Research Papers:

Synthetic nickel-containing superoxide dismutase attenuates para-phenylenediamine-induced bladder dysfunction in rats

Bing-Juin Chiang, Tien-Wen Chen, Shiu-Dong Chung, Way-Zen Lee and Chiang-Ting Chien _

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Oncotarget. 2017; 8:105735-105748. https://doi.org/10.18632/oncotarget.22395

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Bing-Juin Chiang1,2, Tien-Wen Chen1, Shiu-Dong Chung3,4, Way-Zen Lee5 and Chiang-Ting Chien1

1Department of Life Science, College of Science, National Taiwan Normal University, Taipei City 11677, Taiwan

2Department of Urology, Cardinal Tien Hospital, New Taipei City 23148, Taiwan

3Department of Urology, Far-Eastern Memorial Hospital, New Taipei City 220, Taiwan

4Graduate Program in Biomedical Informatics, College of Informatics, Yuan-Ze University, Chungli 320, Taiwan

5Department of Chemistry, College of Science, National Taiwan Normal University, Taipei City 11677, Taiwan

Correspondence to:

Chiang-Ting Chien, email: [email protected]

Shiu-Dong Chung, email: [email protected]

Way-Zen Lee, email: [email protected]

Keywords: urinary bladder; para-phenylenediamine; Ni-SOD mimics; micturition; programmed cell death

Received: May 23, 2017    Accepted: October 05, 2017    Published: November 11, 2017


Para (p)-phenylenediamine and its toxic metabolites induce excess reactive oxygen species formation that results in bladder voiding dysfunction. We determined the effects of synthetic Ni-containing superoxide dismutase mimics and the role of oxidative stress in p-phenylenediamine-induced urinary bladder dysfunction. P-phenylenediamine (60 μg/kg/day) was intraperitoneally administered for 4 weeks to induce bladder injury in female Wistar rats. Synthetic Ni-containing superoxide dismutase mimics, WCT003 (1.5 mg/kg) and WCT006 (1.5 mg/kg), were then intraperitoneally administered for 2 weeks. Transcystometrograms were performed in urethane-anesthetized rats. The in vitro and in vivo reactive oxygen species levels and pathological changes in formalin-fixed bladder sections were evaluated. Western blotting and immunohistochemistry elucidated the pathophysiological mechanisms of oxidative stress-induced apoptosis, autophagy, and pyroptosis. P-phenylenediamine increased voiding frequency, blood and urinary bladder levels of reactive oxygen species, and neutrophil and mast cell infiltration. It also upregulated biomarkers of autophagy (LC3 II), apoptosis (poly (ADP-ribose) polymerase), and pyroptosis (Caspase 1). WCT003 and WCT006 ameliorated reactive oxygen species production, inflammation, apoptosis, autophagy, pyroptosis, and bladder hyperactivity. P-phenylenediamine increased oxidative stress, inflammatory leukocytosis, autophagy, apoptosis, and pyroptosis formation within the urinary bladder. Novel synthetic nickel-containing superoxide dismutase mimics relieved p-phenylenediamine-induced bladder inflammation and voiding dysfunction.

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