{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T13:18:29Z","timestamp":1783430309772,"version":"3.54.6"},"reference-count":36,"publisher":"IMR Press","issue":"6","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council","award":["NSTC 112-2320-B-038-037-MY3"],"award-info":[{"award-number":["NSTC 112-2320-B-038-037-MY3"]}]},{"name":"National Science and Technology Council","award":["NSTC 114-2320-B-038-033-MY3"],"award-info":[{"award-number":["NSTC 114-2320-B-038-033-MY3"]}]},{"DOI":"10.13039\/501100004700","name":"Taipei Medical University","doi-asserted-by":"crossref","award":["DP2-TMU-113-T-04"],"award-info":[{"award-number":["DP2-TMU-113-T-04"]}],"id":[{"id":"10.13039\/501100004700","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Taipei Medical University-Taipei Medical University Hospital","award":["112TMU-TMUH-08"],"award-info":[{"award-number":["112TMU-TMUH-08"]}]},{"DOI":"10.13039\/501100002811","name":"Cathay General Hospital","doi-asserted-by":"crossref","award":["CGH-MR-A11203"],"award-info":[{"award-number":["CGH-MR-A11203"]}],"id":[{"id":"10.13039\/501100002811","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002811","name":"Cathay General Hospital","doi-asserted-by":"crossref","award":["CGH-MR-A11304"],"award-info":[{"award-number":["CGH-MR-A11304"]}],"id":[{"id":"10.13039\/501100002811","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmazie"],"abstract":"<jats:p>Background:Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide and are strongly associated with atherothrombotic events. Thrombus formation results from the interplay between platelet activation and the coagulation cascade. While anticoagulant systems are essential for maintaining hemostasis, these systems can also increase the risk of bleeding complications. Coumarins led to the development of clinically important oral anticoagulants such as warfarin, which inhibits vitamin K epoxide reductase complex subunit 1 (VKORC1), a key enzyme in vitamin K recycling and normal blood clotting. Ferulenol, a prenylated coumarin derived from Ferula communis, has been reported to inhibit VKORC1, indicating a similar anticoagulant mechanism. Indeed, the close interplay between coagulation and platelet activation suggests that ferulenol may also modulate platelet function. However,the role of ferulenol in platelet activation has not yet been fully clarified.Methods:In this study, washed platelets obtained from healthy human donors were used to examine whether ferulenol suppresses platelet activation. To further clarify the underlying mechanisms, this study performed immunoblotting and confocal microscopy. In addition, this study evaluated the in vivo antithrombotic and hemostatic effects of ferulenol using a vascular thrombosis model and a tail bleeding time assay in mice.Results:Collagen (2 \u03bcg\/mL)-induced platelet aggregation was reduced by ferulenol in a concentration-dependent manner from 10 to 40 \u03bcM, with near-complete inhibition at 40 \u03bcM. Ferulenol produced only moderate inhibition of arachidonic acid (AA, 60 \u03bcM)-induced aggregation at 80 \u03bcM and did not significantly affect by thrombin (0.02 U\/mL)-induced platelet responses. Moreover, ferulenol markedly reduced collagen-induced platelet activation markers, including P-selectin expression, intracellular Ca2+ mobilization, and adenosine triphosphate (ATP) release. These inhibitory effects were accompanied by reduced phosphorylation of phospholipase C\u03b32 (PLC\u03b32), cytosolic phospholipase A2 (cPLA2), and mitogen-activated protein kinase (MAPK) family members, including extracellular signal-regulated kinase, p38 MAPK, and c-Jun N-terminal kinase. Ferulenol also suppressed activation of the phosphoinositide 3-kinase (PI3K)\/Akt\/glycogen synthase kinase-3\u03b2 (GSK3\u03b2) signaling pathway. In mice, ferulenol extended the time to thrombotic platelet plug formation, without significantly increasing bleeding time.Conclusions:This study, provides the first evidence that ferulenol inhibits platelet activation. Mechanistically, ferulenol may inhibit collagen-induced platelet activation, at least in part, by suppressing PLC\u03b32 activation, thereby reducing phosphorylation of cPLA2, MAPKs, and PI3K\/Akt\/GSK3\u03b2 signaling proteins. These inhibitory effects were reflected by reduced P-selectin exposure on the platelet surface, suggesting suppression of \u03b1-granule release. In addition, ferulenol reduced dense-granule ATP release and limited the rise in intracellular Ca2+ levels, thereby contributing to the inhibition of platelet aggregation. Therefore, ferulenol may be a promising candidate for preventing thromboembolic events associated with CVDs.<\/jats:p>","DOI":"10.31083\/pharmazie52496","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T12:56:33Z","timestamp":1783428993000},"source":"Crossref","is-referenced-by-count":0,"title":["Ferulenol, a Prenylated Coumarin, Suppresses Collagen-Induced Platelet Activation via PLC\u03b32-Mediated cPLA2 Signaling in Humans"],"prefix":"10.31083","volume":"81","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1748-2993","authenticated-orcid":true,"given":"Wei-Chieh","family":"Huang","sequence":"first","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 110 Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, 111 Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0408-2993","authenticated-orcid":true,"given":"Chia-Yau","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, 110 Taipei, Taiwan"},{"name":"Division of Pediatric Hematology\/Oncology, Department of Pediatrics, Taipei Medical University Hospital, 110 Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yui-Xi","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 110 Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Yuan","family":"Hsu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 110 Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4508-6181","authenticated-orcid":true,"given":"Chih-Wei","family":"Hsia","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Taipei Medical University Hospital, 110 Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4516-5955","authenticated-orcid":true,"given":"Thanasekaran","family":"Jayakumar","sequence":"additional","affiliation":[{"name":"Department of Ecology and Environmental Sciences, Pondicherry University, 605014 Puducherry, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1045-6648","authenticated-orcid":true,"given":"Chao-Chien","family":"Chang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 110 Taipei, Taiwan"},{"name":"Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, 110 Taipei, Taiwan"},{"name":"Department of Cardiovascular Center, Cathay General Hospital, 106 Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8265-3678","authenticated-orcid":true,"given":"Joen-Rong","family":"Sheu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 110 Taipei, Taiwan"},{"name":"Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, 110 Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Bj\u00f6rkegren JLM, Lusis AJ. 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