{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T04:14:41Z","timestamp":1791346481134,"version":"4.3.1"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T00:00:00Z","timestamp":1618444800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T00:00:00Z","timestamp":1618444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"the Ministry of Science and Technology of the Republic of China","award":["MOST 105-2314-B-182A-084"],"award-info":[{"award-number":["MOST 105-2314-B-182A-084"]}]},{"name":"the Ministry of Science and Technology of the Republic of China","award":["MOST 108-2314-B-182A-033-MY3"],"award-info":[{"award-number":["MOST 108-2314-B-182A-033-MY3"]}]},{"DOI":"10.13039\/501100004606","name":"Chang Gung Medical Foundation","doi-asserted-by":"publisher","award":["CMRPG8F1211"],"award-info":[{"award-number":["CMRPG8F1211"]}],"id":[{"id":"10.13039\/501100004606","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004606","name":"Chang Gung Medical Foundation","doi-asserted-by":"publisher","award":["CMRPG8F0051-53"],"award-info":[{"award-number":["CMRPG8F0051-53"]}],"id":[{"id":"10.13039\/501100004606","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004606","name":"Chang Gung Medical Foundation","doi-asserted-by":"publisher","award":["CMRPG8J0431"],"award-info":[{"award-number":["CMRPG8J0431"]}],"id":[{"id":"10.13039\/501100004606","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The pathophysiologies of metabolic syndrome (MS) and overactive bladder (OAB) might overlap. Using fructose-fed rats (FFRs) as a rodent model of MS we investigated the effects of tadalafil (a phosphodiesterase type 5 inhibitor) on the dysregulated insulin signalling in the bladder mucosa and bladder overactivity. Micturition behaviour was evaluated. Concentration\u2013response curves on detrusor relaxation to insulin stimulation were examined. Expression and phosphorylation of proteins in the insulin signalling pathway were evaluated by Western blotting. Levels of detrusor cGMP and urinary nitrite and nitrate (NOx) were measured. We observed FFRs exhibited metabolic traits of MS, bladder overactivity, and impaired insulin-activated detrusor relaxation in organ bath study. A high-fructose diet also impeded insulin signalling, reflected by overexpression of IRS1\/pIRS1<jats:sup>Ser307<\/jats:sup> and pIRS2<jats:sup>Ser731<\/jats:sup> and downregulation of PI3K\/pPI3K<jats:sup>Tyr508<\/jats:sup>, AKT\/pAKT<jats:sup>Ser473<\/jats:sup>, and eNOS\/peNOS<jats:sup>Ser1177<\/jats:sup> in the bladder mucosa, alongside decreased urinary NOx and detrusor cGMP levels. Tadalafil treatment restored the reduced level of mucosal peNOS, urinary NOx, and detrusor cGMP, improved the insulin-activated detrusor relaxation, and ameliorated bladder overactivity in FFRs. These results suggest tadalafil may ameliorate MS-associated bladder overactivity by restoring insulin-activated detrusor relaxation via molecular mechanisms that are associated with preservation of IR\/IRS\/PI3K\/AKT\/eNOS pathway in the bladder mucosa and cGMP production in the bladder detrusor.<\/jats:p>","DOI":"10.1038\/s41598-021-87505-3","type":"journal-article","created":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T10:18:05Z","timestamp":1618481885000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Tadalafil ameliorates bladder overactivity by restoring insulin-activated detrusor relaxation via the bladder mucosal IRS\/PI3K\/AKT\/eNOS pathway in fructose-fed rats"],"prefix":"10.1038","volume":"11","author":[{"given":"Wei-Chia","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Leu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kay L. H.","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You-Lin","family":"Tain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao-Chi","family":"Chuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie Y. H.","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,4,15]]},"reference":[{"key":"87505_CR1","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1111\/luts.12193","volume":"11","author":"YC Chuang","year":"2019","unstructured":"Chuang, Y. C. et al. Prevalence of overactive bladder in China, Taiwan and South Korea: Results from a cross-sectional, population-based study. Low Urin. Tract Symptoms 11, 48\u201355 (2019).","journal-title":"Low Urin. Tract Symptoms"},{"key":"87505_CR2","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1186\/s12889-017-4041-1","volume":"17","author":"P Ranasinghe","year":"2017","unstructured":"Ranasinghe, P. et al. Prevalence and trends of metabolic syndrome among adults in the asia-pacific region: A systematic review. BMC Public Health 17, 101 (2017).","journal-title":"BMC Public Health"},{"key":"87505_CR3","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1007\/s11906-014-0449-5","volume":"16","author":"B Falkner","year":"2014","unstructured":"Falkner, B. & Cossrow, N. D. Prevalence of metabolic syndrome and obesity-associated hypertension in the racial ethnic minorities of the United States. Curr. Hypertens. Rep. 16, 449 (2014).","journal-title":"Curr. Hypertens. Rep."},{"key":"87505_CR4","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1007\/s11884-016-0344-9","volume":"11","author":"WS Reynolds","year":"2016","unstructured":"Reynolds, W. S., Fowke, J. & Dmochowski, R. The burden of overactive bladder on US public health. Curr. Bladder Dysfunct. Rep 11, 8\u201313 (2016).","journal-title":"Curr. Bladder Dysfunct. Rep"},{"key":"87505_CR5","unstructured":"Drake, M. J. Overactive bladder. In Campbell-Walsh Urology (eds Wein, A. J. et al.) 11th edn, Vol. III. Chapt 76, 1796\u20131806 (Elsevier, 2016)."},{"key":"87505_CR6","doi-asserted-by":"publisher","first-page":"e45578","DOI":"10.1371\/journal.pone.0045578","volume":"7","author":"WC Lee","year":"2012","unstructured":"Lee, W. C. et al. Sensory dysfunction of bladder mucosa and bladder oversensitivity in a rat model of metabolic syndrome. PLoS ONE 7, e45578 (2012).","journal-title":"PLoS ONE"},{"key":"87505_CR7","doi-asserted-by":"publisher","first-page":"2259","DOI":"10.1113\/jphysiol.2013.251843","volume":"591","author":"LO Leiria","year":"2013","unstructured":"Leiria, L. O. et al. Insulin relaxes bladder via PI3K\/AKT\/eNOS pathway activation in mucosa: Unfolded protein response-dependent insulin resistance as a cause of obesity-associated overactive bladder. J. Physiol. 591, 2259\u20132273 (2013).","journal-title":"J. Physiol."},{"key":"87505_CR8","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1111\/luts.12156","volume":"10","author":"IH Chen","year":"2018","unstructured":"Chen, I. H., Cheng, J. T. & Tong, Y. C. Metabolic syndrome induced bladder cannabinoid receptor changes in the fructose-fed rats. Low Urin. Tract Symptoms 10, 198\u2013203 (2018).","journal-title":"Low Urin. Tract Symptoms"},{"key":"87505_CR9","doi-asserted-by":"publisher","first-page":"e66636","DOI":"10.1371\/journal.pone.0066636","volume":"8","author":"A Oberbach","year":"2013","unstructured":"Oberbach, A. et al. Molecular fingerprint of high fat diet induced urinary bladder metabolic dysfunction in a rat model. PLoS ONE 8, e66636 (2013).","journal-title":"PLoS ONE"},{"key":"87505_CR10","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1080\/14656566.2019.1589452","volume":"20","author":"FZ Monica","year":"2019","unstructured":"Monica, F. Z. & De Nucci, G. Tadalafil for the treatment of benign prostatic hyperplasia. Expert Opin. Pharmacother. 20, 929\u2013937 (2019).","journal-title":"Expert Opin. Pharmacother."},{"key":"87505_CR11","series-title":"Chapt 79","first-page":"1836","volume-title":"Campbell-Walsh Urology","author":"KE Andersson","year":"2016","unstructured":"Andersson, K. E. & Wein, A. J. Pharmacologic management of lower urinary tract storage and emptying failure. In Campbell-Walsh Urology 11th edn, Vol. III (eds Wein, A. J. et al.) 1836\u20131856 (Elsevier, 2016).","edition":"11"},{"key":"87505_CR12","first-page":"59","volume":"100","author":"H Chen","year":"2017","unstructured":"Chen, H. et al. Efficacy of daily low-dose tadalafil for treating overactive bladder: Results of a randomized, double-blind. Placebo-controlled Trial. Urol. 100, 59\u201364 (2017).","journal-title":"Placebo-controlled Trial. Urol."},{"key":"87505_CR13","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1016\/j.eururo.2019.02.038","volume":"75","author":"B Peyronnet","year":"2019","unstructured":"Peyronnet, B. et al. A compressive review of overactive bladder pathophysiology: On the way to tailored treatment. Eur. Urol. 75, 988\u20131000 (2019).","journal-title":"Eur. Urol."},{"key":"87505_CR14","doi-asserted-by":"publisher","first-page":"1987","DOI":"10.3390\/nu11091987","volume":"11","author":"MR Taskinen","year":"2019","unstructured":"Taskinen, M. R., Packard, C. J. & Boren, J. Dietary fructose and the metabolic syndrome. Nutrients 11, 1987 (2019).","journal-title":"Nutrients"},{"key":"87505_CR15","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s12986-016-0123-9","volume":"13","author":"SK Wong","year":"2016","unstructured":"Wong, S. K. et al. Animal models of metabolic syndrome: A review. Nutr. Metab. 13, 65 (2016).","journal-title":"Nutr. Metab."},{"key":"87505_CR16","doi-asserted-by":"publisher","first-page":"1537","DOI":"10.1016\/j.juro.2007.05.114","volume":"178","author":"YC Tong","year":"2007","unstructured":"Tong, Y. C. & Cheng, J. T. Alterations of M2,3-muscarinic receptor protein and mRNA expression in the bladder of the fructose fed obese rat. J. Urol. 178, 1537\u20131542 (2007).","journal-title":"J. Urol."},{"key":"87505_CR17","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1007\/s00394-012-0342-4","volume":"52","author":"SD Chung","year":"2013","unstructured":"Chung, S. D., Chien, C. T. & Yu, H. J. Alterations in peripheral purinergic and muscarinic signaling of rat bladder after long-term fructose-induced metabolic syndrome. Eur. J. Nutr. 52, 347\u2013359 (2013).","journal-title":"Eur. J. Nutr."},{"key":"87505_CR18","doi-asserted-by":"publisher","first-page":"2565","DOI":"10.1007\/s00125-012-2644-8","volume":"55","author":"KD Copps","year":"2012","unstructured":"Copps, K. D. & White, M. F. Regulation of insulin sensitivity by serine\/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 55, 2565\u20132582 (2012).","journal-title":"Diabetologia"},{"key":"87505_CR19","doi-asserted-by":"publisher","first-page":"e86463","DOI":"10.1371\/journal.pone.0086463","volume":"9","author":"WC Lee","year":"2014","unstructured":"Lee, W. C. et al. Hyposensitivity of C-fiber afferents at the distal extremities as an indicator of early stages diabetic bladder dysfunction in type 2 diabetic women. PLoS ONE 9, e86463 (2014).","journal-title":"PLoS ONE"},{"key":"87505_CR20","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1080\/21681805.2017.1354912","volume":"51","author":"Z Saratlija Novakovic","year":"2017","unstructured":"Saratlija Novakovic, Z., Tesija, R. A. & Puljak, L. Association between metabolic syndrome and overactive bladder: A case-control study. Scand. J. Urol. 51, 470\u2013473 (2017).","journal-title":"Scand. J. Urol."},{"key":"87505_CR21","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.lfs.2018.12.015","volume":"217","author":"L Ren","year":"2019","unstructured":"Ren, L. et al. The IRS\/PI3K\/Akt signaling pathway mediates olanzapine-induced hepatic insulin resistance in male rats. Life Sci. 217, 229\u2013236 (2019).","journal-title":"Life Sci."},{"key":"87505_CR22","doi-asserted-by":"publisher","first-page":"H1558","DOI":"10.1152\/ajpheart.00865.2013","volume":"306","author":"S Koka","year":"2014","unstructured":"Koka, S. et al. Chronic inhibition of phosphodiesterase 5 with tadalafil attenuates mitochondrial dysfunction in type 2 diabetic hearts: Potential role of NO\/SIRT1\/PGC-1alpha signaling. Am. J. Physiol. Heart Circ. Physiol. 306, H1558\u2013H1568 (2014).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"87505_CR23","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1111\/jsm.12391","volume":"11","author":"B Musicki","year":"2014","unstructured":"Musicki, B. et al. Sildenafil promotes eNOS activation and inhibits NADPH oxidase in the transgenic sickle cell mouse penis. J. Sex Med. 11, 424\u2013430 (2014).","journal-title":"J. Sex Med."},{"key":"87505_CR24","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1124\/jpet.118.250076","volume":"367","author":"GM Bertollotto","year":"2018","unstructured":"Bertollotto, G. M. et al. Inhibition of multidrug resistance proteins by MK 571 enhances bladder, prostate and urethra relaxation through cAMP or cGMP accumulation. J. Pharmacol. Exp. Ther. 367, 138\u2013146 (2018).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"87505_CR25","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1161\/01.HYP.34.6.1237","volume":"34","author":"ND Vaziri","year":"1999","unstructured":"Vaziri, N. D. & Wang, X. Q. cGMP-mediated negative-feedback regulation of endothelial nitric oxide synthase expression by nitric oxide. Hypertension 34, 1237\u20131241 (1999).","journal-title":"Hypertension"},{"key":"87505_CR26","doi-asserted-by":"publisher","first-page":"63","DOI":"10.2478\/v10102-011-0012-z","volume":"4","author":"J Kopincov\u00e1","year":"2011","unstructured":"Kopincov\u00e1, J., P\u00fazserov\u00e1, A. & Bern\u00e1tov\u00e1, I. Biochemical aspects of nitric oxide synthase feedback regulation by nitric oxide. Interdiscip. Toxicol. 4, 63\u201368 (2011).","journal-title":"Interdiscip. Toxicol."},{"key":"87505_CR27","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1152\/physrev.00030.2012","volume":"93","author":"L Birder","year":"2013","unstructured":"Birder, L. & Andersson, K. E. Urothelial signaling. Physiol. Rev. 93, 653\u2013680 (2013).","journal-title":"Physiol. Rev."},{"key":"87505_CR28","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.ajur.2015.04.014","volume":"2","author":"B Chughtai","year":"2015","unstructured":"Chughtai, B., Ali, A., Dunphy, C. & Kaplan, S. A. Effect of phosphodiesterase inhibitors in the bladder. Asian J. Urol. 2, 33\u201337 (2015).","journal-title":"Asian J. Urol."},{"key":"87505_CR29","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1111\/j.1743-6109.2009.01511.x","volume":"7","author":"B Febbi","year":"2010","unstructured":"Febbi, B. et al. Characterization of phosphodiesterase type 5 expression and functional activity in the human male lower urinary tract. J. Sex Med. 7, 59\u201369 (2010).","journal-title":"J. Sex Med."},{"key":"87505_CR30","doi-asserted-by":"publisher","first-page":"1570","DOI":"10.2174\/092986708784911524","volume":"215","author":"D Eros","year":"2008","unstructured":"Eros, D. et al. Structure\u2013activity relationships of PDE5 inhibitors. Curr. Med. Chem. 215, 1570\u20131585 (2008).","journal-title":"Curr. Med. Chem."},{"key":"87505_CR31","doi-asserted-by":"publisher","first-page":"e003277","DOI":"10.1161\/JAHA.116.003277","volume":"5","author":"JA Hiemstra","year":"2016","unstructured":"Hiemstra, J. A. et al. Saxagliptin and tadalafil differentially alter cyclic guanosine monophosphate (cGMP) signaling and left ventricular function in aortic-banded mini-swine. J. Am. Heart Assoc. 5, e003277 (2016).","journal-title":"J. Am. Heart Assoc."},{"key":"87505_CR32","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1007\/s40265-015-0416-8","volume":"75","author":"U Hostalek","year":"2015","unstructured":"Hostalek, U., Gwilt, M. & Hildemann, S. Therapeutic use of metformin in prediabetes and diabetes prevention. Drugs 75, 1071\u20131094 (2015).","journal-title":"Drugs"},{"key":"87505_CR33","doi-asserted-by":"publisher","first-page":"34669","DOI":"10.1038\/srep34669","volume":"6","author":"WC Lee","year":"2016","unstructured":"Lee, W. C., Tain, Y. L., Wu, K. L., Leu, S. & Chan, J. Y. Maternal fructose exposure programs metabolic syndrome-associated bladder overactivity in young adult offspring. Sci. Rep. 6, 34669 (2016).","journal-title":"Sci. Rep."},{"key":"87505_CR34","doi-asserted-by":"publisher","first-page":"2470","DOI":"10.1016\/j.juro.2008.01.086","volume":"179","author":"WC Lee","year":"2008","unstructured":"Lee, W. C., Chien, C. T., Yu, H. J. & Lee, S. W. Bladder dysfunction in rats with metabolic syndrome induced by long-term fructose feeding. J. Urol. 179, 2470\u20132476 (2008).","journal-title":"J. Urol."},{"key":"87505_CR35","doi-asserted-by":"publisher","first-page":"30392","DOI":"10.1074\/jbc.M103702200","volume":"276","author":"M Montagnani","year":"2001","unstructured":"Montagnani, M., Chen, H., Barr, V. A. & Quon, M. J. Insulin-stimulated activation of eNOS is dependent of Ca2+ but requires phosphorylation by Akt at Ser1179. J. Biol Chem. 276, 30392\u201330398 (2001).","journal-title":"J. Biol Chem."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-87505-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-87505-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-87505-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T06:47:44Z","timestamp":1670050064000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-87505-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,15]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["87505"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-87505-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,15]]},"assertion":[{"value":"22 June 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 March 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 April 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"8202"}}