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14 pages, 5466 KiB

Open AccessArticle

Vinpocetine Ameliorates Metabolic-Syndrome-Associated Bladder Overactivity in Fructose-Fed Rats by Restoring Succinate-Modulated cAMP Levels and Exerting Anti-Inflammatory Effects in the Bladder Detrusor Muscle

by Wei-Chia Lee, Hong-Ren Yu, You-Lin Tain, Kay L.H. Wu, Yao-Chi Chuang and Julie Y.H. Chan

Biomedicines 2022, 10(11), 2716; https://doi.org/10.3390/biomedicines10112716 - 26 Oct 2022

Cited by 3 | Viewed by 1513

Abstract

Succinate and its receptor, the G protein-coupled receptor 91 (GPR91), have pathological implications in metabolic syndrome (MetS) and its associated bladder dysfunction, particularly in decreasing bladder cAMP levels and promoting proinflammation. Using fructose-fed rats (FFRs), a rat model of MetS, we investigate the [...] Read more.

Succinate and its receptor, the G protein-coupled receptor 91 (GPR91), have pathological implications in metabolic syndrome (MetS) and its associated bladder dysfunction, particularly in decreasing bladder cAMP levels and promoting proinflammation. Using fructose-fed rats (FFRs), a rat model of MetS, we investigate the effects of vinpocetine (a phosphodiesterase-1 inhibitor) and celecoxib (a selective cyclooxygenase-2 inhibitor) on MetS-associated bladder overactivity. Phenotypes of the overactive bladder, including increased micturition frequency and a shortened intercontractile interval in cystometry, were observed in FFRs, together with elevated succinate levels in the liver and serum and the downregulation of GPR91 in the liver and urinary bladder. Treatments with vinpocetine and celecoxib improved tissue fibrosis and ameliorated the overexpression of the inflammatory cytokines, such as IL-1β, in the liver and bladder. In bladder organ bath studies, vinpocetine, but not celecoxib, treatment restored the contraction and relaxation responses of the detrusor muscle strip in response to KCl, carbachol, and forskolin stimulation. At a molecular level, vinpocetine and celecoxib treatments modulated the downstream messengers of GPR91 (i.e., ERK1/2 and JNK), suppressed NF-κB and IL-1β expressions in the bladder, and prevented the fibrogenesis observed in FFRs. The exogenous application of succinate to a bladder organ bath significantly reduced the forskolin-induced cAMP production by the detrusor muscle, which was notably restored in the presence of vinpocetine. Together, these results suggest that vinpocetine may alleviate the MetS-associated bladder overactivity by restoring the succinate-modulated detrusor cAMP production and exerting the anti-inflammatory effects in the bladder detrusor muscle. Full article

(This article belongs to the Special Issue Bladder Dysfunction: From Molecular Pathology to Therapeutic Approaches)

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10 pages, 817 KiB

Open AccessEditor’s ChoiceArticle

Urine Oxidative Stress Biomarkers as Novel Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome

by Yuan-Hong Jiang, Jia-Fong Jhang, Han-Chen Ho, Dan-Yun Chiou and Hann-Chorng Kuo

Biomedicines 2022, 10(7), 1701; https://doi.org/10.3390/biomedicines10071701 - 14 Jul 2022

Cited by 14 | Viewed by 1770

Abstract

Both hypoxia and chronic suburothelial inflammation are important pathophysiological findings in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). This study investigated the roles of urine oxidative stress biomarkers and inflammatory cytokines in patients with IC/BPS. Urine samples were collected from 159 IC/BPS patients [...] Read more.

Both hypoxia and chronic suburothelial inflammation are important pathophysiological findings in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). This study investigated the roles of urine oxidative stress biomarkers and inflammatory cytokines in patients with IC/BPS. Urine samples were collected from 159 IC/BPS patients and 28 controls. The targeted analytes included oxidative stress biomarkers (8-OHdG, 8-isoprostane, and total antioxidant capacity) and inflammatory cytokines (MCP-1, RANTES, CXCL10, Eotaxin, MIP-1β, and IL-8). IC/BPS patients were classified into four clinical subgroups, based on the glomerulation grade and the maximal bladder capacity under anesthesia. Patients with IC/BPS had urine oxidative stress biomarkers and inflammatory cytokines profiles that were distinct from those of the controls and among each subgroup. Both 8-OHdG and 8-isoprostane showed a high diagnostic ability to distinguish type 2 IC/BPS patients (as classified by the European Society for the Study of Interstitial Cystitis) from controls. Additionally, they both showed positive and negative correlations with the glomerulation grade and the maximal bladder capacity under anesthesia, respectively. Limitations included intra-individual variation and sex influence. Urine oxidative stress biomarkers might have a role in diagnosing IC/BPS and differentiating its clinical subtypes. In addition to inflammatory cytokines, urine oxidative stress biomarkers have the potential to be novel biomarkers in patients with IC/BPS. Full article

(This article belongs to the Special Issue Bladder Dysfunction: From Molecular Pathology to Therapeutic Approaches)

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17 pages, 2668 KiB

Open AccessArticle

The Upregulation of Caffeic Acid Phenethyl Ester on Growth Differentiation Factor 15 Inhibits Transforming Growth Factor β/Smad Signaling in Bladder Carcinoma Cells

by Chen-Pang Hou, Ke-Hung Tsui, Syue-Ting Chen, Kang-Shuo Chang, Hsin-Ching Sung, Shu-Yuan Hsu, Yu-Hsiang Lin, Tsui-Hsia Feng and Horng-Heng Juang

Biomedicines 2022, 10(7), 1625; https://doi.org/10.3390/biomedicines10071625 - 07 Jul 2022

Viewed by 1743

Abstract

Growth differentiation factor 15 (GDF15) is known as a TGFβ-like cytokine acting on the TGFβ receptor to modulate target genes. GDF15 is regarded as a tumor suppressor gene in the human bladder and the caffeic acid phenethyl ester (CAPE) induces GDF15 expression to [...] Read more.

Growth differentiation factor 15 (GDF15) is known as a TGFβ-like cytokine acting on the TGFβ receptor to modulate target genes. GDF15 is regarded as a tumor suppressor gene in the human bladder and the caffeic acid phenethyl ester (CAPE) induces GDF15 expression to inhibit the tumor growth in vitro and in vivo. However, the interactions among GDF15, CAPE, and TGFβ/Smads signaling in the human bladder carcinoma cells remain unexplored. Results revealed that TGFβ downregulated the expression of GDF15 via the activation of Smad 2/3 and Smad 1/5. Induction of GDF15 on its downstream genes, NDRG1 and maspin, is dependent on the TGFβ/Smad pathways. Moreover, TGFβ blocked the CAPE-inducing expressions of GDF15, maspin, and NDRG1. Pretreatment of TGF receptor kinase inhibitor not only blocked the activation of TGFβ but also attenuated the activation of GDF15 on the expressions of maspin and NDRG1. The CAPE treatment attenuated the activation of TGFβ on cell proliferation and invasion. Our findings indicate that TGFβ downregulated the expressions of GDF15, maspin, and NDRG1 via TGFβ/Smad signaling. Whereas, CAPE acts as an antagonist on TGFβ/Smad signaling to block the effect of TGFβ on the GDF15 expression and cell proliferation and invasion in bladder carcinoma cells. Full article

(This article belongs to the Special Issue Bladder Dysfunction: From Molecular Pathology to Therapeutic Approaches)

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10 pages, 3157 KiB

Open AccessArticle

Changes in the Ultrastructure of the Bladder Urothelium in Patients with Interstitial Cystitis after Intravesical Injections of Platelet-Rich Plasma

by Yu-Khun Lee, Yuan-Hong Jiang, Jia-Fong Jhang, Han-Chen Ho and Hann-Chorng Kuo

Biomedicines 2022, 10(5), 1182; https://doi.org/10.3390/biomedicines10051182 - 20 May 2022

Cited by 6 | Viewed by 1591

Abstract

Urothelial dysfunction is considered a key pathological mechanism of interstitial cystitis/bladder pain syndrome (IC/BPS). Intravesical platelet-rich plasma (PRP) injections might be effective for treating IC/BPS. This prospective study investigated the changes in electron microscopic findings among IC/BPS patients after intravesical PRP injections. Twenty-six [...] Read more.

Urothelial dysfunction is considered a key pathological mechanism of interstitial cystitis/bladder pain syndrome (IC/BPS). Intravesical platelet-rich plasma (PRP) injections might be effective for treating IC/BPS. This prospective study investigated the changes in electron microscopic findings among IC/BPS patients after intravesical PRP injections. Twenty-six patients with refractory non-ulcer IC/BPS underwent monthly intravesical PRP injections for 4 months. Changes in clinical symptom scores and video urodynamic study parameters were assessed from baseline to after the PRP injections. A post-treatment Global Response Assessment (GRA) score ≥ 2 was considered a successful outcome. The mean GRA score was significantly higher after 4 PRP injections than at baseline. Approximately 42% of patients experienced successful outcomes after PRP treatment. Urothelial ultrastructural defects showed no significant differences between baseline and after the PRP injections. However, patients showed variable improvements in different urothelial defects (grade improvements: urothelium cell layers, 31%; umbrella cell integrity, 42%; umbrella cell surface uroplakin plaque, 54%; tight junctions between adjacent umbrella cells, 46%; lysed organelles, 58%; inflammatory cell infiltration, 31%). Patients with successful treatment outcomes showed significant improvements in urothelial tight junction defects. Repeated intravesical PRP injections are effective for improving IC/BPS symptoms as they promote urothelial ultrastructural defect recovery. Full article

(This article belongs to the Special Issue Bladder Dysfunction: From Molecular Pathology to Therapeutic Approaches)

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14 pages, 3636 KiB

Open AccessEditor’s ChoiceArticle

Use of Urinary Cytokine and Chemokine Levels for Identifying Bladder Conditions and Predicting Treatment Outcomes in Patients with Interstitial Cystitis/Bladder Pain Syndrome

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

Biomedicines 2022, 10(5), 1149; https://doi.org/10.3390/biomedicines10051149 - 17 May 2022

Cited by 14 | Viewed by 3615

Abstract

Background: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a condition causing bladder inflammation. Urinary biomarkers have been assessed as suitable for the diagnosis and treatment. This study aimed at investigating the role of urinary biomarkers in identifying bladder conditions and predicting the treatment outcome [...] Read more.

Background: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a condition causing bladder inflammation. Urinary biomarkers have been assessed as suitable for the diagnosis and treatment. This study aimed at investigating the role of urinary biomarkers in identifying bladder conditions and predicting the treatment outcome of IC/BPS. Methods: A total of 309 patients with IC/BPS and 30 controls were enrolled in this study. All patients underwent a comprehensive urological workup of symptoms, pain severity, and cystoscopic hydrodistention findings including maximal bladder capacity (MBC) and glomerulation grade. Urine samples were collected to investigate the levels of urinary cytokines and chemokines. According to MBC and glomerulation grade, patients with IC/BPS were further classified into the Hunner’s IC (HIC) and non-HIC groups. The urinary biomarkers between IC/BPS and control groups and HIC and non-HIC groups were compared. Moreover, the treatment response was graded according to global response assessment (GRA) scores, and urinary biomarker levels were analyzed based on different GRAs. Results: Patients with IC/BPS had significantly high urinary monocyte chemoattractant protein-1, eotaxin, tumor necrosis factor -alpha (TNF-α), and prostaglandin E2 levels. Significantly higher levels of urinary interleukin-8, C-X-C motif chemokine ligand 10 (CXCL 10), brain-derived neurotrophic factor, eotaxin, and regulated-on-activation, normal T-cell expressed and secreted (RANTES) were noted in HIC than those with non-HIC and controls. Among all biomarkers, TNF-α had the best sensitivity, specificity, positive predictive value, and negative predictive value. There was a significant correlation between biomarker levels and GRA. Conclusions: Significantly higher urine cytokines and chemokine levels were found in patients with IC/BPS. Most urinary biomarkers were significantly associated with MBC, glomerulation grade, and treatment outcome. Full article

(This article belongs to the Special Issue Bladder Dysfunction: From Molecular Pathology to Therapeutic Approaches)

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10 pages, 1347 KiB

Open AccessArticle

Clinical Correlation of Bladder Electron Microscopic Characteristics in Patients with Detrusor Underactivity of Various Etiologies

by Jia-Fong Jhang, Han-Chen Ho, Yuan-Hong Jiang, Yung-Hsiang Hsu and Hann-Chorng Kuo

Biomedicines 2022, 10(5), 1055; https://doi.org/10.3390/biomedicines10051055 - 03 May 2022

Cited by 2 | Viewed by 1373

Abstract

This study aimed to investigate the ultrastructural characteristics of the bladder of patients with detrusor underactivity (DU) of various etiologies. Twenty-five patients with DU and control subjects underwent urodynamic testing and transmission electron microscopic examination of bladder specimens. The epithelium, lamina propria, and [...] Read more.

This study aimed to investigate the ultrastructural characteristics of the bladder of patients with detrusor underactivity (DU) of various etiologies. Twenty-five patients with DU and control subjects underwent urodynamic testing and transmission electron microscopic examination of bladder specimens. The epithelium, lamina propria, and muscle layers were analyzed separately. The DU bladders exhibited total epithelial denudation (52%). In the bladders with remaining epithelium, apical cell uroplakins (44.4%) and tight junction complexes (77.8%) were also noted. The lamina propria was characterized by loose extracellular connective tissue (48%) and a lack of nerve terminals (76%). Smooth muscle shrinkage and a loss of their regular spindle shape (91.6%) were also noted in the detrusor layer. Patients with DU with intact epithelial cell layers had significantly larger void volumes and maximal flow rates than those with mild or severe epithelial denudation. Patients with remaining nerve terminals in lamina propria had a stronger first sensation of filling and smaller residual urine volume than those without nerve terminals. The proportion of ultrastructural defects of the bladder was not significantly different among patients with DU of various etiologies and treatment outcomes. DU bladders were characterized by ultrastructural defects in the entire bladder, and the defects were correlated to clinical parameters. Full article

(This article belongs to the Special Issue Bladder Dysfunction: From Molecular Pathology to Therapeutic Approaches)

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12 pages, 2119 KiB

Open AccessArticle

Bladder Ultrastructure and Urinary Cytokine Abnormality in Patients with Recurrent Urinary Tract Infection and the Changes after Intravesical Platelet-Rich Plasma Injections

by Jia-Fong Jhang, Han-Chen Ho, Yuan-Hsiang Hsu, Yuan-Hong Jiang and Hann-Chorng Kuo

Biomedicines 2022, 10(2), 245; https://doi.org/10.3390/biomedicines10020245 - 24 Jan 2022

Cited by 5 | Viewed by 2636

Abstract

This study investigates the bladder from patients with recurrent urinary tract infection (rUTI) at baseline and after intravesical platelet-rich plasma (PRP) injections. Patients with rUTI who underwent repeated intravesical PRP injections provided bladder and urine specimens at baseline and after treatment. Bladder specimens [...] Read more.

This study investigates the bladder from patients with recurrent urinary tract infection (rUTI) at baseline and after intravesical platelet-rich plasma (PRP) injections. Patients with rUTI who underwent repeated intravesical PRP injections provided bladder and urine specimens at baseline and after treatment. Bladder specimens were investigated with electron microscopy and Western blotting. The urine sample was analyzed with commercially available Milliplex immunoassays. A total of 29 patients were enrolled. At baseline, the rUTI bladders exhibited defects of integrity in umbrella cells, a widened tight junction, and lysed organelles. Intracellular bacterial community incubations in the epithelial cells were also noted. Improvement in bladder defects after PRP injection was noted in 25–42% of patients. Bladder UPK3 expression was significantly lower in the patients with rUTI than in controls. Baseline levels of urinary inflammatory cytokine interleukin (IL)-6, IL-8, and brain-derived neurotrophic factor were higher in the patients with rUTI than in the controls, but there were lower levels of vascular endothelial growth factor and nerve growth factor. In the patients with rUTI who recovered from acute infection, the bladders still had immature urothelium, various ultrastructural defects, and elevated urinary inflammatory cytokines. PRP injection has the potential to promote bladder recovery in some of these patients. Full article

(This article belongs to the Special Issue Bladder Dysfunction: From Molecular Pathology to Therapeutic Approaches)

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13 pages, 2061 KiB

Open AccessArticle

Inflammation and Barrier Function Deficits in the Bladder Urothelium of Patients with Chronic Spinal Cord Injury and Recurrent Urinary Tract Infections

by Shu-Yu Wu, Yuan-Hong Jiang, Jia-Fong Jhang, Yung-Hsiang Hsu, Han-Chen Ho and Hann-Chorng Kuo

Biomedicines 2022, 10(2), 220; https://doi.org/10.3390/biomedicines10020220 - 20 Jan 2022

Cited by 12 | Viewed by 2116

Abstract

Patients with spinal cord injury (SCI) commonly experience neurogenic voiding dysfunctions and urinary tract complications, including recurrent urinary tract infections (rUTI). The bladder mucosa barrier function contributes to UTI prevention. This study investigated changes in bladder urothelium protein expression in patients with SCI [...] Read more.

Patients with spinal cord injury (SCI) commonly experience neurogenic voiding dysfunctions and urinary tract complications, including recurrent urinary tract infections (rUTI). The bladder mucosa barrier function contributes to UTI prevention. This study investigated changes in bladder urothelium protein expression in patients with SCI and rUTI. From June 2011 to November 2017, 23 patients (19 men and 4 women) with chronic SCI were enrolled (mean age: 43 years. Bladder tissues from 6 healthy adults served as the normal control group. Biopsy samples (9 partial cystectomies and 14 bladder biopsies) were analyzed for functional biomarkers using western blot and immunohistochemistry analysis. The barrier function proteins E-cadherin, zonula occludens 1 (ZO-1) and uroplakin III (UPK-3) were significantly reduced, whereas tumor protein p63 (TP63) was significantly increased in SCI patients compared with controls. No significant differences in basal cell progenitor proteins were observed between groups. The proliferation marker Ki-67, the proapoptotic marker BCL-2-associated X protein (BAX), and proinflammatory proteins were increased in patients with SCI compared with controls. No significant differences were observed between SCI patients with and without recently rUTI. These results suggest that SCI patients experience chronic bladder inflammation, increased apoptosis, and reduced barrier function, contributing to rUTI. Full article

(This article belongs to the Special Issue Bladder Dysfunction: From Molecular Pathology to Therapeutic Approaches)

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10 pages, 4952 KiB

Open AccessArticle

Possible Association between Bladder Wall Morphological Changes on Computed Tomography and Bladder-Centered Interstitial Cystitis/Bladder Pain Syndrome

by Jia-Fong Jhang, Yung-Hsiang Hsu, Han-Chen Ho, Yuan-Hong Jiang, Cheng-Ling Lee, Wan-Ru Yu and Hann-Chorng Kuo

Biomedicines 2021, 9(10), 1306; https://doi.org/10.3390/biomedicines9101306 - 24 Sep 2021

Cited by 14 | Viewed by 3713

Abstract

This study aimed to evaluate the clinical significance of urinary bladder wall thickening on computed tomography (CT) among patients with interstitial cystitis/bladder pain syndrome (IC/BPS). Patients with IC/BPS were prospectively enrolled and classified into three groups according to bladder CT finding: smooth bladder [...] Read more.

This study aimed to evaluate the clinical significance of urinary bladder wall thickening on computed tomography (CT) among patients with interstitial cystitis/bladder pain syndrome (IC/BPS). Patients with IC/BPS were prospectively enrolled and classified into three groups according to bladder CT finding: smooth bladder wall, focal bladder thickening, and diffuse bladder thickening. Among the 100 patients with IC/BPS, 49, 36, and 15 had smooth bladder wall, focal bladder thickening, and diffuse bladder thickening on CT, respectively. Patients with Hunner’s lesion showed a higher proportion of diffuse and focal bladder thickening compared to those without the same (p < 0.001). Patients with diffuse bladder thickening displayed smaller first sensation of filling, cystometric bladder capacity, and voided volume compared to the rest (all p < 0.001). Patients with focal and diffuse thickening had a higher proportion of inflammatory cell infiltration, uroepithelial cell denudation, and granulation tissue compared to those with smooth bladder wall (p = 0.045, 0.002, and 0.005, respectively). Bladder wall thickening on CT was correlated with clinical phenotypes of IC/BPS, including histopathological findings. Focal or diffuse bladder wall thickening on CT might indicate the presence of chronic bladder wall inflammation and fibrosis and could be used to differentiate bladder-centered IC/BPS. Full article

(This article belongs to the Special Issue Bladder Dysfunction: From Molecular Pathology to Therapeutic Approaches)

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Review

Jump to: Research

12 pages, 762 KiB

Open AccessReview

Detrusor Underactivity in Men with Bladder Outlet Obstruction

by Hsiang-Ying Lee, Chien-Sheng Wang and Yung-Shun Juan

Biomedicines 2022, 10(11), 2954; https://doi.org/10.3390/biomedicines10112954 - 17 Nov 2022

Cited by 3 | Viewed by 2963

Abstract

Detrusor underactivity (DU) and bladder outlet obstruction (BOO) are both common troublesome causes of lower urinary tract symptoms (LUTS) and often impact on quality of life simultaneously in men. This article aims to focus on DU with BOO in male patients. Methods: Original [...] Read more.

Detrusor underactivity (DU) and bladder outlet obstruction (BOO) are both common troublesome causes of lower urinary tract symptoms (LUTS) and often impact on quality of life simultaneously in men. This article aims to focus on DU with BOO in male patients. Methods: Original articles concerning DU with BOO were identified through literature research from PubMed and EMBASE database. We selected 38 articles in our review, including those concerning pathophysiology, evaluation, treatment and predictors for a successful BOO surgery for DU. Results: DU from BOO can result from several pathophysiological mechanisms. Although urodynamic study (UDS) is considered as a precise method to diagnose DU and BOO, there are some previous studies which proposed a non-invasive method to identify DU related to BOO. The treatment goal of DU is restoring bladder contractility using medication or surgery. Releasing outlet obstruction and resistance is the main strategy to restore bladder contractility when medication to directly increase bladder contractility has had limited efficacy. Conclusions: DU from BOO is poorly understood and is largely under-researched. The etiology and pathophysiology still need to be evaluated. Effective and safe medication to restore bladder contractility is also lacking. It remains valuable to perform further research to reveal the unknown aspects of DU. Full article

(This article belongs to the Special Issue Bladder Dysfunction: From Molecular Pathology to Therapeutic Approaches)

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12 pages, 955 KiB

Open AccessReview

Metabolic Syndrome and Overactive Bladder Syndrome May Share Common Pathophysiologies

by Lin-Nei Hsu, Ju-Chuan Hu, Po-Yen Chen, Wei-Chia Lee and Yao-Chi Chuang

Biomedicines 2022, 10(8), 1957; https://doi.org/10.3390/biomedicines10081957 - 12 Aug 2022

Cited by 19 | Viewed by 3351

Abstract

Metabolic syndrome (MetS) is defined by a group of cardiovascular risk factors, including impaired glucose tolerance, central obesity, hypertension, and dyslipidemia. Overactive bladder (OAB) syndrome consists of symptoms such as urinary urgency, frequency, and nocturia with or without urge incontinence. The high prevalences [...] Read more.

Metabolic syndrome (MetS) is defined by a group of cardiovascular risk factors, including impaired glucose tolerance, central obesity, hypertension, and dyslipidemia. Overactive bladder (OAB) syndrome consists of symptoms such as urinary urgency, frequency, and nocturia with or without urge incontinence. The high prevalences of metabolic syndrome (MetS) and overactive bladder (OAB) worldwide affect quality of life and cause profound negative impacts on the social economy. Accumulated evidence suggests that MetS might contribute to the underlying mechanisms for developing OAB, and MetS-associated OAB could be a subtype of OAB. However, how could these two syndromes interact with each other? Based on results of animal studies and observations in epidemiological studies, we summarized the common pathophysiologies existing between MetS and OAB, including autonomic and peripheral neuropathies, chronic ischemia, proinflammatory status, dysregulation of nutrient-sensing pathways (e.g., insulin resistance at the bladder mucosa and excessive succinate intake), and the probable role of dysbiosis. Since the MetS-associated OAB is a subtype of OAB with distinctive pathophysiologies, the regular and non-specific medications, such as antimuscarinics, beta-3 agonist, and botulinum toxin injection, might lead to unsatisfying results. Understanding the pathophysiologies of MetS-associated OAB might benefit future studies exploring novel biomarkers for diagnosis and therapeutic targets on both MetS and OAB. Full article

(This article belongs to the Special Issue Bladder Dysfunction: From Molecular Pathology to Therapeutic Approaches)

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