{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T05:55:48Z","timestamp":1776491748995,"version":"3.51.2"},"reference-count":65,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,5,1]],"date-time":"2022-05-01T00:00:00Z","timestamp":1651363200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grants-in-Aid for Scientific Research","award":["15H05682"],"award-info":[{"award-number":["15H05682"]}]},{"name":"Grants-in-Aid for Scientific Research","award":["18K09154"],"award-info":[{"award-number":["18K09154"]}]},{"name":"Grants-in-Aid for Scientific Research","award":["20K18086"],"award-info":[{"award-number":["20K18086"]}]},{"name":"Grants-in-Aid for Scientific Research","award":["22K09468"],"award-info":[{"award-number":["22K09468"]}]},{"name":"Grants-in-Aid for Scientific Research","award":["22K09491"],"award-info":[{"award-number":["22K09491"]}]},{"name":"Grants-in-Aid for Scientific Research","award":["DK122153"],"award-info":[{"award-number":["DK122153"]}]},{"name":"National Institutes of Health","award":["15H05682"],"award-info":[{"award-number":["15H05682"]}]},{"name":"National Institutes of Health","award":["18K09154"],"award-info":[{"award-number":["18K09154"]}]},{"name":"National Institutes of Health","award":["20K18086"],"award-info":[{"award-number":["20K18086"]}]},{"name":"National Institutes of Health","award":["22K09468"],"award-info":[{"award-number":["22K09468"]}]},{"name":"National Institutes of Health","award":["22K09491"],"award-info":[{"award-number":["22K09491"]}]},{"name":"National Institutes of Health","award":["DK122153"],"award-info":[{"award-number":["DK122153"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Bladder inflammatory diseases cause various urinary symptoms, such as urinary frequency and painful urination, that impair quality of life. In this study, we used a mouse model of cyclophosphamide (CYP)-induced bladder inflammation and immortalized human urothelial (TRT-HU1) cells to explore the preventive potential of nobiletin (NOB), a polymethoxylated flavone enriched in citrus fruit peel, and investigate its mechanism of action in the bladder. Prophylaxis with PMF90 (60% NOB) attenuated the development of bladder inflammation and urinary symptoms in CYP-treated mice. PMF90 also reduced the upregulation of connexin 43 (Cx43), a major component of gap junction channels, in the bladder mucosa of CYP-treated mice. Stimulation of TRT-HU1 cells with the pro-inflammatory cytokine IL-1\u03b2 increased Cx43 mRNA and protein expression and enhanced gap junction coupling\u2014responses that were prevented by pre-treatment with NOB. In urothelium-specific Cx43 knockout (uCx43KO) mice, macroscopic signs of bladder inflammation and changes in voiding behavior induced by CYP treatment were significantly attenuated when compared to controls. These findings indicate the participation of urothelial Cx43 in the development of bladder inflammation and urinary symptoms in CYP-treated mice and provide pre-clinical evidence for the preventive potential of NOB through its anti-inflammatory effects on IL-1\u03b2 signaling and urothelial Cx43 expression.<\/jats:p>","DOI":"10.3390\/ijms23095037","type":"journal-article","created":{"date-parts":[[2022,5,1]],"date-time":"2022-05-01T06:23:08Z","timestamp":1651386188000},"page":"5037","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Flavonoid Nobiletin Attenuates Cyclophosphamide-Induced Cystitis in Mice through Mechanisms That Involve Inhibition of IL-1\u03b2 Induced Connexin 43 Upregulation and Gap Junction Communication in Urothelial Cells"],"prefix":"10.3390","volume":"23","author":[{"given":"Jin","family":"Kono","sequence":"first","affiliation":[{"name":"Department of Urology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masakatsu","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Urology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan"},{"name":"Department of Urology, Shizuoka General Hospital, Shizuoka 420-8527, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Sengiku","sequence":"additional","affiliation":[{"name":"Department of Urology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan"},{"name":"Sengiku Urology Clinic, Shiga 524-0045, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6811-4029","authenticated-orcid":false,"given":"Sylvia O.","family":"Suadicani","sequence":"additional","affiliation":[{"name":"Department of Urology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Je Tae","family":"Woo","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, College of Bioscience and Biotechnology, Chubu University, Kasugai  487-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1069-2816","authenticated-orcid":false,"given":"Takashi","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Urology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Osamu","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Department of Urology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1144-2755","authenticated-orcid":false,"given":"Hiromitsu","family":"Negoro","sequence":"additional","affiliation":[{"name":"Department of Urology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan"},{"name":"Department of Urology, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1007\/s00192-020-04659-w","article-title":"Efficacy and safety comparison of pharmacotherapies for interstitial cystitis and bladder pain syndrome: A systematic review and Bayesian network meta-analysis","volume":"32","author":"Di","year":"2021","journal-title":"Int. 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