{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:56:21Z","timestamp":1791384981661,"version":"4.3.3"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2017,5,11]],"date-time":"2017-05-11T00:00:00Z","timestamp":1494460800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":["rsc.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,5,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The major obstacle for the development of targeted therapies is the lack of pharmacodynamic (PD) biomarkers to provide an early readout of biological activities. As the modulation of metabolites may reflect the biological changes occurring in the targets, metabolomics is promising to be an efficient way to explore PD biomarkers. In the present study, a liver fibrosis rat model was established by intraperitoneal injection of CCl4 twice weekly for 6 weeks, the treatment of total aglycone extracts of Scutellaria baicalensis (TAES) was begun 4 weeks after the modeling, and gas chromatography-mass spectrometry (GC-MS) based metabolomics combined with pattern recognition and network analysis were carried out for the research on PD biomarkers of TAES on liver fibrosis. After 2 weeks of treatment, TAES shows positive effects on CCl4-induced liver fibrosis. In the metabolomics study, 63 urinary metabolites contributing to liver fibrosis were identified. Six metabolic pathways significantly enriched in metabolomics data were mapped onto a network to determine global patterns of metabolic alterations in liver fibrosis. By topological analysis, 6 metabolites with high centrality in the metabolic sub-network were selected as potential PD biomarkers. Within 24 h of the final administration, the 6 identified urine metabolic biomarkers with response to time variation of TAES were validated as PD biomarkers. This integrative study presents an attractive strategy to explore PD biomarkers, which may give insight into the actual pharmacological effect of target drugs, and the information from PD biomarkers can be combined with pharmacokinetics to select the optimal dose and a schedule of administration for the drugs.<\/jats:p>\n                  <jats:p\/>","DOI":"10.1039\/c7mb00093f","type":"journal-article","created":{"date-parts":[[2017,5,11]],"date-time":"2017-05-11T10:42:04Z","timestamp":1494499324000},"page":"1575-1583","update-policy":"https:\/\/doi.org\/10.1039\/rsc_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Metabolomics combined with pattern recognition and bioinformatics analysis methods for the development of pharmacodynamic biomarkers on liver fibrosis"],"prefix":"10.1093","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4303-1750","authenticated-orcid":false,"given":"Junwei","family":"Fang","sequence":"first","affiliation":[{"name":"Center for Traditional Chinese Medicine and Systems Biology, Shanghai University of Traditional Chinese Medicine a , 1200 Cailun Road, Shanghai 201203 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Fudan University b , 826 Zhangheng Road, Shanghai 201203 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Traditional Chinese Medicine and Systems Biology, Shanghai University of Traditional Chinese Medicine a , 1200 Cailun Road, Shanghai 201203 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingfeng","family":"Qiu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shanghai Jiao Tong University c , Shanghai 200240, P. R. China \u00a0 mfqiu@sjtu.edu.cn"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Traditional Dai Medicine, West Yunnan University of Applied Sciences d , Jinghong 600100, P. R. China \u00a0 dryyz@sina.com"},{"name":"Center for Traditional Chinese Medicine and Systems Biology, Shanghai University of Traditional Chinese Medicine a , 1200 Cailun Road, Shanghai 201203 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,5,11]]},"reference":[{"key":"2026010816063052100_cit1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/clpt.2009.77","article-title":"Biomarkers: Principles, Policies, and Practice","volume":"86","author":"Wagner","year":"2009","journal-title":"Clin. Pharmacol. Ther."},{"key":"2026010816063052100_cit2","first-page":"601","article-title":"et al., New concepts and challenges in the clinical translation of cancer preventive therapies: the role of pharmacodynamic biomarkers","volume":"9","author":"Karen","year":"2015","journal-title":"Ecancermedicalscience"},{"key":"2026010816063052100_cit3","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1158\/2326-6066.CIR-13-0020","article-title":"et al., Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy","volume":"1","author":"Ng","year":"2013","journal-title":"Cancer Immunol. Res."},{"key":"2026010816063052100_cit4","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1158\/1535-7163.MCT-15-0815","article-title":"et al., Plasma metabolomic changes following PI3K inhibition as pharmacodynamic biomarkers: preclinical discovery to Phase I trial evaluation","volume":"15","author":"Ang","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"2026010816063052100_cit5","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/sj.bjc.6606082","article-title":"et al., Assessment of circulating biomarkers for potential pharmacodynamic utility in patients with lymphoma","volume":"104","author":"Greystoke","year":"2011","journal-title":"Br. J. Cancer"},{"key":"2026010816063052100_cit6","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1073\/pnas.1114410109","article-title":"et al., The human circadian metabolome","volume":"109","author":"Dallmann","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026010816063052100_cit7","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.4155\/bio.12.218","article-title":"et al., Application of metabolomics approaches to the study of respiratory diseases","volume":"4","author":"Snowden","year":"2013","journal-title":"Bioanalysis"},{"key":"2026010816063052100_cit8","doi-asserted-by":"crossref","first-page":"e0126735","DOI":"10.1371\/journal.pone.0126735","article-title":"et al., Biochemical Association of Metabolic Profile and Microbiome in Chronic Pressure Ulcer Wounds","volume":"10","author":"Ammons","year":"2015","journal-title":"PLoS One"},{"key":"2026010816063052100_cit9","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.jep.2016.06.014","article-title":"et al., Metabolomics study of renal fibrosis and intervention effects of total aglycone extracts of Scutellaria baicalensis in unilateral ureteral obstruction rats","volume":"192","author":"Fang","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"2026010816063052100_cit10","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1093\/bioinformatics\/btr661","article-title":"et al., Metscape 2 bioinformatics tool for the analysis and visualization of metabolomics and gene expression data","volume":"28","author":"Karnovsky","year":"2012","journal-title":"Bioinformatics"},{"key":"2026010816063052100_cit11","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.taap.2013.11.017","article-title":"et al., Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs","volume":"274","author":"Westra","year":"2014","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"2026010816063052100_cit12","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.clinre.2013.08.014","article-title":"et al., Protective effects of l-carnitine, N-acetylcysteine and genistein in an experimental model of liver fibrosis","volume":"38","author":"Demiroren","year":"2014","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"2026010816063052100_cit13","first-page":"738245","article-title":"et al., Differences of Excess and Deficiency Zheng in Patients with Chronic Hepatitis B by Urinary Metabonomics","volume":"5","author":"Sun","year":"2013","journal-title":"J. Evidence-Based Complementary Altern. Med."},{"key":"2026010816063052100_cit14","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.1021\/pr4011298","article-title":"et al., Study of induction chemotherapy efficacy in oral squamous cell carcinoma using pseudotargeted metabolomics","volume":"13","author":"Ye","year":"2014","journal-title":"J. Proteome Res."},{"key":"2026010816063052100_cit15","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1007\/s11306-011-0376-2","article-title":"et al., Qualitative serum organic acid profiles of HIV-infected individuals not on antiretroviral treatment","volume":"8","author":"Williams","year":"2012","journal-title":"Metabolomics"},{"key":"2026010816063052100_cit16","doi-asserted-by":"crossref","first-page":"4334","DOI":"10.1021\/ac0521596","article-title":"et al., MET-IDEA:\u2009 Data Extraction Tool for Mass Spectrometry-Based Metabolomics","volume":"78","author":"Broeckling","year":"2006","journal-title":"Anal. Chem."},{"key":"2026010816063052100_cit17","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.jpba.2012.09.021","article-title":"et al., Urinary metabonomics characterization of liver fibrosis induced by CCl4 in rats and intervention effects of Xia Yu Xue Decoction","volume":"74","author":"Gou","year":"2013","journal-title":"J. Pharm. Biomed. Anal."},{"key":"2026010816063052100_cit18","doi-asserted-by":"crossref","first-page":"7606","DOI":"10.1021\/ac401793d","article-title":"et al., Ultraperformance liquid chromatography-mass spectrometry based comprehensive metabolomics combined with pattern recognition and network analysis methods for characterization of metabolites and metabolic pathways from biological data sets","volume":"85","author":"Zhang","year":"2013","journal-title":"Anal. Chem."},{"key":"2026010816063052100_cit19","doi-asserted-by":"crossref","first-page":"e97501","DOI":"10.1371\/journal.pone.0097501","article-title":"et al., Global Metabolite Profiling of Synovial Fluid for the Specific Diagnosis of Rheumatoid Arthritis from Other Inflammatory Arthritis","volume":"9","author":"Kim","year":"2014","journal-title":"PLoS One"},{"key":"2026010816063052100_cit20","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1002\/iid3.61","article-title":"et al., The metabolomics of asthma control: a promising link between genetics and disease","volume":"3","author":"McGeachie","year":"2015","journal-title":"Immun., Inflammation Dis."},{"key":"2026010816063052100_cit21","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/srep00052","article-title":"et al., Drug-target network in myocardial infarction reveals multiple side effects of unrelated drugs","volume":"1","author":"Azuaje","year":"2011","journal-title":"Sci. Rep."},{"key":"2026010816063052100_cit22","doi-asserted-by":"crossref","first-page":"3029","DOI":"10.1002\/jssc.201100408","article-title":"et al., Classification and differential metabolite discovery of liver diseases based on plasma metabolic profiling and support vector machines","volume":"34","author":"Lin","year":"2011","journal-title":"J. Sep. Sci."},{"key":"2026010816063052100_cit23","doi-asserted-by":"crossref","first-page":"23334","DOI":"10.1038\/srep23334","article-title":"et al., Metabolic phenotyping for monitoring ovarian cancer patients","volume":"6","author":"Ke","year":"2016","journal-title":"Sci. Rep."},{"key":"2026010816063052100_cit24","doi-asserted-by":"crossref","first-page":"167","DOI":"10.4331\/wjbc.v3.i8.167","article-title":"et al., Dysregulated lipid metabolism in cancer","volume":"3","author":"Zhang","year":"2012","journal-title":"World J. Biol. Chem."},{"key":"2026010816063052100_cit25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13073-016-0289-9","article-title":"et al., Novel personalized pathway-based metabolomics models reveal key metabolic pathways for breast cancer diagnosis","volume":"8","author":"Huang","year":"2016","journal-title":"Genome Med."},{"key":"2026010816063052100_cit26","doi-asserted-by":"crossref","first-page":"e71403","DOI":"10.1371\/journal.pone.0071403","article-title":"et al., Metabolomics and proteomics annotate therapeutic properties of geniposide: targeting and regulating multiple perturbed pathways","volume":"8","author":"Wang","year":"2013","journal-title":"PLoS One"},{"key":"2026010816063052100_cit27","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1093\/bioinformatics\/btq048","article-title":"et al., Metscape:\na Cytoscape plug-in for visualizing and interpreting metabolomic data in the context of human metabolic networks","volume":"26","author":"Gao","year":"2010","journal-title":"Bioinformatics"},{"key":"2026010816063052100_cit28","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1038\/srep01236","article-title":"et al., Extracting insights from the shape of complex data using topology","volume":"3","author":"Lum","year":"2013","journal-title":"Sci. Rep."},{"key":"2026010816063052100_cit29","doi-asserted-by":"crossref","first-page":"110","DOI":"10.3724\/SP.J.1009.2013.00110","article-title":"et al., Traditional Chinese medicine network pharmacology: theory, methodology and application","volume":"11","author":"Li","year":"2013","journal-title":"Chin. J. Nat. Med."},{"key":"2026010816063052100_cit30","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.jchromb.2007.03.029","article-title":"et al., Simultaneous quantification of malonyl-CoA and several other short-chain acyl-CoAs in animal tissues by ion-pairing reversed-phase HPLC\/MS","volume":"853","author":"Gao","year":"2007","journal-title":"J. Chromatogr. B: Anal. Technol. Biomed. Life Sci."},{"key":"2026010816063052100_cit31","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1158\/1078-0432.CCR-09-2167","article-title":"et al., Guidelines for the Development and Incorporation of Biomarker Studies in Early Clinical Trials of Novel Agents","volume":"16","author":"Dancey","year":"2010","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"2026010816063052100_cit32","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.ctrv.2011.04.006","article-title":"et al., Circulating tumor cells as pharmacodynamic biomarker in early clinical oncological trials","volume":"37","author":"Devriese","year":"2011","journal-title":"Cancer Treat. Rev."}],"container-title":["Molecular BioSystems"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/molecular-omics\/article-pdf\/13\/8\/1575\/65479383\/c7mb00093f.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/molecular-omics\/article-pdf\/13\/8\/1575\/65479383\/c7mb00093f.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T21:09:28Z","timestamp":1767906568000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/molecular-omics\/article\/13\/8\/1575\/8327861"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,11]]},"references-count":32,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2017,5,11]]}},"URL":"https:\/\/doi.org\/10.1039\/c7mb00093f","relation":{},"ISSN":["1742-2051","1742-206X"],"issn-type":[{"value":"1742-2051","type":"electronic"},{"value":"1742-206X","type":"print"}],"subject":[],"published-other":{"date-parts":[[2017,8,1]]},"published":{"date-parts":[[2017,5,11]]},"assertion":[{"value":"This document is Similarity Check deposited","name":"similarity_check","explanation":{"URL":"https:\/\/www.crossref.org\/services\/similarity-check\/"},"group":{"name":"similarity_check","label":"SIMILARITY CHECK"}},{"value":"Supplementary Information","URL":"https:\/\/doi.org\/10.1039\/C7MB00093F","name":"related_data","group":{"name":"related_data","label":"RELATED DATA"}},{"value":"Junwei Fang (ORCID)","URL":"http:\/\/orcid.org\/0000-0002-4303-1750","name":"identifier","group":{"name":"author_identifiers","label":"IDENTIFIERS"}},{"value":"The Royal Society of Chemistry has an exclusive publication licence for this journal","name":"copyright_licence","group":{"name":"copyright_licensing","label":"COPYRIGHT AND LICENSING"}},{"value":"Single-blind","order":2,"name":"peer_review_method","group":{"name":"peer_review_method","label":"PEER REVIEW METHOD"}},{"value":"Received 16 February 2017; Accepted 30 April 2017;  Accepted Manuscript published 11 May 2017;  Advance Article published 3 July 2017;  Version of Record published 25 July 2017","order":1,"name":"history","group":{"name":"publication_history","label":"PUBLICATION HISTORY"}}]}}