Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by complex cellular heterogeneity and inflammatory dysfunction in the bladder. However, the molecular pathogenesis of IC/BPS remains poorly understood, and few studies have provided comprehensive analyses. To elucidate the mechanisms underlying disease pathology, we performed integrated single-cell and spatial transcriptomic analyses of human bladder tissue. Comprehensive single-cell multiomics analyses have identified disease-specific alterations across multiple cell types. T helper 17 cells were significantly expanded in Hunner lesions and activated autoimmune and pro-inflammatory signaling pathways, suggesting a critical role in disease progression. Endothelial cells (ECs) shift from homeostatic (EC2) to pro-angiogenic inflammatory phenotypes (EC3), contributing to vascular remodeling. In the monocyte-macrophage lineage, we identified macrophage 2 cells with pro-angiogenic features that engaged in vascular endothelial growth factor-mediated and tumor necrosis factor-mediated interactions that promoted pathological angiogenesis. Smooth muscle cells (SMCs) display notable phenotypic plasticity, transitioning from a contractile to a synthetic state in IC/BPS tissues. Additionally, spatial transcriptomic analysis revealed upregulation of the EDN1-EDNRA/EDNRB signaling axis, suggesting a role for SMCs in bladder hypercontractility. Fibroblasts have emerged as key mediators of nociceptive signaling, with specific subpopulations enriched in neurotrophin-related pathways (for example, NTF3-NTRK2/NTRK3 and NGF-SORT1) and showing active crosstalk with SMCs, potentially contributing to the development of chronic pain. Collectively, these findings delineate a complex stromal-immune-vascular network underlying the pathological remodeling and pain characteristics of IC/BPS. Our study identified novel cellular players and intercellular signaling pathways that may be promising targets for therapeutic interventions.

Mucosa, a vital interface between the body and external environment, often suffers from reactive oxygen burden within its microenvironment, leading to various mucosal inflammatory diseases. Drug delivery directly to inflamed mucosal regions offers a promising therapeutic approach, yet efficacy is compromised by inherent physiological clearance mechanisms. Herein, we developed a covalent mucoadhesive nanoantioxidant self-assembled by a cysteine-modified short peptide (CR8L10) and catalase (CAT) for the treatment of mucosal inflammatory diseases. The obtained CR8L10@CAT nanocomplexes with a cysteine-decorated surface enable robust mucoadhesion by forming dynamic disulfide bonds with mucin-rich mucosa, leading to significantly enhanced CAT retention. Upon intravesical instillation, CR8L10@CAT with improved urine-resistant bladder retention, could be used to treat hard-to-manage interstitial cystitis/bladder pain syndrome (IC/BPS). Notably, intravesically administered CR8L10@CAT effectively eliminated excessive reactive oxygen species (ROS) in the bladder mucosa, thereby inhibiting pro-inflammatory responses, restoring urothelial integrity, and alleviating pain and voiding dysfunction, demonstrating significantly better analgesic effects and superior functional improvement than clinically used intravesical agents. Additionally, inhalation of the mucoadhesive CR8L10@CAT nanoantioxidant also showed enhanced pulmonary retention to effectively mitigate ROS-associated inflammation in treating acute lung injury (ALI). This mucoadhesive CR8L10@CAT nanoantioxidant represents an effective therapeutic strategy to manage different mucosal inflammatory diseases, holding great promise for clinical translation.

Chronic overlapping pain conditions (COPCs) refer to a set of chronic pain disorders that frequently co-occur and may involve partially overlapping mechanisms. The U.S. National Institutes of Health currently recognizes ten COPCs: fibromyalgia, painful temporomandibular disorders, chronic low back pain, chronic migraine headache, chronic tension-type headache, irritable bowel syndrome, endometriosis, interstitial cystitis/bladder pain syndrome, vulvodynia, and myalgic encephalomyelitis/chronic fatigue syndrome. When multiple COPCs coexist, they are associated with a disproportionate multimorbidity burden, including greater pain, poorer psychological well-being, functional limitations, disability, fatigue, sleep disturbances, diminished quality of life, and increased healthcare utilization. Despite their impact, COPCs remain under-recognized, underdiagnosed, and undertreated. Combining structured literature searches and citation tracking with narrative syntheses, this review examines comorbid relationships, the burden of multimorbidity, and potentially overlapping nociplastic mechanisms. By adopting a multimorbidity-based perspective rather than a one-disease, one-treatment approach, it highlights barriers to care-including limited clinical awareness, under-recognition of additional COPCs, limited mechanistic understanding, and fragmented care-and proposes integrated strategies emphasizing prevention, systematic screening, mechanism-informed assessment, and coordinated, patient-centered multimodal management.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory bladder disorder with limited therapeutic options. Grape seed extract (GSE) has potent antioxidant and anti-inflammatory properties; however, its therapeutic application is limited by poor bioavailability. This study aimed to develop grape seed extract-loaded niosomes (GSN) and evaluate their protective efficacy against cyclophosphamide (CYCL)-induced bladder injury model relevant to IC/BPS. Twenty-eight female rats were randomly allocated into four groups (n = 7): control, CYCL-treated, CYCL + GSE, and CYCL + GSN. CYCL was administered intraperitoneally at 75 mg/kg on days 1, 4, and 7, while GSE and GSN were given orally at 100 mg/kg for eight consecutive days. Bladder tissues were examined using histopathology, ultrastructural assessment, immunohistochemistry, oxidative stress biomarkers, gene expression analysis, and molecular docking. CYCL induced marked urothelial injury, inflammatory infiltration, fibrosis, oxidative stress, apoptosis, and disruption of barrier-related markers, accompanied by increased NF-κB, IL-6, caspase-3, MDA, and nitric oxide levels and reduced E-cadherin, SOD, GSH, Nrf2, and ZO2 expression. GSE partially ameliorated these alterations, whereas GSN produced stronger protective effects, restoring bladder histoarchitecture, improving ultrastructural integrity, reducing inflammatory and apoptotic immunoreactivity, and enhancing antioxidant defense markers. GSN also increased Nrf2 and ZO2 mRNA expression, suggesting an association with Nrf2-related antioxidant responses and improved urothelial barrier integrity. Molecular docking further indicated favorable interactions of GSE phytoconstituents with GSK3-β and the KEAP1-Nrf2 complex. Overall, GSN enhanced the therapeutic efficacy of GSE against CYCL-induced bladder injury, possibly through modulation of oxidative stress, inflammation, apoptosis, and barrier-associated pathways. Further protein-level studies are required to confirm direct Nrf2 pathway activation.

Interstitial cystitis/bladder pain syndrome (IC/BPS) and fibromyalgia (FM) are chronic pain conditions frequently discussed within shared conceptual frameworks such as central sensitization. Despite this conceptual overlap, IC/BPS is clinically characterized by pelvic and urinary symptoms, whereas FM is associated with widespread pain, fatigue, sleep disturbance, and other systemic manifestations. Whether these differences are reflected in the organization of symptom-related language within patient-generated discourse remains insufficiently characterized. Patient-generated text related to IC/BPS and FM was collected from disease-specific Reddit communities using identical retrieval procedures, yielding temporally comparable corpora. A predefined evaluative lexicon was constructed from validated clinical questionnaires together with pain-related, affective, and anatomical vocabulary. Symptom-language co-occurrence networks were analyzed using a three-step framework examining global pain-centered network organization, dense-core topology and community structure, and local pain-centered lexical configurations. Both conditions exhibited pain-centered symptom-language networks. However, the FM network showed a greater concentration of symptom-language terms within the immediate network neighborhood of "pain," whereas the IC/BPS network retained a larger peripheral structure. Dense-core analysis revealed distinct topological organization. The IC/BPS dense core retained partial modular differentiation, whereas the FM dense core formed a highly interconnected structure with minimal residual community organization. At the local level, pain-centered lexical neighborhoods also differed between conditions. In IC/BPS, "pain" was preferentially associated with pelvic, urinary, and sensory terms, whereas in FM it was more frequently associated with whole-body, fatigue-, sleep-, chronicity-, and affect-related vocabulary. These findings indicate that two chronic pain conditions sharing substantial conceptual overlap nevertheless exhibit distinct pain-centered symptom-language topologies within patient-generated discourse. Comparative network analysis of patient-generated language may provide a complementary framework for characterizing disease-specific patterns of symptom-language organization in online health communities.

α6β4 nicotinic acetylcholine receptors (nAChRs) represent potential therapeutic targets for pain management; however, studies on the distribution and function of these receptors have been constrained by the scarcity of pharmacological tools. An analogue of α-conotoxin (α-CTx) LvIC from Conus lividus, [D1G, Δ14Q]LvIC, selectively inhibits heterologous rat α6/α3β4 nAChRs (where α6/α3 denotes the chimeric subunit) and represents a promising pharmacological tool. However, its limited stability may restrict further applications. Rational design based on the [D1G, Δ14Q]LvIC analogue led to the identification of a key mutant, [d-Lys11]LvIC, with a half-maximal inhibitory concentration (IC50) of 8.2 nM. The mutant retained the desired activity and substantial selectivity for 11 other nAChR subtypes while demonstrating superior stability in rat serum. Based on these favorable properties, we conjugated the analogue to a BODIPY-FL (BDP) fluorophore to obtain a high-fidelity fluorescent probe, enabling the investigation of α6β4 nAChRs tissue distribution in rats. The fluorescent probe, [d-Lys11]LvIC-BDP, was preliminarily applied to detect a reduction in α6β4 nAChRs expression in a cyclophosphamide (CYP)-induced rat model of interstitial cystitis/bladder pain syndrome (IC/BPS). The development of this fluorescent probe provides an ideal tool for investigating the tissue distribution and functional characterization of α6β4 nAChRs.

Interstitial cystitis (IC) and bladder pain syndrome (BPS) have several clinical phenotypes. However, these subtypes may have similar symptoms, such as bladder pain, frequency, urgency, and functional somatic syndrome. A global consensus has been reached that bladders with characteristic Hunner's ulcer lesions are classified as IC, whereas those without Hunner's ulcer are classified as non-ulcer IC/BPS. To diagnose Hunner's IC, office cystoscopy without anesthesia is usually adequate for visualizing the presence of Hunner's lesions. However, the diagnostic accuracy of cystoscopic hydrodistention for non-ulcer IC/BPS has not been validated. Cystoscopic hydrodistention can detect mucosal dysfunction and chronic inflammation over long periods. Different grades of glomerulation may develop after hydrodistention of the bladder to a pressure of 80 cmH2O, and the maximal bladder capacity under anesthesia can be measured. The cystoscopic characteristics of IC/BPS after hydrodistention are associated with bladder symptoms, bladder wall CT findings, inflammatory urine biomarkers, and histopathological findings in the bladder wall. Cystoscopic hydrodistention can be a useful diagnostic examination and a treatment for IC/BPS. Cystoscopic findings are associated with severe bladder inflammation, clinical symptoms, and treatment outcomes.