{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:11:51Z","timestamp":1792789911840,"version":"4.5.0"},"reference-count":47,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science and Technology Commissioner Project of Zhejiang Provincial Science and Technology Program","award":["2025C03020"],"award-info":[{"award-number":["2025C03020"]}]},{"name":"Science and Technology Commissioner Project of Zhejiang Provincial Science and Technology Program","award":["2024-4-035"],"award-info":[{"award-number":["2024-4-035"]}]},{"DOI":"10.13039\/501100008092","name":"Jinhua Science and Technology Bureau","doi-asserted-by":"publisher","award":["2025C03020"],"award-info":[{"award-number":["2025C03020"]}],"id":[{"id":"10.13039\/501100008092","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008092","name":"Jinhua Science and Technology Bureau","doi-asserted-by":"publisher","award":["2024-4-035"],"award-info":[{"award-number":["2024-4-035"]}],"id":[{"id":"10.13039\/501100008092","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Acute lung injury (ALI) is a respiratory disorder lacking specific targeted therapy. Our preliminary screening revealed that the ethanol extract of the seeds of Podocarpus nakaii (EESPN) alleviated the symptoms of ALI in mice. The objectives of this study were to identify the active constituents in EESPN and study the mechanism involved. Methods: Column chromatography was performed to separate the chemical constituents of EESPN. The structures of the isolates were determined via spectroscopic methods. MTT assays, Western blotting, histological analysis, TUNEL assays, immunofluorescence staining, transcriptomic analysis, and quantitative real-time polymerase chain reaction (qRT\u2013PCR) were employed to evaluate the anti-inflammatory activity and to elucidate the potential mechanism of nagilactone C (3, Nag C) in ALI treatment. Results: Twelve compounds were isolated from EESPN and structurally characterized. The structure of podolactone E (1) was confirmed via single-crystal X-ray diffraction. In vitro, Nag C showed potent anti-inflammatory activity in LPS-induced RAW 264.7 cells. Nag C liposomes significantly ameliorated LPS-induced histopathological damage to the lungs, reduced neutrophil infiltration and inflammatory cytokine levels, increased myeloperoxidase (MPO) activity, and promoted apoptosis in mice. In addition to suppressing inflammation, Nag C also significantly suppressed the phosphorylation of the NF-\u03baB, STAT3, and STAT1 proteins. Conclusions: Nag C is an active constituent of EESPN. It may protect against LPS-induced ALI via inhibition of the STAT signaling pathway. Thus, Nag C is a promising lead compound in the development of novel STAT-targeted anti-inflammatory agents.<\/jats:p>","DOI":"10.3390\/ph18091319","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T12:07:32Z","timestamp":1756901252000},"page":"1319","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Nagilactone C from the Seeds of Podocarpus nakaii May Protect Against LPS-Induced Acute Lung Injury via STAT Signaling Pathway Inhibition"],"prefix":"10.3390","volume":"18","author":[{"given":"Xiaoxiao","family":"Chen","sequence":"first","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China"},{"name":"Pharmaceutical Engineering College, Jinhua University of Vocational Technology, Jinhua 321017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9143-2674","authenticated-orcid":false,"given":"Jing","family":"Tang","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Zhan","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixian","family":"Qiu","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiguang","family":"Shan","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youmin","family":"Ying","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109289","DOI":"10.1016\/j.clim.2023.109289","article-title":"Targeting immunometabolism against acute lung injury","volume":"249","author":"Li","year":"2023","journal-title":"Clin. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1016\/S0140-6736(07)60604-7","article-title":"Acute lung injury and the acute respiratory distress syndrome: A clinical review","volume":"369","author":"Wheeler","year":"2007","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/S0140-6736(22)01485-4","article-title":"Acute respiratory distress syndrome: Causes, pathophysiology, and phenotypes","volume":"400","author":"Bos","year":"2022","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"115382","DOI":"10.1016\/j.bcp.2022.115382","article-title":"JAK-STAT signaling as an ARDS therapeutic target: Status and future trends","volume":"208","author":"Zhang","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Recchia Luciani, G., Barilli, A., Visigalli, R., Sala, R., Dall\u2019Asta, V., and Rotoli, B.M. (2024). IRF1 mediates growth arrest and the induction of a secretory phenotype in alveolar epithelial cells in response to inflammatory cytokines IFN\u03b3\/TNF\u03b1. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25063463"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"156563","DOI":"10.1016\/j.phymed.2025.156563","article-title":"Exploring the therapeutic potential of HAPC in COVID-19-induced acute lung injury","volume":"139","author":"Pu","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zhang, X., Zhou, J., Holbein, B.E., and Lehmann, C. (2023). Iron chelation as a potential therapeutic approach in acute lung injury. Life, 13.","DOI":"10.3390\/life13081659"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Xu, Y., Xin, J., Sun, Y., Wang, X., Sun, L., Zhao, F., Niu, C., and Liu, S. (2024). Mechanisms of sepsis-induced acute lung injury and advancements of natural small molecules in its treatment. Pharmaceuticals, 17.","DOI":"10.3390\/ph17040472"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/S1359-6101(03)00059-5","article-title":"Cytokine-mediated inflammation in acute lung injury","volume":"14","author":"Goodman","year":"2003","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_10","first-page":"S353","article-title":"Acute lung injury-from pathophysiology to treatment","volume":"69","year":"2020","journal-title":"Physiol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12967-023-04828-7","article-title":"Translational medicine for acute lung injury","volume":"22","author":"Zhang","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"104736","DOI":"10.1016\/j.phrs.2020.104736","article-title":"Acute lung injury: The therapeutic role of Rho kinase inhibitors","volume":"155","author":"Abedi","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"116401","DOI":"10.1016\/j.jep.2023.116401","article-title":"A comprehensive review on the medicinal usage of Podocarpus species: Phytochemistry and pharmacology","volume":"310","author":"Deng","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/j.jep.2010.07.019","article-title":"Anti-inflammatory, antioxidant, anti-tyrosinase and phenolic contents of four Podocarpus species used in traditional medicine in South Africa","volume":"136","author":"Abdillahi","year":"2011","journal-title":"J. Ethnopharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s13659-020-00268-8","article-title":"Anticancer activities and mechanism of action of nagilactones, a group of terpenoid lactones isolated from Podocarpus species","volume":"10","author":"Bailly","year":"2020","journal-title":"Nat. Prod. Bioprospect."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.phytol.2017.07.011","article-title":"Anti-inflammatory abietane diterpenoids from the seeds of Podocarpus nagi","volume":"21","author":"Feng","year":"2017","journal-title":"Phytochem. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1007\/s11418-018-1219-5","article-title":"New podolactones from the seeds of Podocarpus nagi and their anti-inflammatory effect","volume":"72","author":"Feng","year":"2018","journal-title":"J. Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1080\/10286020.2017.1319821","article-title":"Anti-neuroinflammatory diterpenoids from the endangered conifer Podocarpus imbricatus","volume":"20","author":"Hu","year":"2018","journal-title":"J. Asian Nat. Prod. Res."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kim, C., Le, D., and Lee, M. (2021). Diterpenoids isolated from Podocarpus macrophyllus inhibited the inflammatory mediators in LPS-induced HT-29 and RAW 264.7 cells. Molecules, 26.","DOI":"10.3390\/molecules26144326"},{"key":"ref_20","unstructured":"Flora of China Editorial Committee (1978). Flora Republicae Popularis Sinicae, Science Press."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1248\/cpb.57.668","article-title":"Cytotoxic bisnor- and norditerpene dilactones having 7\u03b1,8\u03b1-epoxy-9,11-enolide substructure from Podocarpus macrophyllus D","volume":"57","author":"Sato","year":"2009","journal-title":"DON. Chem. Pharm. Bull."},{"key":"ref_22","unstructured":"Ye, Y., Li, J., Yao, S., Gao, A.H., and Ke, C.Q. (2022). Nagilactone Compound and Use Thereof in Preparation of Anti-Tumor Drug. (WO 2022\/143617 A1)."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1021\/np50077a015","article-title":"Cytotoxic norditerpene lactones from Ileostylus micranthus","volume":"54","author":"Bloor","year":"1991","journal-title":"J. Nat. Prod."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1016\/S0031-9422(00)90725-8","article-title":"Norditerpene dilactones from Podocarpus nagi","volume":"34","author":"Ying","year":"1993","journal-title":"Phytochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Galbraith, M.N., Horn, D., and Sasse, J.M. (1971). Podolactones C and D, terpene sulphoxides from Podocarpus neriifolius. J. Chem. Soc. Chem. Commun., 1362\u20131363.","DOI":"10.1039\/c2971001362b"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1021\/jo00179a040","article-title":"Revised strcture of Podolactone C, the antileukemic component of Podocarpus milanjianus Rendle","volume":"49","author":"Cassady","year":"1984","journal-title":"J. Org. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1002\/mrc.1270140203","article-title":"Carbon-13 NMR studies of the biologically active nor-diterpenoid dilactones from Podocarpus Plants","volume":"14","author":"Hayashi","year":"1980","journal-title":"Org. Magn. Reson."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s10600-016-1703-7","article-title":"Chemical constituents of the barks of Podocarpus macrophyllus","volume":"52","author":"Li","year":"2016","journal-title":"Chem. Nat. Compd."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1248\/cpb.58.1399","article-title":"Reinvestigation of the absolute stereochemistry of megastigmane glucoside, icariside B (5)","volume":"58","author":"Matsunami","year":"2010","journal-title":"Chem. Pharm. Bull."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10997","DOI":"10.1016\/0040-4020(95)00655-R","article-title":"Terpenoid and steroid constituents of the Indian ocean soft coral Sinularia maxima","volume":"51","author":"Anjaneyulu","year":"1995","journal-title":"Tetrahedron"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/j.phytochem.2010.02.002","article-title":"Sesquiterpenes and diterpenes from Ambrosia arborescens","volume":"71","author":"Saltos","year":"2010","journal-title":"Phytochemistry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/BF02976201","article-title":"Sesquiterpene components from the flower buds of Magnolia fargesii","volume":"20","author":"Jung","year":"1997","journal-title":"Arch. Pharm. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1080\/14786419.2016.1226829","article-title":"A new cyclopeptide and a new lignan from Podocarpus neriifolius","volume":"31","author":"Wu","year":"2017","journal-title":"Nat. Prod. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/BF01928670","article-title":"Plant growth inhibitory lactones from Podocarpus neriifolius: Structure of podolactone E","volume":"28","author":"Galbraith","year":"1972","journal-title":"Experientia"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1080\/10286020902877739","article-title":"A new dimeric phenylpropanoid and cytotoxic norditerpene constituents from Podocarpus nakaii","volume":"11","author":"Huang","year":"2009","journal-title":"J. Asian Nat. Prod. Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Lin, W., Chen, H.L., Chen, X.J., and Guo, C.R. (2024). The roles of neutrophil-derived myeloperoxidase (MPO) in diseases: The new progress. Antioxidants, 13.","DOI":"10.3390\/antiox13010132"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Millar, M.W., Fazal, F., and Rahman, A. (2022). Therapeutic targeting of NF-\u03baB in acute lunginjury: A double-edged sword. Cells, 11.","DOI":"10.3390\/cells11203317"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.cell.2016.12.012","article-title":"30 years of NF-\u03baB: A blossoming of relevance to human pathobiology","volume":"168","author":"Zhang","year":"2017","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1002\/med.20156","article-title":"Recent developments in anti-inflammatory natural products","volume":"29","author":"Gautam","year":"2009","journal-title":"Med. Res. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"155684","DOI":"10.1016\/j.phymed.2024.155684","article-title":"Immune-inflammatory modulation by natural products derived from edible and medicinal herbs used in Chinese classical prescriptions","volume":"130","author":"Kang","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"113807","DOI":"10.1016\/j.intimp.2024.113807","article-title":"Plant-derived natural compounds for the treatment of acute lung injury: A systematic review of their anti-inflammatory effects in animal models","volume":"146","author":"Chen","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"155562","DOI":"10.1016\/j.phymed.2024.155562","article-title":"Pharmacological mechanisms of traditional Chinese medicine against acute lung injury: From active ingredients to herbal formulae","volume":"135","author":"Liu","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"105224","DOI":"10.1016\/j.phrs.2020.105224","article-title":"Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms","volume":"163","author":"He","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.1007\/s00018-008-8103-5","article-title":"Terpenoids: Natural inhibitors of NF-kappaB signaling with anti-inflammatory and anticancer potential","volume":"65","author":"Salminen","year":"2008","journal-title":"Cell Mol. Life Sci."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Kim, T., Song, B., Cho, K.S., and Lee, I.S. (2020). Therapeutic potential of volatile terpenes and terpenoids from forests for inflammatory diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21062187"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"105817","DOI":"10.1016\/j.bioorg.2022.105817","article-title":"Natural terpenoids with anti-inflammatory activities: Potential leads for anti-inflammatory drug discovery","volume":"124","author":"Ge","year":"2022","journal-title":"Bioorg. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"155373","DOI":"10.1016\/j.phymed.2024.155373","article-title":"A phytomedicine extract exerts an anti-inflammatory response in the lungs by reducing STING-mediated type I interferon release","volume":"130","author":"Zhang","year":"2024","journal-title":"Phytomedicine"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/9\/1319\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:38:39Z","timestamp":1760035119000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/9\/1319"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,3]]},"references-count":47,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ph18091319"],"URL":"https:\/\/doi.org\/10.3390\/ph18091319","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,3]]}}}