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It is also a widely used pharmacological inhibitor of several channels in basic research. Given that the overactivity of several channels, including those inhibitable by <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content>, underlies bladder dysfunction, we tested the potential therapeutic application and mechanism of <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content> in the treatment of voiding dysfunction. In a mouse model of cystitis induced by cyclophosphamide (<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>), <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content> administration prevented the <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>\u2010elicited increase in bladder weight, oedema, haemorrhage, and urothelial injury. <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content> also greatly improved micturition pattern, as manifested by the apparently decreased micturition frequency and increased micturition volume. Western blot results showed that <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content> suppressed <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>\u2010induced increase in protein carbonyls, <jats:styled-content style=\"fixed-case\">COX<\/jats:styled-content>\u20102, and <jats:styled-content style=\"fixed-case\">iNOS<\/jats:styled-content>. Further analysis using cultured urothelial cells revealed that acrolein, the major metabolite of <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>, caused protein oxidation, p38 activation, and urothelial injury. These effects of acrolein were reproduced by <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>4 agonists and significantly prevented by antioxidant <jats:styled-content style=\"fixed-case\">NAC<\/jats:styled-content>, p38 inhibitor <jats:styled-content style=\"fixed-case\">SB<\/jats:styled-content>203580, <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>4 antagonist <jats:styled-content style=\"fixed-case\">RN<\/jats:styled-content>\u20101734, and <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content>. Further studies showed that <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content> potently suppressed <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>4 agonist\u2010initiated calcium influx and subsequent cell injury. <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content> attenuated <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>\u2010induced cystitis <jats:italic>in vivo<\/jats:italic> and reduced acrolein\u2010induced cell injury <jats:italic>in vitro<\/jats:italic>, through mechanisms involving inhibition of <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>4 channels and attenuation of the channel\u2010mediated oxidative stress. <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content> might be a promising agent for the treatment of bladder dysfunction.<\/jats:p>","DOI":"10.1111\/jcmm.13100","type":"journal-article","created":{"date-parts":[[2017,2,28]],"date-time":"2017-02-28T11:19:17Z","timestamp":1488280757000},"page":"1791-1802","source":"Crossref","is-referenced-by-count":18,"title":["Carbenoxolone inhibits <scp>TRPV<\/scp>4 channel\u2010initiated oxidative urothelial injury and ameliorates cyclophosphamide\u2010induced bladder dysfunction"],"prefix":"10.1111","volume":"21","author":[{"given":"Xiling","family":"Zhang","sequence":"first","affiliation":[{"name":"Division of Molecular Signaling Department of Advanced Biomedical Research University of Yamanashi Yamanashi Japan"},{"name":"China Medical University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Gao","sequence":"additional","affiliation":[{"name":"Division of Molecular Signaling Department of Advanced Biomedical Research University of Yamanashi Yamanashi Japan"},{"name":"China Medical University Shenyang 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