{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T11:18:11Z","timestamp":1784027891027,"version":"3.55.0"},"reference-count":43,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T00:00:00Z","timestamp":1652227200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004391","name":"China Medical University Hospital","doi-asserted-by":"publisher","award":["CMU108\u2010MF\u201033"],"award-info":[{"award-number":["CMU108\u2010MF\u201033"]}],"id":[{"id":"10.13039\/501100004391","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004391","name":"China Medical University Hospital","doi-asserted-by":"publisher","award":["DMR\u2010108\u2010079"],"award-info":[{"award-number":["DMR\u2010108\u2010079"]}],"id":[{"id":"10.13039\/501100004391","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011645","name":"Kaohsiung Medical University Chung-Ho Memorial Hospital","doi-asserted-by":"publisher","award":["KMUH105\u20105R46"],"award-info":[{"award-number":["KMUH105\u20105R46"]}],"id":[{"id":"10.13039\/501100011645","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004737","name":"National Health Research Institutes","doi-asserted-by":"publisher","award":["NHRI\u2010EX109\u201010705BI"],"award-info":[{"award-number":["NHRI\u2010EX109\u201010705BI"]}],"id":[{"id":"10.13039\/501100004737","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Gastric cancer (GCa) is a malignancy with few effective treatments. Ursolic acid (UA), a bioactive triterpenoid enriched in <jats:italic>Hedyotis diffusa<\/jats:italic> Willd, known to suppress GCa without identified target. CYP19A1 (cytochrome P450 family 19A1; also known as aromatase, Ar) was correlated to GCa prognosis. Relatedly, Ar silencers, which halt the expression of Ar exhibited anti\u2010GCa effects in experimental models, are currently being investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>The docking simulation score of UA was compared with Ar inhibitors, e.g., letrozole, exemestane, in Ar protein crystallization. <jats:italic>Hedyotis diffusa<\/jats:italic> Willd ethanol extract, UA, or 5\u2010fluracil were applied onto AGS, SC\u2010M1, MKN45 GCa cells for cancer inhibition tests. Immunoblot for measuring gene expressions upon drug treatments, or gene knockdown\/overexpression. Treatments were also applied in a MKN45 implantation tumor model. A web\u2010based GCa cohort for Ar expression association with prognosis was performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Result<\/jats:title><jats:p>The ethanol extracts of <jats:italic>Hedyotis diffusa<\/jats:italic> Willd, enrich with UA, exhibited cytotoxic activity against GCa cells. Molecular docking simulations with the 3D Ar structure revealed an excellent fitting score for UA. UA increase cytotoxic, and suppressed colony, in addition to its Ar silencing capacity. Moreover, UA synergistically facilitated 5\u2010FU, (a standard GCa treatment) regimen in vitro. Consistent with those results, adding estradiol did not reverse the cancer\u2010suppressing effects of UA, which confirmed UA acts as an Ar silencer. Furthermore, UA exhibited tumor\u2010suppressing index (TSI) score of 90% over a 6\u2010week treatment term when used for single dosing in xenograft tumor model. In the clinical setting, Ar expression was found to be higher in GCa tumors than normal parental tissue from the TCGA (The Cancer Genome Atlas) cohort, while high Ar expression associated with poor prognosis. Together, the results indicate UA could be used to treat GCa by silencing Ar expression in GCa. <jats:italic>Hedyotis diffusa<\/jats:italic> Willd ethanol extract could be an functional food supplements.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.4536","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T05:11:12Z","timestamp":1652332272000},"page":"2824-2835","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Ursolic acid silences CYP19A1\/aromatase to suppress gastric cancer growth"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5571-3302","authenticated-orcid":false,"given":"Wen\u2010Lung","family":"Ma","sequence":"first","affiliation":[{"name":"Graduate Institute of Biomedical Sciences Center for Tumor Biology Department of Pharmacology Chinese Medicine Research Center Drug Development Center, and Graduate Institute of Chinese Medicine Graduate Institute of Integrated Medicine School of Medicine China Medical University  Taichung Taiwan"},{"name":"Department of Medical Research Chinese Medicine Research and Development Center, and Department of Obstetrics &amp; Gynecology China Medical University Hospital  Taichung Taiwan"},{"name":"Department of Nursing Department of Biotechnology College of Medical and Health Science Asia University  Taichung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Medical Research Chinese Medicine Research and Development Center, and Department of Obstetrics &amp; Gynecology China Medical University Hospital  Taichung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingchun","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Medical Research Chinese Medicine Research and Development Center, and Department of Obstetrics &amp; Gynecology China Medical University Hospital  Taichung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Ting","family":"Su","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences Center for Tumor Biology Department of Pharmacology Chinese Medicine Research Center Drug Development Center, and Graduate Institute of Chinese Medicine Graduate Institute of Integrated Medicine School of Medicine China Medical University  Taichung Taiwan"},{"name":"Department of Medical Research Chinese Medicine Research and Development Center, and Department of Obstetrics &amp; Gynecology China Medical University Hospital  Taichung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2773-8748","authenticated-orcid":false,"given":"Guan\u2010Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Research Chinese Medicine Research and Development Center, and Department of Obstetrics &amp; Gynecology China Medical University Hospital  Taichung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010Chung","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Medical Research Chinese Medicine Research and Development Center, and Department of Obstetrics &amp; Gynecology China Medical University Hospital  Taichung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang\u2010Chang","family":"Wu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences Center for Tumor Biology Department of Pharmacology Chinese Medicine Research Center Drug Development Center, and Graduate Institute of Chinese Medicine Graduate Institute of Integrated Medicine School of Medicine China Medical University  Taichung Taiwan"},{"name":"Department of Medical Research Chinese Medicine Research and Development Center, and Department of Obstetrics &amp; Gynecology China Medical University Hospital  Taichung Taiwan"},{"name":"Department of Nursing Department of Biotechnology College of Medical and Health Science Asia University  Taichung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching\u2010Chia","family":"Li","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medicine College of Medicine Kaohsiung Medical University  Kaohsiung Taiwan"},{"name":"Department of Urology Kaohsiung Medical University Hospital  Kaohsiung Taiwan"},{"name":"Department of Urology School of Medicine College of Medicine Kaohsiung Medical University  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010Chun","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Medical Research Chinese Medicine Research and Development Center, and Department of Obstetrics &amp; Gynecology China Medical University Hospital  Taichung Taiwan"},{"name":"Department of Nursing Department of Biotechnology College of Medical and Health Science Asia University  Taichung Taiwan"},{"name":"Department of Obstetrics and Gynecology Asia University Hospital  Taichung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan\u2010Cheng","family":"Yang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences Center for Tumor Biology Department of Pharmacology Chinese Medicine Research Center Drug Development Center, and Graduate Institute of Chinese Medicine Graduate Institute of Integrated Medicine School of Medicine China Medical University  Taichung Taiwan"},{"name":"School of Chinese Medicine China Medical University  Taichung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,11]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/hel.12082"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21492"},{"issue":"2019","key":"e_1_2_10_4_1","first-page":"1941","article-title":"GLOBOCAN sources and methods","volume":"144","author":"Ferlay J","year":"2018","journal-title":"Int J Cancer"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.1274"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fsurg.2017.00042"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v20.i7.1635"},{"key":"e_1_2_10_8_1","first-page":"CD004064","article-title":"Chemotherapy for advanced gastric cancer","volume":"8","author":"Wagner AD","year":"2017","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2017.12.006"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.10248"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.1274"},{"key":"e_1_2_10_12_1","first-page":"41","article-title":"Combined modality treatment options for improving the outcome of locally advanced gastric cancer","volume":"2","author":"Roberto Persiani SR","year":"2007","journal-title":"Suppl Tumori"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.21037\/tgh.2016.06.08"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.12998\/wjcc.v3.i1.42"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)00150-9"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2018.09.016"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00418-018-1708-3"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0960-0760(93)90116-E"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12094-018-02019-1"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.13524"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.14605"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21256"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm300930n"},{"key":"e_1_2_10_24_1","first-page":"57","article-title":"Python: a programming language for software integration and development","volume":"17","author":"Sanner MF","year":"1999","journal-title":"J Mol Graph Model"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11040463"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-1947"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/0065-2571(84)90007-4"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-19-0095"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.12771"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/scrt247"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.15218"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.09.026"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S264070"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389450111007011317"},{"key":"e_1_2_10_35_1","first-page":"1683","article-title":"Development and validation of a modified ultrasound\u2010assisted extraction method and a HPLC method for the quantitative determination of two triterpenic acids in Hedyotis diffusa","volume":"8","author":"Yang YC","year":"2013","journal-title":"Nat Prod Commun"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1142\/S0192415X11008750"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2015.2762"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2007.11.021"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1177\/1933719118808912"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2010.11.001"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2009.11.009"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-11-0363"},{"key":"e_1_2_10_43_1","article-title":"The Hedyotis diffusa Willd. (Rubiaceae): a review on phytochemistry, pharmacology, quality control and pharmacokinetics","volume":"21","author":"Chen R","year":"2016","journal-title":"Molecules"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2017.02.004"}],"container-title":["Cancer Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.4536","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cam4.4536","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.4536","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T13:16:47Z","timestamp":1692796607000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cam4.4536"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,11]]},"references-count":43,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2022,7]]}},"alternative-id":["10.1002\/cam4.4536"],"URL":"https:\/\/doi.org\/10.1002\/cam4.4536","archive":["Portico"],"relation":{},"ISSN":["2045-7634","2045-7634"],"issn-type":[{"value":"2045-7634","type":"print"},{"value":"2045-7634","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,11]]},"assertion":[{"value":"2021-07-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-11-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}