{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:44:51Z","timestamp":1790628291231,"version":"4.1.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,4]],"date-time":"2022-02-04T00:00:00Z","timestamp":1643932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["2020-JYB-ZDGG-033"],"award-info":[{"award-number":["2020-JYB-ZDGG-033"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Kangfuxiaoyan suppository (KFXYS) is a commonly used traditional Chinese medicine (TCM) preparation for the treatment of chronic pelvic inflammatory disease (CPID) clinically, and its safety and effectiveness have been well verified. However, the potential mechanism remains unclear. The integrated strategy of metabolomics and network pharmacology was employed in the study to reveal the potential mechanism of KFXYS in the treatment of CPID. Our research consists of five steps. First, the effect of KFXYS in reversing uterine inflammation indexes was verified. Second, based on the comprehensive characterization of 123 chemical ingredients of KFXYS, the ingredients of KFXYS absorbed into blood were identified by UPLC-Q-TOF\/MS, then ADME research was carried out on the main ingredients. Third, the differential metabolites with significant correlation to inflammatory indexes were discovered by metabolomics and correlation analysis. Fourth, the potential targets and pathways of KFXYS in treating CPID were predicted by network pharmacology based on the ingredients which had good ADME behavior. Fifth, the proteins in common pathways of metabolomics and network pharmacology were used to screen the key targets from the potential targets of network pharmacology, and the potential mechanism of KFXYS in treating CPID was clarified. As a result, KFXYS significantly reversed the uterine inflammation indexes, including IL-1 and IL-6. The ingredients absorbed into blood including matrine, sophocarpine, aloin, esculetin-<jats:italic>O<\/jats:italic>-glucuronide, 7,4\u2032-dihydroxyisoflavone-<jats:italic>O<\/jats:italic>-glucuronide, and 4\u2032-methoxyisoflavone-7-<jats:italic>O<\/jats:italic>-glucuronide had good ADME behavior <jats:italic>in vivo<\/jats:italic>. Among the differential metabolites, Leukotriene A4, 5-Hydroxyindoleacetic acid, Ornithine, Arginine, and PC (20:1 (11Z)\/20:4 (8Z,11Z,14Z,17Z)) were significant correlation to inflammation indexes. The integration analysis of metabolomics and network pharmacology shows that KFXYS may regulate the key targets including ARG1, NOS2, NOS3, etc. We speculate that ingredients of KFXYS, such as matrine, sophocarpine, aloin etc. act on the key proteins including ARG1, NOS2, and NOS3, to exert anti-inflammatory effect.<\/jats:p>","DOI":"10.3389\/fphar.2022.812587","type":"journal-article","created":{"date-parts":[[2022,2,4]],"date-time":"2022-02-04T05:53:06Z","timestamp":1643953986000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Integrated Metabolomics and Network Pharmacology Study on the Mechanism of Kangfuxiaoyan Suppository for Treating Chronic Pelvic Inflammatory Disease"],"prefix":"10.3389","volume":"13","author":[{"given":"Zhengyi","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziye","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujing","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulian","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanjia","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejiao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,4]]},"reference":[{"key":"B1","first-page":"250","volume-title":"Obstetrics and Gynecology","author":"Cao","year":"2008"},{"key":"B2","first-page":"1646","volume-title":"Pharmacopoeia of the Peoples Republic of China","author":"Chinese Pharmacopoeia Commission [Cpc]","year":"2020"},{"key":"B3","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1016\/j.ijantimicag.2015.05.004","article-title":"A Review of Antibiotic Therapy for Pelvic Inflammatory Disease","volume":"46","author":"Duarte","year":"2015","journal-title":"Int. J. Antimicrob. Agents"},{"key":"B4","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1016\/j.cell.2016.09.031","article-title":"L-arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity","volume":"167","author":"Geiger","year":"2016","journal-title":"Cell"},{"key":"B5","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1038\/nchembio.118","article-title":"Network Pharmacology: the Next Paradigm in Drug Discovery","volume":"4","author":"Hopkins","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.freeradbiomed.2020.10.002","article-title":"The Potential Link between Inherited G6PD Deficiency, Oxidative Stress, and Vitamin D Deficiency and the Racial Inequities in Mortality Associated with COVID-19","volume":"161","author":"Jain","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1016\/j.bbrc.2018.09.023","article-title":"ODC1 Inhibits the Inflammatory Response and ROS-Induced Apoptosis in Macrophages","volume":"504","author":"Jiang","year":"","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B8","doi-asserted-by":"publisher","first-page":"5871431","DOI":"10.1155\/2018\/5871431","article-title":"Sophocarpine Attenuates LPS-Induced Liver Injury and Improves Survival of Mice through Suppressing Oxidative Stress, Inflammation, and Apoptosis","volume":"2018","author":"Jiang","year":"","journal-title":"Mediators Inflamm."},{"key":"B9","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/j.redox.2016.03.005","article-title":"Glutathione S-Transferase Pi Modulates NF-\u039ab Activation and Pro-inflammatory Responses in Lung Epithelial Cells","volume":"8","author":"Jones","year":"2016","journal-title":"Redox Biol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2239","DOI":"10.4049\/jimmunol.1701686","article-title":"Glutathione Reductase Promotes Fungal Clearance and Suppresses Inflammation during Systemic Candida Albicans Infection in Mice","volume":"203","author":"Kim","year":"2019","journal-title":"J. Immunol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.fct.2019.02.025","article-title":"Aloin Reduces Inflammatory Gene iNOS via Inhibition Activity and P-STAT-1 and NF-\u039ab","volume":"126","author":"Lee","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"3305","DOI":"10.1038\/s41388-020-1217-4","article-title":"MAOA-mediated Reprogramming of Stromal Fibroblasts Promotes Prostate Tumorigenesis and Cancer Stemness","volume":"39","author":"Li","year":"2020","journal-title":"Oncogene"},{"key":"B13","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1017\/s000711450769936x","article-title":"Amino Acids and Immune Function","volume":"98","author":"Li","year":"2007","journal-title":"Br. J. Nutr."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1016\/j.csbj.2021.01.033","article-title":"Integrated Metabolomics and Network Pharmacology to Reveal the Mechanisms of Hydroxysafflor Yellow A against Acute Traumatic Brain Injury","volume":"19","author":"Li","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"B15","doi-asserted-by":"publisher","first-page":"113684","DOI":"10.1016\/j.jep.2020.113684","article-title":"Ainsliaea Fragrans Champ. Extract Prevents Cervicitis in BALB\/c Mice and Regulates MyD88-NF-\u039ab Signaling Pathway in MALP-2-Stimulated RAW264.7 Cells","volume":"269","author":"Lin","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1016\/j.bcp.2003.10.036","article-title":"Regulation of Glutathione S-Transferase P1-1 Gene Expression by NF-kappaB in Tumor Necrosis Factor Alpha-Treated K562 Leukemia Cells","volume":"67","author":"Morceau","year":"2004","journal-title":"Biochem. Pharmacol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"8425","DOI":"10.3390\/ijms22168425","article-title":"MAO-A Inhibition by Metaxalone Reverts IL-1\u03b2-Induced Inflammatory Phenotype in Microglial Cells","volume":"22","author":"Pallio","year":"2021","journal-title":"Ijms"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1410","DOI":"10.3390\/ijms17091410","article-title":"Matrine Exerts a Strong Anti-arthritic Effect on Type II Collagen-Induced Arthritis in Rats by Inhibiting Inflammatory Responses","volume":"17","author":"Pu","year":"2016","journal-title":"Int. J. Mol. Sci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"237","DOI":"10.3389\/fphar.2016.00237","article-title":"Detoxifying Enzymes at the Cross-Roads of Inflammation, Oxidative Stress, and Drug Hypersensitivity: Role of Glutathione Transferase P1-1 and Aldose Reductase","volume":"7","author":"S\u00e1nchez-G\u00f3mez","year":"2016","journal-title":"Front. Pharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1016\/j.fertnstert.2007.04.018","article-title":"Intrauterine Nitric Oxide in Pelvic Inflammatory Disease","volume":"89","author":"Sioutas","year":"2008","journal-title":"Fertil. Steril."},{"key":"B21","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1097\/AOG.0b013e3181e92c54","article-title":"Pelvic Inflammatory Disease","volume":"116","author":"Soper","year":"2010","journal-title":"Obstet. Gynecol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"286","DOI":"10.7661\/j.cjim.20210130.006","article-title":"Guidelines for Clinical Application of Proprietary Chinese Medicine in the Treatment of Sequelae of Pelvic Inflammatory Diseases [J]","volume":"41","year":"20212021","journal-title":"Chin. J. Integr. Tradit. West. Med. (Chin)."},{"key":"B23","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/s0168-8278(02)00105-8","article-title":"Damaged Interlobular Bile Ducts in Primary Biliary Cirrhosis Show Reduced Expression of Glutathione-S-Transferase-Pi and Aberrant Expression of 4-hydroxynonenal","volume":"37","author":"Tsuneyama","year":"2002","journal-title":"J. Hepatol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"153756","DOI":"10.1016\/j.phymed.2021.153756","article-title":"Sophoridine: A Review of its Pharmacology, Pharmacokinetics and Toxicity","volume":"153756","author":"Wang","year":"2021","journal-title":"Phytomedicine"},{"key":"B25","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/aps.2015.24","article-title":"Anti-tumor Activities of Active Ingredients in Compound Kushen Injection","volume":"36","author":"Wang","year":"2015","journal-title":"Acta Pharmacol. Sin."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2747","DOI":"10.3969\/j.issn.1001-1528.2018.12.029","article-title":"Pharmacodynamic Study of Kangfuxiaoyan Suppository in Treatment of Chronic Pelvic Inflammation in Rats[J]","volume":"40","author":"Xie","year":"2018","journal-title":"Chin. Tradit. Pat. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1055\/s-0035-1546153","article-title":"Oxysophocarpine Ameliorates Carrageenan-Induced Inflammatory Pain via Inhibiting Expressions of Prostaglandin E2 and Cytokines in Mice","volume":"81","author":"Yang","year":"2015","journal-title":"Planta. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"533841","DOI":"10.3389\/fphar.2020.533841","article-title":"Formononetin Attenuates Airway Inflammation and Oxidative Stress in Murine Allergic Asthmaflammation and Oxidative Stress in Murine Allergic Asthma","volume":"11","author":"Yi","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"01067","DOI":"10.3389\/fphar.2020.01067","article-title":"A Systematic Review of the Pharmacology, Toxicology and Pharmacokinetics of Matrine","volume":"11","author":"You","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"123","DOI":"10.3389\/fphar.2019.00123","article-title":"Network Pharmacology Databases for Traditional Chinese Medicine: Review and Assessment","volume":"10","author":"Zhang","year":"2019","journal-title":"Front. Pharmacol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1186\/s13020-018-0217-6","article-title":"Metabonomic Study of the Protective Effect of Fukeqianjin Formula on Multi-Pathogen Induced Pelvic Inflammatory Disease in Rats","volume":"13","author":"Zhang","year":"2018","journal-title":"Chin. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1093\/humrep\/dez039","article-title":"Hypomethylation of the GSTM1 Promoter Is Associated with Ovarian Endometriosis","volume":"34","author":"Zhao","year":"2019","journal-title":"Hum. Reprod."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.812587\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,4]],"date-time":"2022-02-04T05:53:13Z","timestamp":1643953993000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.812587\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,4]]},"references-count":32,"alternative-id":["10.3389\/fphar.2022.812587"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.812587","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,4]]},"article-number":"812587"}}