{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T01:45:13Z","timestamp":1782783913424,"version":"3.54.5"},"reference-count":31,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T00:00:00Z","timestamp":1782518400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Qinghai Province Application Foundation Project","award":["2025-ZJ-723"],"award-info":[{"award-number":["2025-ZJ-723"]}]},{"name":"Kunlun Talents, High-End Innovation and Entrepreneurship Leading Talents Program of Qinghai Province","award":["2025"],"award-info":[{"award-number":["2025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hypoxic pulmonary hypertension (HPH) is a progressive vascular disease characterized by an abnormal increase in pulmonary arterial pressure resulting from pulmonary vasoconstriction and pulmonary vascular remodeling (PVR). Excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) are key drivers of PVR. Caragana jubata (Pall.) Poir. (C. jubata), known as \u201czuomaoxing\u201d in Tibetan medicine, is traditionally used to treat blood-related disorders. However, the potential preventive and therapeutic effects of C. jubata on HPH remain unclear. Here, we integrated in vivo pharmacology, serum pharmacochemistry, PASMC assays, DARTS-MS chemoproteomics, and pathway validation to investigate the effects of C. jubata ethanol extract (ECJ) on HPH-associated PVR and the effects of a serum-exposed candidate component on CoCl2-induced PASMC activation. In HPH rats, ECJ reduced mean pulmonary arterial pressure and alleviated right ventricular hypertrophy and PVR. Serum pharmacochemistry detected 47 ECJ-derived serum-exposed features, including one prototype putatively annotated as ginkgolide J. Ginkgolide J attenuated CoCl2-induced PASMC proliferation, Ki-67 positivity, and migration without significantly affecting PASMC viability. DARTS-MS identified 1235 ginkgolide J-associated protease-susceptibility candidate proteins, and pathway validation indicated that ginkgolide J suppressed CoCl2-induced MEK1\/ERK1\/2 activation. These findings suggest that ECJ has potential value against HPH-associated PVR and that ginkgolide J is a candidate anti-proliferative compound in PASMCs.<\/jats:p>","DOI":"10.3390\/ijms27135815","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:55:11Z","timestamp":1782780911000},"page":"5815","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Serum Pharmacochemistry-Guided DARTS-MS Profiling Reveals Potential Mechanisms of Caragana jubata Against Hypoxic Pulmonary Hypertension"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0371-0630","authenticated-orcid":false,"given":"Jiacheng","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Qinghai Minzu University, Xining 810007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Qiao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Qinghai Minzu University, Xining 810007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaoxiang","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Qinghai Minzu University, Xining 810007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyun","family":"Gai","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Qinghai Minzu University, Xining 810007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqing","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Qinghai Minzu University, Xining 810007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuqin","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Qinghai Minzu University, Xining 810007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haotian","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Qinghai Minzu University, Xining 810007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Qinghai Minzu University, Xining 810007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6482-3255","authenticated-orcid":false,"given":"Zhanqiang","family":"Li","sequence":"additional","affiliation":[{"name":"Plateau Medicine Research Center, Qinghai University, Xining 810001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuefu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Qinghai Minzu University, Xining 810007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Qinghai Minzu University, Xining 810007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2401324","DOI":"10.1183\/13993003.01324-2024","article-title":"Definition, classification and diagnosis of pulmonary hypertension","volume":"64","author":"Kovacs","year":"2024","journal-title":"Eur. Respir. J."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Nakamura, K., Akagi, S., Ejiri, K., Taya, S., Saito, Y., Kuroda, K., Takaya, Y., Toh, N., Nakayama, R., and Katanosaka, Y. (2025). Pathophysiology of Group 3 Pulmonary Hypertension Associated with Lung Diseases and\/or Hypoxia. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26020835"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41569-023-00924-9","article-title":"Cardiovascular physiology and pathophysiology at high altitude","volume":"21","author":"Richalet","year":"2024","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1097\/FJC.0000000000000328","article-title":"Signal Mechanisms of Vascular Remodeling in the Development of Pulmonary Arterial Hypertension","volume":"67","author":"Li","year":"2016","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"191","DOI":"10.2119\/molmed.2013.00165","article-title":"Molecular mechanisms of pulmonary arterial remodeling","volume":"20","author":"Crosswhite","year":"2014","journal-title":"Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41572-023-00486-7","article-title":"Pulmonary hypertension","volume":"10","author":"Mocumbi","year":"2024","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Yang, L., Wan, N., Gong, F., Wang, X., Feng, L., and Liu, G. (2023). Transcription factors and potential therapeutic targets for pulmonary hypertension. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1132060"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e70094","DOI":"10.1002\/pul2.70094","article-title":"Role of MiR-542-3p\/Integrin-Linked Kinase\/Myocardin Signaling Axis in Hypoxic Pulmonary Hypertension","volume":"15","author":"Li","year":"2025","journal-title":"Pulm. Circ."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1164\/rccm.201606-1226PP","article-title":"Translational Advances in the Field of Pulmonary Hypertension. From Cancer Biology to New Pulmonary Arterial Hypertension Therapeutics. Targeting Cell Growth and Proliferation Signaling Hubs","volume":"195","author":"Pullamsetti","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/s41580-020-0255-7","article-title":"ERK signalling: A master regulator of cell behaviour, life and fate","volume":"21","author":"Lavoie","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4397","DOI":"10.1007\/s00018-016-2297-8","article-title":"Negative feedback regulation of the ERK1\/2 MAPK pathway","volume":"73","author":"Lake","year":"2016","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1186\/s12931-021-01908-4","article-title":"TRB3 mediates vascular remodeling by activating the MAPK signaling pathway in hypoxic pulmonary hypertension","volume":"22","author":"Cao","year":"2021","journal-title":"Respir. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s12931-022-01927-9","article-title":"Notch4 mediates vascular remodeling via ERK\/JNK\/P38 MAPK signaling pathways in hypoxic pulmonary hypertension","volume":"23","author":"Guo","year":"2022","journal-title":"Respir. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"116275","DOI":"10.1016\/j.jep.2023.116275","article-title":"Determining the chemical profile of Caragana jubata (Pall.) Poir. by UPLC-QTOF-MS analysis and evaluating its anti-ischemic stroke effects","volume":"309","author":"Zhao","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"ref_15","unstructured":"Dimar, T. (1986). Jing Zhu Materia Medica, Shanghai Scientific and Technical Publishers."},{"key":"ref_16","first-page":"599","article-title":"Effect of Tibetan Medicine Zuomaoxing with Different Origins and Characteristics on Rats with Pattern of Toxic Heat-induced Blood Stasis","volume":"41","author":"Yuan","year":"2024","journal-title":"Chin. J. Mod. Appl. Pharm."},{"key":"ref_17","first-page":"152","article-title":"Research progress of traditional Chinese and Tibetan medicine in treating high altitude polycythemia","volume":"40","author":"Ding","year":"2019","journal-title":"Tibet. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1002\/pca.2950","article-title":"Comprehensive quality evaluation of Lignum Caraganae and rapid discrimination of Caragana jubata and Caragana changduensis based on characteristic compound fingerprints by HPLC-UV and HPLC-MS\/MS coupled with chemometrics analysis","volume":"31","author":"Wang","year":"2020","journal-title":"Phytochem. Anal."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1007\/s11655-016-2500-7","article-title":"Protective effects of traditional Tibetan medicine Zuo-Mu-A Decoction (\u4f50\u6728\u963f\u6c64) on the blood parameters and myocardium of high altitude polycythemia model rats","volume":"23","author":"Lu","year":"2017","journal-title":"Chin. J. Integr. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1802040","DOI":"10.1183\/13993003.02040-2018","article-title":"Pulmonary arterial pressure at rest and during exercise in chronic mountain sickness: A meta-analysis","volume":"53","author":"Soria","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Tang, S., Zhou, W.W., Chen, L., Yan, H., Chen, L., and Luo, F.M. (2024). High altitude polycythemia and its maladaptive mechanisms: An updated review. Front. Med., 11.","DOI":"10.3389\/fmed.2024.1448654"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"114798","DOI":"10.1016\/j.bcp.2021.114798","article-title":"Drug affinity responsive target stability (DARTS) accelerated small molecules target discovery: Principles and application","volume":"194","author":"Ren","year":"2021","journal-title":"Biochem. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"21984","DOI":"10.1073\/pnas.0910040106","article-title":"Target identification using drug affinity responsive target stability (DARTS)","volume":"106","author":"Lomenick","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2401095","DOI":"10.1183\/13993003.01095-2024","article-title":"Pathology and pathobiology of pulmonary hypertension: Current insights and future directions","volume":"64","author":"Guignabert","year":"2024","journal-title":"Eur. Respir. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1152\/physiol.00039.2019","article-title":"Cellular Pathways Promoting Pulmonary Vascular Remodeling by Hypoxia","volume":"35","author":"Shimoda","year":"2020","journal-title":"Physiology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"555","DOI":"10.3892\/mmr.2021.12194","article-title":"Ginkgolide J protects human synovial cells SW982 via suppression of p38-dependent production of pro-inflammatory mediators","volume":"24","author":"Zhao","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.neurobiolaging.2007.05.025","article-title":"Protection against \u03b2-amyloid induced abnormal synaptic function and cell death by Ginkgolide J","volume":"30","author":"Vitolo","year":"2009","journal-title":"Neurobiol. Aging"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s10020-019-0125-y","article-title":"The neuroprotective mechanisms of ginkgolides and bilobalide in cerebral ischemic injury: A literature review","volume":"25","author":"Feng","year":"2019","journal-title":"Mol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Li, C., Liu, K., Liu, S., Aerqin, Q., and Wu, X. (2020). Role of ginkgolides in the inflammatory immune response of neurological diseases: A review of current literatures. Front. Syst. Neurosci., 14.","DOI":"10.3389\/fnsys.2020.00045"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8848808","DOI":"10.1155\/2023\/8848808","article-title":"Ginkgolide B Blocks Vascular Remodeling after Vascular Injury via Regulating Tgf\u03b21\/Smad Signaling Pathway","volume":"2023","author":"Wang","year":"2023","journal-title":"Cardiovasc. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/978-1-0716-0954-5_15","article-title":"Drug affinity responsive target stability (DARTS) assay to detect interaction between a purified protein and a small molecule","volume":"2213","author":"Huang","year":"2021","journal-title":"Methods Molecu-Lar Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5815\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T01:07:35Z","timestamp":1782781655000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5815"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,27]]},"references-count":31,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27135815"],"URL":"https:\/\/doi.org\/10.3390\/ijms27135815","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,27]]}}}