅。由于脑部血脑屏障的存在, 以及中药药效成分多需经体内生物转化的代谢特点, 所以研究给药后血清才更符合药效物质探索的条件, 也是中医整体观的良好体现。因此, 本文采用高效液相色谱-四极杆-飞行时间串联质谱(HPLC-Q-TOF-MS/MS) 技术对西黄丸入血成分进行研究, 结合网络药理学分析西黄丸含药血清抗脑胶质瘤的活性成分及可能的作用机制, 期望为西黄丸的药效物质基础提供科学依据。
材料与方法
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实验材料  西黄丸(北京同仁堂科技发展股份有限公司制药厂, 批号: 21041368); MEM培养基(美国Gibco公司, 批号: WH0023X131); 胎牛血清(中国ExCell Bio公司, 批号: 12B255); CCK-8试剂盒(批号: 052822220930)、BCA试剂盒(批号: 111922230206)、0.25%胰蛋白酶-EDTA (批号: 032823230403)、PBS (批号: 080222220930)、RIPA裂解液(批号: 062422220721)、蛋白酶磷酸酶抑制剂混合物(批号: 030922220713)、SDS-PAGE蛋白上样缓冲液(批号: 012422220623) 均购自上海碧云天生物技术有限公司; 预染蛋白Marker (上海翌圣生物科技股份有限公司, 批号: G1312150); NC转印膜(美国Pall公司, 批号: 57444203); 甲醇(色谱级, 批号: I1226007228)、乙腈(色谱级, 批号: SHBP3826) 均购自德国Merck公司; 屈臣氏纯净水购自广州屈臣氏食品饮料有限公司; 去氧胆酸(批号: PS020040)、β-榄香酮酸(批号: PS011568)、11-羰基-β-乙酰乳香酸(AKBA, 批号: PS010981)、β-谷甾醇(批号: PS010030) 和豆甾醇(批号: PS010368) 均购自成都普思生物科技股份有限公司(纯度: HPLC ≥ 98%); 槲皮素(批号: MUST-15090717) 购自成都曼思特生物科技公司(纯度: HPLC ≥ 98%); 熊果酸(批号: 110742-200517) 购自中国食品药品检定研究院(纯度: HPLC ≥ 98%); 谷胱甘肽还原酶(glutathione reductase, GSR) 抗体(批号: 1029351-2)、葡萄糖-6-磷酸脱氢酶(glucose-6-phosphate dehydrogenase, G6PD) 抗体(批号: 1007632-1) 购自英国Abcam公司; β-肌动蛋白(beta actin, β-actin) 抗体(批号: 10029234) 购自武汉三鹰生物技术有限公司; HRP goat anti-rabbit IgG (批号: 9300014001) 和HRP goat anti-mouse IgG (批号: 9300003001) 均购自武汉Abclonal公司。
Shimadzu 20AD高效液相色谱仪、AUW120D十万分之一电子天平(日本SHIMADZU公司); Triple TOFTM 5600质谱仪(美国AB SCIEX公司, 包括Analyst TF 1.6数据采集工作站和Peak View 1.2数据分析软件); Eppendorf Concentrator plus真空浓缩仪、Eppendorf 5811型多功能台式冷冻离心机(德国Eppendorf公司); Milli-Q净水系统(美国Millipore公司); XW80-A涡旋混合器(上海青浦沪西仪器厂); KH-500B超声波清洗器(昆山禾创超声仪器有限公司); 细胞培养箱(美国Thermo Fisher公司); HFsafe-1200LC生物安全柜(上海力申科学仪器有限公司); 显影仪(美国Bio-Rad公司)。
西黄丸含药血清的制备  SPF级雄性SD大鼠(200~220 g) 购自南京市江宁区青龙山动物繁殖场[动物许可证号: SCXK (浙) 2019-0002, 动物实验伦理审批号: ACU221001], 饲养于南京中医药大学实验动物SPF级饲养室, 饲养条件为: 12 h/12 h明暗交替, 自由饮水摄食, 恒温恒湿。所有动物被随机分为2组(每组6只), 即空白组和给药组, 空白组给予0.5% CMC-Na溶液, 给药组给予0.216 g·mL-1西黄丸混悬液(由0.5% CMC-Na溶液配制), 给药体积为5 mL·kg-1 (即给药剂量为1.08 g·kg-1, 临床4倍), 一周适应性饲养后进行实验, 连续灌胃7天, 给药频率12 h/次。于第7天首次灌胃后禁食且自由饮水12 h, 于末次给药后1 h戊巴比妥钠麻醉, 肝门静脉取血, 室温静置15 min, 4 ℃、3 000 r·min-1离心10 min得到血清, 于-80 ℃保存。
混合对照品溶液的制备  称取去氧胆酸、β-榄香酮酸、AKBA、β-谷甾醇、豆甾醇、槲皮素和熊果酸各2 mg, 甲醇溶解并转移至2 mL量瓶定容, 制成1 mg·mL-1的对照品储备液, 取各对照品储备液20 μL至2 mL量瓶, 甲醇稀释配制成10 μg·mL-1的混合对照品溶液, 过0.45 μm微孔滤膜, 即得。
血清样品的预处理  -80 ℃保存的空白血清与含药血清于4 ℃解冻后, 分别取血清2 mL, 加入甲醇6 mL, 涡旋振荡10 min, 4 ℃、18 000 r·min-1离心10 min, 将上清液转移至干净的离心管中, 真空浓缩至干。残余物用50%甲醇200 μL复溶, 涡旋振荡10 min, 超声10 min, 4 ℃、18 000 r·min-1离心10 min, 吸取上清液各150 μL于HPLC-Q-TOF-MS/MS分析。
色谱条件  Purospher STAR RP-18色谱柱(250 mm × 4.6 mm, 5 μm, Merck, Germany); 流动相: 水(A)-乙腈(B); 流速: 1.0 mL·min-1; 进样量: 10 μL; 柱温: 30 ℃; 梯度洗脱程序: 0~15 min, 7%~30% B; 15~25 min, 30%~40% B; 25~45 min, 40%~70% B; 45~65 min, 70%~95% B; 65~80 min, 95%~95% B; 80~86 min, 95%~7% B; 86~95 min, 7% B。
质谱条件  电喷雾离子源(ESI), 正负离子模式下扫描, 质量扫描范围m/z 50~1 500。正离子模式: 辅助气、雾化气: 55 psi; 气帘气: 40 psi; 离子源温度: 550 ℃; 电喷雾电压: 4 500 V; 去簇电压: 100 V; 碰撞能量: 40 V; 碰撞能量扩展: 20 V; 负离子模式: 辅助气、雾化气: 55 psi; 气帘气: 40 psi; 离子源温度: 550 ℃; 电喷雾电压: -4 500 V; 去簇电压: -100 V; 碰撞能量: -40 V; 碰撞能量扩展: 20 V。Analyst TF 1.6采集数据, PeakView 1.2分析数据。通过建立西黄丸化学成分数据库, 包含化合物名称、分子式、化学结构式等信息, 完成对西黄丸含药血清的化学成分的鉴定。
西黄丸含药血清治疗脑胶质瘤的网络药理学分析
西黄丸含药血清成分及靶点的预测  HPLC-Q-TOF-MS/MS鉴定所得到的成分构建西黄丸含药血清化学成分库, 选择PharmMapper数据库(http://www. lilab-ecust.cn/pharmmapper/) 得分≥ 0.7的靶点和SwissTarget Prediction数据库(http://www. swisstargetprediction.ch/) 预测的靶点, 合并删除重复项, 得到成分靶点。
脑胶质瘤疾病靶点筛选  在GeneCards数据库(https://www.genecards.org/)、OMIM数据库(https://www.omim.org/)、PharmGKB数据库(https://www.pharmgkb.org/)、TTD数据库(https://db.idrblab.net/ttd/)、DrugBank数据库(https://go.drugbank.com/), 以“glioma”为搜索词, 获取脑胶质瘤疾病的靶点信息, 合并删除重复项, 得到脑胶质瘤疾病靶点。
西黄丸含药血清“成分-靶点”网络关系图及蛋白互作网络(PPI) 的构建   Cytoscape3.9.1软件构建“成分-靶点”网络关系图。通过STRING数据库构建PPI网络关系图, 并通过Cytoscape3.9.1软件对其进行可视化。
GO分析与KEGG富集分析   将靶点导入STRING数据库, 获取可以揭示这些基因的分子生物学功能、生物学过程、细胞学组分和代谢途径的文件。利用GraphPad-Prism 9.0.2对“enrichment. Component”, “enrichment. Function”, “enrichment. Process”进行可视化处理。利用在线网站Omicshare (http://www.omicshare.com/tools/index.php/) 对“enrichment. KEGG”进行可视化处理。
分子对接  将与排名前2的核心靶点GSR、G6PD有关联的9个潜在活性成分分别与GSR、G6PD进行分子对接。从PubChem数据库(http://pubchem.ncbi.nlm.nih.gov/) 中获取潜在活性成分的结构, 以MOL2格式保存。在PDB数据库(https://www.pdbus.org/) 中下载有配体分子的蛋白, 利用Pymol-2.4.0删除溶剂, Autodocktools-1.5.6将蛋白加氢, 蛋白与分子文件转化成pdbqt格式文件, 用Vina-1.1.1进行对接, 每组对接20次, 取第一个最好的数据为结果, 将与2个核心靶点GSR、G6PD结合能排名前5的潜在活性成分分别与2个核心靶点进行对接后用Pymol-2.4.0进行3D作图。分别提取2个核心靶点中的配体, 再将去除配体和溶剂的剩余核心靶点部分分别与其对应配体在Vina-1.1.1软件中进行对接, 作为对照组。
细胞培养与CCK-8检测T98G细胞活力  T98G细胞以含有10%胎牛血清、青霉素(100 u·mL-1) 和链霉素(100 mg·mL-1) 的MEM培养液, 培养于37 ℃、5% CO2的培养箱中。
以5 000个/孔将T98G细胞接种于96孔板, 每孔100 μL, 培养24 h后更换液体, 分别加入含有不同浓度11-羰基-β-乳香酸(KBA) (0、10、20、40、60、80 μmol·L-1) MEM培养液培养24 h, 每孔加入CCK-8溶液10 μL, 孵育1 h, 采用酶标仪记录450 nm波长处的OD值, 计算相对抑制率。
蛋白印迹法检测蛋白表达  取对数生长期的T98G细胞, 以3×105个/孔接种于6孔板中, 待细胞贴壁后, 给予含有不同浓度KBA (0、7.5、15和30 μmol·L-‍1) MEM培养液, 作用24 h。用PBS溶液洗涤3次, 加入适量细胞裂解液(含1 mmol·L-1蛋白酶抑制剂和1 mmol·L-1磷酸酶抑制剂), 冰上裂解30 min, 于4 ℃下13 000 ×g离心10 min, 吸取上清溶液转移至1.5 mL离心管中, BCA法测定蛋白浓度并加入适量loading buffer, 混合均匀, 95 ℃加热10 min, 放冷后, 分装保存于-20 ℃冰箱中。
使用10%十二烷基硫酸钠聚丙烯酰胺凝胶(SDS-PAGE) 恒压电泳分离上清液中的蛋白, 采用湿转法恒流将其转印到硝酸纤维素(NC) 膜上, 5% BSA封闭1 h后, 分别以GSR (1∶5 000)、G6PD (1∶1 000)、β-actin (1∶50 000) 抗体于4 ℃孵育过夜, 再与相对应的二抗(1∶5 000) 室温孵育1 h。应用超敏ECL化学发光液于Bio-Rad成像系统中可视化印迹条带, 并运用Image J软件进行量化。
统计学分析  采用Graphpad 8.0统计学软件对实验结果进行统计学分析。计量资料以$ \overline{x} $ ± s表示。各组分别与对照组进行单因素方差分析, 以P < 0.05为差异有统计学意义。
结果
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1 西黄丸含药血清的化学成分的鉴定
通过与对照品或文献报道过的成分的色谱保留信息、质谱裂解规律、精确分子量以及碎片离子信息进行对比, 扣除空白组后初步鉴定出入血原型成分28个, 包括萜类化合物17个、脂肪酸类化合物5个和其他类成分6个; 入血代谢产物12个, 以葡萄糖醛酸化、羟基化、乙酰化为主要代谢途径, 鉴定结果见表 1、2和图 1。
1.1 基于HPLC-Q-TOF-MS/MS的西黄丸含药血清入血原型成分鉴定
萜类成分鉴定  入血的萜类成分共有3种, 三萜类化合物14个、二萜类2个以及单萜类1个。化合物P3具有m/z 391.299 1、407.330 0等特征离子碎片, 在负离子模式下形成[M-H]-准分子离子峰为m/z 469.332 3, 子离子m/z 451.321 4由母离子丢失一分子H2O (18 Da) 所得, 此外母离子丢失CH3COOH (60 Da) 裂解为碎片离子m/z 407.330 0, 结合文献[11]推测化合物P3为KBA。
脂肪酸类成分鉴定  化合物P21在负离子模式下形成[M-H]-准分子离子峰为m/z 311.295 6, 可丢失C13H27生成碎片离子m/z 183.013 7, 推测化合物P21为花生酸。
胆汁酸类成分鉴定  化合物P23在负离子模式下形成[M-H]-准分子离子峰为m/z 448.307 5, 碎片离子m/z 74.025 3是由母离子-CO-NH-键断裂生成, 结合文献[12]推测化合物P23为甘氨猪去氧胆酸。
其他类成分鉴定  化合物P26在负离子模式下形成[M-H]-准分子离子峰为m/z 124.007 4, 失去C2H7N (45 Da) 得到碎片离子m/z 79.957 5, 推测化合物P26为牛磺酸。
1.2 基于HPLC-Q-TOF-MS/MS的西黄丸含药血清入血代谢产物鉴定
化合物M1负离子模式下[M-H]-准分子离子峰为m/z 645.368 8, 碎片离子m/z 469.336 1由母离子丢失一分子葡萄糖醛酸(glucuronide acid, GluA, 176 Da) 生成, 子离子m/z 59.017 3为特征碎片离子[11], 碎片离子m/z 583.313 2由母离子丢失COOH和OH生成, 此外碎片离子m/z 601.383 0由母离子脱去一分子CO2生成, 推测化合物M1为KBA葡萄糖醛酸化代谢产物。化合物M2负离子模式下[M-H]-准分子离子峰为m/z 485.328 3, 与文献[11]具有相同碎片离子m/z 423.329 6, 推测化合物M2为KBA羟基化代谢产物。化合物M5负离子模式下[M-H]-准分子离子峰为m/z 301.217 9, 碎片离子m/z 257.227 6和m/z 283.207 5由母离子m/z 301.217 9丢失一分子CO2和H2O生成。化合物M6负离子模式下产生m/z为317.216 6 [M-H]-的准分子离子峰以及碎片离子m/z 273.221 1和m/z 299.201 6, 均比M5高16 Da, 推测M5和M6分别为脱氢松香酸还原产物和还原及羟基化代谢产物。化合物M7负离子模式下[M-H]-准分子离子峰为m/z 527.338 9, 产生碎片离子m/z 59.015 0和m/z 423.328 2, 结合文献[11]推测化合物M7为AKBA羟基化代谢产物。化合物M8负离子模式下[M-H]-准分子离子峰为m/z 689.399 7, 丢失一分子GluA得到碎片离子m/z 513.358 1, 较3-乙酰基-α-乳香酸高16 Da, 推测碎片离子m/z 513.358 1为3-乙酰基-α-乳香酸羟基化代谢产物, 化合物M8为3-乙酰基-α-乳香酸羟基化和葡萄糖醛酸化代谢产物。化合物M12负离子模式下[M-H]-准分子离子峰为m/z 433.293 7, 碎片离子m/z 387.249 2由母离子失去COOH得到, m/z 433.293 7和m/z 387.249 2均比西黄丸中去氧胆酸的碎片离子高42 Da, 推测化合物M12为去氧胆酸乙酰化代谢产物。
2 西黄丸含药血清抗脑胶质瘤的网络药理学分析
2.1 西黄丸含药血清成分靶点的预测
PharmMapper数据库得分≥0.7的靶点和SwissTarget Prediction数据库预测的靶点, 合并删除重复项, 得到成分靶点35个。
2.2 脑胶质瘤疾病靶点筛选
将从GeneCards数据库、OMIM数据库、PharmGKB数据库、TTD数据库、DrugBank数据库获取的脑胶质瘤疾病的靶点, 合并删除重复项, 得到脑胶质瘤疾病靶点5 634个。得到西黄丸含药血清抗脑胶质瘤的潜在靶点14个。
2.3 西黄丸含药血清“成分-靶点”网络关系图及PPI的构建
Cytoscape3.9.1软件构建“成分-靶点”网络关系图如图 2。取上述35个靶点, 将其导入STRING数据库, 物种选择“Homo Sapiens”构建PPI, 得到25个相互作用的节点(图 3), 其中GSR、G6PD、谷氧还蛋白(glutaredoxin, GLRX)、醛酮还原酶1成员B1 (AKR1B1)和ATP柠檬酸裂解酶(ATP-citrate lyase, ACLY) 为核心靶点, 后续实验将围绕度值排名前2的核心靶点(GSR和G6PD) 开展。
2.4 GO分析与KEGG富集分析
可视化处理结果见图 4。KEGG分析的结果显示, 谷胱甘肽代谢通路(glutathione metabolism)、磷酸戊糖途径(pentose phosphate pathway)、黏着斑信号通路(focal adhesion)、RAS信号通路可能参与西黄丸含药血清抗脑胶质瘤的过程。GO富集分析显示西黄丸含药血清抗脑胶质瘤靶点参与的生物学过程为嗜酸性粒细胞化学、氮化合物代谢过程的正向调节、羧酸代谢过程等; 在细胞组分方面, 主要作用于分泌颗粒、富含纤维胶凝蛋白的颗粒内腔、分泌颗粒腔等; 分子功能主要为醛糖醇: NADP+1-氧化还原酶活性、信号传导受体结合、相同蛋白质结合等。
3 分子对接
用Vina-1.1.1软件将与每个靶点结合能排名前5的化合物分别与2个靶点对接, 并通过Pymol-2.4.0进行3D作图, 结果见表 3和图 5。相较于对照组, 化合物P4、M7、P12、P7与GSR靶点之间结合能力更强, 化合物M3、P2与G6PD靶点之间结合能力更强。
4 CCK-8检测T98G细胞活力
不同浓度KBA作用于T98G细胞24 h的细胞活力测定结果显示, 随着KBA浓度的增加, T98G细胞抑制率越高(P < 0.01), 半数抑制浓度IC50为30.96 μmol·L-1, 后续实验根据KBA处理T98G细胞24 h的IC50值为最高浓度, 依次稀释2倍, 选用3个浓度开展。
5 KBA对T98G细胞中GSR、G6PD蛋白的影响
如图 6所示, KBA (15 μmol·L-1) 对T98G细胞中GSR蛋白表达呈下调趋势, KBA (30 μmol·L-1) 显著下调细胞中GSR蛋白表达(P < 0.01); KBA (15和30 μmol·L-1) 对T98G细胞中G6PD蛋白表达分别下调了6%和23%, 但差异无统计学意义。结果表明, KBA可能通过下调谷胱甘肽代谢通路相关蛋白GSR和G6PD发挥抗脑胶质瘤增殖的作用。
讨论
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本研究采用HPLC-Q-TOF-MS/MS技术研究西黄丸的入血成分, 扣除空白血清后分析鉴定出入血原型成分28种和代谢产物12种, 主要来自三萜类、脂肪酸类及胆汁酸类化合物, 代谢途径主要包括葡萄糖醛酸化、羟基化、乙酰化、去乙酰化、还原等单一或复合反应。本文以西黄丸原药及其入血原型成分为基础, 参考现有文献构建西黄丸代谢产物数据库, 包含代谢途径、化学式、特征碎片及相对分子质量等, 借助PeakView1.2软件对其代谢产物进行定性分析与分类。
三萜类成分在SD大鼠血清中主要以17种原型成分和10种代谢产物形式存在, 以五环三萜类AKBA作为代表性成分, 既往研究表明AKBA与其类似物在多种实体肿瘤中发挥抗肿瘤活性[13], AKBA上调人NF-κB抑制蛋白α (IκBα) 表达减弱胶质母细胞瘤细胞的恶性表型, 同时增加细胞对辐射的敏感性[14], AKBA还可发挥逆转肿瘤多重耐药的作用[15]。五环三萜类成分不仅具有良好的抗肿瘤活性, 同时毒性较低, 还可增强其他药物的抗肿瘤作用, 在发展抗肿瘤药物方面具有很大的潜力。
SD大鼠血清中鉴定出的脂肪酸类成分包括2种饱和脂肪酸与3种不饱和脂肪酸, 以硬脂酸为代表性成分, 既往研究表明血清中硬脂酸水平可能成为恶性肺结节早期诊断的潜在生物标志物[16]。不饱和脂肪酸可通过诱导肿瘤细胞凋亡、抑制肝癌细胞HepG2迁移、抑制人结肠癌细胞HT29增殖, 发挥抗肿瘤作用[17-19]。高不饱和脂肪酸能够抑制神经胶质瘤增殖、促进其凋亡[20]。脂肪酸代谢在肿瘤细胞增殖中发挥着重要的作用, 但有研究表明抑制脂肪酸氧化降低了人胶质瘤细胞增殖活性, 并延长了恶性胶质瘤同基因小鼠模型的存活时间[21], 脂肪酸还可用于合成一系列促进肿瘤细胞增殖、迁移、侵袭的脂质信号分子[22]。因此脂肪酸对于恶性肿瘤的药理作用尚不明确, 有待于进一步研究。
胆汁酸类成分以3种原型成分和1种代谢产物存在, 以牛磺酸为代表性成分, 研究表明牛磺酸诱导胶质瘤细胞凋亡并抑制肿瘤衍生的血管内皮生长因子(VEGF) 产生, 从而发挥抗肿瘤作用[23]。此外, 有研究表明同为胆汁酸类的石胆酸能够诱导神经母细胞瘤细胞系凋亡而发挥抗肿瘤作用[24]。
本文将入血成分作为潜在活性成分, 利用网络药理学预测到西黄丸含药血清抗脑胶质瘤的GSR、G6PD等14个靶点。与GSR靶点对应的成分最多, 如P7、P12、P18、P24、M3和M7, 这些成分多归属于乳香和牛黄, GSR可维持氧化态谷胱甘肽(GSSG) 和还原态谷胱甘肽(GSH) 的平衡, GSH可以通过清除ROS保护细胞免受氧化损伤, 有研究表明GSR可通过维持GSSG和GSH的平衡介导胶质母细胞的耐药性[25, 26]。与G6PD靶点对应的成分包括P2、P4和P9, 归属于乳香和没药, G6PD作为三羧酸循环(TCA)的限速酶, 可通过产生大量NADPH将GSSG还原成GSH从而清除ROS来保护细胞。文献表明G6PD与脑胶质瘤细胞增殖能力有关, 敲除G6PD基因后脑胶质瘤细胞增殖能力下降[27], G6PD在脑胶质瘤细胞中过表达以满足高增殖细胞的需求[28]。同时化合物P2、P4和P9也对应着AKR1B1靶点, 除此之外, AKR1BA也对应着化合物P6和P11, 这些成分归属于乳香和没药, AKR1BA是一种NADPH依赖性酶, 催化各种醛和酮还原为相应的醇, 具有抗氧化作用[29]。ACLY和GLRX是拟合出的间接靶点, 研究表明ACLY是脂肪酸合成的限速酶之一, 肿瘤细胞中ACLY乙酰化以保持稳定从而促进脂质合成和细胞增殖, 干扰ACLY表达能显著抑制肿瘤细胞生成[30, 31]。GLRX在体内可参与铁代谢、抗凋亡以及促进细胞增殖的作用, 是维持机体氧化还原平衡的一类重要的抗氧化蛋白[32]。网络药理学结果表明, 牛黄中的化合物P7和P24主要作用于GSR靶点, 乳香中的化合物P2、P4、P6、P11、P12、P18、M3和M7主要作用于GSR、G6PD和AKR1B1靶点, 没药中的化合物P9作用于AKR1B1靶点, 表明西黄丸含药血清中的潜在活性成分可作用于多个靶点发挥治疗脑胶质瘤的作用, 体现了中药复方治疗疾病“多成分-多靶点-多途径”的特点。牛黄作为君药发挥清热解毒之功效, 佐药乳香和没药活血止痛, 而西黄丸中麝香具有芳香通窍、活血散结之性[2], 可绕过血脑屏障直达脑部病所, 而此类挥发性成分多用GC-MS检测, 因此本文存在一定局限性, 后续将通过GC-MS分析鉴定西黄丸含药血清的挥发性成分。
KBA在西黄丸中含量较高[1], 因此选用KBA单体作用于T98G细胞。前期文献证实, G6PDi-1 (G6PD抑制剂) 通过结合G6PD蛋白, 从而抑制G6PD蛋白的表达[33]。在本研究中, 利用分子对接实验发现KBA可靶向结合G6PD与GSR蛋白; 由此猜测KBA可能与G6PDi-1具有相似的作用机制, 抑制G6PD与GSR的蛋白表达。此外, 利用Western blot实验证实, KBA的确可抑制其蛋白表达。由此推测在T98G细胞中KBA具有G6PDi-1类似的生物作用, 可通过与靶点蛋白GSR和G6PD蛋白结合而抑制其蛋白表达, 但具体机制仍有待研究。化合物P8、M3、M7、P17、P6、P11与KBA结构相似, 均属于三萜类成分, 且分子对接结合能均低于KBA, 因此这些成分可能也下调脑胶质瘤细胞中GSR和G6PD蛋白的表达, 具有抗脑胶质瘤的作用。
综上所述, 本研究通过HPLC-Q-TOF-MS/MS鉴定和分析了西黄丸的入血成分, 对其进行抗脑胶质瘤的网络药理学研究, 并通过分子对接和实验探究其机制, 发现西黄丸含药血清可能通过调控谷胱甘肽代谢通路相关蛋白GSR、G6PD发挥抗脑胶质瘤作用, 结果可为西黄丸抗脑胶质瘤的作用机制研究提供一个有价值的依据。
作者贡献: 徐宏彬、姚卫峰、王霞负责实验设计、论文修改以及提供了理论支持; 潘晶完成实验数据、论文写作与修改; 张其海、樊昊雯帮助完成实验数据分析。
利益冲突: 本文作者均声明不存在利益冲突。
基金
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  • 江苏省卫健委医学科研重点项目(ZD2021031)
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2024年第59卷第3期
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doi: 10.16438/j.0513-4870.2023-0750
  • 接收时间：2023-06-16
  • 首发时间：2025-11-28
  • 出版时间：2024-03-12
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  • 收稿日期：2023-06-16
  • 修回日期：2023-09-15
基金
江苏省卫健委医学科研重点项目(ZD2021031)
作者信息
    1.南京中医药大学第二附属医院, 江苏 南京 210017
    2.江苏省苏北人民医院, 江苏 扬州 225001
    3.南京中医药大学第二附属医院 (江苏省第二中医院), 江苏 南京 210017
    4.南京中医药大学药学院, 江苏 南京 210023
    5.宁波大学附属第一医院药学部, 浙江 宁波 315010

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*姚卫峰, Tel: 86-25-85811524, E-mail: ;
徐宏彬, Tel: 86-25-87089123, E-mail:
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2种不同金属材料的力学参数
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Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
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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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