International Journal of Molecular Sciences

Research

13 pages, 929 KB

Open AccessArticle

Effect of Bladder Injections of Botulinum Neurotoxin A on Biomarkers Associated with Inflammation and Urinary Infections in Patients with Neurogenic Detrusor Overactivity-Associated Incontinence: A Pilot, Prospective, Human Study

by Sotirios Gatsos, Elena Constantinou, Dimitrios Koutsoumparis, Michael Samarinas, Konstantinos Drosos, Maria Papaioannou, Andigoni Malousi, Eudoxia G. Hatzivassiliou and Apostolos Apostolidis

Int. J. Mol. Sci. 2026, 27(2), 1110; https://doi.org/10.3390/ijms27021110 - 22 Jan 2026

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Abstract

Conflicting data exist regarding the effect of intradetrusor BoNT/A on the incidence of urinary tract infections (UTIs) in patients with neurogenic detrusor overactivity (NDO), contrary to the increase in UTIs noted in patients with idiopathic OAB. Associations between UTIs, chronic inflammation, and bladder [...] Read more.

Conflicting data exist regarding the effect of intradetrusor BoNT/A on the incidence of urinary tract infections (UTIs) in patients with neurogenic detrusor overactivity (NDO), contrary to the increase in UTIs noted in patients with idiopathic OAB. Associations between UTIs, chronic inflammation, and bladder overactivity are acknowledged, albeit not fully understood. Chronic bladder inflammation is common in both NDO and OAB patients, and both animal and human studies suggest a beneficial effect of BoNT/A on both urinary and systemic levels of inflammatory markers. To explore whether intradetrusor BoNT/A injections affect the background for the incidence of UTIs in humans, we investigated in parallel the effect of intradetrusor BoNT/A on the incidence of UTIs and on the urine mRNA levels of urinary pathogen-detecting Toll-like receptors TLR2, TLR4, and TLR5 and of factors acting as intermediates of immune response and promoters of inflammatory reactions (IL1β, IL6, TNFα, and PGE₂). For this purpose, we recruited 22 patients with NDO-associated incontinence who received at least one bladder BoNT/A injection. Urine specimens for the study of UTIs were obtained before the procedure and at routine urodynamic follow-ups at 4–6 weeks, 6 and 12 months post-BoNT/A, and at clinical relapse, while urine specimens for the study of biomarkers were collected at the time of BoNT/A injection and at the abovementioned follow-ups thereafter. Urine specimens from 10 adult healthy volunteers with no OAB symptoms served as the control group in the biomarker study. The genes of interest in the urine were studied by RNA isolation, reverse transcription, and real-time PCR. The urine mRNAs of all biomarkers tested appeared to be upregulated in the patients’ samples compared with the controls, albeit only TLR2 and TLR5 mRNA increases were statistically significant. A progressive downregulation of TLR2, TLR5, IL1β, and IL6 urine mRNAs was noted at one and six months post-BoNT/A. TNFα and PGE₂ mRNAs showed a transient increase at one month post-BoNT/A followed by a dramatic drop at the six months’ follow-up. A similar trend for progressive decline was also noticed in the prevalence of both positive urine cultures and symptomatic UTIs in the same timepoints and additionally at 12 months post-treatment in patients who still benefited from the BoNT/A treatment. Upon clinical relapse, the mRNA levels of PGE₂, IL1β, and IL6 increased in parallel with an increase in the prevalence of UTIs, while the levels of TLRs and TNF-α did not follow the same trend. In summary, intradetrusor BoNT/A injections achieved significant decreases in the urine mRNA levels of pathogen-detecting TLRs, immune response, and inflammation mediator cytokines and PGE₂ in our cohort of patients with NDO-associated incontinence. In parallel, decreases were noted in both the incidence of symptomatic UTIs and rates of positive urine cultures. At the time of clinical relapse, the markers of inflammation and immune response, but not TLRs, were upregulated in parallel with the increased incidence of UTIs, suggesting that the studied genes PGE₂, IL1β, and IL6 could be further explored as potential biomarkers for inflammation/immune response and UTIs in the neurogenic population. Full article

(This article belongs to the Special Issue Primary and Secondary Bladder Disorders in Neurourology and Inflammatory Diseases)

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16 pages, 2978 KB

Open AccessArticle

Bladder Dysfunction in Sickle Cell Disease Is Associated with Inflammation and Oxidative Stress

by Dalila Andrade Pereira, Fabiano Beraldi Calmasini, Tammyris Helena Rebecchi Silveira, Danillo Andrade Pereira, Mariana G. de Oliveira, Fernando Ferreira Costa and Fábio Henrique Silva

Int. J. Mol. Sci. 2025, 26(19), 9776; https://doi.org/10.3390/ijms26199776 - 8 Oct 2025

Cited by 2 | Viewed by 1214

Abstract

Bladder dysfunction, particularly overactive bladder (OAB), is increasingly recognized as a clinical concern in patients with sickle cell disease (SCD), yet its pathophysiological mechanisms remain poorly understood. This study investigated the relationship between oxidative stress, inflammation, and bladder dysfunction in the Townes transgenic [...] Read more.

Bladder dysfunction, particularly overactive bladder (OAB), is increasingly recognized as a clinical concern in patients with sickle cell disease (SCD), yet its pathophysiological mechanisms remain poorly understood. This study investigated the relationship between oxidative stress, inflammation, and bladder dysfunction in the Townes transgenic SCD mouse model. Cystometric analysis revealed that SCD mice exhibit an OAB phenotype, characterized by increased frequencies of voiding and non-voiding contractions and reduced bladder compliance. In vitro functional assays demonstrated detrusor hypocontractility in SCD mice, associated with a significant reduction in carbachol- and EFS-induced contractions and downregulation of muscarinic M3 receptor expression. Purinergic signaling and calcium-dependent contractility remained preserved. Molecular analyses showed increased mRNA expression of NOX-2 and IL-1β, and elevated protein levels of 3-nitrotyrosine and myeloperoxidase (MPO) activity, indicating redox imbalance and chronic inflammation in bladder tissue. Together, these changes suggest that oxidative and nitrosative stress, combined with inflammation, contribute to bladder remodeling and dysfunction in SCD. This is the first study to characterize bladder alterations in Townes SCD mice, establishing this model as a valuable tool for investigating lower urinary tract complications in SCD. Our findings provide mechanistic insight into the genitourinary manifestations of SCD and identify redox and inflammatory pathways as potential therapeutic targets for bladder dysfunction in affected individuals. Full article

(This article belongs to the Special Issue Primary and Secondary Bladder Disorders in Neurourology and Inflammatory Diseases)

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11 pages, 893 KB

Open AccessArticle

Persistent Elevation in Urinary Neutrophil Gelatinase-Associated Lipocalin Levels Can Be a Predictor of Urinary Tract Infection Recurrence or Persistence in Women

by Min-Ching Liu, Yuan-Hong Jiang, Jia-Fong Jhang, Tien-Lin Chang, Chia-Cheng Yang and Hann-Chorng Kuo

Int. J. Mol. Sci. 2024, 25(23), 12670; https://doi.org/10.3390/ijms252312670 - 26 Nov 2024

Cited by 1 | Viewed by 1781

Abstract

Women commonly experience urinary tract infection (UTI) recurrence. However, there is no effective tool for predicting recurrent UTI after the first UTI episode. Hence, this study aimed to investigate potential urinary inflammatory biomarkers and specific biomarkers for predicting UTI recurrence or persistence after [...] Read more.

Women commonly experience urinary tract infection (UTI) recurrence. However, there is no effective tool for predicting recurrent UTI after the first UTI episode. Hence, this study aimed to investigate potential urinary inflammatory biomarkers and specific biomarkers for predicting UTI recurrence or persistence after antibiotic treatment in women. Forty women who had a history of recurrent UTI within 1 year after the initial episode and acute bacterial cystitis were treated with broad-spectrum antibiotics for 1 week. To measure inflammatory biomarker levels, urine samples were collected at the baseline and after 1 week, 1 month, and 3 months. The levels of urinary pro-inflammatory proteins such as neutrophil gelatinase-associated lipocalin (NGAL), nerve growth factor, CXC-motif chemokine ligand (CXCL)-1, interleukin-8, CXCL-10, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha were measured using commercial kits. Seven healthy age-matched women were included as controls. The changes in urinary biomarker levels at the baseline and various time points were compared between women with and without UTI recurrence within 1 month or within 3 months after the initial antibiotic therapy. At the baseline, patients with a higher urinary white blood cell count had a significantly higher NGAL level than the controls and those with a low white blood cell count. Of the 40 patients with a history of recurrent UTI, 12 presented with UTI persistence or recurrence within 1 month and 19 within 3 months after the initial antibiotic treatment. Among the 28 patients without UTI recurrence at 1 month after treatment, 7 had UTI recurrence within 3 months. Compared with patients without UTI recurrence, those with UTI recurrence had significantly higher urinary NGAL levels at 1 week, 1 month, and 3 months after the initial treatment. This study concludes that persistent elevation in urinary NGAL levels after the initial antibiotic treatment indicated persistent bladder inflammation. Further, it could be a predictor of UTI persistence or recurrence within 1 or 3 months after the initial antibiotic treatment. Patients with a history of recurrent UTI and high urinary NGAL levels after antibiotic treatment might require a longer treatment duration to completely eradicate or prevent UTI recurrence. Full article

(This article belongs to the Special Issue Primary and Secondary Bladder Disorders in Neurourology and Inflammatory Diseases)

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26 pages, 5723 KB

Open AccessArticle

The GPR39 Receptor Plays an Important Role in the Pathogenesis of Overactive Bladder and Corticosterone-Induced Depression

by Jan Wróbel, Paulina Iwaniak, Piotr Dobrowolski, Mirosława Chwil, Ilona Sadok, Tomasz Kluz, Artur Wdowiak, Iwona Bojar, Ewa Poleszak, Marcin Misiek, Łukasz Zapała, Ewa M. Urbańska and Andrzej Wróbel

Int. J. Mol. Sci. 2024, 25(23), 12630; https://doi.org/10.3390/ijms252312630 - 25 Nov 2024

Cited by 5 | Viewed by 2579 | Correction

Abstract

Despite the close and clinically confirmed association between depression and overactive bladder, it remains unclear whether this affective disorder is a factor causing overactive bladder or whether overactive bladder is a specific symptom of psychosomatic disorders. This study examined the effects of repeated [...] Read more.

Despite the close and clinically confirmed association between depression and overactive bladder, it remains unclear whether this affective disorder is a factor causing overactive bladder or whether overactive bladder is a specific symptom of psychosomatic disorders. This study examined the effects of repeated corticosterone administration on the occurrence of symptoms associated with depression and overactive bladder. Additionally, we examined whether administering TC-G 1008, an antidepressant that selectively activates the GPR39 receptor, could alleviate corticosterone-induced depression-like behavior and detrusor overactivity-related changes in cystometric measurements. We also explored its potential to reverse alterations in various biomarkers associated with both conditions in the serum, urinary bladder, and brain of female rats. The administration of corticosterone (20 mg/kg/day for 14 days) yielded anticipated results, including an increase in the duration of immobility during the forced swim test, alterations in parameters specific to bladder overactivity, a decrease in neurotrophins, and an elevation in pro-inflammatory cytokine levels. Treatment with TC-G 1008 (15 mg/kg/day) alleviated symptoms of both detrusor overactivity and depression, while also restoring the levels of biochemical and cystometric markers to normal ranges. Additionally, antidepressants based on GPR39 agonists could enhance the levels of kynurenic acid in the neuroprotective pathway. These results indicate that the GPR39 agonist receptor might be a promising future therapeutic approach for treating overactive bladder that occurs alongside depression. Full article

(This article belongs to the Special Issue Primary and Secondary Bladder Disorders in Neurourology and Inflammatory Diseases)

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12 pages, 1179 KB

Open AccessArticle

Using Urine Biomarkers to Differentiate Bladder Dysfunctions in Women with Sensory Bladder Disorders

by Yu-Chen Chen, Yuan-Hong Jiang, Jia-Fong Jhang and Hann-Chorng Kuo

Int. J. Mol. Sci. 2024, 25(17), 9359; https://doi.org/10.3390/ijms25179359 - 29 Aug 2024

Cited by 8 | Viewed by 2472

Abstract

Sensory bladder disorders encompass several distinct conditions with overlapping symptoms, which pose diagnostic challenges. This study aimed to evaluate urine biomarkers for differentiating between various sensory bladder disorders, including non-Hunner’s interstitial cystitis (NHIC), detrusor overactivity (DO), hypersensitive bladder (HSB), and urodynamically normal women. [...] Read more.

Sensory bladder disorders encompass several distinct conditions with overlapping symptoms, which pose diagnostic challenges. This study aimed to evaluate urine biomarkers for differentiating between various sensory bladder disorders, including non-Hunner’s interstitial cystitis (NHIC), detrusor overactivity (DO), hypersensitive bladder (HSB), and urodynamically normal women. A retrospective analysis of 191 women who underwent a videourodynamic study (VUDS) was conducted, with some also receiving cystoscopic hydrodistention to confirm the presence of NHIC. Participants were categorized into four groups: DO (n = 51), HSB (n = 29), NHIC (n = 81), and normal controls (n = 30). The urine levels of inflammatory and oxidative stress biomarkers were measured. The DO patients exhibited elevated IP-10 levels, while the HSB patients had decreased TAC and 8-OHdG levels. The NHIC patients showed lower IL-2 and higher TNF-α levels. A TNF-α ≥ 1.05 effectively identified NHIC, with an AUROC of 0.889, a sensitivity of 98.8%, and a specificity of 81.3%. An IP-10 ≥ 6.31 differentiated DO with an AUROC of 0.695, a sensitivity of 56.8%, and a specificity of 72.3%. An 8-OHdG ≤ 14.705 and a TAC ≤ 528.7 identified HSB with AUROCs of 0.754 and 0.844, respectively. The combination of 8-OHdG and TAC provided an AUROC of 0.853 for HSB. These findings suggest that TNF-α, IP-10, TAC, 8-OHdG, and IL-2 are promising non-invasive biomarkers for distinguishing between these conditions, which may improve diagnosis and management. Full article

(This article belongs to the Special Issue Primary and Secondary Bladder Disorders in Neurourology and Inflammatory Diseases)

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Review

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17 pages, 1118 KB

Open AccessReview

Urinary Biomarkers for Radiation Cystitis: Current Insights and Future Directions

by Rani Mahyoob and Bernadette M. M. Zwaans

Int. J. Mol. Sci. 2026, 27(2), 565; https://doi.org/10.3390/ijms27020565 - 6 Jan 2026

Cited by 1 | Viewed by 1278

Abstract

Radiation cystitis (RC) is a clinically challenging and often progressive complication of pelvic radiotherapy, marked by urothelial injury, vascular dysfunction, chronic inflammation, and fibrotic remodeling. Early diagnosis remains elusive due to nonspecific symptoms and the absence of validated molecular tools. As a biofluid [...] Read more.

Radiation cystitis (RC) is a clinically challenging and often progressive complication of pelvic radiotherapy, marked by urothelial injury, vascular dysfunction, chronic inflammation, and fibrotic remodeling. Early diagnosis remains elusive due to nonspecific symptoms and the absence of validated molecular tools. As a biofluid in direct contact with the irradiated bladder, urine offers a unique molecular window into RC pathogenesis. In this review, we synthesize the current landscape of urinary biomarkers associated with the acute, latent, and chronic phases of RC, including inflammatory cytokines, oxidative stress products, epithelial injury markers, extracellular vesicles, microRNAs, proteomic signatures, and metabolomic alterations. We also integrate emerging mechanistic insights such as DNA damage responses, ROS generation, mitochondrial dysfunction, urothelial barrier disruption, senescence-associated secretory phenotypes, hypoxia-driven vascular injury, and profibrotic TGF-β signaling, all of which contribute to the release of urinary analytes. By linking phase-specific molecular pathways with corresponding urinary signatures, we highlight opportunities to leverage urine-based measurements for early detection, risk stratification, severity assessment, and therapeutic monitoring. A deeper understanding of the molecular mechanisms shaping urinary biomarker profiles will be essential for advancing precision diagnostics and improving long-term outcomes for patients with radiation cystitis. Full article

(This article belongs to the Special Issue Primary and Secondary Bladder Disorders in Neurourology and Inflammatory Diseases)

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18 pages, 1121 KB

Open AccessReview

Promising Experimental Treatment in Animal Models and Human Studies of Interstitial Cystitis/Bladder Pain Syndrome

by Ju-Chuan Hu, Hong-Tai Tzeng, Wei-Chia Lee, Jian-Ri Li and Yao-Chi Chuang

Int. J. Mol. Sci. 2024, 25(15), 8015; https://doi.org/10.3390/ijms25158015 - 23 Jul 2024

Cited by 7 | Viewed by 7000

Abstract

Interstitial cystitis/bladder pain Syndrome (IC/BPS) remains a mysterious and intricate urological disorder, presenting significant challenges to healthcare providers. Traditional guidelines for IC/BPS follow a hierarchical model based on symptom severity, advocating for conservative interventions as the initial step, followed by oral pharmacotherapy, intravesical [...] Read more.

Interstitial cystitis/bladder pain Syndrome (IC/BPS) remains a mysterious and intricate urological disorder, presenting significant challenges to healthcare providers. Traditional guidelines for IC/BPS follow a hierarchical model based on symptom severity, advocating for conservative interventions as the initial step, followed by oral pharmacotherapy, intravesical treatments, and, in refractory cases, invasive surgical procedures. This approach embraces a multi-tiered strategy. However, the evolving understanding that IC/BPS represents a paroxysmal chronic pain syndrome, often involving extravesical manifestations and different subtypes, calls for a departure from this uniform approach. This review provides insights into recent advancements in experimental strategies in animal models and human studies. The identified therapeutic approaches fall into four categories: (i) anti-inflammation and anti-angiogenesis using monoclonal antibodies or immune modulation, (ii) regenerative medicine, including stem cell therapy, platelet-rich plasma, and low-intensity extracorporeal shock wave therapy, (iii) drug delivery systems leveraging nanotechnology, and (iv) drug delivery systems assisted by energy devices. Future investigations will require a broader range of animal models, studies on human bladder tissues, and well-designed clinical trials to establish the efficacy and safety of these therapeutic interventions. Full article

(This article belongs to the Special Issue Primary and Secondary Bladder Disorders in Neurourology and Inflammatory Diseases)

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Other

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1 pages, 143 KB

Open AccessCorrection

Correction: Wróbel et al. The GPR39 Receptor Plays an Important Role in the Pathogenesis of Overactive Bladder and Corticosterone-Induced Depression. Int. J. Mol. Sci. 2024, 25, 12630

by Jan Wróbel, Paulina Iwaniak, Piotr Dobrowolski, Mirosława Chwil, Ilona Sadok, Tomasz Kluz, Artur Wdowiak, Iwona Bojar, Ewa Poleszak, Marcin Misiek, Łukasz Zapała, Ewa M. Urbańska and Andrzej Wróbel

Int. J. Mol. Sci. 2025, 26(17), 8267; https://doi.org/10.3390/ijms26178267 - 26 Aug 2025

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Abstract

In the published manuscript [...] Full article

(This article belongs to the Special Issue Primary and Secondary Bladder Disorders in Neurourology and Inflammatory Diseases)

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