Overactive bladder (OAB) is a syndrome marked by urinary urgency. Given the crucial role of metabolic anomalies in the pathogenesis of OAB, the aim of this study was to investigate the associations between different triglyceride glucose index (TyG)-related indicators and OAB.

9024 participants aged ≥ 20 years from NHANES 2005-2018 were involved. Weighted multivariate logistic regression was employed to assess the relationship between three TyG-related indicators and OAB with subgroup and interaction analyses. In addition, ROC, DeLong's test and confusion matrix were further utilized to assess the predictive power of different indicators for OAB in the total population versus different subgroups of the population.

TyG-related indicators were positively associated with OAB. The associations were statistically different in age and physical activity subgroups (all p for interaction < 0.1). In the whole population, TyG-WHtR demonstrated the highest predictive ability, with the largest AUC of 0.625 (95 %CI: 0.609, 0.641), and was relatively more predictive in the < 60 years and moderate-to-vigorous physical activity subgroups.

Positive associations of TyG-related indicators with OAB were observed. TyG-WHtR has the strongest predictive performance for OAB in the total population.

Mechanical organ models are crucial for understanding organ function and clinical applications. These models rely on input data regarding smooth muscle properties, typically gathered from experiments involving stimulations at different muscle lengths. However, reproducibility of these experimental results is a major challenge due to rapid changes in active and passive smooth muscle properties during the measurement period. Usually, preconditioning of the tissue is employed to ensure reproducible behavior in subsequent experiments, but this process itself alters the tissue's mechanical properties. To address this issue, three protocols (P1, P2, P3) without preconditioning were developed and compared to preserve the initial mechanical properties of smooth muscle tissue. Each protocol included five repetitive experimental cycles with stimulations at a long muscle length, varying in the number of stimulations at a short muscle length (P1: 0, P2: 1, P3: 2 stimulations). Results showed that P2 and P3 successfully reproduced the initial active force at a long length over five cycles, but failed to maintain the initial passive forces. Conversely, P1 was most effective in maintaining constant passive forces over the cycles. These findings are supported by existing adaptation models. Active force changes are primarily due to the addition or removal of contractile units in the contractile apparatus, while passive force changes mainly result from actin polymerization induced by contractions, leading to cytoskeletal stiffening. This study introduces a new method for obtaining reproducible smooth muscle parameters, offering a foundation for future research to replicate the mechanical properties of smooth muscle tissue without preconditioning.

The standard strategy is to reconstruct bladder by use of bowel segments as material in bladder cancer with radical cystectomy clinically. Both natural derived and non natural derived materials are investigated in bladder reconstruction. Studies on mechanical bladder, bladder transplantation and bladder xenotransplantation are currently limited although heart and kidney transplantation or xenotransplantation are successful to a certain extent, and bone prostheses are applied in clinical contexts. Earlier limited number of studies associated with bladder xenograft from animals to humans were not particular promising in results. Although there have been investigations on pig to human cardiac xenotransplantation with CRISPR Cas9 gene editing, the CRISPR Cas technique is not yet widely researched in porcine bladder related gene editing for the potential of human bladder replacement for bladder cancer. The advancement of technologies such as gene editing, bioprinting and induced pluripotent stem cells allow further research into partial or whole bladder replacement strategies. Porcine bladder is suggested as a potential source material for bladder reconstruction due to its alikeness to human bladder. Challenges that exist with all these approaches need to be overcome. This paper aims to review gene editing technology such as the CRISPR Cas systems as tools in bladder reconstruction, bladder xenotransplantation and hybrid bladder with technologies of induced pluripotent stem cells and genome editing, bioprinting for bladder replacement for bladder reconstruction and to restore normal bladder control function after cystectomy for bladder cancer.

The insidious interrelation between three key factors underscores the critical need to understand the neural control of the lower urinary tract (LUT): the complexity of its functioning, the epidemiology of conditions that can disrupt it, and the nonspecific presentation of related symptoms. This paper examines the importance of understanding neurophysiology of micturition to prevent mismanagement and reduce unnecessary procedures.

This review focuses on the neurophysiology of the micturition cycle, the epidemiology of major health conditions that affect it, and the nonspecific nature of lower urinary tract symptoms (LUTS) concerning underlying pathologies. The review was conducted in accordance with the guidelines of the Scale for Assessment of Narrative Review Articles (SANRA). Only articles in English were included, while case reports, editorials, and expert opinion pieces were excluded.

The ability of the LUT to store and release urine requires precise coordination and is mediated by a complex network involving the brain, spinal cord, peripheral ganglia, and nerves. Epidemiological data reveal a growing global burden of diseases that impact LUT functioning (LUTF). Moreover, the nonspecific nature of LUTS often leads to diagnostic challenges, and inappropriate treatment strategies.

The interplay between the complexity of LUTF, the widespread prevalence of conditions that can disrupt it, and the nonspecific nature of related symptoms frequently complicate urological decision-making. Overlooking associated neurological factors can result in suboptimal outcomes, diminished quality of life, and serious adverse consequences. A systematic approach is crucial to minimizing the risk of misdiagnosis and mismanagement, especially when considering invasive interventions.

Ranolazine (RNZ) is a multifaceted ion channel modulator approved for the treatment of angina. Although various pleiotropic effects on the cardiovascular system have been demonstrated, its efficacy in the urinary system remains not fully understood. Here, we aimed to investigate the effect of RNZ on mouse detrusor smooth muscle (DSM) contractility and the mechanism(s) of its action by using isolated tissue bath technique. RNZ significantly decreased carbachol (CCh)-, KCl- and electrical field stimulation-induced contractility and induced relaxation in DSM concentration-dependently. Furthermore, RNZ-induced relaxation of KCl-precontracted DSM strips was not altered in the presence of 4-aminopyridine, BaCl2, glibenclamide, TEA, propranolol, L-NAME or methylene blue, indicating that K+ channels, nitric oxide/cGMP pathway or β-adrenoreceptors are not involved in the relaxant effect of RNZ. Also, RNZ significantly inhibited the contractile response induced by CaCl2, CCh, and Bay K8644 under Ca++-free conditions. Regarding the molecular docking and cytosolic Ca++ mobilization assays, RNZ showed affinity for the antagonist binding site of L-type Ca++ channels and significantly decreased cytosolic Ca++ level in A7r5 cells. These findings suggest the inhibition of Ca++ influx and release may contribute to RNZ-induced DSM relaxation. Hence, our results provide strong evidence that RNZ has a notable relaxant effect on mouse DSM by inhibiting Ca++ influx and release of Ca++ from intracellular stores and it has the potential to be a therapeutic candidate for LUTS.

This study aimed to assess the relationship between magnesium depletion score (MDS) and overactive bladder (OAB) prevalence.

This study utilized data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. Multivariate logistic regression was employed to investigate the association between MDS and OAB. Restricted cubic spline (RCS) analysis explored the linear or non-linear relationship between MDS and OAB. Interaction analyses were conducted on subgroups to validate the findings.

There was a significant positive association between MDS and OAB. After adjusting for covariates, with each unit increase in MDS, there was an 11% increase in the prevalence of infertility (P < 0.001). In addition, the incidence of OAB was significantly increased in the higher MDS group compared to the low MDS group (MDS = 0) (P for trend < 0.001). The dose-response curve indicated a linear association between MDS and OAB, with higher MDS associated with higher OAB.

The results of this study show a strong positive correlation between MDS and the prevalence of OAB. These findings suggest that monitoring and managing magnesium status may be a potential strategy for reducing the risk of OAB.

Neuromuscular conduction dysfunction-induced underactive bladder (UAB) is a major urological complication associated with diabetes mellitus (DM), and there remain deficiencies in reliable pharmacological treatment options. Astragalus polysaccharides (APS), as an edible active substance in Astragalus membranaceus, have a therapeutic effect on diabetes and its complications. We investigated the effects and mechanism of APS in high-fat-diet-induced (HFD) diabetic UAB mice. APS significantly reduced fasting plasma glucose, insulin, and HOMA-IR index. Furthermore, APS treatment significantly decreased maximum bladder capacity, residual volume, bladder compliance, contraction intervals, empty and full resting pressure, and increased voiding volume and voided efficiency. In addition, APS ameliorated the hyporesponsiveness of purinergic and cholinergic-mediated neuromuscular contraction of the detrusor and improved the dysregulation of inhibitory and excitatory neurotransmission by downregulating the levels of nNOS and VIP, and upregulating ChAT and SP in HFD mice. This study revealed that APS ameliorates diabetic UAB via the normalization of neuromuscular conduction.

Vascular smooth muscle cells (VSMC) are the most abundant cell type in the artery's media layer and regulate vascular tone and lesion remodeling during atherogenesis. Like monocyte-derived macrophages, VSMCs accumulate excess lipids and contribute to the total intimal foam cell population in human coronary plaques and mouse aortic atheroma. While there are extensive studies characterizing the contribution of lipid metabolism in macrophage immunometabolic responses in atherosclerotic plaques, the role of VSMC lipid metabolism in regulating vascular function and lesion remodeling in vivo remains poorly understood. Here, we report that the liver X receptor (LXR) signaling pathway in VSMC is continuously activated during atherogenesis. Notably, we found that LXR deficiency in SMCs under hypercholesterolemic conditions influenced lesion remodeling by altering the fate of dedifferentiated SMCs and promoting the accumulation of VSMC-derived transitional cells. This phenotypic switching was accompanied by reduced indices of plaque stability, characterized by a larger necrotic core area and reduced fibrous cap thickness. Moreover, SMC-specific LXR deficiency impaired vascular function and caused visceral myopathy characterized by maladaptive bladder remodeling and gut lipid malabsorption. Mechanistically, we found that the expression of several genes involved in cholesterol efflux and FA synthesis including Abca1, Srebf1, Scd1, Scd2, Acsl3, and Mid1ip1 was downregulated in mice lacking LXRαβ in SMCs, likely contributing to the phenotypic switching of VSMC in the atherosclerotic lesions.

Urinary bladder vascularized allograft transplantation in humans is currently extensively being investigated worldwide, owing to the theoretical potential of this approach as a therapeutic option for individuals with end-stage, non-oncological bladder conditions or congenital bladder pathologies. To date, a successful attempt at urinary bladder autotransplantation was carried out in a heart-beating brain-dead research human donor. The robot-assisted surgical technique was shown to be optimal for performing this procedure, achieving a good performance in terms of both bladder allograft collection as well as vascular, ureterovesical and vesicourethral anastomoses. The urinary bladder vascularized allograft would be an alternative to traditional urinary diversion methods that rely on the use of intestinal segments, potentially avoiding adverse effects associated with these approaches. However, different from ileal urinary diversion, bladder transplantation would require lifelong immune suppression. Clinical trials are in progress to assess the vascularized bladder allograft transplantation technique, as well as the safety of this procedure in oncological and non-oncological indications.

We describe a rare case of high-grade divergent urothelial carcinoma (UC) of the renal pelvis with neuroendocrine differentiation, specifically a small cell carcinoma (SCC) component. A 70-year-old male who presented with frank hematuria underwent a thorough clinical workup including computed tomography (CT) scan, which showed a large, contrast-enhancing obstructive right renal mass. The mass, when analyzed microscopically, showed two distinct components: high-grade urothelial carcinoma and SCC. Immunohistochemistry analysis confirmed primary dual morphological subtypes and ruled out a metastatic source. Mixed SCC and UC of the renal pelvis are extremely rare diagnoses, and staging of these tumors is difficult, highlighting the importance of integrated diagnostic approaches for an accurate characterization of complex renal tumors.

The BKCa channel, a large-conductance calcium-activated potassium channel, plays a crucial role in maintaining the homeostasis of the micturition cycle and airway-related functions. In this study, we optimized a novel BKCa channel activator, 4d, with a diphenyl ether structure identified from library screening. This led to the discovery of potent activators, 10b (EC50 = 0.12 μM, cell-based assay) and 51b, an orally bioavailable derivative. Compound 10b demonstrated potent in vivo efficacy in a spontaneous hypertensive rat (SHR) of urinary incontinence model, while compound 51b showed dose-dependent cough suppression efficacy with an ED50 of 11.8 mg/kg in a citric acid-induced cough model. Furthermore, we reported the cryo-electron microscopy (cryo-EM) structures of the BKCa channel in complex with 10b and 51b at resolutions of 2.8 and 3.4 Å. Based on structural analyses, we determined the binding sites and key interaction residues of 51b, which were validated via mutation studies.

Pregnancy leads to a number of structural and functional changes in the urinary system, which makes females susceptible to urological complications. This review aims to discuss the epidemiology, complications and prevention and management of urinary tract infections (UTIs), kidney stones and bladder dysfunction in pregnancy. UTIs are the most common urological problem presenting in 10% of pregnant women; Escherichia coli is the most common causative organism. If left untreated, UTIs lead to acute pyelonephritis which occurs in about 2% of pregnant women and which has serious consequences for both the mother and the baby. Kidney stones, although rare, are hazardous, occurring in 1 in 200 to 1 in 1500 pregnancies, and may cause obstructive uropathy, and aggravation of "labor-like" pain. Urological complications are frequent in pregnancy; bladder dysfunction alone has been documented to affect 50% of the pregnant women. Urological complications can have severe consequences when not properly managed including preterm labor and renal dysfunction. In order to have the best pharmacological care, safe use of antibiotics for UTIs is needed along with other measures for kidney stones. This review highlights the importance of a team approach to patient management to optimize outcome and touches briefly on some of the ethical dilemmas that may be encountered when drug therapy in pregnancy is being considered. Therefore, it is feasible to enhance the health of women and the fetus during this period through patient focused care and innovative interventions.

Urological cancers are one of the most prevalent malignancies around the globe. Specifically, bladder cancer severely threatens the health of humans because of its heterogeneous and aggressive nature. Extensive studies have been conducted for many years in order to address the limitations associated with the treatment of solid tumors with selective substances. This article aims to provide a summary of the therapeutic drugs that have received FDA approval or are presently in the testing phase for use in the prevention or treatment of bladder cancer. In this review, FDA-approved drugs for bladder cancer treatment have been listed along with their dose protocols, current status, pharmacokinetics, action mechanisms, and marketed products. The article also emphasizes the novel preparations of these drugs that are presently under clinical trials or are in the approval stage. Thus, this review will serve as a single point of reference for scientists involved in the formulation development of these drugs.

6-Nitrodopamine (6-ND) modulates vas deferens, seminal vesicles, and corpus cavernosum contractility; however, its role on the lower urinary tract organs has not been evaluated. Investigations of isolated urinary bladders from wild-type (WT) mice revealed 6-ND release was comparable to that of dopamine and adrenaline, whereas noradrenaline was hardly detected, as assessed by liquid chromatography coupled to tandem mass spectrometry. In vitro, 6-ND induced concentration-dependent relaxations in carbachol pre-contracted bladders with high potency (pEC50: 8.04 ± 0.86), independently of eNOS/sGC activity. Co-incubation of 6-ND (1-10 μM) antagonizes the contractile effects of acetylcholine (p < 0.05). Experiments using nitric oxide synthase (NOS) knockout mice demonstrated that 6-ND release from isolated urinary bladder was significantly reduced by neuronal NOS (nNOS-/-) deletion and abolished by triple NOSs deletion (n/i/eNOS-/-), while no significant changes were observed in endothelial (eNOS-/-) or inducible (iNOS-/-) knockout mice. Incubation with tetrodotoxin resulted in a significant decrease in 6-ND release in bladders obtained from WT, but not in nNOS-/- mice. The bladders from nNOS-/- and n/i/eNOS-/- mice exhibited significantly higher contractile responses to electric field stimulation (EFS), compared to eNOS-/-, iNOS-/-, or WT bladders. The hyperreactivity observed in triple NOS knockouts was reversed by the incubation with bladder mucosal layer obtained from a donor WT mice, but not with the muscular layer. These findings clearly demonstrate 6-ND is the most potent endogenous relaxing agent of urinary bladder, and inhibition of its release is associated with bladder hyperreactivity.

To explore the association between drugs and urinary retention using the FDA Adverse Event Reporting System (FAERs) database and Mendelian randomization (MR) analysis, providing preliminary insights into the underlying mechanisms.

Drug-adverse reaction reports from the FAERs database from 2004 to 2023 were obtained, and MR analysis was conducted to further validate the causal relationship between drugs and urinary retention using genetic data provided by the IEU OpenGWAS project.

We identified 78 drugs associated with urinary retention, including Mirabegron, Tiotropium, Quetiapine, Amlodipine, etc. MR analysis indicated genetic markers (SNPs rs10500326, rs4815689, and rs1216743) of Amlodipine were associated with an increased risk of urinary retention. Sensitivity analysis demonstrated the robustness and reliability of the results.

This study identified various drugs associated with urinary retention, particularly Amlodipine. This finding provides new clues for further investigation into the mechanisms of drug effects on bladder function and offers important references for clinical practice. However, further randomized controlled trials are needed to validate these associations and explore deeper mechanisms.

This investigation was conducted to elucidate the effects of eugenol on bladder contractility through experimental and in silico approaches.

To assess the impact of eugenol on muscular contractility, longitudinal strips of bladder tissue, measuring 2 mm by 6 mm, were mounted in perfusion chambers connected to an isometric force transducer. Furthermore, molecular docking studies were conducted to explore the potential of eugenol to target the M3 muscarinic acetylcholine receptor (M3R) and voltage-operated calcium channels (VOCCs) in muscle cells, utilizing in silico techniques.

Eugenol exhibited a concentration-dependent inhibitory effect on both the phasic and tonic components of the contraction induced by 60mM K+ and carbachol, completely suppressing this contraction at a concentration of 3mM. Additionally, eugenol inhibited the concentration-contraction curve elicited by Ba2+.

The in vitro and in silico results suggest that the mechanism of eugenol likely involves blockade of VOCCs and/or M3R, implicating eugenol as a promising molecule for the treatment of overactive bladder.

Neurogenic bladder often occurs after pelvic ganglia injury. Its symptoms, like severe urinary retention and incontinence, have a significant impact on individuals' quality of life. Unfortunately, there are currently no effective treatments available for this type of injury. Here, we designed a fiber-enhanced tissue bandage for injured pelvic ganglia. Tight junctions formed in tissue bandages create a mini tissue structure that enhances resistance in an in vivo environment and delivers growth factors to support the healing of ganglia. Strength fibers are similar to clinical bandages and guarantee ease of handling. Furthermore, tissue bandages can be stored at low temperatures over 5 months without compromising cell viability, meeting the requirements for clinical products. A tissue bandage was applied to a male rat with a bilateral major pelvic ganglia crush injury. Compared to the severe neurogenic bladder symptoms observed in the injury and scaffold groups, tissue bandages significantly improved bladder function. We found that tissue bandage increases resistance to mechanical injury by boosting the expression of cytoskeletal proteins within the major pelvic ganglia. Overall, tissue bandages show promise as a practical therapeutic approach for ganglia repair, offering hope for developing more effective treatments for this thorny condition.

Diabetic bladder dysfunction (DBD) comprises a wide spectrum of lower urinary tract symptoms that impact diabetic patients' lives, including urinary frequency, urgency, incontinence, and incomplete bladder emptying. To relieve symptoms, anticholinergics have been widely prescribed and are considered an effective treatment. There is increasing evidence that diabetic patients may benefit from the use of phosphodiesterase 5 (PDE5) inhibitors. This narrative review aims to provide a brief overview of the pathophysiology of DBD along with a focus on cholinergic and phosphodiesterase inhibitors as therapies that benefit DBD. An examination of the literature suggests compelling avenues of research and underscores critical gaps in understanding the mechanisms underlying DBD. New tools and models, especially rodent models, are required to further elucidate the mechanisms of action of current therapies in the treatment of DBS.

Smooth muscle organs of the lower urinary tract comprise the bladder detrusor and urethral wall, which have a reciprocal contractile relationship during urine storage and micturition. As the bladder fills with urine, detrusor smooth muscle cells (DSMCs) remain relaxed to accommodate increases in intravesical pressure while urethral smooth muscle cells (USMCs) sustain tone to occlude the urethral orifice, preventing leakage. While neither organ displays coordinated regular contractions as occurs in small intestine, lymphatics or renal pelvis, they do exhibit patterns of rhythmicity at cellular and tissue levels. In rabbit and guinea-pig urethra, electrical slow waves are recorded from USMCs. This activity is linked to cells expressing vimentin, c-kit and Ca2+-activated Cl- channels, like interstitial cells of Cajal in the gastrointestinal tract. In mouse, USMCs are rhythmically active (firing propagating Ca2+ waves linked to contraction), and this cellular rhythmicity is asynchronous across tissues and summates to form tone. Experiments in mice have failed to demonstrate a voltage-dependent mechanism for regulating this rhythmicity or contractions in vitro, suggesting that urethral tone results from an intrinsic ability of USMCs to 'pace' their own Ca2+ mobilization pathways required for contraction. DSMCs exhibit spontaneous transient contractions, increases in intracellular Ca2+ and action potentials. Consistent across numerous species, including humans, this activity relies on voltage-dependent Ca2+ influx in DSMCs. While interstitial cells are present in the bladder, they do not 'pace' the organ in an excitatory manner. Instead, specialized cells (PDGFRα+ interstitial cells) may 'negatively pace' DSMCs to prevent bladder overexcitability.

Urinary tract infections (UTIs) pose a substantial burden on global healthcare systems. When unraveling the complex pathophysiology of UTIs, bladder models are used to understand complex and multifaceted interactions between different components within the system. This review aimed to bridge the gap between in vitro and in vivo experimental bladder models towards UTI research. We reviewed clinical, animal, and analytical studies and patents from 1959 to the end of 2023. Both in vivo and in vitro models offer unique benefits and drawbacks in understanding UTIs. In vitro models provide controlled environments for studying specific aspects of UTI biology and testing potential treatments, while in vivo models offer insights into how UTIs manifest and progress within living organisms. Thus, both types of models are leading to the development of more effective diagnostic tools and therapeutic interventions against UTIs. Moreover, advanced methodologies involving three-dimensional bladder organoids have also been used to study bladder biology, model bladder-related disorders, and explore new treatments for bladder cancers, UTIs, and urinary incontinence. Narrowing the distance between fundamental scientific research and practical medical applications, these pioneering models hold the key to unlocking new avenues for the development of personalized diagnostics, precision medicine, and ultimately, the alleviation of UTI-related morbidity worldwide.

Hydrogen sulfide (H2S) is known as a chemical gas in nature with both enzymatic and non-enzymatic biosynthesis in different human organs. A couple of studies have demonstrated the function of H2S in regulating the homeostasis of the human body. Additionally, they have shown its synthesis, measurement, chemistry, protective effects, and interaction in various aspects of scientific evidence. Furthermore, many researches have demonstrated the beneficial impacts of H2S on genital organs and systems. According to various studies, it is recognized that H2S-producing enzymes and the endogenous production of H2S are expressed in male and female reproductive systems in different mammalian species. The main goal of this comprehensive review is to assess the potential therapeutic impacts of this gasotransmitter in the male and female urogenital system and find underlying mechanisms of this agent. This narrative review investigated the articles that were published from the 1970s to 2022. The review's primary focus is the impacts of H2S on the male and female urogenital system. Medline, CINAHL, PubMed, and Google scholar databases were searched. Keywords used in this review were "Hydrogen sulfide," "H2S," "urogenital system," and "urogenital tract". Numerous studies have demonstrated the therapeutic and protective effects of sodium hydrosulfide (Na-HS) as an H2S donor on male and female infertility disorders. Furthermore, it has been observed that H2S plays a significant role in improving different diseases such as ameliorating sperm parameters. The specific localization of H2S enzymes in the urogenital system provides an excellent opportunity to comprehend its function and role in various disorders related to this system. It is noteworthy that H2S has been demonstrated to be produced in endocrine organs and exhibit diverse activities. Moreover, it is important to recognize that alterations in H2S biosynthesis are closely linked to endocrine disorders. Therefore, hormones can be pivotal in regulating H2S production, and H2S synthesis pathways may aid in establishing novel therapeutic strategies. H2S possesses pharmacological effects on essential disorders, such as anti-inflammation, anti-apoptosis, and anti-oxidant activities, which render it a valuable therapeutic agent for human urogenital disease. Furthermore, this agent shows promise in ameliorating the detrimental effects of various male and female diseases. Despite the limited clinical research, studies have demonstrated that applying H2S as an anti-oxidant source could ameliorate adverse effects of different conditions in the urogenital system. More clinical studies are required to confirm the role of this component in clinical settings.

Multidrug resistance proteins type 4 (MRP4) and 5 (MRP5) play pivotal roles in the transport of cyclic nucleotides in various tissues. However, their specific functions within the lower urinary tract remain relatively unexplored. This study aimed to investigate the effect of pharmacological inhibition of MRPs on cyclic nucleotide signaling in isolated pig bladder. The relaxation responses of the bladder were assessed in the presence of the MRP inhibitor, MK571. The temporal changes in intra- and extracellular levels of cAMP and cGMP in stimulated tissues were determined by mass spectrometry. The gene (ABCC4) and protein (MRP4) expression were also determined. MK571 administration resulted in a modest relaxation effect of approximately 26% in carbachol-precontracted bladders. The relaxation induced by phosphodiesterase inhibitors such as cilostazol, tadalafil, and sildenafil was significantly potentiated in the presence of MK571. In contrast, no significant potentiation was observed in the relaxation induced by substances elevating cAMP levels or stimulators of soluble guanylate cyclase. Following forskolin stimulation, both intracellular and extracellular cAMP concentrations increased by approximately 15.8-fold and 12-fold, respectively. Similarly, stimulation with tadalafil + BAY 41-2272 resulted in roughly 8.2-fold and 3.4-fold increases in intracellular and extracellular cGMP concentrations, respectively. The presence of MK571 reduced only the extracellular levels of cGMP. This study reveals the presence and function of MRP4 transporters within the porcine bladder and paves the way for future research exploring the role of this transporter in both underactive and overactive bladder disorders.NEW & NOTEWORTHY This study investigates the impact of pharmacological inhibition of MRP4 and MRP5 transporters on cyclic nucleotide signaling in isolated pig bladders. MK571 administration led to modest relaxation, with enhanced effects observed in the presence of phosphodiesterase inhibitors. However, substances elevating cAMP levels remained unaffected. MK571 selectively reduced extracellular cGMP levels. These findings shed light on the role of MRP4 transporters in the porcine bladder, opening avenues for further research into bladder disorders.

Bladder cancer is a leading cancer type in men. The complexity of treatment in late-stage bladder cancer after systemic spread through the lymphatic system highlights the importance of modulating disease-free progression as early as possible in cancer staging. With current therapies relying on previous standards, such as platinum-based chemotherapeutics and immunomodulation with Bacillus Calmette-Guerin, researchers, and clinicians are looking for targeted therapies to stop bladder cancer at its source early in progression. A new era of molecular therapies that target specific features upregulated in bladder cancer cell lines is surfacing, which may be able to provide clinicians and patients with better control of disease progression. Here, we discuss multiple emerging therapies including immune checkpoint inhibitors of the programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway, antibody-drug conjugates, modulation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) cell proliferation pathway, chimeric antigen receptor T-cell therapy, and fibroblast growth factor receptor targeting. Together, these modern treatments provide potentially promising results for bladder cancer patients with the possibility of increasing remission and survival rates.

The immunomodulatory imide drugs (IMiDs) thalidomide, lenalidomide and pomalidomide may exhibit therapeutic efficacy in the prostate. In lower urinary tract symptoms (LUTS), voiding and storage disorders may arise from benign prostate hyperplasia, or overactive bladder. While current therapeutic options target smooth muscle contraction or cell proliferation, side effects are mostly cardiovascular. Therefore, we investigated effects of IMiDs on human detrusor and porcine artery smooth muscle contraction, and growth-related functions in detrusor smooth muscle cells (HBdSMC).

Cell viability was assessed by CCK8, and apoptosis and cell death by flow cytometry in cultured HBdSMC. Contractions of human detrusor tissues and porcine interlobar and coronary arteries were induced by contractile agonists, or electric field stimulation (EFS) in the presence or absence of an IMID using an organ bath. Proliferation was assessed by EdU assay and colony formation, cytoskeletal organization by phalloidin staining, RESULTS: Depending on tissue type, IMiDs inhibited cholinergic contractions with varying degree, up to 50 %, while non-cholinergic contractions were inhibited up to 80 % and 60 % for U46619 and endothelin-1, respectively, and EFS-induced contractions up to 75 %. IMiDs reduced viable HBdSM cells in a time-dependent manner. Correspondingly, proliferation was reduced, without showing pro-apoptotic effects. In parallel, IMiDs induced cytoskeletal disorganization.

IMiDs exhibit regulatory functions in various smooth muscle-rich tissues, and of cell proliferation in the lower urinary tract. This points to a novel drug class effect for IMiDs, in which the molecular mechanisms of action of IMiDs merit further consideration for the application in LUTS.

Transient receptor potential vanilloid 1 (TRPV1) is a calcium-permeable ion channel that is gated by the pungent constituent of red chili pepper, capsaicin, and by related chemicals from the group of vanilloids, in addition to noxious heat. It is expressed mostly in sensory neurons to act as a detector of painful stimuli produced by pungent chemicals and high temperatures. Although TRPV1 is also found outside the sensory nervous system, its expression and function in the bladder detrusor smooth muscle (DSM) remain controversial. Here, by using Ca2+ imaging and patch clamp on isolated rat DSM cells, in addition to tensiometry on multicellular DSM strips, we show that TRPV1 is expressed functionally in only a fraction of DSM cells, in which it acts as an endoplasmic reticulum Ca2+-release channel responsible for the capsaicin-activated [Ca2+]i rise. Carbachol-stimulated contractions of multicellular DSM strips contain a TRPV1-dependent component, which is negligible in the circular DSM but reaches ≤50% in the longitudinal DSM. Activation of TRPV1 in rat DSM during muscarinic cholinergic stimulation is ensured by phospholipase A2-catalysed derivation of arachidonic acid and its conversion by lipoxygenases to eicosanoids, which act as endogenous TRPV1 agonists. Immunofluorescence detection of TRPV1 protein in bladder sections and isolated DSM cells confirmed both its preferential expression in the longitudinal DSM sublayer and its targeting to the endoplasmic reticulum. We conclude that TRPV1 is an essential contributor to the cholinergic contraction of bladder longitudinal DSM, which might be important for producing spatial and/or temporal anisotropy of bladder wall deformation in different regions during parasympathetic stimulation. KEY POINTS: The transient receptor potential vanilloid 1 (TRPV1) heat/capsaicin receptor/channel is localized in the endoplasmic reticulum membrane of detrusor smooth muscle (DSM) cells of the rat bladder, operating as a calcium-release channel. Isolated DSM cells are separated into two nearly equal groups, within which the cells either show or do not show TRPV1-dependent [Ca2+]i rise. Carbachol-stimulated, muscarinic ACh receptor-mediated contractions of multicellular DSM strips contain a TRPV1-dependent component. This component is negligible in the circular DSM but reaches ≤50% in longitudinal DSM. Activation of TRPV1 in rat DSM during cholinergic stimulation involves phospholipase A2-catalysed derivation of arachidonic acid and its conversion by lipoxygenases to eicosanoids, which act as endogenous TRPV1 agonists.

The underlying pathophysiology behind a diagnosis of acontractile or underactive detrusor at invasive urodynamics is very heterogeneous. Lack of etiological classification currently limits the possibility of stratifying therapy.

This subject was discussed at a think-tank on the subject at the International Consultation on Incontinence-Research Society held in Bristol, June 2023. This manuscript is a result of those deliberations and the subsequent discussions of the think-tank.

There are challenges in defining abnormalities of detrusor contraction with resultant implications for available evidence. Pathology at any level of the neuromuscular pathway can impair or prevent a detrusor voiding contraction. Attempts have been made to identify clinical markers that might predict an underactive detrusor but strong supporting evidence is lacking. Hence, a holistic approach to phenotyping requires specialized neuro-imaging as well as physiological investigations. Several general measures can help individuals with an abnormal detrusor contraction. The search for a molecule to enhance the detrusor voiding contraction remains elusive but there are promising new candidates. Neuromodulation can help select individuals but data is not well stratified by underlying etiology. Manipulation of central neurotransmitters might offer an alternate therapeutic option.

A better understanding of the underlying pathophysiologies behind an abnormality of the detrusor voiding contraction is needed for improving management. Towards this goal, the think-tank proposes a classification of the underactive detrusor that might help in selecting and reporting more well-defined patient cohorts.

Patients with sickle cell disease (SCD) display an overactive bladder (OAB). Intravascular hemolysis in SCD is associated with various severe SCD complications. However, no experimental studies have evaluated the effect of intravascular hemolysis on bladder function. This study aimed to assess the effects of intravascular hemolysis on the micturition process and the contractile mechanisms of the detrusor smooth muscle (DSM) in a mouse model with phenylhydrazine (PHZ)-induced hemolysis; furthermore, it aimed to investigate the role of intravascular hemolysis in the dysfunction of nitric oxide (NO) signaling and in increasing oxidative stress in the bladder. Mice underwent a void spot assay, and DSM contractions were evaluated in organ baths. The PHZ group exhibited increased urinary frequency and increased void volumes. DSM contractile responses to carbachol, KCl, α-β-methylene-ATP, and EFS were increased in the PHZ group. Protein expression of phosphorylated endothelial NO synthase (eNOS) (Ser-1177), phosphorylated neuronal NO synthase (nNOS) (Ser-1417), and phosphorylated vasodilator-stimulated phosphoprotein (VASP) (Ser-239) decreased in the bladder of the PHZ group. Protein expression of oxidative stress markers, NOX-2, 3-NT, and 4-HNE, increased in the bladder of the PHZ group. Our study shows that intravascular hemolysis promotes voiding dysfunction correlated with alterations in the NO signaling pathway in the bladder, as evidenced by reduced levels of p-eNOS (Ser-1177), nNOS (Ser-1417), and p-VASP (Ser-239). The study also showed that intravascular hemolysis increases oxidative stress in the bladder. Our study indicates that intravascular hemolysis promotes an OAB phenotype similar to those observed in patients and mice with SCD.

Backgroud: This study investigates the potential of vasodilator drugs as additive therapy in the treatment of urological cancers, particularly in combination with the antineoplastic agent 5-fluorouracil (5-FU). Methods: The study evaluated the cytotoxic effects of sildenafil, tezosentan and levosimendan alone and in combination with 5-FU on urological cancer cell lines. The assessment included MTT assays, colony formation assays and wound healing assays to determine cell viability, proliferative capacity, and migratory behavior, respectively. Results: Sildenafil and tezosentan showed limited cytotoxic effects, while levosimendan demonstrated moderate anticancer activity. The combination of levosimendan and 5-FU exhibited an additive interaction, enhancing cytotoxicity against cancer cells while sparing normal cells. Levosimendan also inhibited cell migration and proliferation, potentially through mechanisms involving the modulation of cAMP levels and nitric oxide production. Conclusions: The findings suggest that levosimendan can be used in conjunction with 5-FU to reduce the required dose of 5-FU, thereby minimizing side effects without compromising therapeutic efficacy. This study offers a new perspective for enhancing therapeutic outcomes in patients with urological cancers.

3-D bioprinting is a promising technology to fabricate custom geometries for tissue engineering. However, most bioprintable hydrogels are weak and fragile, difficult to handle and cannot mimetic the mechanical behaviors of the native soft elastic tissues. We have developed a visible light crosslinked, single-network, elastic and biocompatible hydrogel system based on an acrylated triblock copolymer of poly(ethylene glycol) PEG and polycaprolactone (PCL) (PEG-PCL-DA). To enable its application in bioprinting of soft tissues, we have modified the hydrogel system on its printability and biodegradability. Furthermore, we hypothesize that this elastic material can better transmit pulsatile forces to cells, leading to enhanced cellular response under mechanical stimulation. This central hypothesis was tested using vascular conduits with smooth muscle cells (SMCs) cultured under pulsatile forces in a custom-made bioreactor. The results showed that vascular conduits made of PEG-PCL-DA hydrogel faithfully recapitulate the rapid stretch and recoil under the pulsatile pressure from 1 to 3 Hz frequency, which induced a contractile SMC phenotype, consistently upregulated the core contractile transcription factors. In summary, our work demonstrates the potential of elastic hydrogel for 3D bioprinting of soft tissues by fine tuning the printability, biodegradability, while possess robust elastic property suitable for manual handling and biomechanical stimulation.

Bladder cancer (BCa) is characterised by high prevalence, multifocality, and frequent recurrence, imposing significant clinical and economic burdens. Accurate staging, particularly distinguishing non-muscle-invasive bladder cancer (NMIBC) from muscle-invasive bladder cancer (MIBC) disease, is crucial for guiding treatment decisions. This narrative review explores the potential implications of incorporating multiparametric magnetic resonance imaging (mpMRI) and the Vesical Imaging Reporting Data System (VI-RADS) into BCa staging, focusing on repeat transurethral resection of bladder tumour (re-TURBT).

A comprehensive search of PubMed, EMBASE, and MEDLINE databases identified studies published from 2018 to 2023 discussing mpMRI or VI-RADS in the context of re-TURBT for BCa staging. Studies meeting inclusion criteria underwent qualitative analysis.

Six recent studies met inclusion criteria. VI-RADS scoring, accurately predicted muscle invasion, aiding in NMIBC/MIBC differentiation. VI-RADS scores of ≥3 indicated MIBC with high sensitivity and specificity. VI-RADS potentially identified patients benefiting from re-TURBT and those for whom it could be safely omitted.

mpMRI and VI-RADS offer promising prospects for BCa staging, potentially correlating more closely with re-TURBT and radical cystectomy histopathology than initial TURBT. However, validation and careful evaluation of clinical integration are needed. Future research should refine patient selection and optimise mpMRI's role in BCa management.

VI-RADS scoring could revolutionise BCa staging, especially regarding re-TURBT. There is potential that VI-RADS correlates more with the histopathology of re-TURBT and radical cystectomy than initial TURBT. While promising, ongoing research is essential to validate utility, refine selection criteria, and address economic considerations. Integration of VI-RADS into BCa staging holds potential benefits for patients and health care systems.

Uterine muscle contractility is essential for reproductive processes including sperm and embryo transport, and during the uterine cycle to remove menstrual effluent. Even still, uterine contractions have primarily been studied in the context of preterm labor. This is partly due to a lack of methods for studying the uterine muscle contractility in the intact organ. Here, we describe an imaging-based method to evaluate mouse uterine contractility of both the longitudinal and circular muscles in the cycling stages and in early pregnancy. By transforming the image-based data into three-dimensional spatiotemporal contractility maps, we calculate waveform characteristics of muscle contractions, including amplitude, frequency, wavelength, and velocity. We report that the native organ is highly contractile during the progesterone-dominant diestrus stage of the cycle when compared to the estrogen-dominant proestrus and estrus stages. We also observed that during the first phase of uterine embryo movement when clustered embryos move toward the middle of the uterine horn, contractions are dynamic and non-uniform between different segments of the uterine horn. In the second phase of embryo movement, contractions are more uniform and rhythmic throughout the uterine horn. Finally, in Lpar3-/- uteri, which display faster embryo movement, we observe global and regional increases in contractility. Our method provides a means to understand the wave characteristics of uterine smooth muscle in response to modulators and in genetic mutants. Better understanding uterine contractility in the early pregnancy stages is critical for the advancement of artificial reproductive technologies and a possibility of modulating embryo movement during clinical embryo transfers.

Fibrosarcoma is a challenging cancer originating from fibrous tissues, marked by aggressive growth and limited treatment options. The discovery of non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and small interfering RNAs (siRNAs), has opened new pathways for understanding and treating this malignancy. These ncRNAs play crucial roles in gene regulation, cellular processes, and the tumor microenvironment. This review aims to explore the impact of ncRNAs on fibrosarcoma's pathogenesis, progression, and resistance to treatment, focusing on their mechanistic roles and therapeutic potential. A comprehensive review of literature from databases like PubMed and Google Scholar was conducted, focusing on the dysregulation of ncRNAs in fibrosarcoma, their contribution to tumor growth, metastasis, drug resistance, and their cellular pathway interactions. NcRNAs significantly influence fibrosarcoma, affecting cell proliferation, apoptosis, invasion, and angiogenesis. Their function as oncogenes or tumor suppressors makes them promising biomarkers and therapeutic targets. Understanding their interaction with the tumor microenvironment is essential for developing more effective treatments for fibrosarcoma. Targeting ncRNAs emerges as a promising strategy for fibrosarcoma therapy, offering hope to overcome the shortcomings of existing treatments. Further investigation is needed to clarify specific ncRNAs' roles in fibrosarcoma and to develop ncRNA-based therapies, highlighting the significance of ncRNAs in improving patient outcomes in this challenging cancer.

Overactive bladder syndrome is a common chronic condition with a significant impact on quality of life and economic burden. Persistence with pharmacologic therapy has been limited by efficacy and side effects. A greater understanding of the pathophysiology of overactive bladder has led to the initial evaluation of several drugs affecting ion channels, the autonomic nervous system, and enzymes which may provide useful alternatives for the management of overactive bladder.

A comprehensive review was performed using PubMed and Cochrane databases as well as reviewing clinical trials in the United States. The current standard of care for overactive bladder will be discussed, but this paper focuses on investigational drugs currently in preclinical studies and phase I and II clinical trials.

Current therapies for overactive bladder have limitations in efficacy and side effects. A greater understanding of the pathophysiology of overactive bladder has identified the role(s) of other pathways in the overactive bladder syndrome. Targeting alternative pathways including ion channels and enzymes may provide alternative therapies of overactive bladder and a more tailored approach to the management of overactive bladder.

Urine storage and excretion require a network of interactions in the urinary tract and the central nervous system, which is mediated by a reservoir of water in the bladder and the outlet to the bladder neck, urethra, and external urethral sphincter. Through communicating and coordinating each other, micturition system eventually showed a switch-like activity pattern.

At cervicothoracic and lumbosacral spine, the spinal reflex pathway of the lower urinary tract (LUT) received mechanosensory input from the urothelium to regulate the bladder contraction activity, thereby controlled urination voluntarily. Impairment of above-mentioned any level could result in lower urinary tract dysfunction, placed a huge burden on patients and society. Specific expression of purinergic receptors and transient receptor potential (TRP) channels are thought to play an important role in urinary excretion in the LUT.

This article reviewed the knowledge about the voiding reflex and described the role and function of TRP channels during voiding.

Isthmocele is a gynecological condition characterized by a disruption in the uterine scar, often associated with prior cesarean sections. This anatomical anomaly can be attributed to inadequate or insufficient healing of the uterine wall following a cesarean incision. It appears that isthmocele may impact a woman's quality of life as well as her reproductive capacity. The incidence of isthmocele can range from 20% to 70% in women who have undergone a cesarean section. This review aims to sum up the current knowledge about the effect of isthmocele on fertility and the possible therapeutic strategies to achieve pregnancy. However, currently, there is not sufficiently robust evidence to indicate the need for surgical correction in all asymptomatic patients seeking fertility. In cases where surgical correction of isthmocele is deemed necessary, it is advisable to evaluate residual myometrial thickness (RMT). For patients with RMT >2.5-3 mm, hysteroscopy appears to be the technique of choice. In cases where the residual tissue is lower, recourse to laparotomic, laparoscopic, or vaginal approaches is warranted.

Partial cystectomy procedures for urinary bladder-related dysfunction involve long recovery periods, during which urodynamic studies (UDS) intermittently assess lower urinary tract function. However, UDS are not patient-friendly, they exhibit user-to-user variability, and they amount to snapshots in time, limiting the ability to collect continuous, longitudinal data. These procedures also pose the risk of catheter-associated urinary tract infections, which can progress to ascending pyelonephritis due to prolonged lower tract manipulation in high-risk patients. Here, we introduce a fully bladder-implantable platform that allows for continuous, real-time measurements of changes in mechanical strain associated with bladder filling and emptying via wireless telemetry, including a wireless bioresorbable strain gauge validated in a benchtop partial cystectomy model. We demonstrate that this system can reproducibly measure real-time changes in a rodent model up to 30 d postimplantation with minimal foreign body response. Studies in a nonhuman primate partial cystectomy model demonstrate concordance of pressure measurements up to 8 wk compared with traditional UDS. These results suggest that our system can be used as a suitable alternative to UDS for long-term postoperative bladder recovery monitoring.