{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T16:53:28Z","timestamp":1770483208423,"version":"3.49.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:00Z","timestamp":1770336000000},"content-version":"vor","delay-in-days":23,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"name":"Qinchuangyuan Traditional Chinese Medicine Industry Innovation Agglomeration Area Project","award":["L2024-QCY-ZYYJJQ-X195"],"award-info":[{"award-number":["L2024-QCY-ZYYJJQ-X195"]}]},{"name":"Innovation Team Project of Shaanxi Provincial Department of Education","award":["24JP047"],"award-info":[{"award-number":["24JP047"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-026-35413-9","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T09:47:55Z","timestamp":1768384075000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The mechanism of indigo naturalis and its active ingredients against ulcerative colitis"],"prefix":"10.1038","volume":"16","author":[{"given":"Ke-Yu","family":"Ma","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bao-Long","family":"Hou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"An-Qi","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"An-Li","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo-Rui","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan-Ni","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,1,14]]},"reference":[{"key":"35413_CR1","doi-asserted-by":"publisher","first-page":"1756","DOI":"10.1016\/s0140-6736(16)32126-2","volume":"389","author":"R Ungaro","year":"2017","unstructured":"Ungaro, R., Mehandru, S., Allen, P. B., Peyrin-Biroulet, L. & Colombel, J. F. Ulcerative colitis. Lancet 389, 1756\u20131770. https:\/\/doi.org\/10.1016\/s0140-6736(16)32126-2 (2017).","journal-title":"Lancet"},{"key":"35413_CR2","doi-asserted-by":"publisher","unstructured":"Li, B. et al. Luteolin alleviates inflammation and modulates gut microbiota in ulcerative colitis rats. Life Sci. 269 https:\/\/doi.org\/10.1016\/j.lfs.2020.119008 (2021).","DOI":"10.1016\/j.lfs.2020.119008"},{"key":"35413_CR3","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1093\/ibd\/izab277","volume":"28","author":"Y Wan","year":"2022","unstructured":"Wan, Y., Yang, L., Jiang, S., Qian, D. & Duan, J. Excessive apoptosis in ulcerative colitis: crosstalk between apoptosis, ROS, ER Stress, and intestinal homeostasis. Inflamm. Bowel Dis. 28, 639\u2013648. https:\/\/doi.org\/10.1093\/ibd\/izab277 (2022).","journal-title":"Inflamm. Bowel Dis."},{"key":"35413_CR4","doi-asserted-by":"publisher","unstructured":"Zakerska-Banaszak, O. et al. Dysbiosis of gut microbiota in Polish patients with ulcerative colitis: a pilot study. Sci. Rep-Uk. 11 https:\/\/doi.org\/10.1038\/s41598-021-81628-3 (2021).","DOI":"10.1038\/s41598-021-81628-3"},{"key":"35413_CR5","first-page":"1635","volume":"37","author":"AI Jacltnowitz","year":"1980","unstructured":"Jacltnowitz, A. I. Ulcerative colitis and its treatment. Am. J. Hosp. Pharm. 37, 1635\u20131646 (1980).","journal-title":"Am. J. Hosp. Pharm."},{"key":"35413_CR6","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/s1734-1140(11)70575-8","volume":"63","author":"AB Pithadia","year":"2011","unstructured":"Pithadia, A. B. & Jain, S. Treatment of inflammatory bowel disease (IBD). Pharmacol. Rep. 63, 629\u2013642. https:\/\/doi.org\/10.1016\/s1734-1140(11)70575-8 (2011).","journal-title":"Pharmacol. Rep."},{"key":"35413_CR7","doi-asserted-by":"publisher","unstructured":"Wehkamp, J. & Stange, E. F. Recent advances and emerging therapies in the non-surgical management of ulcerative colitis. F1000Research 7, (2018). https:\/\/doi.org\/10.12688\/f1000research.15159.1","DOI":"10.12688\/f1000research.15159.1"},{"key":"35413_CR8","doi-asserted-by":"publisher","first-page":"3242","DOI":"10.3748\/wjg.v25.i25.3242","volume":"25","author":"YL Zhang","year":"2019","unstructured":"Zhang, Y. L. et al. Gut microbiota contributes to the distinction between two traditional Chinese medicine syndromes of ulcerative colitis. World J. Gastroentero. 25, 3242\u20133255. https:\/\/doi.org\/10.3748\/wjg.v25.i25.3242 (2019).","journal-title":"World J. Gastroentero"},{"key":"35413_CR9","doi-asserted-by":"publisher","unstructured":"Chen, J., Shen, B. & Jiang, Z. Traditional Chinese medicine prescription Shenling BaiZhu powder to treat ulcerative colitis: clinical evidence and potential mechanisms. Front. Pharmacol. 13 https:\/\/doi.org\/10.3389\/fphar.2022.978558 (2022).","DOI":"10.3389\/fphar.2022.978558"},{"key":"35413_CR10","doi-asserted-by":"publisher","unstructured":"Qi-yue, Y. et al. From natural dye to herbal medicine: a systematic review of chemical constituents, Pharmacological effects and clinical applications of Indigo naturalis. Chin. Med-Uk. 15 https:\/\/doi.org\/10.1186\/s13020-020-00406-x (2020).","DOI":"10.1186\/s13020-020-00406-x"},{"key":"35413_CR11","doi-asserted-by":"publisher","first-page":"59","DOI":"10.3831\/kpi.2024.27.2.59","volume":"27","author":"H Kim","year":"2024","unstructured":"Kim, H. et al. Indigo naturalis in inflammatory bowel disease: mechanisms of action and insights from clinical trials. J. Pharmacopunct. 27, 59\u201369. https:\/\/doi.org\/10.3831\/kpi.2024.27.2.59 (2024).","journal-title":"J. Pharmacopunct."},{"key":"35413_CR12","doi-asserted-by":"publisher","unstructured":"Xiao, H. T. et al. Qing-dai powder promotes recovery of colitis by inhibiting inflammatory responses of colonic macrophages in dextran sulfate sodium-treated mice. Chin. Med-Uk. 10 https:\/\/doi.org\/10.1186\/s13020-015-0061-x (2015).","DOI":"10.1186\/s13020-015-0061-x"},{"key":"35413_CR13","doi-asserted-by":"publisher","unstructured":"Wang, M. et al. Traditional Chinese medicine: A promising strategy to regulate the imbalance of bacterial flora, impaired intestinal barrier and immune function attributed to ulcerative colitis through intestinal microecology. J. Ethnopharmacol. 318 https:\/\/doi.org\/10.1016\/j.jep.2023.116879 (2024).","DOI":"10.1016\/j.jep.2023.116879"},{"key":"35413_CR14","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1007\/s40257-017-0266-0","volume":"18","author":"B Farahnik","year":"2017","unstructured":"Farahnik, B., Sharma, D., Alban, J. & Sivamani, R. K. Topical botanical agents for the treatment of psoriasis: a systematic review. Am. J. Clin. Dermatol. 18, 451\u2013468. https:\/\/doi.org\/10.1007\/s40257-017-0266-0 (2017).","journal-title":"Am. J. Clin. Dermatol."},{"key":"35413_CR15","doi-asserted-by":"publisher","unstructured":"Lin, Y. K. et al. Efficacy and safety of Indigo naturalis ointment in treating atopic dermatitis: A randomized clinical trial. J. Ethnopharmacol. 250 https:\/\/doi.org\/10.1016\/j.jep.2019.112477 (2020).","DOI":"10.1016\/j.jep.2019.112477"},{"key":"35413_CR16","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1080\/25785826.2019.1599158","volume":"42","author":"M Naganuma","year":"2019","unstructured":"Naganuma, M. Treatment with Indigo naturalis for inflammatory bowel disease and other immune diseases. Immunol. Med. 42, 16\u201321. https:\/\/doi.org\/10.1080\/25785826.2019.1599158 (2019).","journal-title":"Immunol. Med."},{"key":"35413_CR17","doi-asserted-by":"publisher","unstructured":"Gu, S. et al. Clinical, Pharmacology and in vivo studies of QingDai (indigo naturalis) promotes mucosal healing and symptom improvement in ulcerative colitis by regulating the AHR-Th17\/Treg pathway. J. Inflamm-Lond. 21 https:\/\/doi.org\/10.1186\/s12950-024-00413-x (2024).","DOI":"10.1186\/s12950-024-00413-x"},{"key":"35413_CR18","doi-asserted-by":"publisher","unstructured":"Yang, Q. et al. Exploring the mechanism of Indigo naturalis in the treatment of ulcerative colitis based on TLR4\/MyD88\/NF-\u03baB signaling pathway and gut microbiota. Front. Pharmacol. 12 https:\/\/doi.org\/10.3389\/fphar.2021.674416 (2021).","DOI":"10.3389\/fphar.2021.674416"},{"key":"35413_CR19","doi-asserted-by":"publisher","unstructured":"Liang, Y. N. et al. Indigo naturalis ameliorates dextran sulfate Sodium-Induced colitis in mice by modulating the intestinal microbiota community. Molecules 24 https:\/\/doi.org\/10.3390\/molecules24224086 (2019).","DOI":"10.3390\/molecules24224086"},{"key":"35413_CR20","doi-asserted-by":"publisher","unstructured":"Wang, Z. et al. Guchang Zhixie Wan protects mice against dextran sulfate sodium-induced colitis through modulating the gut microbiota in colon. J. Ethnopharmacol. 260 https:\/\/doi.org\/10.1016\/j.jep.2020.112991 (2020).","DOI":"10.1016\/j.jep.2020.112991"},{"key":"35413_CR21","doi-asserted-by":"publisher","unstructured":"Wang, Z. et al. Tryptanthrin protects mice against dextran sulfate Sodium-Induced colitis through Inhibition of TNF-\u03b1\/NF-\u03baB and IL-6\/STAT3 pathways. Molecules 23 https:\/\/doi.org\/10.3390\/molecules23051062 (2018).","DOI":"10.3390\/molecules23051062"},{"key":"35413_CR22","doi-asserted-by":"publisher","first-page":"36658","DOI":"10.18632\/oncotarget.17560","volume":"8","author":"Q Tianjie","year":"2017","unstructured":"Tianjie, Q., Haitao, L. & Shuai, L. Indirubin improves antioxidant and anti-inflammatory functions in lipopolysaccharide-challenged mice. Oncotarget 8, 36658\u201336663. https:\/\/doi.org\/10.18632\/oncotarget.17560 (2017).","journal-title":"Oncotarget"},{"key":"35413_CR23","doi-asserted-by":"publisher","unstructured":"Hou, Y. et al. Targeting upregulation of the immunosuppressive activity of MDSCs with indirubin as a novel strategy to alleviate psoriasis. Int. Immunopharmacol. 123 https:\/\/doi.org\/10.1016\/j.intimp.2023.110710 (2023).","DOI":"10.1016\/j.intimp.2023.110710"},{"key":"35413_CR24","doi-asserted-by":"publisher","unstructured":"Cenalmor, A. et al. Evaluation of Anti-Neuroinflammatory activity of Isatin derivatives in activated microglia. Molecules 28 https:\/\/doi.org\/10.3390\/molecules28124882 (2023).","DOI":"10.3390\/molecules28124882"},{"key":"35413_CR25","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1089\/jmf.2023.K.0132","volume":"26","author":"A Fan","year":"2023","unstructured":"Fan, A. et al. Liquid Chromatography-Tandem mass Spectrometry-Based metabolomics analysis of Indigo naturalis treatment of ulcerative colitis in mice. J. Med. Food. 26, 877\u2013889. https:\/\/doi.org\/10.1089\/jmf.2023.K.0132 (2023).","journal-title":"J. Med. Food"},{"key":"35413_CR26","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/j.jare.2021.07.002","volume":"37","author":"Q Shen","year":"2022","unstructured":"Shen, Q., Huang, Z., Yao, J. & Jin, Y. Extracellular vesicles-mediated interaction within intestinal microenvironment in inflammatory bowel disease. J. Adv. Res. 37, 221\u2013233. https:\/\/doi.org\/10.1016\/j.jare.2021.07.002 (2022).","journal-title":"J. Adv. Res."},{"key":"35413_CR27","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1007\/s00535-016-1292-z","volume":"52","author":"S Kawai","year":"2016","unstructured":"Kawai, S. et al. Indigo naturalis ameliorates murine dextran sodium sulfate-induced colitis via Aryl hydrocarbon receptor activation. J. Gastroenterol. 52, 904\u2013919. https:\/\/doi.org\/10.1007\/s00535-016-1292-z (2016).","journal-title":"J. Gastroenterol."},{"key":"35413_CR28","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.3892\/etm.2017.4701","volume":"14","author":"Y Wang","year":"2017","unstructured":"Wang, Y. et al. Effects of Indigo naturalis on colonic mucosal injuries and inflammation in rats with dextran sodium sulphate-induced ulcerative colitis. Exp. Ther. Med. 14, 1327\u20131336. https:\/\/doi.org\/10.3892\/etm.2017.4701 (2017).","journal-title":"Exp. Ther. Med."},{"key":"35413_CR29","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1002\/med.21599","volume":"40","author":"MA Cinelli","year":"2020","unstructured":"Cinelli, M. A., Do, H. T., Miley, G. P. & Silverman, R. B. Inducible nitric oxide synthase: Regulation, structure, and Inhibition. Med. Res. Rev. 40, 158\u2013189. https:\/\/doi.org\/10.1002\/med.21599 (2020).","journal-title":"Med. Res. Rev."},{"key":"35413_CR30","doi-asserted-by":"publisher","unstructured":"Wen, Z. et al. HMGB1 modulates macrophage metabolism and polarization in ulcerative colitis by inhibiting Cpt1a expression. Front. Biosci-Landmrk. 29 https:\/\/doi.org\/10.31083\/j.fbl2911387 (2024).","DOI":"10.31083\/j.fbl2911387"},{"key":"35413_CR31","doi-asserted-by":"publisher","first-page":"6425","DOI":"10.1002\/jcp.26429","volume":"233","author":"A Shapouri-Moghaddam","year":"2018","unstructured":"Shapouri-Moghaddam, A. et al. Macrophage plasticity, polarization, and function in health and disease. J. Cell. Physiol. 233, 6425\u20136440. https:\/\/doi.org\/10.1002\/jcp.26429 (2018).","journal-title":"J. Cell. Physiol."},{"key":"35413_CR32","doi-asserted-by":"publisher","unstructured":"Guo, H. et al. Mo3Se4 nanoparticle with ROS scavenging and multi-enzyme activity for the treatment of DSS-induced colitis in mice. Redox Biol. 56 https:\/\/doi.org\/10.1016\/j.redox.2022.102441 (2022).","DOI":"10.1016\/j.redox.2022.102441"},{"key":"35413_CR33","doi-asserted-by":"publisher","unstructured":"Qin, X., Niu, Z., Chen, H. & Hu, Y. Macrophage-derived Exosomal HMGB3 regulates silica-induced pulmonary inflammation by promoting M1 macrophage polarization and recruitment. Part. Fibre Toxicol. 21 https:\/\/doi.org\/10.1186\/s12989-024-00568-8 (2024).","DOI":"10.1186\/s12989-024-00568-8"},{"key":"35413_CR34","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1080\/13510002.2019.1658377","volume":"24","author":"F Xu","year":"2019","unstructured":"Xu, F., Xu, J., Xiong, X. & Deng, Y. Salidroside inhibits MAPK, NF-\u03baB, and STAT3 pathways in psoriasis-associated oxidative stress via SIRT1 activation. Redox Rep. 24, 70\u201374. https:\/\/doi.org\/10.1080\/13510002.2019.1658377 (2019).","journal-title":"Redox Rep."},{"key":"35413_CR35","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1146\/annurev.immunol.14.1.649","volume":"14","author":"AS Baldwin","year":"1996","unstructured":"Baldwin, A. S. & THE NF-\u03baB AND I\u03baB PROTEINS new discoveries and insights. Annu. Rev. Immunol. 14, 649\u2013683 (1996).","journal-title":"Annu. Rev. Immunol."},{"key":"35413_CR36","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1080\/00365521.2016.1235224","volume":"52","author":"D Muthas","year":"2016","unstructured":"Muthas, D. et al. Neutrophils in ulcerative colitis: a review of selected biomarkers and their potential therapeutic implications. Scand. J. Gastroentero. 52, 125\u2013135. https:\/\/doi.org\/10.1080\/00365521.2016.1235224 (2016).","journal-title":"Scand. J. Gastroentero"},{"key":"35413_CR37","doi-asserted-by":"publisher","unstructured":"Lee, M. R. et al. Metagonimus Miyatai ameliorates dextran sodium sulfate-induced colitis in mice. Parasitol. Int. 74 https:\/\/doi.org\/10.1016\/j.parint.2019.05.002 (2020).","DOI":"10.1016\/j.parint.2019.05.002"},{"key":"35413_CR38","doi-asserted-by":"publisher","unstructured":"Tang, L. et al. Combination of Youhua Kuijie prescription and sulfasalazine can alleviate experimental colitis via IL-6\/JAK2\/STAT3 pathway. Front. Pharmacol. 15 https:\/\/doi.org\/10.3389\/fphar.2024.1437503 (2024).","DOI":"10.3389\/fphar.2024.1437503"},{"key":"35413_CR39","doi-asserted-by":"publisher","unstructured":"Li, C., Deng, L., Pu, M., Ye, X. & Lu, Q. Coptisine alleviates colitis through modulating gut microbiota and inhibiting TXNIP\/NLRP3 inflammasome. J. Ethnopharmacol. 335 https:\/\/doi.org\/10.1016\/j.jep.2024.118680 (2024).","DOI":"10.1016\/j.jep.2024.118680"},{"key":"35413_CR40","doi-asserted-by":"publisher","unstructured":"Li, L. et al. Sanhuang Xiexin Decoction ameliorates secondary liver injury in DSS-induced colitis involve regulating inflammation and bile acid metabolism. J. Ethnopharmacol. 299 https:\/\/doi.org\/10.1016\/j.jep.2022.115682 (2022).","DOI":"10.1016\/j.jep.2022.115682"},{"key":"35413_CR41","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.abb.2018.01.004","volume":"640","author":"Y Aratani","year":"2018","unstructured":"Aratani, Y. & Myeloperoxidase Its role for host defense, inflammation, and neutrophil function. Arch. Biochem. Biophys. 640, 47\u201352. https:\/\/doi.org\/10.1016\/j.abb.2018.01.004 (2018).","journal-title":"Arch. Biochem. Biophys."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-35413-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-35413-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-35413-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T21:02:54Z","timestamp":1770411774000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-35413-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,14]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["35413"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-35413-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,14]]},"assertion":[{"value":"22 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 January 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5220"}}