{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:31:29Z","timestamp":1790353889244,"version":"4.1.0"},"reference-count":33,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,15]],"date-time":"2021-10-15T00:00:00Z","timestamp":1634256000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 107-2320-B-038-035-MY2"],"award-info":[{"award-number":["MOST 107-2320-B-038-035-MY2"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 108-2320-B-038-031-MY3"],"award-info":[{"award-number":["MOST 108-2320-B-038-031-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004700","name":"Taipei Medical University","doi-asserted-by":"publisher","award":["DP2-107-21121-N-02"],"award-info":[{"award-number":["DP2-107-21121-N-02"]}],"id":[{"id":"10.13039\/501100004700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002811","name":"Cathay General Hospital","doi-asserted-by":"publisher","award":["CGH-MR-A11005"],"award-info":[{"award-number":["CGH-MR-A11005"]}],"id":[{"id":"10.13039\/501100002811","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Cathay General Hospital-Taipei Medical University","award":["108CGH-TMU-07"],"award-info":[{"award-number":["108CGH-TMU-07"]}]},{"name":"Taipei Medical University-Wan Fang Hospital","award":["107TMU-WFH-06"],"award-info":[{"award-number":["107TMU-WFH-06"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The role of activated platelets in acute and chronic cardiovascular diseases (CVDs) is well established. Therefore, antiplatelet drugs significantly reduce the risk of severe CVDs. Evodia rutaecarpa (Wu-Chu-Yu) is a well-known Chinese medicine, and rutaecarpine (Rut) is a main bioactive component with substantial beneficial properties including vasodilation. To address a research gap, we investigated the inhibitory mechanisms of Rut in washed human platelets and experimental mice. At low concentrations (1\u20135 \u03bcM), Rut strongly inhibited collagen-induced platelet aggregation, whereas it exerted only a slight or no effect on platelets stimulated with other agonists (e.g., thrombin). Rut markedly inhibited P-selectin expression; adenosine triphosphate release; [Ca2+]i mobilization; hydroxyl radical formation; and phospholipase C (PLC)\u03b32\/protein kinase C (PKC), mitogen-activated protein kinase, and phosphoinositide 3-kinase (PI3K)\/Akt\/glycogen synthase kinase-3\u03b2 (GSK3\u03b2) phosphorylation stimulated by collagen. SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor) did not reverse Rut-mediated antiplatelet aggregation. Rut was not directly responding to vasodilator-stimulated phosphoprotein phosphorylation. Rut significantly increased the occlusion time of fluorescence irradiated thrombotic platelet plug formation. The findings demonstrated that Rut exerts a strong effect against platelet activation through the PLC\u03b32\/PKC and PI3K\/Akt\/GSK3\u03b2 pathways. Thus, Rut can be a potential therapeutic agent for thromboembolic disorders.<\/jats:p>","DOI":"10.3390\/ijms222011109","type":"journal-article","created":{"date-parts":[[2021,10,15]],"date-time":"2021-10-15T13:35:47Z","timestamp":1634304947000},"page":"11109","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Rutaecarpine, an Alkaloid from Evodia rutaecarpa, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K\/Akt\/GSK3\u03b2 \u00a0Signal Axis through a Cyclic Nucleotides\/VASP\u2014Independent Mechanism"],"prefix":"10.3390","volume":"22","author":[{"given":"Chun-Jen","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Chieh","family":"Huang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Ting","family":"Lin","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan-Hsin","family":"Shu","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Chung Shan Medical University, Taichung 402, Taiwan"},{"name":"Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8265-3678","authenticated-orcid":false,"given":"Joen-Rong","family":"Sheu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7077-5627","authenticated-orcid":false,"given":"Oanh-Thi","family":"Tran","sequence":"additional","affiliation":[{"name":"International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4508-6181","authenticated-orcid":false,"given":"Chih-Wei","family":"Hsia","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanasekaran","family":"Jayakumar","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2056-4607","authenticated-orcid":false,"given":"Periyakali Saravana","family":"Bhavan","sequence":"additional","affiliation":[{"name":"Department of Zoology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Ying","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao-Chien","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Cardiovascular Center, Cathay General Hospital, Taipei 106, Taiwan"},{"name":"School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/j.1527-3466.1999.tb00017.x","article-title":"Pharmacological effects of rutaecarpine, an alkaloid isolated from Evodia eutaecarpa","volume":"17","author":"Sheu","year":"1999","journal-title":"Cardiovasc. 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