UPK3A+ umbrella cell damage mediated by TLR3-NR2F6 triggers programmed destruction of urothelium in Hunner-type interstitial cystitis/painful bladder syndrome.

Urothelial damage and barrier dysfunction emerge as the foremost mechanisms in Hunner-type interstitial cystitis/bladder pain syndrome (HIC). Although treatments aimed at urothelial regeneration and repair have been employed, their therapeutic effectiveness remains limited due to the inadequate understanding of specific cell types involved in damage and the lack of specific molecular targets within these mechanisms. Therefore, we harnessed single-cell RNA sequencing to elucidate the heterogeneity and developmental trajectory of urothelial cells within HIC bladders. Through reclustering, we identified eight distinct clusters of urothelial cells. There was a significant reduction in UPK3A+ umbrella cells and a simultaneous increase in progenitor-like pluripotent cells (PPCs) within the HIC bladder. Pseudotime analysis of the urothelial cells in the HIC bladder revealed that cells faced challenges in differentiating into UPK3A+ umbrella cells, while PPCs exhibited substantial proliferation to compensate for the loss of UPK3A+ umbrella cells. The urothelium in HIC remains unrepaired, despite the substantial proliferation of PPCs. Thus, we propose that inhibiting the pivotal signaling pathways responsible for the injury to UPK3A+ umbrella cells is paramount for restoring the urothelial barrier and alleviating lower urinary tract symptoms in HIC patients. Subsequently, we identified key molecular pathways (TLR3 and NR2F6) associated with the injury of UPK3A+ umbrella cells in HIC urothelium. Finally, we conducted in vitro and in vivo experiments to confirm the potential of the TLR3-NR2F6 axis as a promising therapeutic target for HIC. These findings hold the potential to inhibit urothelial injury, providing promising clues for early diagnosis and functional bladder self-repair strategies for HIC patients. © 2024 The Pathological Society of Great Britain and Ireland.

The association of dietary intake of riboflavin and thiamine with kidney stone: a cross-sectional survey of NHANES 2007-2018.

BACKGROUND: Kidney stone disease (KSD) is a common condition that affects 10% population in the United States (US). The relationship between thiamine and riboflavin intake and KSD has not been well-studied. We aimed to investigate the prevalence of KSD and the association between dietary thiamine and riboflavin intake with KSD in the US population. METHODS: This large-scale, cross-sectional study included subjects from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. KSD and dietary intake were collected from questionnaires and 24-hour recall interviews. Logistic regression and sensitivity analyses were performed to investigate the association. RESULTS: This study included 26,786 adult participants with a mean age of 50.12 ± 17.61 years old. The prevalence of KSD was 9.62%. After adjusting for all potential covariates, we found that higher riboflavin intake was negatively related to KSD compared with dietary intake of riboflavin < 2 mg/day in the fully-adjusted model (OR = 0.541, 95% CI = 0.368 to 0.795, P = 0.002). After stratifying by gender and age, we found that the impact of riboflavin on KSD still existed in all age subgroups (P < 0.05) but only in males (P = 0.001). No such associations were found between dietary intake of thiamine and KSD in any of the subgroups. CONCLUSIONS: Our study suggested that a high intake of riboflavin is independently inversely associated with kidney stones, especially in male population. No association was found between dietary intake of thiamine and KSD. Further studies are needed to confirm our results and explore the causal relationships.

Identification of key genes in human urothelial cells corresponding to interstitial cystitis/bladder pain syndrome in a lipopolysaccharide-induced cystitis model.

AIMS: The cellular functions of bladder urothelial cells in interstitial cystitis/bladder pain syndrome (IC/BPS) have not been well revealed and understood. Thus, the study aims to identify key genes and significant pathways in urothelium corresponding to IC/BPS in a lipopolysaccharide (LPS)-induced cystitis model and provide novel clues related to diagnosis and treatment of IC/BPS. METHODS: Human urothelial cells (HUCs) were incubated with LPS (50 µg/ml for 24 h). Microarray was applied to analyze the differentially expressed genes (DEGs) between HUCs under LPS treatment and the control group. DEGs in the two groups were identified and then used for enrichment analysis. Subsequently, protein-protein interaction (PPI) network based on DEGs was constructed. Lastly, the top five key genes were identified through the Cytoscape (version 3.7.2) using the "Clustering Coefficient" algorithm. RESULTS: One hundred and seventy-one DEGs (96 upregulated genes and 75 downregulated genes) were identified between the LPS treatment and control group. The established PPI network was composed of 169 nodes and 678 edges. Moreover, C19orf33, TRIM31, MUC21, ELF3, and IFI27 were identified as hub genes in the PPI network. Subsequently, a statistically increased expression level of TRIM31 and ELF3 was validated by real-time quantitative-polymerase chain reaction and immunohistochemistry in bladder tissues from 20 patients with IC/BPS. CONCLUSIONS: TRIM31 and ELF3 may be the two hub genes in urothelium corresponding to IC/BPS. More studies are warranted to further validate the findings. The identified marker genes may be useful targets for further studies to develop diagnostic tools and more effective therapies for a broader group of women with IC/PBS.

Transurethral endoscopic enucleation of the prostate using a diode laser versus bipolar plasmakinetic for benign prostatic obstruction: a meta-analysis.

To evaluate the clinical efficacy and safety of diode laser enucleation of the prostate (DiLEP) versus bipolar plasma kinetic enucleation of the prostate (PKEP) in the management of benign prostatic hyperplasia (BPH). A systematic literature search was undertaken using PubMed, Embase, Web of Science, Cochrane Library, and CKNI databases to identify eligible studies published before April 2019. The quality of evidence and methodology was assessed. Primary outcomes were clinical and demographic characteristics and postoperative efficacy including maximum flow rate (Qmax), postvoid residual (PVR), quality of life (QoL), and International Prostate Symptom Score (IPSS); secondary outcomes were intraoperative variables and major complications. Meta-analyses of extracted data were performed with the RevMan version 5.2. The overall effects were determined by the Z-test, and a p value less than 0.05 was considered with significant difference. A fixed- or random-effect model was chosen to fit the pooled heterogeneity (determined by Chi-squared test and I2). As qualified trials were few, subgroup analyses were not performed. Four randomized controlled trials (RCTs) involving 451 patients were enrolled in our meta-analysis. In the included trials, all the diode (wavelength at 980 nm and 1470 nm) lasers applied output at continuous wave mode; the energy settings ranged from 120 to 160 W for enucleation and 30 to 60 W for coagulation. DiLEP provided less perioperative hemoglobin decrease (MD = - 3.22; 95% CI (- 5.15, - 1.29); p = 0.001; I2 = 65%), less postoperative catheterization time (MD = - 17.82; 95% CI (- 32.74, - 2.90); p = 0.02; I2 = 96%), less postoperative irrigation time (MD = - 7.15; 95% CI (- 13.67, - 0.62); p = 0.03; I2 = 98%), and lower incidence of urinary irritative symptoms (OR = 0.31; 95% CI (0.14, 0.67); p = 0.003; I2 = 0%) compared with PKEP. During the 1, 3, 6, and 12-month postoperative follow-up, no statistically significant difference was found in Qmax, IPSS, QoL, and PVR between the procedures. As regards other perioperative and postoperative parameters and major complications, we found no significant difference. Both DiLEP and PKEP are safe and efficient methods for the treatment of BPH. However, DiLEP showed less perioperative hemoglobin decrease, less postoperative catheterization time, less postoperative irrigation time, and lower rates of postoperative irritative symptoms compared with the PKEP group.

Enucleation of the prostate for benign prostatic hyperplasia thulium laser versus holmium laser: a systematic review and meta-analysis.

To evaluate the clinical efficacy and safety of thulium laser vapoenucleation/enucleation of the prostate (ThuEP) versus holmium laser enucleation of the prostate (HoLEP) in the management of benign prostatic hyperplasia (BPH). A systematic literature search was performed using PubMed, Embase, and Web of Science to identify eligible studies published before July 2018. Meta-analysis of extracted data was performed with RevMan version 5.3. We chose the fixed- or random-effect model to fit the pooled heterogeneity. Five eligible studies including two randomized controlled trials (RCTs) and three non-RCTs involving 1010 patients were enrolled in our meta-analysis. ThuEP provided less enucleation time when compared with HoLEP (WMD = - 7.73, 95% CI - 14.39-1.07, P = 0.02). During the 1st, 6th, and 12th months of postoperative follow-ups, statistically significant differences were found in Qmax (WMD = 2.05, 95% CI 0.52~3.58) and PVR (WMD = - 6.50, 95% CI - 7.35~- 5.66, P < 0.001) in the 1st month after the operation, also in IPSS (IPSS: WMD = - 1.29, 95% CI - 2.39~- 0.19, P = 0.02) in the 12th month after the operation. As regards other perioperative, postoperative parameters, and complication rates, we found no significant difference. Both ThuEP and HoLEP provided satisfactory micturition improvement with low morbidity after the 1st and 6th months of the operation. However, ThuEP showed higher enucleation efficacy and less intraoperative blood loss and may get a better outcome as compared to the HoLEP group in the early postoperative period with regard to Qmax/PVR and IPSS after the 1st and 12th months of the operation respectively.

Perioperative Safety of Bladder Hydrodistention in Patients on Antithrombotic Therapy.

IMPORTANCE: Bladder hydrodistention (BH) is commonly used to diagnose and treat patients with interstitial cystitis/bladder pain syndrome (IC/BPS), but the overall assessment of bleeding complications for patients taking antithrombotics is lacking. OBJECTIVES: The study aimed to investigate if perioperative complications were more common in patients with IC/BPS receiving antithrombotic therapy after BH. STUDY DESIGN: We retrospectively reviewed patients with IC/BPS who underwent hydrodistention during January 2010 and May 2021. Patients with and without antithrombotic drugs were identified and grouped, and their medical records were reviewed. Perioperative data and symptom scores were assessed. The rates of complications in the 2 groups were recorded at 3 months and at the last visit postoperatively. RESULTS: A total of 387 patients were eventually included. Among them, 29 (7.5%) patients were receiving systemic antithrombotic therapy and 358 (92.5%) were not. Compared with the non-antithrombotic group, patients receiving antithrombotic therapy demonstrated a longer hospital stay ( P = 0.033) and a longer catheterization time ( P = 0.034). Moreover, the patients with antithrombotic drugs had increased odds of bladder tamponade (odds ratio, 6.76; P = 0.019) and urinary retention (odds ratio, 5.79; P = 0.033) both 3 months postoperatively and last follow-up, but this is not statistically different between patients with and without Hunner lesions. No thromboembolic events were identified during the study period. CONCLUSIONS: Although a small number of patients with IC/BPS needed anticoagulants, longer hospital stays, longer catheterization time, and increased odds of bladder tamponade and urinary retention were observed in patients receiving antithrombotic therapy. Still, a comprehensive management scheme to balance bleeding complications and antithrombotic agents is needed for individuals.

Remodelling landscape of tissue-engineered bladder with porcine small intestine submucosa using single-cell RNA sequencing.

OBJECTIVE: Bioscaffolds are widely used for tissue engineering, but failed and inconsistent preclinical results have hampered the clinical use of bioscaffolds for tissue engineering. We aimed to construct a cellular remodelling landscape and to identify the key cell subpopulations and important genes driving bladder remodelling. METHODS: Twenty-four reconstructed mouse bladders using porcine small intestinal submucosa (PSIS) were harvested at 1, 3, and 6 weeks to perform single-cell RNA sequencing. Cell types were identified and their differentially expressed genes (DEGs) at each stage were used for functional analysis. Immunofluorescence was used to validate the specific cell type. RESULTS: The remodelling landscape included 13 cell types. Among them, fibroblasts, smooth muscle cells (SMCs), endothelial cells, and macrophages had the most communications with other cells. In the process of regeneration, DEGs of fibroblasts at 1, 3, and 6 weeks were mainly involved in wound healing, extracellular matrix organization, and regulation of development growth, respectively. Among these cells, Saa3+ fibroblasts might mediate tissue remodelling. The DEGs of SMCs at 1, 3, and 6 weeks were mainly involved in the inflammatory response, muscle cell proliferation, and mesenchyme development, respectively. Moreover, we found that Notch3+ SMCs potentially modulated contractility. From 1 to 6 weeks, synchronous development of endothelial cells was observed by trajectory analysis. CONCLUSIONS: A remoulding landscape was successfully constructed and findings might help surficial modifications of PSIS and find a better alternative. However, more in vivo and in vitro studies are needed to further validate these results.

The association between heavy metal exposure and erectile dysfunction in the United States.

Literature regarding the impacts of heavy metal exposure on erectile dysfunction (ED) is scarce. We aimed to evaluate the correlation between 10 urinary metals and ED in a large, nationally representative adult male sample. The dataset was extracted from the National Health and Nutrition Examination Survey (NHANES) during the period of 2001-2002 and 2003-2004. Weighted proportions and multivariable logistic regression analysis adjusted for confounding variables were utilized to determine the relationship between metal exposure and ED. Weighted quantile sum (WQS) regression was utilized to evaluate the impact of a mixture of urinary metals on ED. A total of 1328 participants were included in our study. In multivariable logistic regression analysis, cobalt (Co) and antimony (Sb) were positively associated with ED (odds ratio [OR]: 1.36, 95% confidence interval [CI]: 1.10-1.73, P = 0.020; and OR: 1.41, 95% CI: 1.12-1.77, P = 0.018, respectively) after full adjustment. Men in tertile 4 for Co (OR: 1.49, 95% CI: 1.02-2.41, P for trend = 0.012) and Sb (OR: 1.53, 95% CI: 1.08-2.40, P for trend = 0.041) had significantly higher odds of ED than those in tertile 1. Furthermore, the WQS index was significantly linked with increased odds of ED after full adjustment (OR: 1.31, 95% CI: 1.04-1.72, P < 0.05). Our study expanded on previous literature indicating the possible role of heavy metal exposure in the etiology of ED. The evaluation of heavy metal exposure should be included in the risk assessment of ED.

YAP/Smad3 promotes pathological extracellular matrix microenviroment-induced bladder smooth muscle proliferation in bladder fibrosis progression.

Fibrosis is a chronic inflammation process with excess extracellular matrix (ECM) deposition that cannot be reversed. Patients suffer from bladder dysfunction caused by bladder fibrosis. Moreover, the interactive mechanisms between ECM and bladder fibrosis are still obscure. Hence, we assessed the pivotal effect of Yes-associated protein (YAP) on the proliferation of bladder smooth muscle in fibrosis process. We identified that stiff ECM increased the expression and translocation of YAP in the nucleus of human bladder smooth muscle cell (hBdSMC). Sequencings and proteomics revealed that YAP bound to Smad3 and promoted the proliferation of hBdSMC via MAPK/ERK signaling pathway in stiff ECM. Moreover, CUT and TAG sequencing and dual-luciferase assays demonstrated that Smad3 inhibited the transcription of JUN. The YAP inhibitor CA3 was used in a partial bladder outlet obstruction (pBOO) rat model. The results showed that CA3 attenuated bladder smooth muscle proliferation. Collectively, YAP binding with Smad3 in the nucleus inhibited the transcription of JUN, and promoted the proliferation of bladder smooth muscle through the MAPK/ERK signaling pathway. The current study identified a novel mechanism of mechanical force induced bladder fibrosis that provided insights in YAP-associated organ fibrosis.

Integrating single-cell RNA sequencing with spatial transcriptomics reveals immune landscape for interstitial cystitis.

Interstitial cystitis (IC) is a severely debilitating and chronic disorder with unclear etiology and pathophysiology, which makes the diagnosis difficult and treatment challenging. To investigate the role of immunity in IC bladders, we sequenced 135,091 CD45+ immune cells from 15 female patients with IC and 9 controls with stress urinary incontinence using single-cell RNA sequencing (scRNA-seq). 22 immune subpopulations were identified in the constructed landscape. Among them, M2-like macrophages, inflammatory CD14+ macrophages, and conventional dendritic cells had the most communications with other immune cells. Then, a significant increase of central memory CD4+ T cells, regulatory T cells, GZMK+CD8+ T cells, activated B cells, un-switched memory B cells, and neutrophils, and a significant decrease of CD8+ effector T cells, Th17 cells, follicular helper T cells, switched memory B cells, transitional B cells, and macrophages were noted in IC bladders. The enrichment analysis identified a virus-related response during the dynamic change of cell proportion, furthermore, the human polyomavirus-2 was detected with a positive rate of 95% in urine of patients with IC. By integrating the results of scRNA-seq with spatial transcriptomics, we found nearly all immune subpopulations were enriched in the urothelial region or located close to fibroblasts in IC bladders, but they were discovered around urothelium and smooth muscle cells in control bladders. These findings depict the immune landscape for IC and might provide valuable insights into the pathophysiology of IC.

Different Tract Sizes of Miniaturized Percutaneous Nephrolithotomy Versus Retrograde Intrarenal Surgery: A Systematic Review and Meta-Analysis.

PURPOSE: Miniaturized percutaneous nephrolithotomy (MPCNL), including minipercutaneous nephrolithotomy (PCNL), ultramini-PCNL, and micro-PCNL, have been developed recently. The aim of this meta-analysis was to compare the safety and efficacy of different tract sizes of MPCNL with retrograde intrarenal surgery (RIRS) in the management of kidney stones. MATERIALS AND METHODS: We searched PubMed, Embase, and Web of Science to identify case-control trials and randomized controlled trials, which evaluated MPCNL vs RIRS before February 2017. Two reviewers independently evaluated the methodologic quality of the included studies, and the disagreements were solved by discussion. Meta-analysis was performed with Review Manager version 5.3 software. RESULTS: Fourteen publications involving 1279 patients were included. Mini-PCNL provided a significantly higher stone-free rate (SFR; odds ratio [OR] OR 1.66; p = 0.005), especially for lower pole renal stones (OR 2.65; p = 0.003), but brought longer hospital stay (weighted mean difference [WMD] 1.23; p = 0.0001) and larger hemoglobin drop (WMD 0.77; p < 0.00001). There were no statistically significant differences between mini-PCNL and RIRS in the complications (OR 0.77; p = 0.23) and operative time (WMD: -6.52; p = 0.42). For ultramini-PCNL and micro-PCNL, the safety and efficacy were similar to RIRS. CONCLUSIONS: Mini-PCNL offers a significantly higher SFR than RIRS, for lower pole renal stones, the advantage of mini-PCNL is more obvious. However, RIRS is associated with shorter hospital stay and less hemoglobin drop. For ultramini-PCNL and micro-PCNL, tract size is smaller than mini-PCNL, and the SFR is similar to RIRS. In terms of the evidence at present, we recommend mini-PCNL for patients focusing more on the high SFR.