Caffeine improves bladder function in streptozotocin-induced diabetic rats.

AIMS: To examine the protective effects of caffeine in rats with diabetes mellitus (DM) by using urodynamics. METHODS: Female Sprague-Dawley rats (n = 24) were divided into four groups: control group, DM group, DM + caffeine (5 mg/kg/day), and DM + caffeine (10 mg/kg/day). DM was induced by streptozotocin (STZ). Cystometric studies were conducted on all rats. After 8 weeks of treatment with caffeine, the urodynamic parameters, including bladder capacity, residual urine volume, voiding time, and peak voiding pressure, were measured. RESULTS: DM rats had a higher bladder capacity and post-void residual urine volume (PVR), an increased voiding time and peak voiding pressure, and a markedly lower voiding efficiency than the control group rats. After treatment with caffeine, bladder capacity, post-void residual urine volume, and peak voiding pressure were significant lower than those in the DM group, but voiding efficiency was markedly higher. CONCLUSION: The results suggested that caffeine (5 or 10 mg/kg/day) may improve the bladder function at 8 weeks after STZ induction. Thus, this may represent a potential strategy to increase voiding efficiency in diabetes.

Anti-vascular endothelial growth factor treatment decreases bladder pain in cyclophosphamide cystitis: a Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network animal model study.

OBJECTIVE: To investigate whether treatment with anti-vascular endothelial growth factor (VEGF)-neutralizing antibodies can reduce pain and voiding dysfunction in the cyclophosphamide (CYP) cystitis model of bladder pain in mice. MATERIALS AND METHODS: Adult female mice received anti-VEGF-neutralizing antibodies (10 mg/kg i.p. B20-4.1.1 VEGF mAb) or saline (control) pre-treatment, followed by CYP (150 mg/kg i.p.) to induce acute cystitis. Pelvic nociceptive responses were assessed by applying von Frey filaments to the pelvic area. Spontaneous micturition was assessed using the void spot assay. RESULTS: Systemic anti-VEGF-neutralizing antibody treatment significantly reduced the pelvic nociceptive response to CYP cystitis compared with control (saline). In the anti-VEGF pre-treatment group, there was a significant increase in pelvic hypersensitivity, measured by the area under the curve (AUC) using von Frey filaments at 5 h post-CYP administration (P = 0.004); however, by 48 h and 96 h post-CYP administration, pelvic hypersensitivity had reduced by 54% and 47%, respectively, compared with the 5 h post-CYP administration time point, and were no longer significantly different from baseline (P = 0.22 and 0.17, respectively). There was no difference in urinary frequency and mean voided volume between the two pre-treatment groups. CONCLUSION: Systemic blockade of VEGF signalling with anti-VEGF-neutralizing antibodies was effective in reducing pelvic/bladder pain in the CYP cystitis model of bladder pain. Our data support the further investigation of the use of anti-VEGF antibodies to manage bladder pain or visceral pain.

Artesunate Suppresses the Growth of Prostatic Cancer Cells through Inhibiting Androgen Receptor.

Prostatic cancer (PCa) is a leading cause of cancer related death in males and is often regarded as a kind of androgen-sensitive cancer. Artesunate (ART), a semi-synthetic derivative of the Chinese herb Artemisia annua, is such an anti-cancer agent. However, the effects and mechanism of ART on PCa cells remains unclear. The study aims to elaborate the mechanism of the involvement of androgen receptor (AR) in anti-prostatic cancer (PCa) of artesunate (ART). PCa cells 22rvl were used in vivo and in vitro, and the viability and apoptosis were conducted using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay, respectively. Ectopic expressions of AR and DNA methyltransferase (DNMT) were detected in cells in overexpression or interference of AR or DNMT3b. ART dose-dependently suppressed tumor growth, inhibited cell viability, enhanced apoptosis, decreased AR expression, and increased the expression and the catalytic activity of DNMT3b in 22rv1 cells either in transplanted mice or in vitro. Furthermore, AR downregulated DNMT3b expression, and overexpression of AR or interference of DNMT3b could reverse ART-induced cytotoxicity and apoptosis in 22rvl cells, whereas overexpression of DNMT3b could not change the effect profiles of ART on the cells. The results indicated that ART suppressed tumor growth of prostatic cancer cells through AR-DNMT3b pathway, underlying ART will allow for the utilization of this Chinese therapeutic agent for the potential treatment of prostate cancer.

Sulforaphane attenuates di-N-butylphthalate-induced reproductive damage in pubertal mice: Involvement of the Nrf2-antioxidant system.

di-N-butylphthalate (DBP) is a ubiquitous environmental pollutant used for plastic coating and in the cosmetics industry. It has toxic effects on body health, especially the male reproductive system. Here, we investigated the effects of DBP on the male reproductive system of pubertal mice and explored the protective role of sulforaphane (SFN). The results showed that DBP significantly reduced the anogenital distance, testicular weight, sperm count and motility, and plasma and testicular testosterone levels and significantly increased the oxidative stress, sperm abnormalities, and testicular cell apoptosis. SFN supplementation ameliorated these effects. After DBP stimulation, the transcription factor nuclear factor erythroid-related factor 2 (Nrf2) was adaptively increased together with its target genes, such as HO-1 and NQO1. Upregulation of Nrf2 by SFN reduced the DBP-mediated intracellular oxidative toxicity and also increased testosterone secretion and spermatogenesis, which were decreased by DBP. These findings indicate that SFN can attenuate DBP-induced reproductive damage in pubertal mice via Nrf2-associated pathways.

[Saw palmetto fruit extract improves LUTS in type â ¢A prostatitis patients].

OBJECTIVE: To assess the clinical efficacy of the saw palmetto fruit extract (SPFE) in the treatment of lower urinary tract symptoms (LUTS) in patients with type ⅢA prostatitis. METHODS: This retrospective study included 54 cases of type ⅢA prostatitis treated in the Outpatient Department of our hospital from January to December 2015. The patients were aged 35.06 ± 5.85 years, with a mean disease course of 3.8 ± 2.1 years, and all received oral medication of SPFE Capsules at the dose of 320 mg qd for 12 weeks. We assessed the therapeutic effects by comparing the NIH-chronic prostatitis symptom indexes (NIH-CPSI), voiding diary, International Prostate Symptom Scores (IPSS), and results of urodynamic examination before and after treatment. RESULTS: Compared with the baseline, both NIH-CPSI and IPSS were significantly decreased after medication (27.61 ± 3.76 vs 18.6 ± 5.34, P <0.01; 20.44 ± 4.51 vs 10.96±4.62, P <0.01), and urodynamic examination and voiding diary showed dramatic post-medication improvement in the average urinary flow rate (ï¼»8.05±1.42ï¼½ vs ï¼»12.05±2.60ï¼½ ml/s, P <0.01 ), maximum urinary flow rate (ï¼»14.22±1.74ï¼½ vs ï¼»21.32±4.51ï¼½ ml/s, P <0.01), residual urine volume (ï¼»46.15±16.57ï¼½ vs ï¼»14.55±10.21ï¼½ ml, P <0.01), maximum urethral closure pressure (ï¼»76.52±3.53ï¼½ vs ï¼»65.32±4.75ï¼½ cm H2O, P <0.01), mean urinary volume (ï¼»124.63±40.55ï¼½ vs ï¼»285.93±58.68ï¼½ ml, P <0.01), urination frequency (16.96±4.17 vs 8.96±2.50, P <0.01), and nocturia frequency (8.94±3.23 vs 3.15±1.90, P <0.01). No apparent adverse reactions were observed in any of the patients. CONCLUSIONS: SPFE Capsules can safely and effectively improve LUTS and thus the quality of life of patients with type ⅢA prostatitis.

The relationship between depression and overactive bladder/urinary incontinence symptoms in the clinical OAB population.

BACKGROUND: To investigate the relationship between depression and overactive bladder (OAB)/urinary incontinence symptoms among the clinical OAB population. METHODS: Patients who were diagnosed with overactive bladder (OAB) and age-matched control subjects without OAB were enrolled. Depression symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS-D). OAB/incontinence symptoms were assessed using the validated questionnaires: ICIQ-UI, ICIQ-OAB, UDI-6, IIQ-7, and OAB-q. RESULTS: 27.5 % of OAB patients in our study had depression (HADS ≥8), and 12 % of OAB patients had moderate to severe depression (HADS-D ≥11). OAB patients reported significantly higher HADS-D depression scores compared to age-matched controls (5.3 ± 3.9 versus 2.8 ± 3.9, p = 0.004). OAB patients with depression reported more severe incontinence symptoms (ICIQ-UI), greater bother and more impact on quality of life (UDI-6, IIQ-7) compared to OAB patients without depression (p = 0.001, 0.01, <0.001, respectively). However there were no differences in ICIQ-OAB and OAB-q. Among OAB patients, there were positive correlations between the severity of depression symptoms and OAB/incontinence symptoms (p-values <0.001 to 0.035). CONCLUSIONS: 27.5 % of OAB patients have depression. OAB patients with depression reported more severe urinary incontinence symptoms, greater bother and more impact on quality of life compared to those without depression. Future studies are needed to further examine the mechanistic links between depression and OAB/urinary incontinence.

Leveraging Random Effects in Cistrome-Wide Association Studies for Decoding the Genetic Determinants of Prostate Cancer.

Cistrome-wide association studies (CWAS) are pivotal for identifying genetic determinants of diseases by correlating genetically regulated cistrome states with phenotypes. Traditional CWAS typically develops a model based on cistrome and genotype data to associate predicted cistrome states with phenotypes. The random effect cistrome-wide association study (RECWAS), reevaluates the necessity of cistrome state prediction in CWAS. RECWAS utilizes either a linear model or marginal effect for initial feature selection, followed by kernel-based feature aggregation for association testing is introduced. Through simulations and analysis of prostate cancer data, a thorough evaluation of CWAS and RECWAS is conducted. The results suggest that RECWAS offers improved power compared to traditional CWAS, identifying additional genomic regions associated with prostate cancer. CWAS identified 102 significant regions, while RECWAS found 50 additional significant regions compared to CWAS, many of which are validated. Validation encompassed a range of biological evidence, including risk signals from the GWAS catalog, susceptibility genes from the DisGeNET database, and enhancer-domain scores. RECWAS consistently demonstrated improved performance over traditional CWAS in identifying genomic regions associated with prostate cancer. These findings demonstrate the benefits of incorporating kernel methods into CWAS and provide new insights for genetic discovery in complex diseases.

Iguratimod ameliorates antibody-mediated rejection after renal transplant by modulating the Th17/Treg paradigm.

BACKGROUND: Iguratimod (IGU) is widely used in clinical practice due to its stable anti-inflammatory effects. Our previous studies have confirmed that the proportion of Th17/Treg balance in patients taking IGU altered significantly. This study aims to explore the role of IGU in antibody-mediated rejection (ABMR) and its potential mechanisms. METHODS: We conducted bioinformatics analysis of sequencing data from the GEO database to analyze the abundance of immune cell infiltration in transplanted kidney tissues. In vivo, IGU was intervened in a mice secondary skin transplantation model and a mice kidney transplantation ABMR model, and histological morphology of the grafts were examined by pathological staining, while relevant indicators were determined through qRT-PCR, immunohistochemistry, and enzyme-linked immunosorbent assay, observed T cell differentiation by flow cytometry, and preliminarily assessed the immunosuppressive effect of IGU. In vitro, we established Th17 and Treg cell induction and stimulation differentiation culture systems and added IGU for intervention to explore its effects on their differentiation. RESULTS: Through bioinformatics analysis, we found that Th17 and Treg may play important roles in the occurrence and development of ABMR. In vivo, we found that IGU could effectively reduce the damage caused by ABMR to the grafts, alleviate the infiltration of inflammatory cells in the graft tissues, and reduce the deposition of C4d in the grafts. Moreover, it is also found that IGU regulated the differentiation of Th17 and Treg cells in the spleen and peripheral blood and reduced the expression of IL-17A in the grafts and serum. In addition, same changes were observed in the induction and differentiation culture system of Th17 and Treg cells in vitro after the addition of IGU. CONCLUSION: IGU can inhibit the progression of ABMR by regulating the differentiation of Th17 and Treg cells, providing novel insights for optimizing clinical immunosuppressive treatment regimens.

Efficacy of peripheral electrical nerve stimulation on improvements of urodynamics and voiding diary in patients with neurogenic lower urinary tract dysfunction: a systematic review and meta-analysis.

BACKGROUND: Peripheral electrical nerve stimulation is a routinely recommended treatment for non-neurogenic overactive bladder but has not been approved for patients with neurogenic lower urinary tract dysfunction (NLUTD). This systematic review and meta-analysis was to elucidate the efficacy and safety of electrostimulation and thus provide firm evidence for treating NLUTD. MATERIALS AND METHODS: We systematically performed the literature search through PubMed, Web of Science, and Cochrane Library databases in March 2022. The eligible studies were identified across the inclusion criteria and the data on urodynamic outcomes, voiding diary parameters, and safety was collected to quantitatively synthesize the pooled mean differences (MDs) with 95% CIs. Subgroup analyses and sensitivity analyses were subsequently used to investigate the possible heterogeneity. This report was achieved in accordance with the preferred reporting items for systematic reviews and meta-analyses statement. RESULTS: A total of 10 studies involving 464 subjects and 8 studies with 400 patients were included for systematic review and meta-analysis, respectively. The pooled effect estimates indicated that electrostimulation could significantly improve urodynamic outcomes, including maximum cystometric capacity (MD=55.72, 95% CI 15.73, 95.72), maximum flow rate (MD=4.71, 95% CI 1.78, 7.65), maximal detrusor pressure (MD=-10.59, 95% CI -11.45, -9.73), voided volume (MD=58.14, 95% CI 42.97, 73.31), and post-void residual (MD=-32.46, 95% CI -46.63, -18.29); for voiding diary parameters, patients undergoing electrostimulation showed lower MDs of incontinence episodes per 24 h (MD=-2.45, 95% CI -4.69, -0.20) and overactive bladder symptom score (MD=-4.46, 95% CI -6.00, -2.91). In addition to surface redness and swelling, no stimulation-related severe adverse events were reported else. CONCLUSIONS: The current evidence demonstrated that peripheral electrical nerve stimulation might be effective and safe for managing NLUTD, whereas more reliable data from large-scale randomized controlled trials are necessary to strengthen this concept.

Identification of an immune subtype-related prognostic signature of clear cell renal cell carcinoma based on single-cell sequencing analysis.

Background: There is growing evidence that immune cells are strongly associated with the prognosis and treatment of clear cell renal cell carcinoma (ccRCC). Our aim is to construct an immune subtype-related model to predict the prognosis of ccRCC patients and to provide guidance for finding appropriate treatment strategies. Methods: Based on single-cell analysis of the GSE152938 dataset from the GEO database, we defined the immune subtype-related genes in ccRCC. Immediately afterwards, we used Cox regression and Lasso regression to build a prognostic model based on TCGA database. Then, we carried out a series of evaluation analyses around the model. Finally, we proved the role of VMP1 in ccRCC by cellular assays. Result: Initially, based on TCGA ccRCC patient data and GEO ccRCC single-cell data, we successfully constructed a prognostic model consisting of five genes. Survival analysis showed that the higher the risk score, the worse the prognosis. We also found that the model had high predictive accuracy for patient prognosis through ROC analysis. In addition, we found that patients in the high-risk group had stronger immune cell infiltration and higher levels of immune checkpoint gene expression. Finally, cellular experiments demonstrated that when the VMP1 gene was knocked down, 786-O cells showed reduced proliferation, migration, and invasion ability and increased levels of apoptosis. Conclusion: Our study can provide a reference for the diagnosis and treatment of patients with ccRCC.

Echinacoside Ameliorates Cyclophosphamide-Induced Bladder Damage in Mice.

Interstitial cystitis (IC) is featured by apoptosis and chronic inflammation in bladder tissue. We aimed to evaluate the effect of echinacoside (ECH), which is known to modulate inflammation and apoptosis on IC using relevant models. We established a mouse model of cystitis using cyclophosphamide (CYP) and treated human urothelium cells (SV-HUC-1) with lipopolysaccharide (LPS) + ATP as in vitro model. The bladder function was tested by urodynamics. Apoptosis of bladder cells was assessed by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Expressions of apoptosis-associated and inflammation-related proteins were assessed using western blotting. Treatment with ECH significantly improved bladder function, reduced inflammatory damage, and decreased apoptosis in the models. Furthermore, ECH decreased the phosphorylation levels of IκB and NF-κB(p65), and upregulated the expression of peroxisome proliferator-activated receptor gamma (PPARγ), which are related to apoptosis and inflammation in CYP-induced mouse cystitis. Moreover, ECH did not reduce apoptosis of urothelial cells after treatment with PPARγ antagonist GW9662. Our findings suggest that ECH might have protective effect against IC in bladder and be mediated through modulation of the PPARγ/NF-κB pathway.

Medium-term Clinical Efficacy and Complications of Plasmakinetic Enucleation of the Prostate Versus Transurethral Resection of the Prostate for Benign Prostatic Hyperplasia.

OBJECTIVE: To compare surgical characteristics, clinical efficacy, and complications of plasmakinetic enucleation of the prostate (PKEP) and transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: From January 2015 to May 2018, 370 patients underwent TURP were included into the TURP group. Meanwhile, another 370 patients underwent PKEP (matched by age, prostate volume, and duration of BPH) were included into the PKEP group. Then, the differences of surgical characteristics, clinical efficacy, and complications were compared between the two groups. RESULTS: The operative time, intraoperative irrigation volume, postoperative irrigation time and irrigation volume, drop in hemoglobin, blood transfusion, postoperative catheterization time, and hospital stay of the PKEP group were significantly less than those of the TURP group (P <.05). No significant differences were observed in the resected tissue weight, visual analogue scale score, and total cost of hospitalization (P >.05); The quality of life score of the PKEP group was significantly lower than that of the TURP group (P <.05). No significant differences of maximum flow rate, postvoid residual urine, Serum prostate-specific antigen, international prostate symptom score and International Index of Erectile Function score were observed (P >.05); The incidences of urinary tract irritation, massive hemorrhage, secondary hemorrhage, bladder spasm, clot retention, and retrograde ejaculation of the PKEP group were significantly lower than those of the TURP group (P <.05). CONCLUSION: PKEP and TURP are comparable regarding cost burden and clinical efficacy in medium-term follow-up. However, PKEP should be given a priority for BPH treatment because of less complication rate and better safety profile.

Neoadjuvant Chemohormonal Therapy in Prostate Cancer Before Radical Prostatectomy: A Systematic Review and Meta-Analysis.

Objective: This meta-analysis was to investigate the effects of neoadjuvant chemohormonal therapy (NCHT) on patients with prostate cancer (PCa) before radical prostatectomy (RP) and attempt to provide meaningful evidence. Methods: A systematic search was performed using the PubMed, Web of Science, and Cochrane Library databases in February 2022 based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The relevant studies were critically screened and we extracted the data of demography, postoperative pathology, and survival to calculate the pooled effect sizes. Subgroup analyses and sensitivity analyses were used to explore the source of heterogeneity. Results: Six identified studies involving 1717 subjects were included according to the selection criteria. There was no significant difference between NCHT plus RP and RP alone groups regarding lymph node involvement (risk ratio [RR]=1.03, 95% confidence interval [CI]: 0.57-1.87, P=0.92). However, NCHT prior to RP significantly decreased the rates of positive surgical margin (PSM, RR=0.35, 95% CI: 0.22-0.55, P<0.0001) and seminal vesicle invasion (SVI, RR=0.78, 95% CI: 0.65-0.95, P=0.01), and increase pathological downstaging (RR=1.64, 95% CI: 1.17-2.29, P=0.004). Additionally, biochemical recurrence-free survival (BRFS) and overall survival (OS) were significantly prolonged under the administration of NCHT (HR=0.54, 95% CI: 0.34-0.85, P=0.008 and HR=0.67, 95% CI: 0.48-0.94, P=0.02, respectively). Conclusions: Compared to the RP alone group, patients with NCHT plus RP showed significant improvements in PSM, SVI, pathological downstaging, BRFS, and OS, whereas further multicenter randomized controlled trials are needed to consolidate this concept.

Sacral Neuromodulation Using a Novel Device with a Six-contact-point Electrode for the Treatment of Patients with Refractory Overactive Bladder: A Multicenter, Randomized, Single-blind, Parallel-control Clinical Trial.

BACKGROUND: A novel sacral neuromodulation system (SacralStim) which has an electrode with six contact points was recently designed. OBJECTIVE: To evaluate the effectiveness and safety of the SacralStim system for treating patients with refractory overactive bladder (OAB). DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, randomized, single-blind clinical trial. Patients with refractory OAB were enrolled from January 2018 to May 2020. INTERVENTION: Participants were randomly allocated to the treatment group (SNM on) or the control group (SNM off) for a single-blind period of 12 ± 2 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the percentage of patients with a reduction in the average number of voids/24 h of at least 50% at the 12-wk follow-up visit. Other follow-up evaluations, including voiding diary outcomes, questionnaires on Overactive Bladder Symptom Score (OABSS), quality of life (QoL), device satisfaction, and causes of adverse events (AEs), were performed over the first 48 wk after implantation. RESULTS AND LIMITATIONS: The therapeutic success rate at 12 wk was 56.76% in the treatment group and 11.11% in the control group (p < 0.001). There were significant differences in voiding diary variables between the two groups, including changes in the average number of voids/24 h, micturition volume/void, and improvement in the urge incontinence ratio. No severe AEs occurred. A limitation is the sham stimulation used as a control in the study. A head-to-head study is required to make a direct comparison of devices with six and four contact points. CONCLUSIONS: This clinical trial provides strong evidence that patients with refractory OAB benefit from the novel SacralStim system. More research is required for direct comparison of the SacralStim system with traditional four-contact-point devices. PATIENT SUMMARY: This study confirms the effectiveness and safety of a novel SacralStim system that stimulates the sacral nerve for treatment of overactive bladder. The system has an electrode with six contact points and can provide more programming options after implantation.

Caffeine improves bladder function in diabetic rats via a neuroprotective effect.

Diabetic cystopathy (DCP) is one of the most common complications of diabetes mellitus (DM). A previous study reported that caffeine may improve bladder dysfunction in rats with DM. The aim of the present study was to investigate the mechanisms behind the capacity for caffeine to improve bladder function in rats with DM. Sprague Dawley rats were divided into four groups: control, caffeine, DM and DM plus caffeine treatment (DM + caffeine). Bladder function was measured by urodynamic analyses. The levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and calcitonin gene-related peptide (CGRP) in the bladder tissue were detected by ELISA. Apoptosis in the dorsal root ganglion (DRG) was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. The expression levels of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, cleaved caspase-3, caspase-9 and cleaved caspase-9 proteins in the DRG were detected by western blotting. Following treatment with caffeine, the urination time and micturition interval of rats with DM were improved, the bladder wet weight was decreased, and the maximum voiding pressure was increased. Relative to that in the DM group, the expression levels of NGF, BDNF and CGRP in the bladder tissue of DM + caffeine rats increased; cellular apoptosis in the DRG of DM + caffeine rates decreased; and the expression levels of Bcl-2, Bax, cleaved caspase-3 and cleaved caspase-9 proteins in the DRG of DM + caffeine rats were restored to a certain extent. In conclusion, caffeine promotes bladder function in rats with DM through a protective effect on DRG.

CGRP protects bladder smooth muscle cells stimulated by high glucose through inhibiting p38 MAPK pathway in vitro.

This study aimed to explore the effect of calcitonin gene-related peptide (CGRP) on bladder smooth muscle cells (BSMCs) under high glucose (HG) treatment in vitro. BSMCs from Sprague-Dawley rat bladders were cultured and passaged in vitro. The third-generation cells were cultured and divided into control group, HG group, HG + CGRP group, HG + CGRP + asiatic acid (AA, p-p38 activator) group, CGRP group, AA group, HG + CGRP + CGRP-8-37 (CGRP receptor antagonist) group and HG + LY2228820 (p38 MAPK inhibitor) group. The cell viability, apoptosis, malondialdehyde (MDA) and superoxide dismutase (SOD) levels of BSMCs were observed by the relevant detection kits. The expressions of α-SM-actin, p38 and p-p38 were detected by qRT-PCR or Western blot analysis. Compared with the control group, the cell viability, SOD and α-SM-actin levels of BSMCs were decreased and apoptotic cells, MDA and p-p38 levels were increased after HG treatment, while these changes could be partly reversed when BSMCs were treated with HG and CGRP or LY2228820 together. Moreover, AA or CGRP-8-37 could suppress the effect of CGRP on BSMCs under HG condition. Our data indicate that CGRP protects BSMCs from oxidative stress induced by HG in vitro, and inhibit the α-SM-actin expression decrease through inhibiting the intracellular p38 MAPK signaling pathway.

Nrf2 Pathway Ameliorates Bladder Dysfunction in Cyclophosphamide-Induced Cystitis via Suppression of Oxidative Stress.

OBJECTIVE: To investigate the protective effect and molecular mechanism of nuclear factor E2-related factor 2 (Nrf2) pathway in interstitial cystitis (IC). METHODS: We established a mouse model of IC by cyclophosphamide (CYP) in wild-type mice and Nrf2 gene knockout mice. We examined the histological and functional alterations, the changes of oxidative stress markers, and the expression of the antioxidant genes downstream of Nrf2 pathway. RESULTS: After CYP administration, the mice showed urinary frequency and urgency, pain sensitization, decreased contractility, bladder edema, and oxidative stress disorder. Notably, the Nrf2-/- CYP mice had more severe symptoms. The mRNA and protein levels of antioxidant genes downstream of Nrf2 pathway were significantly upregulated in the Nrf2+/+ CYP mice, while there were no significant changes in the Nrf2-/- CYP mice. CONCLUSION: Nrf2 pathway protects bladder injury and ameliorates bladder dysfunction in IC, possibly by upregulating antioxidant genes and inhibiting oxidative stress.

Management and Follow-Up Practices of Women With Recurrent Stress Urinary Incontinence Following Transobturator Mid-urethral Synthetic Sling Procedure: A 6-Year Retrospective Monocentric University-Based Study.

Purpose: The purpose of this study is to evaluate the efficacy of management and follow-up practices in repeat retropubic mid-urethral synthetic sling (MUS) procedure after transobturator tape/tension-free vaginal tape-obturator (TOT/TVT-O) failure, and to clarify the possible etiology of recurrent stress urinary incontinence. Methods: The charts of all women patients who underwent tension-free vaginal tape (TVT) slings after previous failed transobturator MUS procedures between February 2012 and November 2018 at a single center were reviewed retrospectively. The transperineal ultrasound was performed to assess the pre-operative or post-operative urethral mobility and location of the slings. Furthermore, some essential evaluations were also made, mainly including medical history, physical examination, 1 h pad test, and urodynamic study. Finally, primary outcomes were evaluated according to the above items at 3, 6, and 12 months after the second operation, respectively. Results: Thirty-five patients were included in the primary transobturator MUS sling procedure. At the 6 months follow-up, 32 (91.42%) patients were socially continent and negative in 1 h pad test. The transperineal ultrasound measurement results revealed that the bladder neck descent (BND) values were significantly decreased after the repeat sling operation, and better urinary continence function was observed according to the post-operative urodynamic study. Multifactorial etiologies resulted in recurrent stress urinary incontinence (SUI), including poor surgical technique, inadequate sling tension when treating ISD, and inappropriate sling position. Then the detail of the surgical procedure varied with the results of pre-operative evaluations, affecting the validity of the second sling. Conclusion: Recurrent SUI has resulted from multi factors, pre-operative urodynamic study and transperineal ultrasound might be valuable tools to guide repeat sling operation and predict post-operative outcomes. A repeat TVT procedure may be regarded as a remedial measure for a failed transobturator MUS operation.

Combined Signature of the Urinary Microbiome and Metabolome in Patients With Interstitial Cystitis.

Interstitial cystitis (IC) is a clinical syndrome characterized by frequency, urgency, and bladder pain or pelvic pain; however, the underlying pathophysiological mechanisms and diagnostic markers are unknown. In this study, microbiome and metabolome analysis were used to explain the urine signatures of IC patients. Urine samples from 20 IC patients and 22 control groups were analyzed by using 16S rRNA sequence and liquid chromatography coupled with mass spectrometry. Four opportunistic pathogen genera, including Serratia, Brevibacterium, Porphyromonas, and Citrobacter, were significantly upregulated in IC group. The altered metabolite signatures of the metabolome may be related to sphingosine metabolism, amino acid metabolism, and fatty acid biosynthesis. Meanwhile, the associations were observed between different metabolites and microbiomes of IC. The present study suggests that the combined signatures of IC in urine microbiome and metabolome may become its prospective diagnostic markers.

[Proteomic analysis of the testis and differential expression of Annexin A3 in hypospadiac rats].

OBJECTIVE: To investigate the effect of in utero exposure to di-n-butyl phthalate (DBP) on the protein expression in the penile tissue of hypospadiac rats, isolate and identify differentially expressed proteins, and determine the role of the differential expression of Annexin A3 in the development of hypospadia in the rat offspring after maternal exposure to DBP. METHODS: Twenty pregnant SD rats were randomly assigned to an experimental group, intragastrically administered DBP at 800 mg/kg, and a control group, given soybean oil at 5 ml/kg, both for 5 days. Three days after birth, the penises of the newborn rats were removed, and the total protein extracted for 2D-electrophoretic separation and image analysis. Differentially expressed protein spots were screened and identified by mass spectrometry, and the changes in the expression of Annexin A3 detected by Western blotting and immunohistochemistry. RESULTS: Thirty-one differentially expressed protein spots were screened, of which 17 were identified by mass spectrometry and the SwissProt database, including pyruvate kinase M2, alpha-enolase, and Annexin A3. Western blot showed that Annexin A3 was mainly located in the urethral epithelia and had a lower expression in the hypospadiac rats (1.851 +/- 0.014, n = 10) than in the controls (2.603 +/- 0.012, n = 10) (P < 0.05). CONCLUSION: A pedigree of differentially expressed proteins in the penises of DBP-induced hypospadia and normal rats was established by the proteomic method. The differential expression of Annexin A3 may play an important role in the development of hypospadia.