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INTRODUCTION AND OBJECTIVE:It is reported that the bladder functions are under the regulation of clock genes, which regulate circadian rhythm in organisms, and dysregulation of circadian bladder fu...

INTRODUCTION AND OBJECTIVES:The objective of this study was to evaluate the influence of ingested L-citrulline and L-arginine on the progression of bladder dysfunction in rats with chronic pelvic i...

positively associated with MMP-2 (p1⁄40.0074) and MMP-9/NGAL (p

Increased gap junctions contribute to bladder overactivity but the factors and mechanisms involved in gap junction regulation in the bladder are not well established. We examined whether and how platelet derived growth factor regulates connexin43 in bladder smooth muscle cells.Cultured rat bladder smooth muscle cells were treated with growth factors with or without agents that interfere with phosphatidylinositol 3-kinase, mitogen activated protein kinase and β-catenin signaling pathways. Connexin43 expression was examined by Western and Northern blot, and immunochemistry. Functional gap junctions were evaluated by scrape-loading dye transfer assay. Bladder smooth muscle cell contraction was measured by collagen gel contraction.1) Platelet derived growth factor induced phosphatidylinositol 3-kinase and mitogen activated protein kinase dependent accumulation of nuclear β-catenin. This was followed by increased connexin43 expression. 2) Down-regulation of β-catenin by specific siRNA abolished the connexin43 increasing effect of platelet derived growth factor while β-catenin stimulation due to glycogen synthase kinase inhibition mimicked that effect. 3) Basic fibroblast growth factor and epidermal growth factor also induced connexin43 expression. Their effects were potentiated by platelet derived growth factor. 4) Gap junction inhibition attenuated the bladder smooth muscle cell contraction induced by platelet derived growth factor. Consistently fibroblasts from connexin43 knockout (Cx43-/-) mice showed a much weaker contractile response to platelet derived growth factor than cells from connexin43-wild (Cx43+/+) litter mates.Platelet derived growth factor induces connexin43 expression and bladder smooth muscle cell contraction by activating β-catenin signaling. As a convergence point for many signal pathways, β-catenin may be targeted to treat bladder overactivity.

INTRODUCTION AND OBJECTIVES: Resveratrol(3,5,40-trihydroxy-trans-stilbene), a natural phytoalexin present in grapes, peanuts, mulberries and red wine, is thought to boost endothelial function by increasing endothelial nitric oxide synthase (eNOS) expression, by enhancing eNOS activity and by reduction of reacitive oxygen species (ROS) levels. Its effects on the function of the chronic ischemic bladder are not known. The objective of this study is to investigate the possible beneficial activities of resveratrol in a rat model of chronic ischemiarelated bladder dysfunction. METHODS: Male Sprague-Dawley rats were divided into control (n1⁄410), arterial endothelial injury (AI; n1⁄410), and AI with resveratrol treatment (AI-res; n1⁄410). AI and AI-res groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet following AI. AI-res rats received resveratrol (1mg/kg/day) orally for 12 weeks. The control group received a regular diet. After 12 weeks, urodynamic investigation was performed in awake animals. RESULTS: Iliac arteries from both AI and AI-resveratrol rats showed neo-intimal formation and luminal occlusion. The body weight of the three groups had no difference. Micturition interval (MI), bladder capacity (Bcap) and voided volume (VV) in theAI groupwere significantly less than those in the control group (p

INTRODUCTION AND OBJECTIVES: Hyaluronic acid (HA), a glycosaminoglycan, is associated with prostate cancer (PCa) progression and metastasis. 4-methylumbelliferone (4-MU) is a dietary supplement that inhibits HA-synthesis. In this study we evaluated chemopreventive and therapeutic efficacy of 4-MU to prevent PCa growth and metastasis in three PCa models. METHODS: Efficacy of daily oral gavage of 4-MU was evaluated in 3 PCa models: Model 1: TRAMP mice (n 1⁄4 8-20/group) were treated with vehicle or 4-MU (450 mg/kg) by starting stage-specific treatment at 8 (PIN stage), 12 (adenocarcinoma) and 22 (invasive carcinoma) weeks of age. Model 2: Mice were treated with 4-MU (200 mg/kg or 450 mg/kg) following intracardiac injection of Luciferase expressing PC3-ML cells. 3. Palpable DU145 xenografts were treated with 4-MU (200 and 450 mg/kg). Effect of 4-MU on EMT markers, HA receptors was evaluated by Q-PCR, immunoblotting and/or immunohistochemistry in PCa cells and xenograft tissues. HA add back and overexpression studies were conducted to evaluate the mechanism of action of 4-MU. RESULTS: In the TRAMP model, at 28 wks, 100% of vehicle treated mice developed PCa, but tumor growth and progression was inhibited in all 4-MU treated groups; P+SV weight (g): vehicle: 3.2 2.9; 8 wk: 0.43 0.14; 12 wk: 0.35 0.04; 22 wk: 1.0 0.35 g. The P+SV weight in TRAMP mice at 22 wks of age was 0.9 0.04, showing that late stage administration of 4-MU halted further tumor progression. Animals in 8, 12 and 22 week groups remained tumor free until 52, 44 and 34 wks respectively, even after stopping treatment at 28 wks. While 55% of vehicle treated animals developed metastasis, none of the treated groups had metastasis. In the PC3-ML intracardiac model, 100% of the mice in the vehicle group but none in the treatment group developed skeletal metastasis. In the DU145 model, 4-MU inhibited tumor growth. No serum/organ toxicity or weight loss was observed in any treatment groups. In all models, 4-MU treatment downregulated HA, HA receptors (CD44, RHAMM) and EMT markers (b-catenin, Zeb2) by >2-fold) but up-regulated E-cadherin. HA addition and overexpression of myristoylated AKt inhibited 4-MU effects. CONCLUSIONS: 4-MU is a potent non-toxic, oral chemopreventive agent, which inhibits PCa growth and metastasis by abrogating HA-signaling and reversing EMT.

sham, CN crushed, CN crushed with SHH treatment, CN crushed with BSA treatment and CN cut (n1⁄424) adult (P120) Sprague Dawley rats. RESULTS: Our results show that SHH and its receptors patched (PTCH1) and smoothened (SMO) are localized in normal PG neurons, and SMO undergoes anterograde transport by the CN to signal to down stream targets. When the CN is crushed, PG neurons die, SHH protein is decreased in neurons but not the associated glia, SMO localization changes to the neuronal cell surface and is not transported by the CN. With SHH PA treatment, PG neurons remain intact with normal SHH pathway signaling. SHH is taken up at the injury site and undergoes retrograde transport to PG neurons, allowing SMO transport to occur as under normal conditions. CONCLUSIONS: These results show that SHH is neuroprotective and promotes CN regeneration by preventing neuronal death in the PG and maintaining normal signaling mechanisms to down stream targets. This study is significant because understanding how regeneration occurs can provide novel avenues to further enhance regeneration and to prevent ED.

tion of 0.03mg/kg or higher concentrations of NaHS compared with controls. However, there were no significant changes in cystometric parameters, EUS-EMG activities or mean blood pressures during the cumulative administration of NaHS. CONCLUSIONS: These results suggest that H2S has a direct relaxant effect on urethral smooth muscle in the lower urinary tract to reduce urethral outlet resistance and that activities of bladder smooth muscle, urethral striated muscle and vascular smooth muscle were not altered by the systemic application of H2S donor at physiological concentrations.