{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:10:53Z","timestamp":1760159453576,"version":"build-2065373602"},"reference-count":37,"publisher":"IMR Press","issue":"9","license":[{"start":{"date-parts":[[2025,9,28]],"date-time":"2025-09-28T00:00:00Z","timestamp":1759017600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JT","award":["A1600134"],"award-info":[{"award-number":["A1600134"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Steroid hormones are widely used as anti-allergic drugs because of their potent anti-inflammatory properties and ability to suppress histamine release by 60\u201380%. Ursodeoxycholic acid (UDCA; 3\u03b1,7\u03b2-dihydroxy-5\u03b2-cholan-24-oic acid), used to treat liver disease, exerts immunosuppressive effects by binding to glucocorticoid receptors and inhibiting histamine release from mast cells. In contrast, other bile acids, such as chenodeoxycholic acid (CDCA; 3\u03b1,7\u03b1-dihydroxy-5\u03b2-cholan-24-oic acid) and deoxycholic acid (DCA; 3\u03b1,12\u03b1-dihydroxy-5\u03b2-cholan-24-oic acid), have been reported to promote histamine release. The mechanisms underlying these divergent effects remain unclear, raising questions regarding structural differences, receptor interactions, and downstream signaling. To address this knowledge gap, we examined the effects of several bile acids and C24 bile alcohols on the degranulation of rat basophilic leukemia (RBL-2H3) cells, a model for mast cell activation. Methods: The effects of bile acids and alcohols on degranulation were tested in stimulated RBL-2H3 cells; furthermore, whether they affected store-operated calcium (SOC) channel-mediated Ca2+ entry\u2014a critical step in mast cell degranulation\u2014was investigated. To identify molecular targets, biotinylated bile acids were immobilized on magnetic beads and incubated with lipid raft fractions from RBL-2H3 cells to capture the interacting proteins. Results: All tested bile acids and alcohols significantly suppressed RBL-2H3 cell degranulation, thereby correlating with reduced extracellular Ca2+ influx via SOC channels. Further analysis revealed interference by Orai1, a key subunit of calcium release-activated calcium (CRAC) channels. This interaction appears to be mediated by the steroidal structures of the bile acids and alcohols. Conclusions: These findings demonstrate that bile acids and alcohols inhibit SOC-mediated Ca2+ entry by directly interacting with Orai1, thereby blocking mast cell degranulation. Although the concentrations required for this effect were near cytotoxic levels owing to detergent-like properties, the results uncovered a novel molecular interaction between steroid structures and Orai1. This mechanistic insight provides a foundation for the development of targeted small molecule modulators of Orai1-mediated calcium entry, offering potential therapeutic strategies for allergic and inflammatory disorders.<\/jats:p>","DOI":"10.31083\/fbl44504","type":"journal-article","created":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T04:43:39Z","timestamp":1760157819000},"source":"Crossref","is-referenced-by-count":0,"title":["Unconjugated Bile Acids and Alcohols Inhibit Degranulation of Stimulated RBL-2H3 Cells"],"prefix":"10.31083","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1887-4078","authenticated-orcid":true,"given":"Michiko","family":"Yoshii","sequence":"first","affiliation":[{"name":"Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, 734-8553 Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ai","family":"Tarao","sequence":"first","affiliation":[{"name":"Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, 734-8553 Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuko","family":"Ichinose","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences, Hiroshima University, 734-8553 Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomi","family":"Iwasa","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences, Hiroshima University, 734-8553 Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumi","family":"Tanaka","sequence":"first","affiliation":[{"name":"Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, 734-8553 Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8230-315X","authenticated-orcid":true,"given":"Yuhki","family":"Yanase","sequence":"first","affiliation":[{"name":"Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, 734-8553 Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6699-7657","authenticated-orcid":true,"given":"Koichiro","family":"Ozawa","sequence":"first","affiliation":[{"name":"Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, 734-8553 Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"16242","published-online":{"date-parts":[[2025,9,28]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Oh-hora M, Rao A. 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