{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T12:33:13Z","timestamp":1788093193100,"version":"build-2803163510"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009110","name":"Natural Science Foundation of Xinjiang Uygur Autonomous Region","doi-asserted-by":"publisher","award":["2022D01C190"],"award-info":[{"award-number":["2022D01C190"]}],"id":[{"id":"10.13039\/100009110","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Restoring intestinal barrier function is considered an effective strategy for the treatment of Inflammatory Bowel Disease (IBD). Rhynchophylline (Rhy), a bioactive alkaloid sourced from the traditional herbs Uncariarhynchophylla used in Chinese medicine, is known for its antihypertensive, anti-asthmatic, and antitumor properties. This study explores the pharmacological effects and molecular mechanisms of Rhy in treating IBD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In vitro cell inflammation injury model was established, and the inflammatory factors, cell permeability, cell proliferation, and intercellular tight junction protein expression were measured after Rhy intervention, which verified the anti-inflammatory activity and enhancement of intestinal barrier function of Rhy. In vivo animal model of acute and chronic colitis was established, and Rhy was administered orally at three dose levels to evaluate the protective effects of Rhy on acute and chronic colitis in animals. The signaling pathways that enhance the intestinal barrier function of Rhy were identified through transcriptomics, gene knockout techniques, and molecular dynamics simulations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In vitro results indicate that the levels of inflammatory markers\u2013including IL-6, TNF-\u03b1, and NO\u2013can be decreased by Rhy, demonstrating anti-inflammatory activity. It significantly lowers cellular permeability, promotes the proliferation of intestinal epithelial cells, and upregulates the expression of tight junction proteins Claudin4, Occludin, and ZO-1. These effects improve cellular morphology and improve the robustness of the intestinal barrier. In vivo, using three types of colitis animal models, Rhy shows significant protective effects on mice with acute and chronic colitis. It markedly reduces weight loss and Disease Activity Index (DAI) scores, prevents colonic shortening, reduces intestinal permeability, and decreases serum levels of IL-6, TNF-\u03b1, CXCL1, and IL-1\u03b2. These effects restore the structural integrity of colonic tissues and alleviate symptoms of acute and chronic colitis. Additionally, Rhy activates the AhR-NR4A1 pathway. This activation upregulates Claudin4, Occludin, and ZO-1 to repair the intestinal barrier and exert anti-colitic effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings highlight Rhy improve the function and inhibits inflammation, providing dual beneficial activities in the epithelial lining of the gut to prevent and treat colitis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1629012","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T04:13:27Z","timestamp":1757909607000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Mechanistic study on the restoration of intestinal barrier integrity and alleviation of inflammatory bowel disease by rhynchophylline via the AhR-NR4A1 pathway"],"prefix":"10.3389","volume":"16","author":[{"given":"Xuwen","family":"Mao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lufeng","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuche","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,15]]},"reference":[{"key":"B1","unstructured":"Feedback control of AHR signalling regulates intestinal immunity - PubMed\n          \n          28146477\n          \n          2024"},{"key":"B2","doi-asserted-by":"publisher","first-page":"R109","DOI":"10.1530\/JME-22-0076","article-title":"Aryl hydrocarbon receptor (AhR)-mediated signaling as a critical regulator of skeletal cell biology","volume":"69","author":"Alhamad","year":"2022","journal-title":"J. Mol. Endocrinol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"312","DOI":"10.3390\/clockssleep3020020","article-title":"Cellular effects of rhynchophylline and relevance to sleep regulation","volume":"3","author":"Ballester Roig","year":"2021","journal-title":"Clocks Sleep."},{"key":"B4","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.cell.2014.03.011","article-title":"Role of the microbiota in immunity and inflammation","volume":"157","author":"Belkaid","year":"2014","journal-title":"Cell"},{"key":"B5","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1093\/toxsci\/kfq360","article-title":"Aryl hydrocarbon receptor activation by TCDD reduces inflammation associated with Crohn\u2019s disease","volume":"120","author":"Benson","year":"2011","journal-title":"Toxicol. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1008976","DOI":"10.3389\/fphar.2022.1008976","article-title":"Improved diagnosis of inflammatory bowel disease and prediction and monitoring of response to anti-TNF alpha treatment based on measurement of signal transduction pathway activity","volume":"13","author":"Bouwman","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1007\/s10238-016-0434-1","article-title":"Disruption of the hedgehog signaling pathway in inflammatory bowel disease fosters chronic intestinal inflammation","volume":"17","author":"Buongusto","year":"2017","journal-title":"Clin. Exp. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1111\/j.1365-2982.2012.01921.x","article-title":"Intestinal barrier function in health and gastrointestinal disease","volume":"24","author":"Camilleri","year":"2012","journal-title":"Neurogastroenterol. Motil."},{"key":"B9","doi-asserted-by":"publisher","first-page":"438","DOI":"10.37201\/req\/056.2024","article-title":"Human intestinal microbiome: role in health and disease","volume":"37","author":"Cant\u00f3n","year":"2024","journal-title":"Rev. Esp. Quimioter."},{"key":"B10","doi-asserted-by":"publisher","first-page":"15.25.1","DOI":"10.1002\/0471142735.im1525s104","article-title":"Dextran sulfate sodium (DSS)-induced colitis in mice","volume":"104","author":"Chassaing","year":"2014","journal-title":"Curr. Protoc. Immunol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"761981","DOI":"10.3389\/fimmu.2021.761981","article-title":"Interaction between commensal Bacteria, immune response and the intestinal barrier in inflammatory bowel disease","volume":"12","author":"Chen","year":"2021","journal-title":"Front. Immunol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1436481","DOI":"10.3389\/fphar.2024.1436481","article-title":"The beneficial pharmacological effects of Uncaria rhynchophylla in neurodegenerative diseases: focus on alkaloids","volume":"15","author":"Chen","year":"2024","journal-title":"Front. Pharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"972984","DOI":"10.3389\/fonc.2022.972984","article-title":"Therapeutic potential of NR4A1 in cancer: focus on metabolism","volume":"12","author":"Deng","year":"2022","journal-title":"Front. Oncol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1007\/s11739-023-03374-w","article-title":"Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review","volume":"19","author":"Di Vincenzo","year":"2024","journal-title":"Intern Emerg. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1186\/s12906-021-03389-w","article-title":"Molecular mechanism of epicedium treatment for depression based on network pharmacology and molecular docking technology","volume":"21","author":"Dong","year":"2021","journal-title":"BMC Complement. Med. Ther."},{"key":"B16","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/j.reprotox.2020.08.008","article-title":"Aryl hydrocarbon receptor (AhR) agonist \u03b2-naphthoflavone regulated gene networks in human primary trophoblasts","volume":"96","author":"El-Dairi","year":"2020","journal-title":"Reprod. Toxicol."},{"key":"B17","unstructured":"Eriodictyol attenuates dextran sodium sulphate-induced colitis in mice by regulating the sonic hedgehog signalling pathway - PubMed\n          \n          34348563\n          \n          2024"},{"key":"B18","doi-asserted-by":"publisher","first-page":"13","DOI":"10.3389\/fcimb.2018.00013","article-title":"Impact of the gut Microbiota on intestinal immunity mediated by Tryptophan metabolism","volume":"8","author":"Gao","year":"2018","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1170","DOI":"10.3390\/pharmaceutics13081170","article-title":"Recent advances in the anti-inflammatory activity of plant-derived Alkaloid rhynchophylline in neurological and cardiovascular diseases","volume":"13","author":"Geetha","year":"2021","journal-title":"Pharmaceutics"},{"key":"B20","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1016\/j.ccell.2018.03.015","article-title":"The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy","volume":"33","author":"Gopalakrishnan","year":"2018","journal-title":"Cancer Cell"},{"key":"B21","doi-asserted-by":"publisher","first-page":"4041","DOI":"10.1016\/j.molcel.2021.09.016","article-title":"NR4A1 regulates expression of immediate early genes, suppressing replication stress in cancer","volume":"81","author":"Guo","year":"2021","journal-title":"Mol. Cell"},{"key":"B22","doi-asserted-by":"publisher","first-page":"116635","DOI":"10.1016\/j.jep.2023.116635","article-title":"Rhynchophylline inhibits methamphetamine dependence via modulating the miR-181a-5p\/GABRA1 axis","volume":"314","author":"Jiang","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.jcyt.2019.12.008","article-title":"Rhynchophylline promotes stem cell autonomous metabolic homeostasis","volume":"22","author":"Kaneko","year":"2020","journal-title":"Cytotherapy"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1053\/j.gastro.2019.07.058","article-title":"Inflammation-induced occludin downregulation limits epithelial apoptosis by suppressing Caspase-3 expression","volume":"157","author":"Kuo","year":"2019","journal-title":"Gastroenterology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1038\/ni.2187","article-title":"AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of notch","volume":"13","author":"Lee","year":"2011","journal-title":"Nat. Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e239","DOI":"10.1371\/journal.pmed.0050239","article-title":"Analysis of germline GLI1 variation implicates hedgehog signalling in the regulation of intestinal inflammatory pathways","volume":"5","author":"Lees","year":"2008","journal-title":"PLoS Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1038\/nri.2017.7","article-title":"Dysbiosis and the immune system","volume":"17","author":"Levy","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"903762","DOI":"10.3389\/fphar.2022.903762","article-title":"Relief effects of icariin on inflammation-induced decrease of tight junctions in intestinal epithelial cells","volume":"13","author":"Li","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/s41586-019-0979-8","article-title":"Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction","volume":"567","author":"Liu","year":"2019","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","first-page":"109948","DOI":"10.1016\/j.intimp.2023.109948","article-title":"Rhynchophylline relieves nonalcoholic fatty liver disease by activating lipase and increasing energy metabolism","volume":"117","author":"Liu","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/s41575-020-00399-w","article-title":"The intestinal barrier, an arbitrator turned provocateur in IBD","volume":"18","author":"Mehandru","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B32","unstructured":"METTL3 overexpression aggravates LPS-induced cellular inflammation in mouse intestinal epithelial cells and DSS-induced IBD in mice - PubMed\n          \n          35165276\n          \n          2024"},{"key":"B33","unstructured":"MiR-124a mediates the impairment of intestinal epithelial integrity by targeting Aryl hydrocarbon receptor in Crohn\u2019s disease - PubMed\n          \n          32607693\n          \n          2024"},{"key":"B34","unstructured":"Mulberry anthocyanins ameliorate DSS-Induced ulcerative colitis by improving intestinal barrier function and modulating Gut Microbiota - PubMed\n          \n          36139747\n          \n          2024"},{"key":"B35","doi-asserted-by":"publisher","first-page":"6293","DOI":"10.3390\/molecules28176293","article-title":"Natural products: a dependable source of therapeutic alternatives for inflammatory bowel disease through regulation of tight junctions","volume":"28","author":"Peng","year":"2023","journal-title":"Molecules"},{"key":"B36","doi-asserted-by":"publisher","first-page":"4331","DOI":"10.3390\/ijms20184331","article-title":"Molecular docking: shifting paradigms in drug discovery","volume":"20","author":"Pinzi","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"G280","DOI":"10.1152\/ajpgi.00338.2019","article-title":"Nr4A1 modulates inflammation-associated intestinal fibrosis and dampens fibrogenic signaling in myofibroblasts","volume":"321","author":"Pulakazhi Venu","year":"2021","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"4053","DOI":"10.3748\/wjg.v28.i30.4053","article-title":"Gut microbiota, inflammatory bowel disease and colorectal cancer","volume":"28","author":"Quaglio","year":"2022","journal-title":"World J. Gastroenterol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"2706","DOI":"10.3390\/ijms24032706","article-title":"Health benefits of coffee consumption for cancer and other diseases and mechanisms of action","volume":"24","author":"Safe","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B40","doi-asserted-by":"publisher","first-page":"e23522","DOI":"10.1371\/journal.pone.0023522","article-title":"Activation of aryl hydrocarbon receptor (AhR) leads to reciprocal epigenetic regulation of FoxP3 and IL-17 expression and amelioration of experimental colitis","volume":"6","author":"Singh","year":"2011","journal-title":"PLoS One"},{"key":"B41","doi-asserted-by":"publisher","first-page":"115371","DOI":"10.1016\/j.bcp.2022.115371","article-title":"Functions of the aryl hydrocarbon receptor (AHR) beyond the canonical AHR\/ARNT signaling pathway","volume":"208","author":"Sondermann","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/nature18846","article-title":"Diet-microbiota interactions as moderators of human metabolism","volume":"535","author":"Sonnenburg","year":"2016","journal-title":"Nature"},{"key":"B43","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1038\/s41575-021-00430-8","article-title":"AHR in the intestinal microenvironment: safeguarding barrier function","volume":"18","author":"Stockinger","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"107277","DOI":"10.1016\/j.anireprosci.2023.107277","article-title":"Knock-down of aryl hydrocarbon receptor (AhR) affects the lncRNA-mediated response of porcine granulosa cells (AVG-16 cell line) to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)","volume":"255","author":"Swigonska","year":"2023","journal-title":"Anim. Reprod. Sci."},{"key":"B45","unstructured":"The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease - PubMed\n          \n          30718831\n          \n          2024"},{"key":"B46","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1177\/1756283X16644242","article-title":"The intestinal microbiome, barrier function, and immune system in inflammatory bowel disease: a tripartite pathophysiological circuit with implications for new therapeutic directions","volume":"9","author":"Vindigni","year":"2016","journal-title":"Ther. Adv. Gastroenterol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1248\/bpb.33.669","article-title":"Metabolism and pharmacokinetics of rhynchophylline in rats","volume":"33","author":"Wang","year":"2010","journal-title":"Biol. Pharm. Bull."},{"key":"B48","doi-asserted-by":"publisher","first-page":"175390","DOI":"10.1016\/j.ejphar.2022.175390","article-title":"Rhynchophylline ameliorates cerebral ischemia by improving the synaptic plasticity in a middle cerebral artery occlusion induced stroke model","volume":"940","author":"Wang","year":"2023","journal-title":"Eur. J. Pharmacol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1016\/j.jsps.2022.06.008","article-title":"Celastrol and Rhynchophylline in the mitigation of simulated muscle atrophy under in vitro","volume":"30","author":"Wastag","year":"2022","journal-title":"Saudi Pharm. J."},{"key":"B50","doi-asserted-by":"publisher","first-page":"153743","DOI":"10.1016\/j.phymed.2021.153743","article-title":"Shaoyao decoction attenuates DSS-induced ulcerative colitis, macrophage and NLRP3 inflammasome activation through the MKP1\/NF-\u03baB pathway","volume":"92","author":"Wei","year":"2021","journal-title":"Phytomedicine"},{"key":"B51","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1002\/path.4670","article-title":"NUR77 exerts a protective effect against inflammatory bowel disease by negatively regulating the TRAF6\/TLR-IL-1R signalling axis","volume":"238","author":"Wu","year":"2016","journal-title":"J. Pathol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"346","DOI":"10.2174\/1570161117666190704092841","article-title":"Uncaria rhynchophylla and its Major constituents on central nervous System: a review on their pharmacological actions","volume":"18","author":"Yang","year":"2020","journal-title":"Curr. Vasc. Pharmacol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.jep.2010.08.041","article-title":"Antihypertensive and neuroprotective activities of rhynchophylline: the role of rhynchophylline in neurotransmission and ion channel activity","volume":"132","author":"Zhou","year":"2010","journal-title":"J. Ethnopharmacol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1629012\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T04:13:30Z","timestamp":1757909610000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1629012\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,15]]},"references-count":53,"alternative-id":["10.3389\/fphar.2025.1629012"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1629012","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,15]]},"article-number":"1629012"}}