{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T02:36:32Z","timestamp":1780972592571,"version":"3.54.1"},"reference-count":50,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"vor","delay-in-days":197,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Diabetes Research"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>\n                    <jats:bold>Background:<\/jats:bold>\n                    Diabetic nephropathy (DN), a prevalent microvascular complication of diabetes, is characterized by chronic inflammation, oxidative stress, and renal thrombosis. This study is aimed at assessing the therapeutic effects of costunolide (COS) on DN and investigating its mechanism of action in reducing inflammation and platelet activation\u2013mediated thrombosis by inhibiting the formation of neutrophil extracellular traps (NETs).\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods:<\/jats:bold>\n                    A DN mouse model was established using a high\u2010sugar, high\u2010fat diet combined with streptozotocin (STZ) administration, followed by treatment with varying doses of COS. The efficacy of COS was assessed through renal function indicators, including 24\u2010h urinary protein levels, serum creatinine, and blood urea nitrogen, alongside renal histopathological analyses using hematoxylin\u2010eosin, Masson\u2019s trichrome, and periodic acid\u2013Schiff staining. Transcriptomic analysis was performed to identify gene expression changes in renal tissues after COS treatment. Based on transcriptomic findings, the impact of COS on inflammatory and platelet activation\u2013related markers (IL\u20101\n                    <jats:italic>\u03b2<\/jats:italic>\n                    , IL\u20106, TNF\u2010\n                    <jats:italic>\u03b1<\/jats:italic>\n                    , CCL2, and CD41) was further evaluated. Additionally, the expression of NET formation\u2010related factors (MPO, CitH3, IGTAM, PAD4, C3, and fibrinogen) was analyzed using immunofluorescence, western blot, and ELISA. To validate the in vivo findings, isolated neutrophils were treated with COS in vitro to assess its inhibitory effects on NET formation, including markers such as SYTOX Green, CitH3, ROS, and PAD4.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results:<\/jats:bold>\n                    COS treatment significantly improved renal function and mitigated histopathological damage in DN mice. Transcriptomic analysis indicated that COS modulated pathways associated with inflammation and platelet activation, including the complement and coagulation cascades, biosynthesis of cofactors, cytokine\u2013cytokine receptor interactions, NET formation, and NOD\u2010like receptor signaling. COS markedly reduced the expression of inflammatory markers (IL\u20101\n                    <jats:italic>\u03b2<\/jats:italic>\n                    , IL\u20106, TNF\u2010\n                    <jats:italic>\u03b1<\/jats:italic>\n                    , and CCL2) and the platelet activation marker CD41 in renal tissues. Moreover, COS decreased the expression of NET\u2010related proteins, including MPO, CitH3, PAD4, IGTAM, C3, and fibrinogen, while lowering the CitH3\/H3 ratio. In vitro, COS significantly inhibited PMA\u2010induced NET formation in neutrophils, as evidenced by reduced SYTOX Green\u2009+\u2009CitH3\n                    <jats:sup>+<\/jats:sup>\n                    expression and decreased levels of PAD4 and ROS.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Conclusion:<\/jats:bold>\n                    COS alleviates inflammation and platelet activation\u2013mediated thrombosis in DN mice, potentially by inhibiting excessive NET formation. These findings highlight the therapeutic potential of COS in managing DN.\n                  <\/jats:p>","DOI":"10.1155\/jdr\/1159325","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T04:35:27Z","timestamp":1752813327000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Costunolide Reduces DN Inflammatory Response and Renal Thrombosis by Inhibiting NET Formation"],"prefix":"10.1155","volume":"2025","author":[{"given":"Xiangjing","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengli","family":"Lou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanying","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0695-385X","authenticated-orcid":false,"given":"Yijing","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,17]]},"reference":[{"key":"e_1_2_10_1_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-023-02056-3"},{"key":"e_1_2_10_2_2","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.81892"},{"key":"e_1_2_10_3_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1185317"},{"key":"e_1_2_10_4_2","doi-asserted-by":"publisher","DOI":"10.5045\/br.2022.2021204"},{"key":"e_1_2_10_5_2","doi-asserted-by":"publisher","DOI":"10.2337\/db22-0153"},{"key":"e_1_2_10_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01933-x"},{"key":"e_1_2_10_7_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020003377"},{"key":"e_1_2_10_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.15852"},{"key":"e_1_2_10_9_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1253667"},{"key":"e_1_2_10_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00592-014-0676-x"},{"key":"e_1_2_10_11_2","doi-asserted-by":"publisher","DOI":"10.3390\/nu14142965"},{"key":"e_1_2_10_12_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20122926"},{"key":"e_1_2_10_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2024.155581"},{"key":"e_1_2_10_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2022.09.014"},{"key":"e_1_2_10_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2023.154822"},{"key":"e_1_2_10_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-022-00928-0"},{"key":"e_1_2_10_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115086"},{"key":"e_1_2_10_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2023.154959"},{"key":"e_1_2_10_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.17686"},{"key":"e_1_2_10_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102787"},{"key":"e_1_2_10_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1005743107"},{"key":"e_1_2_10_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1991.tb08010.x"},{"key":"e_1_2_10_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2014.116"},{"key":"e_1_2_10_24_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2017.10.026"},{"key":"e_1_2_10_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-021-00393-8"},{"key":"e_1_2_10_26_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pathol.4.110807.092150"},{"key":"e_1_2_10_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2024.155705"},{"key":"e_1_2_10_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehac109"},{"key":"e_1_2_10_29_2","doi-asserted-by":"publisher","DOI":"10.1080\/09537104.2020.1782868"},{"key":"e_1_2_10_30_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1092385"},{"key":"e_1_2_10_31_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI84538"},{"key":"e_1_2_10_32_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.70001"},{"key":"e_1_2_10_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2018.08.005"},{"key":"e_1_2_10_34_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25179625"},{"key":"e_1_2_10_35_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.20.7734"},{"key":"e_1_2_10_36_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0064443"},{"key":"e_1_2_10_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2021.105066"},{"key":"e_1_2_10_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2022.104640"},{"key":"e_1_2_10_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/jleuko\/qiad080"},{"key":"e_1_2_10_40_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2015080923"},{"key":"e_1_2_10_41_2","doi-asserted-by":"publisher","DOI":"10.1160\/TH15-02-0162"},{"key":"e_1_2_10_42_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0806538"},{"key":"e_1_2_10_43_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.304114"},{"key":"e_1_2_10_44_2","doi-asserted-by":"publisher","DOI":"10.1160\/TH14-05-0455"},{"key":"e_1_2_10_45_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-01-624023"},{"key":"e_1_2_10_46_2","doi-asserted-by":"publish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