{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T12:51:07Z","timestamp":1780145467582,"version":"3.54.0"},"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T00:00:00Z","timestamp":1710288000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81402100"],"award-info":[{"award-number":["81402100"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20211123"],"award-info":[{"award-number":["BK20211123"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013058","name":"Jiangsu Provincial Key Research and Development Program","doi-asserted-by":"publisher","award":["BE2023760"],"award-info":[{"award-number":["BE2023760"]}],"id":[{"id":"10.13039\/501100013058","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Melatonin (MEL) is an indole amine molecule primarily produced in the pineal gland. Melatonin has been shown in numerous studies to have antifibrotic effects on the kidney, liver, and other organs. However, it is still unclear how melatonin works in bladder fibrosis. We explored how melatonin affects animals with bladder fibrosis and the underlying mechanisms.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Materials and methods<\/jats:title>\n<jats:p>MEL was used to treat human bladder smooth muscle cells (HBdSMCs) after they were stimulated with transforming growth factor-\u03b21 (TGF-\u03b21) <jats:italic>in vitro<\/jats:italic>. Proteomic analysis and bioinformatic analysis of the altered expression of these proteins were subsequently performed on HBdSMCs from the different processing methods. To construct an <jats:italic>in vivo<\/jats:italic> bladder fibrosis model, we injected protamine sulfate (PS) and lipopolysaccharide (LPS) twice a week into the rat bladder for six weeks. After two weeks of PS\/LPS treatment, the mice in the treatment group were treated with MEL (20 mg\/kg\/d) for 4 weeks. Finally, we detected the expression of fibrosis markers from different perspectives. The TGF-\u03b21\/Smad pathway and epithelial\u2013mesenchymal transition (EMT) in cell and bladder tissues were also identified. Further proteomic analysis was also performed.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p><jats:italic>In vitro<\/jats:italic>, we found that TGF-\u03b21 treatment enhanced the expression of the fibrosis markers collagen III and \u03b1-SMA in HBdSMCs. E-cadherin expression decreased while the TGF-\u03b21\/Smad pathway was activated. Vimentin and N-cadherin expression was also elevated at the same time. Similar findings were observed in the LPS group. After MEL treatment, the expression of collagen III and \u03b1-SMA decreased, the expression of E-cadherin increased, and the expression of vimentin and N-cadherin also decreased. According to our quantitative proteomics analysis, CCN1 and SQLE may be important proteins involved in the development of bladder fibrosis. MEL decreased the expression of these genes, leading to the relief of bladder fibrosis. Bioinformatics analysis revealed that the extracellular space structure related to metabolic pathways, actin filament binding, and stress fibers can serve as a pivotal focus in the management of fibrosis.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Melatonin attenuates bladder fibrosis by blocking the TGF-\u03b21\/Smad pathway and EMT. CCN1 appears to be a possible therapeutic target for bladder fibrosis.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0295104","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T17:26:10Z","timestamp":1710350770000},"page":"e0295104","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Melatonin serves as a novel treatment in bladder fibrosis through TGF-\u03b21\/Smad and EMT"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9084-7672","authenticated-orcid":true,"given":"Yang","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weixin","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haomin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0913-860X","authenticated-orcid":true,"given":"Binghai","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,3,13]]},"reference":[{"issue":"4","key":"pone.0295104.ref001","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/s41390-020-01329-x","article-title":"The TGF-\u03b21 pathway is early involved in neurogenic bladder fibrosis of juvenile rats","volume":"90","author":"Y Chen","year":"2021","journal-title":"Pediatric Research"},{"issue":"2","key":"pone.0295104.ref002","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/iub.1968","article-title":"MicroRNA\u2010101 protects bladder of BOO from hypoxia\u2010induced fibrosis by attenuating TGF\u2010\u03b2\u2010smad2\/3 signaling","volume":"71","author":"N Wang","year":"2018","journal-title":"IUBMB Life"},{"issue":"2","key":"pone.0295104.ref003","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.cellsig.2014.11.001","article-title":"miR-133 modulates TGF-\u03b21-induced bladder smooth muscle cell hypertrophic and fibrotic response: Implication for a role of microRNA in bladder wall remodeling caused by bladder outlet obstruction","volume":"27","author":"LJ Duan","year":"2015","journal-title":"Cellular Signalling"},{"key":"pone.0295104.ref004","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.matbio.2017.12.016","article-title":"Targeting TGF-\u03b2 signaling for the treatment of fibrosis","volume":"68\u201369","author":"AH Gy\u00f6rfi","year":"2018","journal-title":"Matrix Biology"},{"issue":"7","key":"pone.0295104.ref005","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1038\/nm.2807","article-title":"Mechanisms of fibrosis: therapeutic translation for fibrotic disease","volume":"18","author":"TA Wynn","year":"2012","journal-title":"Nature Medicine"},{"key":"pone.0295104.ref006","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.cbi.2018.07.008","article-title":"New insights into TGF-\u03b2\/Smad signaling in tissue fibrosis","volume":"292","author":"H-H Hu","year":"2018","journal-title":"Chemico-Biological Interactions"},{"issue":"1","key":"pone.0295104.ref007","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.cell.2016.06.028","article-title":"Emt: 2016","volume":"166","author":"MA Nieto","year":"2016","journal-title":"Cell"},{"issue":"10","key":"pone.0295104.ref008","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/nrm3434","article-title":"TGF\u03b2 signalling in context","volume":"13","author":"J. 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