Chiang Bing-Juin, Chen Tien-Wen, Chung Shiu-Dong, Lee Way-Zen, Chien Chiang-Ting
Department of Life Science, College of Science, National Taiwan Normal University, Taipei City 11677, Taiwan.
Department of Urology, Cardinal Tien Hospital, New Taipei City 23148, Taiwan.
Oncotarget. 2017 Nov 11;8(62):105735-105748. doi: 10.18632/oncotarget.22395. eCollection 2017 Dec 1.
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 and 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.
对苯二胺及其有毒代谢产物会诱导过量活性氧的形成，从而导致膀胱排尿功能障碍。我们确定了合成的含镍超氧化物歧化酶模拟物的作用以及氧化应激在对苯二胺诱导的膀胱功能障碍中的作用。对雌性Wistar大鼠腹腔注射对苯二胺（60μg/kg/天），持续4周以诱导膀胱损伤。然后腹腔注射合成的含镍超氧化物歧化酶模拟物WCT003（1.5mg/kg）和WCT006（1.5mg/kg），持续2周。在经乌拉坦麻醉的大鼠中进行膀胱压力容积测定。评估福尔马林固定的膀胱切片中的活性氧水平和病理变化。蛋白质免疫印迹和免疫组织化学阐明了氧化应激诱导的细胞凋亡、自噬和焦亡的病理生理机制。对苯二胺增加了排尿频率、血液和膀胱中的活性氧水平，以及中性粒细胞和肥大细胞浸润。它还上调了自噬（LC3 II）、细胞凋亡（聚（ADP-核糖）聚合酶）和焦亡（半胱天冬酶1）的生物标志物。WCT003和WCT006改善了活性氧的产生、炎症、细胞凋亡、自噬、焦亡和膀胱功能亢进。对苯二胺增加了膀胱内的氧化应激、炎症性白细胞增多、自噬、细胞凋亡和焦亡的形成。新型合成含镍超氧化物歧化酶模拟物减轻了对苯二胺诱导的膀胱炎症和排尿功能障碍。
