{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T14:37:46Z","timestamp":1781879866499,"version":"3.54.5"},"reference-count":46,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T00:00:00Z","timestamp":1686700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170093"],"award-info":[{"award-number":["82170093"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Luteolin (Lut), a natural flavonoid compound existing in Perilla frutescens (L.) Britton, has been proven to play a protective role in the following biological aspects: inflammatory, viral, oxidant, and tumor-related. Lut can alleviate acute lung injury (ALI), manifested mainly by preventing the accumulation of inflammation-rich edematous fluid, while the protective actions of Lut on transepithelial ion transport in ALI were seldom researched. We found that Lut could improve the lung appearance\/pathological structure in lipopolysaccharide (LPS)-induced mouse ALI models and reduce the wet\/dry weight ratio, bronchoalveolar protein, and inflammatory cytokines. Meanwhile, Lut upregulated the expression level of the epithelial sodium channel (ENaC) in both the primary alveolar epithelial type 2 (AT2) cells and three-dimensional (3D) alveolar epithelial organoid model that recapitulated essential structural and functional aspects of the lung. Finally, by analyzing the 84 interaction genes between Lut and ALI\/acute respiratory distress syndrome using GO and KEGG enrichment of network pharmacology, we found that the JAK\/STAT signaling pathway might be involved in the network. Experimental data by knocking down STAT3 proved that Lut could reduce the phosphorylation of JAK\/STAT and enhance the level of SOCS3, which abrogated the inhibition of ENaC expression induced by LPS accordingly. The evidence supported that Lut could attenuate inflammation-related ALI by enhancing transepithelial sodium transport, at least partially, via the JAK\/STAT pathway, which may offer a promising therapeutic strategy for edematous lung diseases.<\/jats:p>","DOI":"10.3390\/ijms241210122","type":"journal-article","created":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T01:32:57Z","timestamp":1686792777000},"page":"10122","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Luteolin Enhances Transepithelial Sodium Transport in the Lung Alveolar Model: Integrating Network Pharmacology and Mechanism Study"],"prefix":"10.3390","volume":"24","author":[{"given":"Lei","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiman","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9973-6354","authenticated-orcid":false,"given":"Hongguang","family":"Nie","sequence":"additional","affiliation":[{"name":"Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Chemistry, School of Forensic Medicine, China Medical University, Shenyang 110122, China"},{"name":"Liaoning Province Key Laboratory of Forensic Bio-Evidence Sciences, Shenyang 110122, China"},{"name":"Center of Forensic Investigation, China Medical University, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8033-1824","authenticated-orcid":false,"given":"Yan","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1186\/s12931-021-01897-4","article-title":"Ferulic acid ameliorates lipopolysaccharide-induced tracheal injury via cGMP\/PKGII signaling pathway","volume":"22","author":"Xie","year":"2021","journal-title":"Respir. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1007\/s12026-021-09176-6","article-title":"Dexmedetomidine alleviates pulmonary edema through the epithelial sodium channel (ENaC) via the PI3K\/Akt\/Nedd4-2 pathway in LPS-induced acute lung injury","volume":"69","author":"Jiang","year":"2021","journal-title":"Immunol. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2568","DOI":"10.1016\/j.biocel.2013.08.009","article-title":"Alveolar epithelial cells: Master regulators of lung homeostasis","volume":"45","author":"Guillot","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2566","DOI":"10.3390\/ijms22052566","article-title":"The history and mystery of alveolar epithelial type II cells: Focus on their physiologic and pathologic role in lung","volume":"22","author":"Ruaro","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1093\/abbs\/gmaa052","article-title":"Regulation of alveolar type 2 stem\/progenitor cells in lung injury and regeneration","volume":"52","author":"Wu","year":"2020","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"L240","DOI":"10.1152\/ajplung.00065.2022","article-title":"Effects of hypoxia on respiratory diseases: Perspective view of epithelial ion transport","volume":"323","author":"Zhou","year":"2022","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/s10157-023-02332-2","article-title":"Blockade of Indoleamine 2,3-Dioxygenase attenuates lipopolysaccharide-induced kidney injury by inhibiting TLR4\/NF-\u03baB signaling","volume":"27","author":"Wu","year":"2023","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1111\/1440-1681.13734","article-title":"Rosmarinic acid protects against lipopolysaccharide-induced cardiac dysfunction via activating Sirt1\/PGC-1\u03b1 pathway to alleviate mitochondrial impairment","volume":"50","author":"Peng","year":"2023","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"109898","DOI":"10.1016\/j.intimp.2023.109898","article-title":"Network pharmacology and in vivo studies reveal the pharmacological effects and molecular mechanisms of Celastrol against acute hepatic injury induced by LPS","volume":"117","author":"Yang","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4877","DOI":"10.2174\/1381612825666191204092456","article-title":"Alveolar type 2 epithelial cells as potential therapeutics for acute lung injury\/acute respiratory distress syndrome","volume":"25","author":"Zhang","year":"2019","journal-title":"Curr. Pharm. Des."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s13287-022-02793-4","article-title":"Prkg2 regulates alveolar type 2-mediated re-alveolarization","volume":"13","author":"Zhang","year":"2022","journal-title":"Stem Cell Res. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5847876","DOI":"10.1155\/2020\/5847876","article-title":"Organoids as a powerful model for respiratory diseases","volume":"2020","author":"Li","year":"2020","journal-title":"Stem Cells Int."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ahmed, H.M. (2018). Ethnomedicinal, phytochemical and pharmacological investigations of Perilla frutescens (L.) britt. Molecules, 24.","DOI":"10.3390\/molecules24010102"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.fct.2016.11.023","article-title":"Phytochemical and phytopharmacological review of Perilla frutescens L. (Labiatae), a traditional edible-medicinal herb in China","volume":"108","author":"Yu","year":"2017","journal-title":"Food Chem. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Chen, X., Xu, X., Lv, J., Huang, J., Lyu, L., and Liu, L. (2023). Potential mechanisms of perillae folium against COVID-19: A network pharmacology approach. J. Med. Food, ahead of print.","DOI":"10.1089\/jmf.2022.K.0029"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1055\/a-0998-7985","article-title":"Luteolin attenuates diabetic nephropathy through suppressing inflammatory response and oxidative stress by inhibiting STAT3 pathway","volume":"129","author":"Zhang","year":"2021","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"108612","DOI":"10.1016\/j.biopha.2019.108612","article-title":"Luteolin, a flavonoid, as an anticancer agent: A review","volume":"112","author":"Imran","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3509","DOI":"10.1002\/ptr.7044","article-title":"Anticancer activity of the plant flavonoid luteolin against preclinical models of various cancers and insights on different signalling mechanisms modulated","volume":"35","author":"Ganai","year":"2021","journal-title":"Phytother. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s00011-018-1137-8","article-title":"Luteolin activates ERK1\/2\u2212 and Ca2+-dependent HO\u22121 induction that reduces LPS-induced HMGB1, iNOS\/NO, and COX\u22122 expression in RAW264.7 cells and mitigates acute lung injury of endotoxin mice","volume":"67","author":"Park","year":"2018","journal-title":"Inflamm. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8883962","DOI":"10.1155\/2021\/8883962","article-title":"Luteolin regulates the differentiation of regulatory T cells and activates IL-10 dependent macrophage polarization against acute lung injury","volume":"2021","author":"Xie","year":"2021","journal-title":"J. Immunol. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"114654","DOI":"10.1016\/j.jep.2021.114654","article-title":"Luteolin attenuates lipopolysaccharide-induced acute lung injury\/acute respiratory distress syndrome by activating alveolar epithelial sodium channels via cGMP\/PI3K pathway","volume":"282","author":"Hou","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"717652","DOI":"10.3389\/fphar.2021.717652","article-title":"Mechanisms underlying the effects of Lianhua Qingwen on sepsis-induced acute lung injury: A network pharmacology approach","volume":"12","author":"Yang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Djeujo, F.M., Stablum, V., Pangrazzi, E., and Ragazzi, E. (2023). Luteolin and vernodalol as bioactive compounds of leaf and root vernonia amygdalina extracts: Effects on \u03b1-glucosidase, glycation, ROS, cell Viability, and in silico ADMET parameters. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15051541"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.3389\/fimmu.2020.01585","article-title":"Alveolar epithelial cells promote IGF-1 production by alveolar macrophages through TGF-\u03b2 to suppress endogenous inflammatory signals","volume":"11","author":"Mu","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/s42003-022-03481-y","article-title":"Macrophage-derived exosomal aminopeptidase N aggravates sepsis-induced acute lung injury by regulating necroptosis of lung epithelial cell","volume":"5","author":"Gong","year":"2022","journal-title":"Commun. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"812164","DOI":"10.3389\/fimmu.2022.812164","article-title":"A 4-benzene-Indol derivative alleviates LPS-induced acute lung injury through inhibiting the NLRP3 inflammasome","volume":"13","author":"Li","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1080\/14728222.2018.1501361","article-title":"The epithelial sodium channel as a therapeutic target for cystic fibrosis lung disease","volume":"22","author":"Moore","year":"2018","journal-title":"Expert. Opin. Ther. Targets"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1124\/jpet.121.000712","article-title":"Resolvin conjugates in tissue regeneration 1 promote alveolar fluid clearance by activating alveolar epithelial sodium channels and Na, K-ATPase in lipopolysaccharide-induced acute lung injury","volume":"379","author":"Yang","year":"2021","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4736","DOI":"10.1111\/jcmm.15146","article-title":"Maresin conjugates in tissue regeneration 1 improves alveolar fluid clearance by up-regulating alveolar ENaC, Na, K-ATPase in lipopolysaccharide-induced acute lung injury","volume":"24","author":"Han","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1097\/SHK.0000000000001945","article-title":"The WNK4\/SPAK pathway stimulates alveolar fluid clearance by up-regulation of epithelial sodium channel in mice with lipopolysaccharide-induced acute respiratory distress syndrome","volume":"58","author":"Deng","year":"2022","journal-title":"Shock"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Hua, Y., Han, A., Yu, T., Hou, Y., Ding, Y., and Nie, H. (2022). Small extracellular vesicles containing miR-34c derived from bone marrow mesenchymal stem cells regulates epithelial sodium channel via targeting MARCKS. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23095196"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e105912","DOI":"10.15252\/embj.2020105912","article-title":"An organoid-derived bronchioalveolar model for SARS-CoV-2 infection of human alveolar type II-like cells","volume":"40","author":"Lamers","year":"2021","journal-title":"EMBO J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3391","DOI":"10.2147\/DDDT.S222296","article-title":"Paclitaxel alleviated sepsis-induced acute lung injury by activating MUC1 and suppressing TLR-4\/NF-\u03baB pathway","volume":"13","author":"Wang","year":"2019","journal-title":"Drug. Des. Devel Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"583","DOI":"10.21037\/atm-22-1884","article-title":"G9a promotes inflammation in Streptococcus pneumoniae induced pneumonia mice by stimulating M1 macrophage polarization and H3K9me2 methylation in FOXP1 promoter region","volume":"10","author":"Li","year":"2022","journal-title":"Ann. Transl. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"R387","DOI":"10.1152\/ajpregu.00144.2020","article-title":"Evolution of epithelial sodium channels: Current concepts and hypotheses","volume":"319","author":"Wichmann","year":"2020","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Zhou, W., Wang, Y., Lu, A., and Zhang, G. (2016). Systems pharmacology in small molecular drug discovery. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17020246"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"154538","DOI":"10.1016\/j.phymed.2022.154538","article-title":"Mechanism of action of Daqinjiao decoction in treating cerebral small vessel disease explored using network pharmacology and molecular docking technology","volume":"108","author":"Wang","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1080\/07853890.2022.2034931","article-title":"The mechanism of triptolide in the treatment of connective tissue disease-related interstitial lung disease based on network pharmacology and molecular docking","volume":"54","author":"Zhu","year":"2022","journal-title":"Ann. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"859","DOI":"10.21037\/atm-21-1750","article-title":"Protective effect of anisodamine on bleomycin-induced acute lung injury in immature rats via modulating oxidative stress, inflammation, and cell apoptosis by inhibiting the JAK2\/STAT3 pathway","volume":"9","author":"Zhao","year":"2021","journal-title":"Ann. Transl. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1186\/s12931-020-01595-7","article-title":"Bone marrow mesenchymal stem cells derived miRNA-130b enhances epithelial sodium channel by targeting PTEN","volume":"21","author":"Zhang","year":"2020","journal-title":"Respir. Res."},{"key":"ref_41","first-page":"402","article-title":"Luteolin affects lung epithelial ion transport by regulating epithelial sodium channels","volume":"31","author":"Liu","year":"2020","journal-title":"Tradit. Chin. Drug Res. Clin. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2660","DOI":"10.1016\/j.fct.2011.07.012","article-title":"Luteolin attenuates the pulmonary inflammatory response involves abilities of antioxidation and inhibition of MAPK and NF\u03baB pathways in mice with endotoxin-induced acute lung injury","volume":"49","author":"Kuo","year":"2011","journal-title":"Food Chem. Toxicol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"863646","DOI":"10.3389\/fphar.2022.863646","article-title":"MiR-130a-3p alleviates inflammatory and fibrotic phases of pulmonary fibrosis through proinflammatory factor TNF-\u03b1 and profibrogenic receptor TGF-\u03b2RII","volume":"13","author":"Ding","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/vox.12895","article-title":"An animal model of transfusion-related acute lung injury and the role of soluble CD40 ligand","volume":"115","author":"Hu","year":"2020","journal-title":"Vox Sang."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1097\/SHK.0000000000000767","article-title":"Soluble epoxide hydrolase inhibitor attenuates lipopolysaccharide-induced acute lung injury and improves survival in mice","volume":"47","author":"Zhou","year":"2017","journal-title":"Shock"},{"key":"ref_46","first-page":"8030143","article-title":"Danggui buxue tang ameliorates bleomycin-induced pulmonary fibrosis by suppressing the TLR4\/NLRP3 signaling pathway in rats","volume":"2021","author":"Wang","year":"2021","journal-title":"Evid. Based Complement. Altern. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/12\/10122\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:54:53Z","timestamp":1760126093000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/12\/10122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,14]]},"references-count":46,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["ijms241210122"],"URL":"https:\/\/doi.org\/10.3390\/ijms241210122","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,14]]}}}