Pentosan polysulfate sodium (PPS) remains an oral treatment option for selected patients with bladder pain syndrome, but recognition of PPS-associated pigmentary maculopathy has created uncertainty about long-term prescribing. The central clinical problem is that reported retinal-risk estimates vary markedly between studies.

Urinary tract infections (UTIs) are a major risk factor for interstitial cystitis/bladder pain syndrome (IC/BPS), yet the mechanisms driving chronic pelvic pain and associated symptoms remain poorly understood. Here, we investigated the role of microglia and Toll-like receptor 4 (TLR4) in a mouse model of post-UTI chronic pelvic pain (PUPP). Infection with E. coli induced persistent pelvic allodynia that was significantly attenuated by microglial depletion (PLX5622) or inhibition (minocycline), indicating a key role for microglia in pain maintenance. In contrast, microglial depletion did not improve urinary dysfunction or anxiety- and depression-like behaviors. Prefrontal cortex microglia of PUPP mice exhibited reduced microglial branching complexity and a less ramified phenotype, indicative of an activated microglial state. Transcriptomic profiling of brain CD11b+ cells revealed a reactive microglial signature enriched for chemokines, NFΚB-related genes, and immediate early response genes, alongside pathways involved in immune regulation and leukocyte recruitment. Both general and microglia-specific TLR4 deletion reduced pelvic allodynia and reduced microglial morphological features of activation. Consistent with this, pharmacological TLR4 inhibition in vitro suppressed LPS-induced NFΚB activation, cytokine secretion, and CD68 expression. Together, these findings identify microglial TLR4 as a critical mediator of post-UTI chronic pelvic pain.

BackgroundChronic pelvic pain (CPP) affects an estimated 6-27% of women and is associated with substantial impairment in quality of life (QoL). Common conditions include endometriosis, vulvodynia, and interstitial cystitis. Management typically involves multiple biomedical and psychological strategies, often used in combination, yet their independent associations with QoL and pain interference remain unclear.ObjectivesTo examine associations between six pain management strategies (surgery, hormonal medication, non-hormonal medications/therapies, analgesia, alternative therapies, and psychological therapy) and World Health Organization Quality of Life (WHOQOL-BREF) domains, and pain interference in women with CPP.DesignCross-sectional survey study.MethodsWomen with CPP (N = 147) completed an online questionnaire. Outcomes included WHOQOL-BREF Physical, Psychological, Social, and Environment domains, global QoL, and pain interference. Multiple linear regression models examined associations with QoL domains and pain interference, adjusting for simultaneous strategy use. Ordinal logistic regression examined global quality of life.ResultsSurgery was associated with lower Physical QoL (p = .007). Analgesia was associated with poorer Physical (p = .033), Psychological (p = .022), and Environmental quality of life (p = .041). Psychological therapy was associated with higher Psychological (p = .037) and Environment QoL (p = .023). Use of non-hormonal medications/therapies was associated with greater pain interference (p = .016). No clear associations were observed for Social QoL or global QoL.ConclusionOverall patterns are consistent with a biopsychosocial understanding of CPP. Surgery and analgesia were associated with lower QoL in selected domains, which may reflect greater symptom severity, treatment complexity, or confounding by indication. Psychological therapy was associated with higher psychological and environmental QoL while non-hormonal medications/therapies suggested greater pain interference. Findings suggest earlier integration of psychological care, regular review of analgesic use, and routine monitoring of quality of life and pain interference within multidisciplinary CPP pathways. Causal inferences are limited by the cross-sectional design.

Interstitial cystitis (IC) and overactive bladder (OAB) are chronic pelvic conditions with shared symptoms of urinary urgency, increased frequency, and nocturia with pain in the bladder. IC is characterized by bladder pain and inflammation without a clear etiology, whereas OAB involves detrusor overactivity in the absence of infection. Despite this symptomatic overlap, IC and OAB differ in underlying pathophysiology and require distinct treatment and medical care. A specific diagnostic strategy is currently lacking and highlights the need of a robust diagnostic method for effective treatment. Raman spectroscopy provides sensitive and nondestructive molecular fingerprints; when combined with artificial intelligence (AI)-driven analysis of spectral data, it offers a promising approach to overcoming the limitations of exclusion-based diagnoses. In this study, urinary samples were collected from healthy individuals (n = 117), IC patients (n = 19), and OAB patients (n = 45) for the acquisition of Raman spectra using Au-ZnO nanorod surface-enhanced Raman spectroscopy (SERS) chips. To obtain biological interpretable Raman spectra per group and high accuracy of classification performance, the linear models PCA-PLS-DA and PCA-LDA and tree-based nonlinear models XGBoost and LightGBM were applied and reached up to 92% accuracy with interpretable and pathologic relative Raman features for discriminating among healthy control, IC, and OAB. This approach suggests that urine-based SERS Raman spectra combined with machine learning could serve as a promising diagnostic platform to support disease-specific clinical decision.

Inflammatory diseases of the urinary system, including urinary tract infection (UTI), catheter-associated urinary tract infection (CAUTI), interstitial cystitis/bladder pain syndrome (IC/BPS), and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), are associated with high recurrence, complex pathogenesis, and limited therapeutic durability. Conventional treatments are constrained by antimicrobial resistance, biofilm persistence, intracellular bacterial reservoirs, urine washout, urothelial and prostatic barriers, indwelling device surfaces, and heterogeneous neuroimmune inflammatory mechanisms. Nanoparticles provide versatile platforms to address these challenges through tunable physicochemical properties, controlled release, local retention, tissue penetration, and intrinsic material functions. This review summarizes the pathological basis and therapeutic limitations of major inflammatory urinary disorders and discusses recent advances in organic, inorganic, and hybrid nanoplatforms. In infectious diseases, nanoparticles can enhance antibiotic delivery, promote biofilm penetration and intracellular pathogen clearance, and functionalize catheter or stent surfaces with antibacterial, antibiofilm, and anti-encrustation properties. In noninfectious disorders, they support intravesical retention, glycosaminoglycan-layer repair, oxidative-stress modulation, immune regulation, pain-pathway intervention, and prostatic or rectal delivery. Emerging applications in upper UTI and renal inflammatory injury further expand their therapeutic scope. Finally, we discuss current translational barriers, including model fidelity, long-term safety, manufacturing control, clinical evidence, and rational functional integration.

[This corrects the article DOI: 10.1016/j.mtbio.2026.103112.].

Sex differences in neuroimmune crosstalk have been identified in preclinical research, yet sex divergent immune pathways in people with chronic pain remain poorly understood. We previously identified ex vivo whole-blood stimulation of toll-like receptor-4 (TLR4), a highly conserved innate immune receptor, as a marker of nociplastic pain in female patients with urologic pain, but whether this occurs in males is unknown. Male (n=73) and female (n=135) patients with chronic urologic pain recruited from university-based tertiary urology clinics were compared on pain, urinary symptoms, and immune response to ex vivo TLR4 stimulation. Cross-sectional analyses demonstrated that female patients with widespread or comorbid pain exhibited heightened global TLR4 responses compared to female patients with pelvic-localized pain and male patients. Conversely, male patients with comorbid pain demonstrated downregulated regulatory TLR4 responses compared to male patients with pelvic-localized pain. These findings reveal distinct immunological phenotypes between male and female chronic pain patients based on pain distribution (pelvic-localized versus widespread/comorbid). This work provides foundational evidence for sex-specific immune mechanisms, with implications for the identification and treatment of nociplastic pain.

Pentosan polysulfate sodium (PPS) is a glycosaminoglycan mimic that is the only current active pharmaceutical ingredient (API) for the oral treatment of interstitial cystitis. PPS is an inherently complex API due to variations in chain length, backbone structure, sulfation pattern, and end group, making discriminating between batch-to-batch as well as manufacturer-to-manufacturer differences difficult. In this study, high-throughput liquid handling and time-of-flight secondary-ion mass spectrometry (ToF-SIMS) are used to enable the rapid chemical analysis (450 samples in 6 h) of small amounts (<150 ng) of PPS. Chemical discrimination between PPS produced by different manufacturers and, in one case, batch-to-batch variation of the same manufacturer were achieved. Analysis of samples using an OrbiSIMS instrument is used to provide confident, putative assignment of the discriminating ions to enable structural interpretation of the variance observed between samples. Together with analysis of samples spiked with NaSO4, free sulfate, degree of sulfation along with the sulfate pattern are implicated as key differences between manufacturers/batches. This approach is likely to be highly beneficial for the rapid quality control of PPS.

Background/Objectives: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory bladder disorder that lacks an effective treatment agent. Fucoidan (FUC), isolated from Fucus vesiculosus, is a sulfated polysaccharide that exhibits potent anti-inflammatory and anti-fibrotic activities. This study investigated the protective effects and underlying mechanisms of FUC in IC/BPS. Methods: NLRP3 inflammasome activation and AKT signaling were evaluated by Western blotting, qRT-PCR, immunofluorescence, pharmacological inhibition, gene silencing, and overexpression. Molecular docking assessed potential FUC-protein interactions. In vivo mouse model evaluated the protective effects and toxicity of FUC. Results: In SV-HUC-1 cells, FUC significantly attenuated TNF-α-induced expression of NLRP3 and cleaved caspase-1 and c-IL-1β expression at both the transcriptional and protein levels. Residual inflammasome activity after FUC treatment remained further suppressible by MCC950 or siNLRP3. FUC also reduced TNFα-induced AKT phosphorylation, whereas AKT silencing and overexpression enhanced and partially reversed the inhibitory effect of FUC on inflammasome signaling, respectively. The molecular docking results suggested potential interactions between FUC and key inflammasome-related proteins, including NLRP3, caspase-1, IL-1β, and AKT. In interstitial cystitis mice, FUC mitigated cyclophosphamide (CYP)-induced bladder injury, reduced bladder expression of inflammasome-associated markers, and exhibited no significant toxicity in major organs. Conclusions: These findings indicate that FUC alleviates urothelial inflammatory injury and experimental cystitis, at least in part, by suppressing the AKT/NLRP3 inflammasome axis, supporting its potential as a therapeutic candidate for IC/BPS.

Bladder sensory neurons are essential components of lower urinary tract sensory encoding and micturition reflex control. They detect bladder filling, stretch, inflammatory mediators, and pathogen-associated stimuli, and they communicate with urothelial cells, immune cells, and stromal cells through neuropeptides such as calcitonin gene-related peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP). Under physiological conditions, this neuro-immune-urothelial axis contributes to bladder homeostasis. Under pathological conditions, including neural injury, infection, inflammation, or epithelial barrier disruption, TRP channels, purinergic signaling, neurotrophic factors, chemokines, and voltage-gated ion channels can induce peripheral sensitization, increased excitability of dorsal root ganglion (DRG) neurons, spinal plasticity, and central sensitization, thereby contributing to urinary frequency, urgency, bladder pain, and detrusor overactivity in neurogenic bladder and interstitial cystitis/bladder pain syndrome (IC/BPS). This review summarizes the anatomical and functional organization of bladder sensory afferents, sensory neuron-associated molecular signaling, neuro-immune-urothelial interactions, disease-specific mechanisms, and targeted therapeutic strategies. We also discuss the translational potential and limitations of interventions targeting TRPV1/TRPV4/TRPA1, P2X3, CGRP, SP/neurokinin receptors, NGF, ion channels, botulinum toxin, and neuromodulation. These mechanisms provide a framework for understanding neurogenic mechanisms in bladder disorders and for developing targeted interventions.

Bladder dysfunction is a prevalent age-related condition that severely impairs quality of life in older adults and commonly manifests as lower urinary tract symptoms (LUTS), including frequency, urgency, incontinence, and nocturia. Cellular senescence, characterized by irreversible cell-cycle arrest accompanied by persistent metabolic activity, is increasingly recognized as a contributor to age-associated tissue degeneration. Senescent cells secrete a diverse array of inflammatory cytokines, chemokines, growth factors, and matrix-remodeling enzymes, collectively termed the senescence-associated secretory phenotype (SASP), which can disrupt tissue homeostasis through autocrine and paracrine signaling. Yet the bladder remains relatively understudied, and evidence linking cellular senescence and SASP to bladder dysfunction is fragmented and predominantly preclinical. Key uncertainties concern cell-specific SASP sources, causality, bladder-specific biomarkers, and validation in human tissues. To address this gap, this review critically integrates and evaluates bladder-specific evidence across ageing-related dysfunction, radiation-induced bladder injury, chemotherapy-induced cystitis, and interstitial cystitis/bladder pain syndrome, while distinguishing direct mechanistic evidence from indirect or pathway-based associations. We further synthesize emerging senescence-targeted strategies, including senolytics and senomorphics, and highlight the context- and cell-dependent nature of therapeutic responses. By defining the current strength and limitations of the evidence and identifying key translational priorities, this review provides an integrated framework for understanding how cellular senescence and SASP may contribute to bladder dysfunction and for guiding the development of mechanism-based, biomarker-informed interventions.

BACKGROUND Chronic pelvic pain (CPP) is a prevalent, multifactorial condition with neuropathic, visceral, myofascial, and psychogenic components; a subset of patients remain refractory to multimodal pharmacotherapy and conventional interventional procedures. Pulsed radiofrequency (PRF) of the dorsal root ganglia (DRG) is a minimally invasive neuromodulatory technique that can attenuate pathological nociceptive transmission while preserving neural integrity. We describe 3 patients with severe, treatment-refractory CPP of predominantly neuropathic origin who underwent sacral DRG PRF as rescue therapy. CASE REPORT Case 1 was a 46-year-old man with a 7-year history of neuropathic penile pain following circumcision. Case 2 was a 54-year-old woman with an 11-year history of urethral burning pain and urgency after anal sphincterotomy. Case 3 was a 39-year-old woman with an 18-year history of CPP related to interstitial cystitis, vulvodynia, and pelvic floor myofascial dysfunction. All 3 had failed extensive pharmacological, nerve block, and neuromodulation therapies. Bilateral PRF of the S2-S4 DRG produced reductions in pain intensity (Numeric Rating Scale, NRS) of 55.6-62.5% at 3 months, partially sustained at 6 months (42.9-50.0%), with parallel improvements in neuropathic pain scores, quality of life, and reduced analgesic use, without procedure-related complications. CONCLUSIONS In these 3 refractory CPP cases, sacral DRG PRF was associated with clinically meaningful, although partially attenuating, symptomatic improvement. Given the small, uncontrolled sample, these findings represent preliminary clinical observations suggesting possible benefit in carefully selected patients and should be regarded as hypothesis-generating rather than evidence of established clinical effectiveness.