{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:01:31Z","timestamp":1790654491755,"version":"4.1.0"},"reference-count":80,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,8,15]],"date-time":"2023-08-15T00:00:00Z","timestamp":1692057600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"GoodCap Pharmaceuticals"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Intestinal inflammation and dysbiosis can lead to inflammatory bowel diseases (IBD) and systemic inflammation, affecting multiple organs. Developing novel anti-inflammatory therapeutics is crucial for preventing IBD progression. Serotonin receptor type 2A (5-HT2A) ligands, including psilocybin (Psi), 4-Acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), and ketanserin (Ket), along with transient receptor potential (TRP) channel ligands like capsaicin (Cap), curcumin (Cur), and eugenol (Eug), show promise as anti-inflammatory agents. In this study, we investigated the cytotoxic and anti-inflammatory effects of Psi, 4-AcO-DMT, Ket, Cap, Cur, and Eug on human small intestinal epithelial cells (HSEIC). HSEIC were exposed to tumor necrosis factor (TNF)-\u03b1 and interferon (IFN)-\u03b3 for 24 h to induce an inflammatory response, followed by treatment with each compound at varying doses (0\u2013800 \u03bcM) for 24 to 96 h. The cytotoxicity was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and protein expression by Western blot (WB) analysis. As single treatments, Psi (40 \u03bcM), Cur (0.5 \u03bcM), and Eug (50 \u03bcM) significantly reduced COX-2 levels without cytotoxic effects. When combined, Psi (40 \u03bcM) and Cur (0.5 \u03bcM) exhibited synergy, resulting in a substantial decrease in COX-2 protein levels (\u221228\u00d7 fold change), although the reduction in IL-6 was less pronounced (\u22121.6\u00d7 fold change). Psi (20 \u03bcM) and Eug (25 \u03bcM) demonstrated the most favorable outcomes, with significant decreases in COX-2 (\u221219\u00d7 fold change) and IL-6 (\u221210\u00d7 fold change) protein levels. Moreover, the combination of Psi and Eug did not induce cytotoxic effects in vitro at any tested doses. This study is the first to explore the anti-inflammatory potential of psilocybin and 4-AcO-DMT in the intestines while highlighting the potential for synergy between the 5-HT2A and TRP channel ligands, specifically Psi and Eug, in alleviating the TNF-\u03b1\/IFN-\u03b3-induced inflammatory response in HSEIC. Further investigations should evaluate if the Psi and Eug combination has the therapeutic potential to treat IBD in vivo.<\/jats:p>","DOI":"10.3390\/cimb45080427","type":"journal-article","created":{"date-parts":[[2023,8,15]],"date-time":"2023-08-15T11:15:08Z","timestamp":1692098108000},"page":"6743-6774","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Anti-Inflammatory Effects of Serotonin Receptor and Transient Receptor Potential Channel Ligands in Human Small Intestinal Epithelial Cells"],"prefix":"10.3390","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8122-2788","authenticated-orcid":false,"given":"Gregory Ian","family":"Robinson","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7260-1938","authenticated-orcid":false,"given":"Bo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeva","family":"Zahoruiko","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4037-8086","authenticated-orcid":false,"given":"Marta","family":"Gerasymchuk","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darryl","family":"Hudson","sequence":"additional","affiliation":[{"name":"GoodCap Pharmaceuticals, Calgary, AB T2P 0R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Kovalchuk","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8137-6928","authenticated-orcid":false,"given":"Igor","family":"Kovalchuk","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,15]]},"reference":[{"key":"ref_1","first-page":"129","article-title":"A Review on Inflammatory Bowel Diseases: Recent Molecular Pathophysiology Advances","volume":"16","author":"Abdulla","year":"2022","journal-title":"Biologics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e065186","DOI":"10.1136\/bmjopen-2022-065186","article-title":"Global, regional and national burden of inflammatory bowel disease in 204 countries and territories from 1990 to 2019: A systematic analysis based on the Global Burden of Disease Study 2019","volume":"13","author":"Wang","year":"2023","journal-title":"BMJ Open"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1111\/jgh.14872","article-title":"The epidemiology of inflammatory bowel disease: East meets west","volume":"35","author":"Mak","year":"2020","journal-title":"J. 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