{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T14:57:47Z","timestamp":1762181867862,"version":"build-2065373602"},"reference-count":81,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"internal research fund of Kanazawa University"},{"name":"internal research fund of Hiroshima University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Juzentaihoto (JTT), a traditional Kampo formula composed of ten medicinal herbs, is widely prescribed in Japan for immune enhancement and general health maintenance. This exploratory, open-label pilot study aimed to evaluate the feasibility and immunomodulatory effects of JTT in cancer patients and to explore its potential mechanisms of action. Methods: Ten cancer patients received oral JTT (7.5 g\/day) for 14 days, while healthy volunteers served as a reference group. Peripheral natural killer (NK) cell phenotypes and CD95 expression were analyzed by flow cytometry, and serum Fas ligand (FasL) concentrations were measured by ELISA. Complementary in vitro assays using PBS-extracted, autoclaved JTT were conducted to assess Fas\/FasL-mediated apoptosis in Jurkat and primary T cells by flow cytometry and Western blotting for cleaved caspase-8 and -3. Additional experiments with staurosporine (intrinsic apoptosis) and TRAIL in OSC-19 carcinoma cells were performed to determine pathway specificity. Results: In patients, most NK-cell markers showed no statistically significant within-subject changes, although a trend-level increase in NKp46 and a significant reduction in NK-cell CD95 expression (paired p = 0.014) were observed. Between-group differences primarily reflected baseline disparities between cancer patients and healthy controls. In vitro, JTT (50\u2013100 \u00b5g\/mL) partially attenuated FasL-induced apoptosis and reduced cleaved caspase-3 without affecting cleaved caspase-8, suggesting selective downstream modulation of the extrinsic pathway. Conclusions: Within the limitations of a small, non-randomized cohort without placebo, these findings are hypothesis-generating and indicate that JTT selectively modulates Fas-mediated lymphocyte apoptosis without promoting tumor immune evasion. Further randomized trials and mechanistic studies incorporating co-culture or 3D tumor\u2013immune models are warranted to confirm these observations and identify active constituents.<\/jats:p>","DOI":"10.3390\/ph18111658","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:47:58Z","timestamp":1762177678000},"page":"1658","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunomodulatory Effects of Juzentaihoto on Fas-Mediated Apoptosis: Insights from Cancer Patients and In Vitro Models"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8386-137X","authenticated-orcid":false,"given":"Quang Trung","family":"Ngo","sequence":"first","affiliation":[{"name":"Kampo Clinical Center, Hiroshima University Hospital, 1 Chome-2-3 Kasumi, Minami Ward, Hiroshima 734-8551, Hiroshima, Japan"},{"name":"Faculty of Traditional Medicine, Hai Phong University of Medicine and Pharmacy, Hai Phong 180000, Vietnam"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1794-6666","authenticated-orcid":false,"given":"Jorge Luis","family":"Espinoza","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Kanazawa University, Kanazawa 920-0942, Ishikawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4778-7810","authenticated-orcid":false,"given":"Hongyang","family":"Li","sequence":"additional","affiliation":[{"name":"Kampo Clinical Center, Hiroshima University Hospital, 1 Chome-2-3 Kasumi, Minami Ward, Hiroshima 734-8551, Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8886-9517","authenticated-orcid":false,"given":"Masafumi","family":"Inokuchi","sequence":"additional","affiliation":[{"name":"Department of Breast Oncology, Kanazawa Medical University, Kahoku-gun, Kanazawa 920-0293, Ishikawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yosuke","family":"Nakanishi","sequence":"additional","affiliation":[{"name":"Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Ishikawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9116-3363","authenticated-orcid":false,"given":"Eriko","family":"Morishita","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Science, Graduate School of Medical Science, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-0942, Ishikawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9568-8682","authenticated-orcid":false,"given":"Takamasa","family":"Katagiri","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Science, Graduate School of Medical Science, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-0942, Ishikawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiro","family":"Kawahara","sequence":"additional","affiliation":[{"name":"Kampo Clinical Center, Hiroshima University Hospital, 1 Chome-2-3 Kasumi, Minami Ward, Hiroshima 734-8551, Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomokazu","family":"Yoshizaki","sequence":"additional","affiliation":[{"name":"Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Ishikawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1822-9976","authenticated-orcid":false,"given":"Akiyoshi","family":"Takami","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology, School of Medicine, Aichi Medical University, Nagakute 480-1195, Aichi, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3277-0646","authenticated-orcid":false,"given":"Keiko","family":"Ogawa-Ochiai","sequence":"additional","affiliation":[{"name":"Kampo Clinical Center, Hiroshima University Hospital, 1 Chome-2-3 Kasumi, Minami Ward, Hiroshima 734-8551, Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1080\/01926230701320337","article-title":"Apoptosis: A review of programmed cell death","volume":"35","author":"Elmore","year":"2007","journal-title":"J. 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