Potential Urine and Serum Biomarkers in Patients with Bladder Pain Syndrome/Interstitial Cystitis.

BACKGROUND: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a common chronic disease, and its aetiology and pathogenesis remain unclear. This study aimed to identify potential urine and serum biomarkers in patients with IC/BPS to further understand the pathogenesis and diagnosis of the disease. METHODS: Patients with IC/BPS diagnosed and treated in the First Hospital of Hebei Medical University from 1 July 2021 to 30 July 2023 were selected. The urine and serum biomarkers of 50 patients with IC/BPS were investigated and compared with the urine and serum samples of 50 healthy controls. IBM SPSS Statistics 26.0 was used for statistical analysis of the recorded data by using chi-square test, T-test and logistic regression analysis. RESULTS: Overall, 50 patients with IC/BPS (mean age, 54.20 ± 8.15 years) were included in the study. Those with history of urinary diseases, anxiety or depression were susceptible to IC/BPS. Levels of interleukin (IL)-6, tumor necrosis factor-α (TNF-α), nerve growth factor, and prostaglandin E2 (PGE2) in urine, as well as IL-8, TNF-α, and PGE2 in serum, were found to significantly increase in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). These differences were statistically significant (p < 0.05). Multifactor analysis showed that anxiety, depression, IL-6, IL-8, TNF-α and PEG2 are risk factors for patients with IC/BPS. CONCLUSIONS: Multiple biomarkers were identified in the urine and serum of patients with IC/BPS, suggesting a potential close relationship to the pathogenesis of IC/BPS.

Use of the Systemic Immune-Inflammation Index to Predict Treatment Efficacy in Patients with Bladder Pain Syndrome.

OBJECTIVE: To determine the relationship between bladder pain syndrome (BPS) and systemic inflammatory index (SII) and to examine the impact of treatment protocols on it. STUDY DESIGN: Observational Study. Place and Duration of the Study: Department of Urology, Tekirdag Namik Kemal University, Tekirdag, Turkiye, from January 2017 to December 2022. METHODOLOGY: A retrospective analysis was conducted on 30 BPS patients who underwent medical therapy. Upon diagnosis, the patients completed the king's health questionnaire (KHQ), beck depression questionnaire (BDQ), beck anxiety questionnaire (BAQ), and short form (SF-36) quality of life form. Peripheral blood SII was measured. After six months of regular therapy, the SII was recalculated when the patients completed the same forms again. The SII was compared between instances when patients reported more complaints, higher form scores, and instances when they reported fewer and lower scores. RESULTS: The patients had a mean age of 46.1 ± 13.6 years, with four males and 26 females. The mean follow-up duration was 76.3 ± 24.5 months. Five patients of KHQ subcategories showed statistically significant decreases following therapy (52 to 39.17, 66.66 to 54.16, 54.40 to 41.07, 75.55 to 58.14, and 60.55 to 40.47). All patients of SF-36 components increased (p = 779, p = 0.393, p = 0.007, p = 0.004, p = 0.008, p = 0.041, p = 0.010, and p = 0.767, respectively). BDQ and BAQ decreased after therapy (11.55 to 11.41 and 11.86 to 11.24, respectively). Lymphocyte count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and SII decreased significantly (p = 0.001, 0.019, 0.002 and 0.039, respectively). CONCLUSION: SII, lymphocyte count, NLR, and PLR decreased after treatment, similar to BDQ and BAQ. SII is a simple and feasible method for evaluating the treatment efficacy of BPS. KEY WORDS: Bladder pain syndrome, Lymphocyte, Neutrophil, Systemic immune inflammation index, Platelet.

The potential mechanism of treating IC/BPS with hyperbaric oxygen by reducing vascular endothelial growth inhibitor and hypoxia-inducible factor-1α.

Background/aim: To investigate the roles of vascular endothelial growth inhibitor (VEGI) and hypoxia-inducible factor-1α (HIF-1α) in the treatment of refractory interstitial cystitis/bladder pain syndrome (IC/BPS) with hyperbaric oxygen (HBO). Materials and methods: A total of 38 patients were included. They were assessed before and 6 months after HBO treatment. Three-day voiding diaries were recorded, and O'leary-Sant scores, visual analog scale (VAS) scores, quality of life (QoL) scores, pelvic pain, and urgency/frequency (PUF) scores were evaluated. Bladder capacity was assessed by cystoscopy. Bladder mucosa was collected for Western blot, qRT-PCR, and immunofluorescence staining to compare the expression of VEGI and HIF-1α before and after treatment. Results: Compared with before treatment, patients showed significant improvements in 24-h voiding frequency (15.32 ± 5.38 times), nocturia (3.71 ± 1.80 times), O'leary-Sant score (20.45 ± 5.62 points), VAS score (41.76 ± 17.88 points), QoL score (3.03 ± 1.44 points), and PUF score (19.95 ± 6.46 points) after treatment (p < 0.05). There was no significant difference in bladder capacity before and after treatment (p ≥ 0.05). The expression levels of VEGI and HIF-1α protein and mRNA were significantly decreased 6 months after treatment compared with before treatment. Immunofluorescence staining results showed that the double positive expression of VEGI and HIF-1α protein in bladder tissue of IC/BPS patients after HBO treatment quantitatively decreased significantly. Conclusion: This study identified a possible mechanism by which VEGI and HIF-1α expression decreased after HBO treatment due to hypoxia reversal, which improved symptoms in IC/BPS patients.

Current updates relating to treatment for interstitial cystitis/bladder pain syndrome: systematic review and network meta-analysis.

BACKGROUND: Despite the publication of several meta-analyses regarding the efficacy of certain therapies in helping individuals with interstitial cystitis (IC) / bladder pain syndrome (BPS), these have not provided a comprehensive review of therapeutic strategies. The study aimed to determine the efficacy of various therapies for IC/BPS and identify potential moderating factors using randomized controlled trials (RCTs). METHODS: We queried the PubMed, Cochrane, and Embase databases to identify prospective RCTs using inclusion criteria: 1) patients diagnosed with IC, 2) interventions included relevant treatments, 3) comparisons were a specified control or placebo, 4) outcomes were mean differences for individual symptoms and structured questionnaires. The pairwise meta-analysis and network meta-analysis (NMA) were performed to compare the treatments used in IC/BPS. Hedges' g standardized mean differences (SMDs) were used for improvement in all outcomes using random-effects models. Efficacy outcomes included individual symptoms such as pain, frequency, urgency, and nocturia, as well as structured questionnaires measuring IC/BPS symptoms. RESULTS: A comprehensive literature search was conducted which identified 70 RCTs with 3,651 patients. The analysis revealed that certain treatments, such as instillation and intravesical injection, showed statistically significant improvements in pain and urgency compared to control or placebo groups in traditional pairwise meta-analysis. However, no specific treatment demonstrated significant improvement in all outcomes measured in the NMA. The results of moderator analyses to explore influential variables indicated that increasing age was associated with increased nocturia, while longer follow-up periods were associated with decreased frequency. CONCLUSION: This systematic review and meta-analysis provide insights into the efficacy of various treatments for IC. Current research suggests that a combination of therapies may have a positive clinical outcome for patients with IC, despite the fact that treatment for this condition is not straightforward. TRIAL REGISTRATION: PROSPERO CRD42022384024.

Intravesical Interferon Therapy vs Hyaluronic Acid for Pain Among Female Individuals With Interstitial Cystitis: A Randomized Clinical Trial.

Importance: Interstitial cystitis (IC) is a debilitating condition. Although viral infection is a potential etiological cause, few studies have detected the effect of antiviral treatment. Objective: To determine the efficacy and safety of intravesical interferon instillation compared with hyaluronic acid in female patients with IC. Design, Setting, and Participants: This double-masked, randomized phase 2/3 clinical trial with parallel group design was implemented from October 2022 to April 2023 and had a 6-month follow-up period. The study was conducted at a single center. Eligible participants were female patients aged 18 to 70 years with a diagnosis of IC for more than 6 months. The last visit took place in October 2023. Data were analyzed between October and November 2023. Intervention: Patients were randomized 1:1 to receive either intravesical instillation of interferon or hyaluronic acid. Main Outcomes and Measures: The primary end point was change in visual analog scale pain score. Secondary end points included changes in voiding frequency, functional bladder capacity, symptom index, and global response assessment. Adverse events were closely monitored. Results: Among the 52 patients, the mean (SD) age was 50.0 (14.1) years and they were randomized to either the interferon group (26 [50%]) or hyaluronic acid (26 [50%]). The visual analog pain score showed the interferon group decreased more significantly than hyaluronic acid (-1.3; 95% CI, -2.3 to -0.3; P = .02) at month 6, with 20 patients (77%) exhibiting a 30% or higher reduction in pain compared with baseline. Secondary end points of voiding frequency, functional bladder capacity, and nocturia episodes showed no significant difference between 2 therapies. However, interferon showed a significantly higher reduction in the Interstitial Cystitis Symptom Index (-3.0; 95% CI, -5.3 to -0.7; P = .01) and the Problem Index (-2.5; 95% CI, -4.5 to -0.4; P = .02) at month 6, with 22 patients (85%) presenting as moderately or markedly improved. The frequencies of adverse events were similar between 2 groups. Only 1 patient discontinued hyaluronic acid because of poor effectiveness. Conclusions and Relevance: In this randomized clinical trial, female patients with IC could benefit from intravesical interferon therapy, without serious adverse events. These results offered hope for antiviral approaches in IC, but larger-scale, multicenter trials and long-term follow-up should be considered. Trial Registration: ClinicalTrials.gov Identifier: NCT05912946.

[Outpatient treatment and quality of life of patients with interstitial cystitis and Hunners lesion: cohort cross-sectional study].

AIM: To assess the quality of life of patients with interstitial cystitis (IC) and to study effective options used to control symptoms on outpatient basis. MATERIALS AND METHODS: The results of a descriptive prospective cross-sectional cohort study are presented. The medical charts of patients who were treated in the City Clinical Hospital named after Spasokukotsky from 2021 to 2023 were analyzed. Eighty inpatient medical charts of various patients with a final diagnosis of IC with Hunner's lesion were identified. Only 53 patients were interviewed due to the inclusion/exclusion criteria. Respondents were asked to complete a survey consisting of 15 questions. The survey was carried out online for patients who did not require surgical treatment at the time of the study, and offline for patients admitted for repeated surgical treatment. RESULTS: The average age of respondents was 59.011.1 years. 58% (31) of patients noted the presence of constant pain in the pelvic area during the day, while 85% (45) of patients reported pain outside the bladder area, in the urethra and perineum. The intensity of pain in the pelvic area was 4.9 (2.3-5.6) points. Higher pain scores 6.24 (5.8-9.0) were observed in 47% (25) of patients admitted for repeat surgical treatment. 62% (33) of patients had a titer of bacteria in a urine test above 104, while 51% (27) of patients experienced relief of symptoms after taking antibacterial drugs. For the treatment and symptomatic relief, the following are most often used: pentosan sodium polysulfate (26%, n=14), antibacterial drugs of the nitrofuran group (25%, n=13), amitriptyline (15%, n=8), non-steroidal anti-inflammatory drugs (11%, n=6) patients. 23% (12) of respondents received intravesical therapy. The time from the onset of symptoms to the final diagnosis was 48 (24-96) months. CONCLUSIONS: Although infection is a criterion for excluding the diagnosis of IC, more than 62% of patients have positive urine culture. The results obtained indicate the need to improve existing approaches to the diagnosis of IC, as well as to develop treatment algorithms for painful bladder syndrome to control symptoms.

MIF-Modulated Spinal Proteins Associated with Persistent Bladder Pain: A Proteomics Study.

Bladder pain is a prominent symptom in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). We studied spinal mechanisms of bladder pain in mice using a model where repeated activation of intravesical Protease Activated Receptor-4 (PAR4) results in persistent bladder hyperalgesia (BHA) with little or no bladder inflammation. Persistent BHA is mediated by spinal macrophage migration inhibitory factor (MIF), and is associated with changes in lumbosacral proteomics. We investigated the contribution of individual spinal MIF receptors to persistent bladder pain as well as the spinal proteomics changes associated with relief of persistent BHA by spinal MIF antagonism. Female mice with persistent BHA received either intrathecal (i.t.) MIF monoclonal antibodies (mAb) or mouse IgG1 (isotype control antibody). MIF antagonism temporarily reversed persistent BHA (peak effect: 2 h), while control IgG1 had no effect. Moreover, i.t. antagonism of the MIF receptors CD74 and C-X-C chemokine receptor type 4 (CXCR4) partially reversed persistent BHA. For proteomics experiments, four separate groups of mice received either repeated intravesical scrambled peptide and sham i.t. injection (control, no pain group) or repeated intravesical PAR4 and: sham i.t.; isotype IgG1 i.t. (15 µg); or MIF mAb (15 µg). L6-S1 spinal segments were excised 2 h post-injection and examined for proteomics changes using LC-MS/MS. Unbiased proteomics analysis identified and relatively quantified 6739 proteins. We selected proteins that showed significant changes compared to control (no pain group) after intravesical PAR4 (sham or IgG i.t. treatment) and showed no significant change after i.t. MIF antagonism. Six proteins decreased during persistent BHA (V-set transmembrane domain-containing protein 2-like confirmed by immunohistochemistry), while two proteins increased. Spinal MIF antagonism reversed protein changes. Therefore, spinal MIF and MIF receptors mediate persistent BHA and changes in specific spinal proteins. These novel MIF-modulated spinal proteins represent possible new targets to disrupt spinal mechanisms that mediate persistent bladder pain.

Identification of key pathways and mRNAs in interstitial cystitis/bladder pain syndrome treatment with quercetin through bioinformatics analysis of mRNA-sequence data.

BACKGROUND: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic condition with painful bladder. At present, the pathogenesis of IC/BPS is still unknown. Quercetin (QCT) is a kind of natural flavonoid with wide sources and multiple biological activities. The purpose of this study was to explore the effects of QCT on mRNA expression and related regulatory signal pathways in IC model rats. METHODS: LL-37 was used to induce the IC/BPS model rats. 20 mg/kg QCT was injected intraperitoneally into IC/BPS rats. ELISA, HE, Masson and TB staining were used to evaluate the level of inflammation and pathology. The concentration of QCT in rats was detected by HPLC. The mRNA sequencing was used to detect the differentially expressed (DE) mRNA in each group. The over-expression experiment of Lpl was carried out in IC/BPS model rats. RESULTS: QCT treatment significantly decreased the level of MPO, IL-1ß, IL-6 and TNF-α induced by LL-37 in rats, and alleviated bladder injury and mast cell degranulation. There were significant differences in mRNA sequencing data between groups, and the hub gene Lpl were screened by Cytohubba. The expression of Lpl was downregulated in IC/BPS rats. QCT intervention promoted Lpl expression. Overexpression of Lpl reduced the bladder injury induced by LL-37, increased GAG level and decreased the expression of MPO, IL-1ß, IL-6 and TNF-α. CONCLUSION: In this study, we provided the DE mRNA in IC/BPS rats treated with QCT, the signaling pathways for DE enrichment, screened out the hub genes, and revealed that Lpl overexpression alleviated IC/BPS model rats.

Psychosexological correlates of 372 women with vulvodynia, overactive pelvic floor, postcoital cystitis, and interstitial cystitis.

BACKGROUND: Among the plethora of urogynecological conditions possibly affecting women, some of them, less explored, have significant impacts on sexological and psychological health, with a mutual influence. AIM: The aim of this study was to investigate the sexological and psychological correlates of four urogynecological pathologies in a sample of women of childbearing age: overactive pelvic floor, vulvodynia, postcoital cystitis, and interstitial cystitis. Women cured of these conditions were also included, to assess the same aspects after the remission of physical symptoms. METHODS: We recruited 372 women with an average age of 33.5 years through an online platform shared by a popular forum for women with urogynecological pathologies between March and May 2021. The participants filled out a socio-anamnestic questionnaire and a set of psychometric tests. OUTCOMES: Participant data were collected by use of the Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Toronto Alexithymia Scale-20, Female Sexual Function Index, and Orgasmometer-F, and the SPSS (Statistical Package for Social Sciences) v.26 was used for data analysis. RESULTS: Overactive pelvic floor was reported by 66.4% of the women, vulvodynia by 55%, postcoital cystitis by 58.8%, and interstitial cystitis by 8.3%, and these conditions were often comorbid with each other, with 9.4% and 7% of women reporting having suffered psychological and sexual abuse, respectively. The presence of past abuse was correlated with overactive pelvic floor (P < .05), vulvodynia (P < .01), and major depression (P < .01). Significantly more depression occurred in women with vulvodynia than in the other subgroups (P < .05), except for women with only an overactive pelvic floor. There was no difference between the subgroups in the occurrence of alexithymia, sexual function, and orgasm (P < .05). Interestingly, the prevalence of sexual dysfunction increased in cured women. CLINICAL IMPLICATIONS: The lack of significant differences, except for depression, between the pathological subgroups suggests a similar clinical and psychological relevance of the four pathologies studied. The persistence of sexual dysfunctions in cured women may be related to a residual dysfunctional relational modality with the partner. STRENGTHS AND LIMITATIONS: The evaluation of both psychological and sexological variables in a group of less-explored urogynecological conditions represents a strength of this study, while a lack of a face-to-face assessment could represent a limitation. CONCLUSION: The results of the present study should promote psychosexological interventions in women with these diseases, both during the pathological state and after remission.

Combination of urinary biomarkers and machine-learning models provided a higher predictive accuracy to predict long-term treatment outcomes of patients with interstitial cystitis/bladder pain syndrome.

PURPOSE: To identify predictive factors for satisfactory treatment outcome of the patients with IC/BPS using urine biomarkers and machine-learning models. METHODS: The IC/BPS patients were prospectively enrolled and provide urine samples. The targeted analytes included inflammatory cytokines, neurotrophins, and oxidative stress biomarkers. The patients with overall subjective symptom improvement of ≥ 50% were considered to have satisfactory results. Binary logistic regression, receiver-operating characteristic (ROC) curve, machine-learning decision tree, and random forest models were used to analyze urinary biomarkers to predict satisfactory results. RESULTS: Altogether, 57.4% of the 291 IC/BPS patients obtained satisfactory results. The patients with satisfactory results had lower levels of baseline urinary inflammatory cytokines and oxidative biomarkers than patients without satisfying results, including interleukin-6, monocyte chemoattractant protein-1 (MCP-1), C-X-C motif chemokine 10 (CXCL10), oxidative stress biomarkers 8-hydroxy-2'-deoxyguanosine (8-OHDG), 8-isoprostane, and total antioxidant capacity (TAC). Logistic regression and multivariable analysis revealed that lower levels of urinary CXCL10, MCP-1, 8-OHDG, and 8-isoprostane were independent factors. The ROC curve revealed that MCP-1 level had best area under curve (AUC: 0.797). In machine-learning decision tree model, combination of urinary C-C motif chemokine 5, 8-isoprostane, TAC, MCP-1, and 8-OHDG could predict satisfactory results (accuracy: 0.81). The random forest model revealed that urinary 8-isoprostance, MCP-1, and 8-OHDG levels had the most important influence on accuracy. CONCLUSION: Machine learning decision tree model provided a higher accuracy for predicting treatment outcome of patients with IC/BPS than logistic regression, and levels of 8-isoprostance, MCP-1, and 8-OHDG had the most important influence on accuracy.

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.

Urinary Sphingosine-1-Phosphate as a Biomarker for Bladder Pain Syndrome.

IMPORTANCE: Sphingosine-1-phosphate (S1P) is a signaling molecule involved in inflammation and bladder contraction. OBJECTIVES: The aims of this case-control pilot study were to compare urinary S1P concentrations in bladder pain syndrome (BPS) participants to controls and determine whether these concentrations correlate with disease severity and duration. STUDY DESIGN: Adult females with BPS and controls were enrolled. Bladder pain syndrome participants completed an O'Leary-Sant questionnaire. Information on duration of symptoms and treatment history was obtained. Urinary S1P and creatinine concentrations were determined. Mann-Whitney U tests were used to compare groups, and Spearman correlation was used to test for associations between concentrations and duration and severity of symptoms. RESULTS: Twenty-five participants were in each group. Median S1P concentration was 1,225 ng/dL in the BPS group and 2,183 ng/dL in the control group, which was significantly different (P < 0.0001). This difference did not persist when normalized to urinary creatinine (P = 0.58). No differences were noted in urinary S1P concentrations between treated and untreated participants (P = 0.53) or with symptom scores of 13 or greater and less than 13 (P = 0.69). Sphingosine-1-phosphate levels did not correlate with O'Leary-Sant scores (P = 0.08) or duration of symptoms (P = 0.67). Results did not change when using S1P concentrations normalized to creatinine. CONCLUSIONS: This study demonstrated successful quantification of human urinary S1P concentrations. A difference in urinary S1P was found between BPS participants and controls but not when normalized to creatinine. While this is the first study to investigate urinary S1P as a biomarker for BPS, results suggest that it may have a potential role as a biomarker requiring further research.

Effects of onabotulinum toxin-A injection on sexual function in women with refractory interstitial cystitis/bladder pain syndrome: A prospective study.

OBJECTIVES: To determine the effect of intravesical onabotulinum toxin-A (BoNT-A) treatment on sexual functions in female patients with refractory interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: Female patients with IC/BPS refractory to previous treatments were included in the study between January 2020 and April 2022. Patients were treated with the trigone-sparing injection (Group 1) or trigone-included injection (Group 2) techniques. 100 Units of BoNT-A was applied submucosally on 20 different points. The patients were evaluated with visual analog scale (VAS), O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI), Interstitial Cystitis Problem Index (ICPI), Female Sexual Function Index (FSFI) questionnaires, 3-day voiding diary, uroflowmetry, and post-voiding residual volume analysis in the preoperative period, as well as on the 30th and 90th days postoperatively. For the repeated measurements, analysis of variance was used to assess the time-dependent variation across groups. RESULTS: The baseline FSFI score of the patients was 15.96 ± 3.82. Following the treatment, the FSFI scores were 22.43 ± 4.93 and 24.41 ± 5.94 on the 30th and 90th days, respectively (p < .001). We observed statistically significant improvement in all FSFI subdomains (p < .05). Statistically significant improvements with treatment on ICSI, ICPI, and VAS scores were achieved (p < .05). Preoperative FSFI scores were similar in Group 1 and Group 2 (p = .147). While the preoperative FSFI scores were 17.00 ± 3.73 and 14.84 ± 3.72 for Group 1 and Group 2, respectively, the scores after the treatment were 22.85 ± 5.01 and 21.98 ± 5.01 on the 30th day, and 24.62 ± 6.06 and 24.19 ± 6.05 on the 90th day postoperatively. Significant improvement was observed in FSFI scores with treatment, and no difference was observed between the two groups in terms of treatment response (p = .706). CONCLUSIONS: Intravesical BoNT-A injection in the treatment of women with refractory IC/BPS improves sexual functions. It also significantly improves pain and symptom scores. Both trigone-sparing and trigone-including injections are similarly safe and effective.

Therapeutic Effects of AF219 on Interstitial Cystitis/Bladder Pain Syndrome Induced by Cyclophosphamide or Water Avoidance Stress in Rats.

INTRODUCTION AND HYPOTHESIS: To evaluate the effect of AF219, a P2X3 receptor antagonist, in animal models of interstitial cystitis/bladder pain syndrome (IC/BPS) induced by cyclophosphamide (CYP) or water avoidance stress (WAS). METHODS: Thirty-two adult female Wistar albino rats were used in each IC/BPS model. Assessment of nociception and anxiety and severity of inflammation in the bladder were assessed by behavioral experiments and histopathological examinations respectively. The contraction responses of the bladder were evaluated in vitro and protein levels of P2X3, P2X7, Trk-A, TRPV1, and TRPA1 were analyzed by Western blot. RESULTS: The IC/BPS groups had shorter response times to noxious stimuli, exhibited more anxiety-like behavior, had higher inflammation-based histological scores, and showed greater increased contraction responses to carbachol, adenosine triphosphate, and electrical field stimulation in in vitro bladder strips than controls for both models (p < 0.05). The improvements in behavioral and bladder contraction responses and inflammation scores in the IC/BPS + AF219 groups were similar to control findings (p > 0.05). Exposure to WAS or CYP increased P2X3 expression in the bladder compared with the controls (p < 0.05). Apart from TRPA1, the levels of P2X7, Trk-A, and TRPV1 were also higher in the IC/BPS groups than in the controls (p < 0.05). No significant differences were observed between IC/BPS + AF219 and controls regarding P2X3, P2X7, Trk-A, and TRPV1 in the WAS model (p > 0.05). Moreover, P2X3 and P2X7 levels were significantly lower in IC/BPS + AF219 than in the AF219-untreated WAS model (p < 0.05). CONCLUSIONS: These findings suggest that P2X3 receptors play a significant role in bladder functional responses, nociception, and also the pathogenesis of IC/BPS. AF219 may be a promising therapeutic strategy for IC/BPS. Comparing AF219 with current IC/BPS treatment agents in future studies may yield valuable insights into its efficacy.

Bioenergetic profiles of peripheral mononuclear cells and systemic inflammation in women with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS).

Inflammation is thought to contribute to the etiology of interstitial cystitis/bladder pain syndrome (IC/BPS). It is well-known that disruption in metabolism in immune cells contributes to inflammation in several inflammatory diseases. The purpose of this study was to investigate whether cellular bioenergetics is altered in monocytes and lymphocytes from women with IC/BPS, and if these alterations correlate with systemic inflammatory markers. Age and BMI matched adult healthy women (HS; n = 18) and women with IC/BPS (n = 18) were included in the study. Blood was collected to assess cellular bioenergetics in monocytes and lymphocytes using a Seahorse XF96 Analyzer and plasma cytokine levels were measured using Meso Scale Discovery immunoassays. The correlation between bioenergetic parameters, cytokines, and demographics was determined using Pearson correlation coefficients. Means of the two groups were compared using the two-group t-test. Patients with IC/BPS had reduced monocyte oxygen consumption rates and glycolytic rates compared to healthy subjects. In contrast, lymphocytes from these patients had increased oxygen consumption rates and glycolytic rates. Several cytokines and chemokines including Interferon-gamma (IFN-É£), tumor necrosis factor alpha (TNF-ɑ), Interleukin-6 (IL-6), Interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) levels were significantly elevated in the plasma of patients with IC/BPS. However, Transforming growth factor (TGF-ß) and Interleukin-10 (IL-10) levels were significantly decreased in IC/BPS patients compared to HS. In addition, Interferon gamma (IFN-É£), TNF-ɑ, IL-8, and TGF-ß levels correlated with several bioenergetic parameters in monocytes or lymphocytes from healthy subjects. In contrast, TNF-ɑ and IL-8 correlated with bioenergetic parameters in monocytes from IC/BPS patients. Monocyte and lymphocyte cellular bioenergetics and plasma cytokine levels are different in patients with IC/PBS compared to HS. It appears that systemic inflammation is greater in this cohort which may negatively impact immune cell function. The relationship between cellular bioenergetics and inflammation in monocytes and lymphocytes could be important in understanding the pathogenesis of IC/PBS and warrants further investigation.

Multi-omics analyses uncover metabolic signatures and gene expression profiles of interstitial cystitis/bladder pain syndrome.

BACKGROUND AND OBJECTIVE: We explore molecular and metabolic pathways involved in interstitial cystitis (IC) with integrating multi-omics analysis for identifying potential diagnostic and therapeutic targets. METHODS: Mouse models of IC/bladder pain syndrome (BPS) were established by intraperitoneal injection of cyclophosphamide and bladder tissue samples were collected for metabolomics and transcriptome analysis. RESULTS: We found a total of 82 and 145 differential metabolites in positive ion modes and negative ion modes, respectively. Glycerophospholipid metabolism, choline metabolism in cancer, and nucleotide metabolism pathways were significantly enriched in the IC/BPS group. Transcriptome analysis demonstrated that 1069 upregulated genes and 1087 downregulated genes were detected. Importantly, the stronger enrichment for cell cycle pathway was observed in IC/BPS than that in normal bladder tissue, which may be involved in the process of bladder remodeling. Moreover, the inflammatory response and inflammatory factors related pathways were enriched in the IC/BPS group. CONCLUSIONS: Our findings provide critical directions for further exploration of the molecular pathology underlying IC/BPS.

The effects of a galectin-3 inhibitor on bladder pain syndrome in mice with cyclophosphamide-induced cystitis.

AIMS: To explore the effect of blocking galectin-3 in the bladder pain syndrome associated with interstitial cystitis. METHODS: A galectin-3 inhibitor was used to treat mice with cyclophosphamide-induced cystitis. The expression of galectin-3 in bladder tissues and urine was examined by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), respectively. Suprapubic-pelvic pain, bladder voiding, bladder pain-like nociceptive behavior, and referred hyperalgesia were assessed. The weights of the bladders were also measured, and inflammatory cell infiltration and inflammatory cytokine levels were examined by histopathological evaluation. The inflammatory cytokines interleukin 1ß (IL-1ß), nerve growth factor (NGF), IL-6, and tumor necrosis factor α (TNF-α) were measured by ELISA. RESULTS: Increases in galectin-3 levels, inflammation, bladder weight, and bladder pain-related symptoms were observed in bladders with cyclophosphamide-induced cystitis. Administration of the galectin-3 inhibitor significantly mitigated bladder pain-related symptoms and inflammatory response. In response to the 500 µM dose of the galectin-3 inhibitor, nociceptive behaviors, nociceptive score, and bladder-to-body weight ratios were reduced by 65.1%, 65.3%, and 40.3%, respectively, while 500 µM Gal-3 inhibitor increased pelvic pain threshold by 86.7%. Moreover, galectin-3 inhibitor treatment inhibited the inflammation. Compared to untreated CYP-induced mice, there were significant changes in the levels of IL-1ß (41.72 ± 2.05 vs. 18.91 ± 2.26 pg/mg tissues), NGF (9.64 ± 0.38 vs. 1.88 ± 0.05 pg/mg tissues), IL-6 (42.67 + 1.51 vs. 21.26 + 2.78 pg/mg tissues, and TNF-α (22.02 ± 1.08 vs. 10.70 ± 0.80 pg/mg tissues) in response to the highest dose of the Gal-3 inhibitor subgroup (500 µM), and 500 µM Gal-3 inhibitor reduced mast cell infiltration ratios by 71.8%. CONCLUSIONS: The galectin-3 inhibitor relieved pelvic pain, urinary symptoms, and bladder inflammation in mice with cyclophosphamide-induced cystitis. Thus, galectin-3 inhibitors may be novel agents in interstitial cystitis treatment.

Machine Learning-Based Classification of Transcriptome Signatures of Non-Ulcerative Bladder Pain Syndrome.

Lower urinary tract dysfunction (LUTD) presents a global health challenge with symptoms impacting a substantial percentage of the population. The absence of reliable biomarkers complicates the accurate classification of LUTD subtypes with shared symptoms such as non-ulcerative Bladder Pain Syndrome (BPS) and overactive bladder caused by bladder outlet obstruction with Detrusor Overactivity (DO). This study introduces a machine learning (ML)-based approach for the identification of mRNA signatures specific to non-ulcerative BPS. Using next-generation sequencing (NGS) transcriptome data from bladder biopsies of patients with BPS, benign prostatic obstruction with DO, and controls, our statistical approach successfully identified 13 candidate genes capable of discerning BPS from control and DO patients. This set was validated using Quantitative Polymerase Chain Reaction (QPCR) in a larger patient cohort. To confirm our findings, we applied both supervised and unsupervised ML approaches to the QPCR dataset. A three-mRNA signature TPPP3, FAT1, and NCALD, emerged as a robust classifier for non-ulcerative BPS. The ML-based framework used to define BPS classifiers establishes a solid foundation for comprehending the gene expression changes in the bladder during BPS and serves as a valuable resource and methodology for advancing signature identification in other fields. The proposed ML pipeline demonstrates its efficacy in handling challenges associated with limited sample sizes, offering a promising avenue for applications in similar domains.

Validation of Distinct Bladder Pain Phenotypes Utilizing the MAPP Research Network Cohort.

INTRODUCTION AND HYPOTHESIS: As interstitial cystitis/bladder pain syndrome (IC/BPS) likely represents multiple pathophysiologies, we sought to validate three clinical phenotypes of IC/BPS patients in a large, multi-center cohort using unsupervised machine learning (ML) analysis. METHODS: Using the female Genitourinary Pain Index and O'Leary-Sant Indices, k-means unsupervised clustering was utilized to define symptomatic phenotypes in 130 premenopausal IC/BPS participants recruited through the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) research network. Patient-reported symptoms were directly compared between MAPP ML-derived phenotypic clusters to previously defined phenotypes from a single center (SC) cohort. RESULTS: Unsupervised ML categorized IC/BPS participants into three phenotypes with distinct pain and urinary symptom patterns: myofascial pain, non-urologic pelvic pain, and bladder-specific pain. Defining characteristics included presence of myofascial pain or trigger points on examination for myofascial pain patients (p = 0.003) and bladder pain/burning for bladder-specific pain patients (p < 0.001). The three phenotypes were derived using only 11 features (fGUPI subscales and ICSI/ICPI items), in contrast to 49 items required previously. Despite substantial reduction in classification features, unsupervised ML independently generated similar symptomatic clusters in the MAPP cohort with equivalent symptomatic patterns and physical examination findings as the SC cohort. CONCLUSIONS: The reproducible identification of IC/BPS phenotypes, distinguishing bladder-specific pain from myofascial and genital pain, using independent ML analysis of a multicenter database suggests these phenotypes reflect true pathophysiologic differences in IC/BPS patients.