{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T05:26:26Z","timestamp":1777353986378,"version":"3.51.4"},"reference-count":76,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T00:00:00Z","timestamp":1743811200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kracie Pharma Ltd."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Cancer cachexia, often observed in patients with advanced-stage cancer, is characterized by the loss of body weight and appetite. The Japanese herbal medicine Ninjinyoeito (NYT), which is composed of 12 crude herbal components, has been used as a therapeutic in Japan to improve anorexia and fatigue, which are commonly observed in cancer patients with cachexia. We have previously reported that Citrus unshiu peel (CUP) contained in NYT can enhance food intake by activating the orexin 1 receptor (OX1R). Using the CellKey\u2122 system, which offers detection of OXR activity in intracellular impedance changes, NYT and CUP were found to activate OX1R, which in turn was inhibited by SB-674042, a selective OX1R antagonist. Among the flavonoids contained in CUP, nobiletin and hesperidin, but not naringin, activated OX1R. Furthermore, some monoterpenes contained in CUP, including limonene and linalool, but not terpineol, activated OX1R. In addition, nobiletin and limonene synergistically activated OX1R when added simultaneously. However, neither NYT nor CUP induced OX2R activity. The results collectively suggested that the CUP contained in NYT activates OX1R, but not OX2R, and that flavonoids and monoterpenes in CUP can synergistically activate OX1R. These findings could provide evidence supporting the therapeutic potential of NYT in cancer patients with cachexia.<\/jats:p>","DOI":"10.3390\/biom15040533","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T05:59:00Z","timestamp":1744091940000},"page":"533","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Flavonoids and Monoterpenes from Citrus unshiu Peel Contained in Ninjinyoeito Synergistically Activate Orexin 1 Receptor: A Possible Mechanism of the Orexigenic Effects of Ninjinyoeito"],"prefix":"10.3390","volume":"15","author":[{"given":"Kaori","family":"Ohshima","sequence":"first","affiliation":[{"name":"Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan"},{"name":"Department of Pathology, Immunology, and Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kanako","family":"Miyano","sequence":"additional","affiliation":[{"name":"Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan"},{"name":"Laboratory of Pharmacotherapeutics, Faculty of Pharmacy, Juntendo University, Chiba 279-0013, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6481-0294","authenticated-orcid":false,"given":"Miki","family":"Nonaka","sequence":"additional","affiliation":[{"name":"Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan"},{"name":"Center for Neuroscience of Pain, The Jikei University School of Medicine, Tokyo 105-8461, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sayaka","family":"Aiso","sequence":"additional","affiliation":[{"name":"Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan"},{"name":"Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mao","family":"Fukuda","sequence":"additional","affiliation":[{"name":"Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan"},{"name":"Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saho","family":"Furuya","sequence":"additional","affiliation":[{"name":"Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan"},{"name":"Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0049-0084","authenticated-orcid":false,"given":"Hideaki","family":"Fujii","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1208-1453","authenticated-orcid":false,"given":"Yasuhito","family":"Uezono","sequence":"additional","affiliation":[{"name":"Department of Pain Control Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan"},{"name":"Center for Neuroscience of Pain, The Jikei University School of Medicine, Tokyo 105-8461, Japan"},{"name":"Pharmacological Department of Herbal Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan"},{"name":"Department of Comprehensive Oncology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/ncponc0112","article-title":"Therapy insight: Cancer anorexia-cachexia syndrome\u2014When all you can eat is yourself","volume":"2","author":"Laviano","year":"2005","journal-title":"Nat. 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