{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T08:58:46Z","timestamp":1790585926234,"version":"4.1.0"},"reference-count":29,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Rep Immunol"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Problem<\/jats:title>\n                    <jats:p>Tokishakuyakusan (TSS) is a traditional Japanese Kampo medicine widely used to support pregnancy; however, its molecular mechanisms remain poorly understood. This study aimed to elucidate the progesterone\u2010related immunomodulatory mechanisms underlying the pregnancy\u2010supportive effects of TSS using a mouse model of progesterone withdrawal induced by mifepristone.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Pregnant mice were fed either a control diet or a diet containing 1% TSS from mating until late gestation. On day 15 postcoitus, all mice received low\u2010dose mifepristone to induce functional progesterone withdrawal. Cytokine and chemokine profiles in serum, corpus uteri, and placenta were analyzed using multiplex assays, and uterine expression of progesterone\u2010responsive and inflammatory genes were evaluated by real\u2010time RT\u2010PCR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Mifepristone administration induced a systemic proinflammatory response, characterized by increased serum levels of G\u2010CSF, IL\u20106, KC, and MCP\u20101. TSS administration increased G\u2010CSF without affecting fetal number, fetal weight, or placental weight. In the corpus uteri, TSS significantly suppressed IL\u20106 protein expression, whereas placental cytokine profiles were largely unaffected. Furthermore, TSS significantly increased uterine mRNA expression of the progesterone\u2010responsive anti\u2010inflammatory molecules secretory leukocyte peptidase inhibitor (SLPI) and progranulin (PGRN).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings suggest that TSS mitigates inflammation associated with progesterone withdrawal by suppressing uterine IL\u20106 and increasing the expression of progesterone\u2010responsive anti\u2010inflammatory molecules such as SLPI and PGRN. These findings suggest that TSS may modulate progesterone\u2010responsive anti\u2010inflammatory pathways through increased expression of SLPI and PGRN while suppressing uterine IL\u20106.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/aji.70318","type":"journal-article","created":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T00:05:33Z","timestamp":1788566733000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunomodulatory Effects of Tokishakuyakusan on Progesterone Withdrawal\u2013Induced Uterine Inflammation in Pregnant Mice"],"prefix":"10.1111","volume":"96","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1480-5785","authenticated-orcid":false,"given":"Takeshi","family":"Nagamatsu","sequence":"first","affiliation":[{"name":"Department of Obstetrics, Gynecology International University of Health and Welfare  Narita Chiba Japan"},{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manami","family":"Yanagisawa","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5762-0065","authenticated-orcid":false,"given":"Yohei","family":"Tokita","sequence":"additional","affiliation":[{"name":"TSUMURA Kampo Research Laboratories, Kampo Research and Development Division TSUMURA &amp; CO.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7926-8625","authenticated-orcid":false,"given":"Keisuke","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6487-6361","authenticated-orcid":false,"given":"Tomohiro","family":"Otani","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5491-3871","authenticated-orcid":false,"given":"Ayumi","family":"Taguchi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2974-9109","authenticated-orcid":false,"given":"Mari","family":"Ichinose","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0865-604X","authenticated-orcid":false,"given":"Keiich","family":"Kumasawa","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Iriyama","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijgo.13477"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.70033"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/aji.13021"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2020.113288"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/aji.13182"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2023.123250"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2022.106177"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00217-8"},{"issue":"1","key":"e_1_2_9_10_1","first-page":"36","article-title":"Mifepristone: Current Knowledge and Emerging Prospects","volume":"112","author":"Kakade A. 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