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.

A new technique for the treatment of ureteric stricture after kidney transplantation.

OBJECTIVE: To evaluate the safety and effectiveness of endoscopic treatments with Allium® metal ureteric stent (AMUS) for ureteric strictures after kidney transplantation (KT). PATIENTS AND METHODS: In a prospective manner, we gathered clinical data from 68 patients who underwent endoscopic treatments with AMUS for ureteric strictures after KT between January 2019 and March 2022. The definition of surgical success was the unobstructed drainage of the AMUS, or in cases where there was AMUS migration, occlusion or encrustation and subsequently removed, there is no worsening of renal hydronephrosis in the patient during the follow-up period. RESULTS: Based on the specific circumstances of the ureteric strictures, three distinct types of surgery were selected for treatment. The overall success rate of endoscopic treatments for ureteric strictures following KT was 90% (61/68) during a follow-up period of 1 year. Surgical complications included haematuria (18%), pain (10%), urinary tract infections (7.4%), and lower urinary tract symptoms (7.4%). The incidences of stent migration, occlusion, and encrustation were 10%, 2.9%, and 1.5%, respectively. Postoperatively, significant improvements were observed in various parameters. At 1 month after surgery, there was a notable decrease in blood creatinine levels (105.5 vs 90.4 mol/L), urea nitrogen levels (6.6 vs 5.4 mmol/L), and hydronephrosis volume (64.4 vs 43.9 mL). Additionally, the serum estimated glomerular filtration rate increased from 49.5 to 64.4 mL/min/1.73 m2. The follow-up results of patients at 1 year after surgery were similar to those observed at 1 month after surgery. CONCLUSIONS: Systemic endoscopic treatments with AMUS were found to be safe and effective for ureteric strictures after KT with short-term follow-ups. This technique offers a novel option for the treatment of post-KT strictures.

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.

The preventive effects of colony-stimulating factor 1 receptor (CSF-1R) inhibition on bladder outlet obstruction induced remodeling.

INTRODUCTION: Bladder outlet obstruction (BOO) is a common problem that can affect bladder structure and function. Currently, there is no effective drugs available to prevent BOO-induced remodeling. Previous reports have demonstrated that the pathogenesis of BOO is associated with macrophage infiltration and polarization, which is physiologically dependent on colony-stimulating factor 1 receptor (CSF-1R) activation. Here we utilized a highly selective CSF-1R inhibitor, GW2580, to determine its preventive effects on BOO-induced remodeling. METHODS: A total of 24 Sprague-Dawley rats were randomly divided into sham, BOO + vehicle, and BOO + GW2580 group. GW2580 or vehicle control was administrated by oral gavage at daily doses of 40 mg/kg for 6 weeks. Bladder samples were collected for histopathology, immunohistochemistry, immunofluorescence, western blotting, and flow cytometry analysis. RESULTS: Our results demonstrated that bladder fibrosis was ameliorated by GW2580 compared with the vehicle group (22.01% ± 5.13% vs. 32.15% ± 7.24%, p < 0.01). Furthermore, treatment with GW2580 induced an inhibition of macrophage infiltration (4.41% ± 1.28% vs. 13.57% ± 3.42%, p < 0.001) and M2 macrophage polarization (10.67% ± 4.15% vs. 28.59% ± 6.38%, p < 0.001). There was also a decrease of profibrotic F4/80+  α-smooth muscle actin+ (α-SMA+ ) macrophage to myofibroblast transition (9.11% ± 2.58% vs. 17.33% ± 4.01%, p < 0.001) and CD163+ TGF-ß1+ cells (7.68% ± 2.10% vs. 14.17% ± 4.09%, p < 0.01) in the GW2580 group when compared with the vehicle group. CONCLUSIONS: In summary, our findings showed that GW2580 is a worthwhile candidate for a follow-up study to test in the treatment of BOO-induced remodeling.

Step-by-step technique for the endoscopic treatment of ureteric stricture.

OBJECTIVE: To outline our step-by-step technique for the endoscopic treatment of ureteric stricture. MATERIALS AND METHODS: Between January 2019 and June 2020, 25 patients with ureteric strictures underwent ureteric bypass and were included in this study. The ureteric bypass surgery included three key steps. First, holmium laser endoureterotomy was used to establish a small channel. Then, balloon dilatation was performed to create a large channel. Finally, an Allium stent was inserted. RESULTS: Over a median follow-up time of 12 months, the success rate of ureteric bypass surgery was 92.0% (23/25). The median operating time was 78 min. The incidence of pain was 16% (4/25), and the incidence of fever was 4.0% (1/25). The preoperative hydronephrosis volume and urea nitrogen levels decreased significantly after surgery. CONCLUSIONS: We performed ureteric bypass for patients with ureteric strictures. This technique was found to be safe and effective over a short follow-up time. For patients who are not suitable for surgical reconstruction, the ureteric bypass technique is a good choice.

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.

Metal stent for the ureteral stricture after surgery and/or radiation treatment for malignancy.

BACKGROUND: To assess the efficacy and safety of self-expanding metal ureteral stent for the stricture following surgery and/or radiation for malignancy. METHODS: We performed 36 metal ureteral stent insertion procedures (32 patients) between May 2019 and June 2020. The main inclusion criterion was the patients with ureteral stricture due to surgery and/or radiation treatment for malignancy. The diagnosis of stricture was ascertained by history and radiographic imaging. The etiologies underlying the strictures were: surgery and/or radiation therapy for cervical and rectal cancer, surgery for ovarian cancer. The primary outcome was the stent patency rate, and the secondary outcomes were the postoperative complications and glomerular filtration rate (GFR). Stent patency was defined as stent in situ without evident migration, unanticipated stent exchange or recurrent ureteral obstruction. Cost analysis was calculated from stent cost, anesthesia cost and operating room fee. RESULTS: The pre-metallic stent GFR was 22.53 ± 6.55 mL/min/1.73 m2. Eight patients were on double-J stents before insertion of metallic stents. The total annual cost of per patient in our study was $10,600.2 US dollars (range $9394.4-$33,527.4 US dollars). During a median follow-up time of 16 months (range 8-21 months), 27 cases (31 sides, 84%) remained stent patency. Twelve patients died from their primary malignancy carrying a patency stent. Stent migration was observed in 4 patients within 10 months after insertion. Ectopic stents were endoscopically removed and replaced successfully. Three stents were occluded, and no encrustation was seen in our study. Three and four patients had postoperative fever and gross hematuria, respectively. Infection was observed in 2 cases, mandating antibiotics therapy. In addition, postoperative volume of hydronephrosis postoperatively was significantly reduced compared with preoperation (54.18 ± 15.42 vs 23.92 ± 8.3, P = 0.019). However, no statistically significant differences regarding GFR, creatinine levels, blood urea nitrogen and hemoglobin existed between preoperation and last follow-up. CONCLUSIONS: The current study demonstrated that metal ureteral stent is effective and safe in the treatment of stricture following surgery and/or radiation therapy for malignant cancer. Patients hydronephrosis could be improved by the stent placement.

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.

Cyclic hydrostatic pressure promotes uroplakin expression in human urothelial cells through activation of ERK1/2 signaling.

OBJECTIVES: To investigate the effect of cyclic hydrostatic pressure on the expression of uroplakins and the role of extracellular regulated protein kinases 1/2 (ERK1/2) in the hydrostatic pressure-induced uroplakin expression of human urothelial cells (UCs). METHODS: Human UCs were seeded into a cell culture flask and subjected to cyclic hydrodynamic pressures for 24 h. Pressure parameters were set as follows: static, 100 cm H2O, 200 cm H2O and 300 cm H2O pressure. Real-time polymerase chain reaction (RT-PCR) and western blot were used to detect the expression of uroplakins. The role of the ERK1/2 was investigated using ERK1/2 inhibitor. RESULTS: Compared with the 0 cm H2O control group, 200 cm H2O hydrostatic pressure significantly increased the expression of uroplakins, however, 100 cm and 300 cm pressures could not promote uroplakin expression. Hence, ERK1/2 expression was also detected under 200 cm H2O hydrostatic pressure. Western blot showed that 200 cm H2O pressure promoted the expression of ERK1/2. ERK1/2 inhibitor decreased the pressure-induced ERK1/2 activivation and uroplakin expression. CONCLUSIONS: Cyclic hydrostatic pressure increases the expression of uroplakins via activating ERK1/2 signaling pathway in human UCs, and 200 cm H2O pressure may be an optimal stress parameter to promote the uroplakin expression.

Physiological stretch induced proliferation of human urothelial cells via integrin α6-FAK signaling pathway.

AIMS: To test a kind of stretch pattern which is the optimum stress parameter to promote human urothelial cells (HUCs) proliferation, and to investigate the roles of integrin subunits and their pathway in the HUCs proliferation induced by physiological stretch. METHODS: HUCs were seeded on silicone membrane, and subjected to four kinds of stretch (0,5%,10%,15% elongation) for 24 h, as controlled by a BioDynamic® bioreactor. Cell proliferation, viability and cycle distribution were examined using Cell Counting Kit-8 and flow cytometry, respectively. The gene and protein expression of integrin subunits and focal adhesion kinase (FAK) in each group were assessed by Real-time PCR(RT-PCR) and western blot, respectively. Small interfering RNAs (siRNA) were applied to knockdown integrin α6 and FAK expression in HUCs, and FAK inhibitor was used to validate the role of α6 and FAK in cell proliferation under physiological stretch. RESULTS: The proliferation of HUCs were highest in the 5% elongation group compared to static control, 10% and 15% elongation group. RT-PCR and western blot showed that 5% cyclic stretch significantly promoted the expression of integrin α6 and FAK. The stretch-induced cell proliferation and FAK expression was inhibited by siRNA of integrin α6. Further study with FAK inhibitor revealed that elongation promoted proliferation though integrin α6 and FAK signaling pathway. CONCLUSIONS: Physiological stretch induced HUCs proliferation via integrin α6-FAK signaling pathway, and 5% elongation may be the optimal stress parameter to promote the cell proliferation.

Metal ureteral stents for ureteral stricture: 2 years of experience with 246 cases.

BACKGROUND: Metal ureteral stents (MUS) has gained popularity as an endoscopic treatment alternative for the management of ureteral strictures. The aim of this study was to evaluate the safety, efficacy, and tolerability of MUS for treating ureteral strictures and to identify any factors that could influence the success of this intervention. METHODS: This study is a prospective analysis of the efficacy and safety of MUS for treating ureteral strictures in a single-center setting. The study enrolled 246 patients who had been diagnosed with ureteral strictures and had undergone MUS placement between January 2019 and July 2021. The patients were followed-up for a duration of 2 years. RESULTS: The overall success rate of MUS placement was 71.7%. Furthermore, the success rate of ureteral strictures after kidney transplantation (78.2%) was significantly higher than common ureteral strictures (73.0%) or recurrent ureteral strictures (67.6%). Additionally, postsurgery, there was a considerable reduction in hydronephrosis volume (68.9±96.1 vs. 32.1±48.8 cm 3 ), blood creatinine level (103.7±49.8 vs. 94.4±47.5 mol/l) and urea nitrogen level (6.7±7.2 vs. 5.1±2.4 mmol/l). The study also reported that the rate of adverse events associated with MUS was relatively low, included hematuria (7.9%), pain (6.8%), urinary tract infection (6.4%), and lower urinary tract symptoms (5.3%). CONCLUSIONS: MUS appear to be a safe and effective treatment option for ureteral strictures, with a high success rate and low complication rate. These results have important implications for the management of ureteral strictures and can help guide clinical decision-making in the selection of treatment options.

ß-Adrenoceptors regulate urothelial inflammation and zonula occludens in the bladder outlet obstruction model.

BACKGROUND: The purpose of this study was to evaluate the effects of ß-adrenoceptors (ADRBs) on the urothelial inflammation and zonula occludens (ZO) in a rat PBOO model and in an in vitro model. METHODS: The PBOO model was established by ligating the bladder neck of rats. Twenty rats were divided into 4 groups: sham operation, PBOO + normal saline, PBOO + ADRB2 agonist, PBOO + ADRB3 agonist. PBOO rats were with treated with ADRBs agonists for 3 weeks. Human urothelial cells (HUCs) were subjected to ADRBs agonist treatment or hydrostatic pressure in an in vitro model. RESULTS: In the PBOO group, there was a significant increase in the expression of MCP-1, IL-6 and RANTES compared to the sham group. By contrast, there was a post-PBOO decline in the expression of ZO-1 and ZO-2 in the urothelium. ADRB2 or ADRB3 agonists exhibited downregulated inflammatory cytokine expression and increased ZO expression in the PBOO model. The regulation of inflammation and ZO by ADRB2 and ADRB3 agonists in an in vitro model was found consistent with that in the PBOO model. Moreover, RhoA and ROCK inhibitors suppressed the expression of hydrostatic pressure-induced inflammatory cytokines. Additionally, RhoA agonist reversed the inhibitory effect of ADRBs agonists on the inflammatory secretion from HUCs. CONCLUSIONS: ADRB2 and ADRB3 agonists increased ZO protein expression in HUCs in a rat PBOO model and in an in vitro model. Furthermore, ADRB2 and ADRB3 agonists inhibited the secretion of inflammatory cytokines from HUCs by regulating the RhoA/ROCK signaling pathways.

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.

Cellular mechanotransduction in health and diseases: from molecular mechanism to therapeutic targets.

Cellular mechanotransduction, a critical regulator of numerous biological processes, is the conversion from mechanical signals to biochemical signals regarding cell activities and metabolism. Typical mechanical cues in organisms include hydrostatic pressure, fluid shear stress, tensile force, extracellular matrix stiffness or tissue elasticity, and extracellular fluid viscosity. Mechanotransduction has been expected to trigger multiple biological processes, such as embryonic development, tissue repair and regeneration. However, prolonged excessive mechanical stimulation can result in pathological processes, such as multi-organ fibrosis, tumorigenesis, and cancer immunotherapy resistance. Although the associations between mechanical cues and normal tissue homeostasis or diseases have been identified, the regulatory mechanisms among different mechanical cues are not yet comprehensively illustrated, and no effective therapies are currently available targeting mechanical cue-related signaling. This review systematically summarizes the characteristics and regulatory mechanisms of typical mechanical cues in normal conditions and diseases with the updated evidence. The key effectors responding to mechanical stimulations are listed, such as Piezo channels, integrins, Yes-associated protein (YAP) /transcriptional coactivator with PDZ-binding motif (TAZ), and transient receptor potential vanilloid 4 (TRPV4). We also reviewed the key signaling pathways, therapeutic targets and cutting-edge clinical applications of diseases related to mechanical cues.

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.

Actomyosin Activity and Piezo1 Activity Synergistically Drive Urinary System Fibroblast Activation.

Mechanical cues play a crucial role in activating myofibroblasts from quiescent fibroblasts during fibrosis, and the stiffness of the extracellular matrix is of significant importance in this process. While intracellular force mediated by myosin II and calcium influx regulated by Piezo1 are the primary mechanisms by which cells sense and respond to mechanical forces, their intercellular mechanical interaction remains to be elucidated. Here, hydrogels with tunable substrate are used to systematically investigate the crosstalk of myosin II and Piezo1 in fibroblast to myofibroblast transition (FMT). The findings reveal that the two distinct signaling pathways are integrated to convert mechanical stiffness signals into biochemical signals during bladder-specific FMT. Moreover, it is demonstrated that the crosstalk between myosin II and Piezo1 sensing mechanisms synergistically establishes a sustained feed-forward loop that contributes to chromatin remodeling, induces the expression of downstream target genes, and ultimately exacerbates FMT, in which the intracellular force activates Piezo1 by PI3K/PIP3 pathway-mediated membrane tension and the Piezo1-regulated calcium influx enhances intracellular force by the classical FAK/RhoA/ROCK pathway. Finally, the multifunctional Piezo1 in the complex feedback circuit of FMT drives to further identify that targeting Piezo1 as a therapeutic option for ameliorating bladder fibrosis and dysfunction.

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.

Antifibrotic Effects of Tetrahedral Framework Nucleic Acids by Inhibiting Macrophage Polarization and Macrophage-Myofibroblast Transition in Bladder Remodeling.

Bladder outlet obstruction (BOO) is a prevalent condition arising from urethral stricture, posterior urethral valves, and benign prostatic hyperplasia. Long-term obstruction can lead to bladder remodeling, which is characterized by inflammatory cell infiltration, detrusor hypertrophy, and fibrosis. Until now, there are no efficacious therapeutic options for BOO-induced remodeling. Tetrahedral framework nucleic acids (tFNAs) are a type of novel 3D DNA nanomaterials that possess excellent antifibrotic effects. Here, to determine the treatment effects of tFNAs on BOO-induced remodeling is aimed. Four single-strand DNAs are self-assembled to form tetrahedral framework DNA nanostructures, and the antifibrotic effects of tFNAs are investigated in an in vivo BOO animal model and an in vitro transforming growth factor beta1 (TGF-ß1)-induced fibrosis model. The results demonstrated that tFNAs could ameliorate BOO-induced bladder fibrosis and dysfunction by inhibiting M2 macrophage polarization and the macrophage-myofibroblast transition (MMT) process. Furthermore, tFNAs regulate M2 polarization and the MMT process by deactivating the signal transducer and activator of transcription (Stat) and TGF-ß1/small mothers against decapentaplegic (Smad) pathways, respectively. This is the first study to reveal that tFNAs might be a promising nanomaterial for the treatment of BOO-induced remodeling.

The Association Between Metabolic Syndrome and Prostate Cancer Risk: A Large-Scale Investigation and Study of Chinese.

Background: To investigate the association between metabolic syndrome (MetS) and its components and prostate cancer (PCa). Methods: This study enrolled 482 943 consecutive men who underwent routine health checkups at the Health Management Center of West China Hospital Between 2010 and 2017. For patients with elevated prostate-specific antigen (PSA) levels or color Doppler ultrasound indicating abnormal prostates, we recommended prostate puncture and follow-up. We used the chi-square test and independent t-test for categorical variables and continuous variables, respectively. We used logistic regression analysis to evaluate the effects of MetS and its components on prostate cancer risk. Results: We found that the incidence of PCa in Chinese men over 40 years of age was 0.1%. Among the 85882 participants, 31.5% (27016/85882) of the patients were diagnosed with MetS. PCa was associated with older age, higher PSA levels, lighter weight and shorter height, hypertension, elevated fasting blood glucose (FBG) and HDL cholesterol level, lower triglycerides. After excluded the interference of other factors in multivariate logistic analysis, we found that MetS, hypertension, hyperlipidemia, hyperglycemia, and obesity were not related to the risk of PCa. High age and PSA levels were risk factors for prostate cancer. Conclusions: High age and PSA levels were risk factors for prostate cancer. MetS, hypertension, hyperlipidemia, hyperglycemia, and obesity were not related to the risk of PCa.