{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T16:15:48Z","timestamp":1791648948973,"version":"4.3.4"},"reference-count":26,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K01723"],"award-info":[{"award-number":["24K01723"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Tokyo University of Science Research Grants"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Chronic inflammation contributes to the development of lifestyle-related diseases, and dietary phytochemicals are recognized as important modulators of inflammatory responses. However, the synergistic anti-inflammatory effects of phytochemical combinations and their underlying mechanisms remain insufficiently understood. Methods: The anti-inflammatory activities of menthol (ME), 1,8-cineole (CI), \u03b2-eudesmol (EU), and capsaicin (CA) were evaluated in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Pro-inflammatory gene expression was quantified by quantitative PCR, intracellular Ca2+ signaling was assessed by calcium imaging, and the involvement of transient receptor potential (TRP) channels was examined using selective inhibitors. Synergistic effects were analyzed based on changes in half-maximal effective concentrations (EC50). Results: All compounds suppressed LPS-induced pro-inflammatory genes, including tumor necrosis factor-alpha (Tnf) and interleukin-6 (Il6), in a dose-dependent manner, with CA showing the lowest EC50 for Tnf expression (0.087 \u00b5M). Notably, combinations of CA with ME or CI exhibited strong synergy, reducing their EC50 values by 699-fold and 154-fold, respectively, without cytotoxicity. These effects likely resulted from the synergic interaction between ME\/CI-induced TRP-mediated signaling and CA-activated, TRP-independent signaling. Conclusions: Specific combinations of plant-derived functional components can markedly enhance anti-inflammatory efficacy, supporting dietary strategies that harness multiple phytochemicals for inflammation control and disease prevention.<\/jats:p>","DOI":"10.3390\/nu18030376","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T17:52:38Z","timestamp":1769190758000},"page":"376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Functional Phytochemicals Cooperatively Suppress Inflammation in RAW264.7 Cells"],"prefix":"10.3390","volume":"18","author":[{"given":"Kaori","family":"Terashita","sequence":"first","affiliation":[{"name":"Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Kohakura","sequence":"additional","affiliation":[{"name":"Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsura","family":"Sugawara","sequence":"additional","affiliation":[{"name":"Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Miyagawa","sequence":"additional","affiliation":[{"name":"Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3371-0469","authenticated-orcid":false,"given":"Gen-ichiro","family":"Arimura","sequence":"additional","affiliation":[{"name":"Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/nature07201","article-title":"Origin and physiological roles of inflammation","volume":"454","author":"Medzhitov","year":"2008","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/nri2448","article-title":"Exploring the full spectrum of macrophage activation","volume":"8","author":"Mosser","year":"2008","journal-title":"Nat. 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