{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T07:02:42Z","timestamp":1782802962235,"version":"3.54.5"},"reference-count":36,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,21]],"date-time":"2024-09-21T00:00:00Z","timestamp":1726876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shandong Provincial Key Research and Development Program Major Technological Innovation Project","award":["2021CXGC010508"],"award-info":[{"award-number":["2021CXGC010508"]}]},{"name":"Shandong Provincial Key Research and Development Program Major Technological Innovation Project","award":["82022072"],"award-info":[{"award-number":["82022072"]}]},{"name":"Shandong Provincial Key Research and Development Program Major Technological Innovation Project","award":["81872991"],"award-info":[{"award-number":["81872991"]}]},{"name":"Shandong Provincial Key Research and Development Program Major Technological Innovation Project","award":["202228038"],"award-info":[{"award-number":["202228038"]}]},{"name":"Shandong Provincial Key Research and Development Program Major Technological Innovation Project","award":["2023JDRC0041"],"award-info":[{"award-number":["2023JDRC0041"]}]},{"name":"Shandong Provincial Key Research and Development Program Major Technological Innovation Project","award":["ZYYCXTD-D-202209"],"award-info":[{"award-number":["ZYYCXTD-D-202209"]}]},{"name":"National Natural Science Foundation of China","award":["2021CXGC010508"],"award-info":[{"award-number":["2021CXGC010508"]}]},{"name":"National Natural Science Foundation of China","award":["82022072"],"award-info":[{"award-number":["82022072"]}]},{"name":"National Natural Science Foundation of China","award":["81872991"],"award-info":[{"award-number":["81872991"]}]},{"name":"National Natural Science Foundation of China","award":["202228038"],"award-info":[{"award-number":["202228038"]}]},{"name":"National Natural Science Foundation of China","award":["2023JDRC0041"],"award-info":[{"award-number":["2023JDRC0041"]}]},{"name":"National Natural Science Foundation of China","award":["ZYYCXTD-D-202209"],"award-info":[{"award-number":["ZYYCXTD-D-202209"]}]},{"name":"Innovation Team Program of Jinan City","award":["2021CXGC010508"],"award-info":[{"award-number":["2021CXGC010508"]}]},{"name":"Innovation Team Program of Jinan City","award":["82022072"],"award-info":[{"award-number":["82022072"]}]},{"name":"Innovation Team Program of Jinan City","award":["81872991"],"award-info":[{"award-number":["81872991"]}]},{"name":"Innovation Team Program of Jinan City","award":["202228038"],"award-info":[{"award-number":["202228038"]}]},{"name":"Innovation Team Program of Jinan City","award":["2023JDRC0041"],"award-info":[{"award-number":["2023JDRC0041"]}]},{"name":"Innovation Team Program of Jinan City","award":["ZYYCXTD-D-202209"],"award-info":[{"award-number":["ZYYCXTD-D-202209"]}]},{"name":"Science and Technology Innovation Talent Program of Sichuan Province","award":["2021CXGC010508"],"award-info":[{"award-number":["2021CXGC010508"]}]},{"name":"Science and Technology Innovation Talent Program of Sichuan Province","award":["82022072"],"award-info":[{"award-number":["82022072"]}]},{"name":"Science and Technology Innovation Talent Program of Sichuan Province","award":["81872991"],"award-info":[{"award-number":["81872991"]}]},{"name":"Science and Technology Innovation Talent Program of Sichuan Province","award":["202228038"],"award-info":[{"award-number":["202228038"]}]},{"name":"Science and Technology Innovation Talent Program of Sichuan Province","award":["2023JDRC0041"],"award-info":[{"award-number":["2023JDRC0041"]}]},{"name":"Science and Technology Innovation Talent Program of Sichuan Province","award":["ZYYCXTD-D-202209"],"award-info":[{"award-number":["ZYYCXTD-D-202209"]}]},{"name":"Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine","award":["2021CXGC010508"],"award-info":[{"award-number":["2021CXGC010508"]}]},{"name":"Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine","award":["82022072"],"award-info":[{"award-number":["82022072"]}]},{"name":"Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine","award":["81872991"],"award-info":[{"award-number":["81872991"]}]},{"name":"Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine","award":["202228038"],"award-info":[{"award-number":["202228038"]}]},{"name":"Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine","award":["2023JDRC0041"],"award-info":[{"award-number":["2023JDRC0041"]}]},{"name":"Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine","award":["ZYYCXTD-D-202209"],"award-info":[{"award-number":["ZYYCXTD-D-202209"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Leonurus japonicus Houtt is an exceptional medicinal herb used to treat obstetrical and gynecological diseases in traditional Chinese medicine, and it has significant effects on the treatment of dysmenorrhea and postpartum hemorrhage. This study investigated the effects of coumarins with diverse substituent groups from L.\u00a0japonicus on isolated uterine smooth muscle and the preliminary mechanism of the most effective compound. Eight coumarins isolated from L.\u00a0japonicus were assessed for their effects on the isolated uterine smooth muscle of nonpregnant rats in vitro. Coumarins 1 and 2 significantly promoted the contraction of rat uterine smooth muscle strips, whereas coumarins 3\u20135 showed remarkable relaxing effects against oxytocin (OT)-induced rat uterine smooth muscle contraction. Further mechanism investigations revealed that bergapten (coumarin 1) significantly increased the level of Ca2+ in uterine tissues by promoting extracellular Ca2+ influx and intracellular Ca2+ release, which were related to the activation of L-type Ca2+ channels and \u03b1-receptors. By contrast, osthole (coumarin 5), an \u03b1 receptor antagonist, inhibited OT-induced uterine smooth muscle contraction by decreasing the level of Ca2+ in uterine tissues via inhibition of extracellular Ca2+ influx and intracellular Ca2+ release. This study demonstrates that the coumarins from L. japonicus are effective substances for regulating uterine smooth muscle contraction, but different coumarins with diverse substituent groups have different, even opposite effects. It can be inferred that coumarins are closely related to the efficacy of L.\u00a0japonicus in the treatment of dysmenorrhea and postpartum hemorrhage.<\/jats:p>","DOI":"10.3390\/ijms251810162","type":"journal-article","created":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T03:36:38Z","timestamp":1727062598000},"page":"10162","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Coumarins with Different Substituents from Leonurus japonicus Have Opposite Effects on Uterine Smooth Muscle"],"prefix":"10.3390","volume":"25","author":[{"given":"Yunqiu","family":"Fan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenhao","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqin","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinmei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Institute of Traditional Chinese Medicine Innovation, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6222-8340","authenticated-orcid":false,"given":"Liang","family":"Xiong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Miao, L.-L., Zhou, Q.-M., Peng, C., Liu, Z.-H., and Xiong, L. (2019). Leonurus japonicus (Chinese motherwort), an excellent traditional medicine for obstetrical and gynecological diseases: A comprehensive overview. Biomed. Pharmacother., 117.","DOI":"10.1016\/j.biopha.2019.109060"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.jep.2013.12.052","article-title":"Leonurus japonicus Houtt.: Ethnopharmacology, phytochemistry and pharmacology of an important traditional Chinese medicine","volume":"152","author":"Shang","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5738193","DOI":"10.1155\/2016\/5738193","article-title":"The Effect of Leonurus sibiricus Plant Extracts on Stimulating Repair and Protective Activity against Oxidative DNA Damage in CHO Cells and Content of Phenolic Compounds","volume":"2016","author":"Sitarek","year":"2015","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.phytochem.2017.12.016","article-title":"Phytochemistry and pharmacology of the genus Leonurus: The herb to benefit the mothers and more","volume":"147","author":"Zhang","year":"2018","journal-title":"Phytochemistry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"115129","DOI":"10.1016\/j.jep.2022.115129","article-title":"Leonurus japonicus Houttuyn induces reactive oxygen species-mediated apoptosis via regulation of miR-19a-3p\/PTEN\/PI3K\/AKT in U937 and THP-1 cells","volume":"291","author":"Park","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.phytochem.2017.11.003","article-title":"Alkaloids and flavonoid glycosides from the aerial parts of Leonurus japonicus and their opposite effects on uterine smooth muscle","volume":"145","author":"Liu","year":"2018","journal-title":"Phytochemistry"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Bu, L., Dai, O., Zhou, F., Liu, F., Chen, J.-F., Peng, C., and Xiong, L. (2020). Traditional Chinese medicine formulas, extracts, and compounds promote angiogenesis. Biomed. Pharmacother., 132.","DOI":"10.1016\/j.biopha.2020.110855"},{"key":"ref_8","first-page":"4356","article-title":"Coumarins from Leonurus japonicus and their anti-platelet aggregative activity","volume":"39","author":"Yang","year":"2014","journal-title":"Chin. J. Chin. Mater. Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Li, Y., Xiang, L., Wang, C., Song, Y., Miao, J., and Miao, M. (2020). Protection against acute cerebral ischemia\/reperfusion injury by Leonuri Herba Total Alkali via modulation of BDNF-TrKB-PI3K\/Akt signaling pathway in rats. Biomed. Pharmacother., 133.","DOI":"10.1016\/j.biopha.2020.111021"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Bu, L., Zhou, Q.-M., Peng, C., Shu, H.-Z., Zhou, F., Wu, G.-X., Liu, F., Tian, H., and Xiong, L. (2024). New sesquineolignan glycoside isomers from the aerial parts of Leonurus japonicus and their absolute configurations. Arab. J. Chem., 17.","DOI":"10.1016\/j.arabjc.2024.105932"},{"key":"ref_11","first-page":"551","article-title":"New di-spirocyclic labdane diterpenoids from the aerial parts of Leonurus japonicus","volume":"21","author":"Cao","year":"2023","journal-title":"Chin. J. Nat. Med."},{"key":"ref_12","first-page":"24","article-title":"Effects of different extracts from Leonurus japonicus Houtt. on isolated smooth muscle of uterus","volume":"5","author":"Li","year":"2014","journal-title":"Pharm. Chin. Clin. Mater. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Fierascu, R.C., Fierascu, I., Ortan, A., Fierascu, I.C., Anuta, V., Velescu, B.S., Pituru, S.M., Dinu-Pirvu, C.E., Fierascu, R.C., and Fierascu, I. (2019). Leonurus cardiaca L. as a Source of Bioactive Compounds: An Update of the European Medicines Agency Assessment Report (2010). BioMed Res. Int., 2019.","DOI":"10.1155\/2019\/4303215"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1111\/1440-1681.12608","article-title":"Daphnetin inhibits TNF-\u03b1 and VEGF-induced angiogenesis through inhibition of the IKKs\/I\u03baB\u03b1\/NF-\u03baB, Src\/FAK\/ERK1\/2 and Akt signalling pathways","volume":"43","author":"Kumar","year":"2016","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Sharifi-Rad, J., Cruz-Martins, N., L\u00f3pez-Jornet, P., Lopez, E.P.-F., Harun, N., Yeskaliyeva, B., Beyatli, A., Sytar, O., Shaheen, S., and Sharopov, F. (2021). Natural Coumarins: Exploring the Pharmacological Complexity and Underlying Molecular Mechanisms. Oxidative Med. Cell. Longev., 2021.","DOI":"10.1155\/2021\/6492346"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.ejphar.2007.06.043","article-title":"Imperatorin induces vasodilatation possibly via inhibiting voltage dependent calcium channel and receptor-mediated Ca2+ influx and release","volume":"573","author":"He","year":"2007","journal-title":"Eur. J. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"993","DOI":"10.2174\/1573406411309070013","article-title":"Structural Modeling and Identification of Imperatorin as Novel L-type Calcium Channel Blocker","volume":"9","author":"Lu","year":"2013","journal-title":"Med. Chem."},{"key":"ref_18","first-page":"48","article-title":"Isolation and evaluation of the myorelaxant effect of bergapten on isolated rat jejunum","volume":"54","author":"Mendel","year":"2015","journal-title":"Pharm. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kirsch, G., Abdelwahab, A.B., and Chaimbault, P. (2016). Natural and Synthetic Coumarins with Effects on Inflammation. Molecules, 21.","DOI":"10.3390\/molecules21101322"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Stefanachi, A., Leonetti, F., Pisani, L., Catto, M., and Carotti, A. (2018). Coumarin: A Natural, Privileged and Versatile Scaffold for Bioactive Compounds. Molecules, 23.","DOI":"10.3390\/molecules23020250"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Carneiro, A., Matos, M.J., Uriarte, E., and Santana, L. (2021). Trending Topics on Coumarin and Its Derivatives in 2020. Molecules, 26.","DOI":"10.3390\/molecules26020501"},{"key":"ref_22","first-page":"1709","article-title":"The effects of second messenger cAMP and its relative components on the contraction of uterine smooth muscle of rat","volume":"21","author":"Shu","year":"2017","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1111\/j.1476-5381.1986.tb10238.x","article-title":"The effects of long-term infusion of salbutamol, diltiazem and nifedipine on uterine contractions in the ovariectomized, post-partum rat","volume":"88","author":"Abel","year":"1986","journal-title":"Br. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Wong, J., Chiang, Y.-F., Shih, Y.-H., Chiu, C.-H., Chen, H.-Y., Shieh, T.-M., Wang, K.-L., Huang, T.-C., Hong, Y.-H., and Hsia, S.-M. (2020). Salvia sclarea L. Essential Oil Extract and Its Antioxidative Phytochemical Sclareol Inhibit Oxytocin-Induced Uterine Hypercontraction Dysmenorrhea Model by Inhibiting the Ca2+\u2013MLCK\u2013MLC20 Signaling Cascade: An Ex Vivo and In Vivo Study. Antioxidants, 9.","DOI":"10.3390\/antiox9100991"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Jung, S.-H., Heo, H.-Y., Choe, J.-W., Kim, J., and Lee, K. (2021). Anti-Melanogenic Properties of Velutin and Its Analogs. Molecules, 26.","DOI":"10.3390\/molecules26103033"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zhang, H., Pan, D., Wu, X., Su, W., Tang, X., Zhao, D., Sun, L., Song, B., Bai, X., and Li, X. (2020). Platelet Protease Activated Receptor 1 Is Involved in the Hemostatic Effect of 20(S)-Protopanaxadiol by Regulating Calcium Signaling. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.549150"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Tong, Q., Zhu, P.-C., Zhuang, Z., Deng, L.-H., Wang, Z.-H., Zeng, H., Zheng, G.-Q., Wang, Y., Tong, Q., and Zhu, P.-C. (2019). Notoginsenoside R1 for Organs Ischemia\/Reperfusion Injury: A Preclinical Systematic Review. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.01204"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Takayanagi, Y., and Onaka, T. (2021). Roles of Oxytocin in Stress Responses, Allostasis and Resilience. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010150"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1177\/1933719111398150","article-title":"Effects of Progesterone Treatment on Expression of Genes Involved in Uterine Quiescence","volume":"18","author":"Soloff","year":"2011","journal-title":"Reprod. Sci."},{"key":"ref_30","first-page":"57","article-title":"Effect of erythromycin on contractile response of uterine smooth muscle strips in non-pregnant rats","volume":"55","author":"Liu","year":"2003","journal-title":"Pol. J. Pharmacol."},{"key":"ref_31","first-page":"295","article-title":"Different mechanisms mediated the potentiation uterine smooth muscle caused by Polygala tenuifolia decoction progesterone in virginal rats","volume":"30","author":"Xu","year":"2005","journal-title":"J. Chin. Mater. Medica"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"760","DOI":"10.3109\/13880209.2011.631930","article-title":"Relaxant effect induced by wogonin from Scutellaria baicalensis on rat isolated uterine smooth muscle","volume":"50","author":"Shih","year":"2012","journal-title":"Pharm. Biol."},{"key":"ref_33","first-page":"399","article-title":"Effect of Nutgrass galingale rhizome decotion on contractile activity of uterine smooth muscle strips of non-pregnant rats in vitro","volume":"28","author":"Li","year":"2007","journal-title":"J. Xi\u2019an Jiaotong Univ. (Med. Sci.)"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1177\/1933719110391278","article-title":"The Effects of Wild Ginger (Costus speciosus (Koen) Smith) Rhizome Extract and Diosgenin on Rat Uterine Contractions","volume":"18","author":"Lijuan","year":"2011","journal-title":"Reprod. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"113713","DOI":"10.1016\/j.jep.2020.113713","article-title":"Chemical composition and uterine smooth muscle relaxant activity of essential oils from 10 kinds of blood-activating and stasis-resolving Chinese medicinal herbs","volume":"269","author":"Ni","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Guo, Y., Zhang, Y., Hou, Y., Guo, P., Wang, X., Zhang, S., and Yang, P. (2021). Anticonstriction Effect of MCA in Rats by Danggui Buxue Decoction. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.749915"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/10162\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:01:55Z","timestamp":1760112115000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/10162"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,21]]},"references-count":36,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["ijms251810162"],"URL":"https:\/\/doi.org\/10.3390\/ijms251810162","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,21]]}}}