Brain-Derived Neurotrophic Factor Is Indispensable to Continence Recovery after a Dual Nerve and Muscle Childbirth Injury Model.

In women, stress urinary incontinence (SUI), leakage of urine from increased abdominal pressure, is correlated with pudendal nerve (PN) injury during childbirth. Expression of brain-derived neurotrophic factor (BDNF) is dysregulated in a dual nerve and muscle injury model of childbirth. We aimed to use tyrosine kinase B (TrkB), the receptor of BDNF, to bind free BDNF and inhibit spontaneous regeneration in a rat model of SUI. We hypothesized that BDNF is essential for functional recovery from the dual nerve and muscle injuries that can lead to SUI. Female Sprague-Dawley rats underwent PN crush (PNC) and vaginal distension (VD) and were implanted with osmotic pumps containing saline (Injury) or TrkB (Injury + TrkB). Sham Injury rats received sham PNC + VD. Six weeks after injury, animals underwent leak-point-pressure (LPP) testing with simultaneous external urethral sphincter (EUS) electromyography recording. The urethra was dissected for histology and immunofluorescence. LPP after injury and TrkB was significantly decreased compared to Injury rats. TrkB treatment inhibited reinnervation of neuromuscular junctions in the EUS and promoted atrophy of the EUS. These results demonstrate that BDNF is essential to neuroregeneration and reinnervation of the EUS. Treatments aimed at increasing BDNF periurethrally could promote neuroregeneration to treat SUI.

Puerarin protects fibroblasts against mechanical stretching injury through Nrf2/TGF-ß1 signaling pathway.

INTRODUCTION AND HYPOTHESIS: Stress urinary incontinence (SUI) is the most common form of urinary incontinence in women, which affects women's quality of life worldwide. Mechanical injury of the pelvic floor may disrupt the pelvic supportive tissues and connections via the remodeling of extracellular matrix (ECM), which is supposed to be one of the main pathological mechanisms of SUI. METHODS: The SUI mouse model was established using vaginal distension (VD). Leak point pressure (LPP), maximum cystometric capacity (MCC), collagen, Nrf2 and TGF-ß1 in the anterior vaginal wall were measured in either wild-type or Nrf2-knockout (Nrf2-/-) female C57BL/6 mice with or without puerarin treatment. Then, the mechanical stretching (MS) loaded on L929 cells was generated by a four-point bending device. mTGF-ß1 or LY2109761 (an inhibitor of TGF-ß1) was used to verify the protective effect of puerarin after Nrf2 knockdown or overexpression. RESULTS: The collagen content of the anterior vaginal tissues in VD mice and LPP and MCC was decreased significantly. Besides, the expression levels of Nrf2, TGF-ß1, collagen I and collagen III of MS group were downregulated in L929 cells. Puerarin pretreatment could reverse mechanical injury-induced collagen downregulation and Nrf2/TGF-ß1 signaling inhibition. Moreover, both LY2109761 pretreatment and Nrf2 knockdown could attenuate the protective effect of puerarin in the mechanical injury-induced ECM remodeling, whereas exogenous TGF-ß1 could counteract the effect of Nrf2 downregulation. CONCLUSIONS: Puerarin protected fibroblasts from mechanical injury-induced ECM remodeling through the Nrf2/TGF-ß1 signaling pathway. This might be a new strategy for the treatment of SUI.

Mechanism of miR-34a in the metabolism of extracellular matrix in fibroblasts of stress urinary incontinence via Nampt-mediated autophagy.

Stress urinary incontinence (SUI) is a troublesome hygienic problem that afflicts the female population and is associated with extracellular matrix (ECM). Herein, we investigated the effects of microRNA (miR)-34a on ECM metabolism in fibroblasts of SUI via mediating nicotinamide phosphoribosyl transferase (Nampt/NAmPRTase) and hope to find novel insights in the treatment of SUI. Firstly, the anterior vaginal wall tissues of SUI patients and the female vaginal wall fibroblasts (FVWFs) of non-SUI subjects were collected and identified. Then, FVWFs were treated with 10 ng/mL of interleukin 1 beta (IL-1ß) to establish SUI cell models. Subsequently, miR-34a and Nampt expressions in both types of cells were detected via RT-qPCR. It was found that miR-34a was poorly expressed, while Nampt was highly expressed in SUI. Subsequently, IL-1ß-treated FVWFs were transfected with miR-34a-mimic and pcDNA3.1-Nampt, respectively. Thereafter, RT-qPCR and Western blot detected that miR-34a overexpression increased COL1A, ACAN, and TIMP-1; decreased MMP-2 and MMP-9; and elevated LC3 II/I ratio, Beclin-1 expression, and the autophagosome number in IL-1ß-treated FVWFs, while Nampt upregulation reversed the above outcomes. Then, dual-luciferase reporter gene assay detected that Nampt is a downstream target of miR-34a. Together, miR-34a overexpression promoted autophagy, inhibited ECM degradation in IL-1ß-treated FVWFs, and ameliorated SUI via suppressing Nampt.

Enhanced Myogenesis by Silencing Myostatin with Nonviral Delivery of a dCas9 Ribonucleoprotein Complex.

Stress urinary incontinence (SUI) and pelvic floor disorder (PFD) are common conditions with limited treatment options in women worldwide. Regenerative therapy to restore urethral striated and pelvic floor muscles represents a valuable therapeutic approach. We aim to determine the CRISPR interference-mediated gene silencing effect of the nonviral delivery of nuclease-deactivated dCas9 ribonucleoprotein (RNP) complex on muscle regeneration at the cellular and molecular level. We designed four myostatin (MSTN)-targeting sgRNAs and transfected them into rat myoblast L6 cells together with the dCas9 protein. Myogenesis assay and immunofluorescence staining were performed to evaluate muscle differentiation, while CCK8 assay, cell cycle assay, and 5-ethynyl-2'-deoxyuridine staining were used to measure muscle proliferation. Reverse transcription-polymerase chain reaction and Western blotting were also performed to examine cellular signaling. Myogenic factors (including myosin heavy chain, MSTN, myocardin, and serum response factor) increased significantly after day 5 during myogenesis. MSTN was efficiently silenced after transfecting the dCas9 RNP complex, which significantly promoted more myotube formation and a higher fusion index for L6 cells. In cellular signaling, MSTN repression enhanced the expression of MyoG and MyoD, phosphorylation of Smad2, and the activity of Wnt1/GSK-3ß/ß-catenin pathway. Moreover, MSTN repression accelerated L6 cell growth with a higher cell proliferation index as well as a higher expression of cyclin D1 and cyclin E. Nonviral delivery of the dCas9 RNP complex significantly promoted myoblast differentiation and proliferation, providing a promising approach to improve muscle regeneration for SUI and PFD. Further characterization and validation of this approach in vivo are needed.

Effect of electroacupuncture on the degradation of collagen in pelvic floor supporting tissue of stress urinary incontinence rats.

INTRODUCTION AND HYPOTHESIS: To examine the changes induced by electroacupuncture in stress urinary incontinence (SUI) rats, including the urodynamics and collagen degradation-related cytokine molecular biological expression changes, and to explore the effect and mechanism of EA treatment in SUI. METHODS: Female SPF Sprague-Dawley rats were randomly assigned to five groups (n = 10): sham, model, electroacupuncture control, electroacupuncture, and blocker. The leak point pressure (LPP) and maximum bladder capacity (MBC) were measured for each group of rats, and collagen I, collagen III, matrix metalloproteinases (MMPs), and tissue inhibitor of metalloproteinase (TIMPs) in the anterior vaginal wall of rats in each group were determined by reverse transcription-polymerase chain reaction and western blotting. The data were analyzed by one-way analysis of variance or Kruskal-Wallis test. RESULTS: Electroacupuncture Shenshu (BL23) and Huiyang (BL35) increased the LPP and MBC in SUI rats (P < 0.05). Electroacupuncture treatment significantly increased the protein expression of collagen I and collagen III in the anterior vaginal wall of SUI rats (P < 0.05) and significantly reduced the protein expression of MMP1, MMP2, and MMP9 (P < 0.05). CONCLUSIONS: Electroacupuncture stimulation can alleviate the signs of SUI, and its mechanism is related to the degradation of collagen in the anterior vaginal wall.

Nampt promotes fibroblast extracellular matrix degradation in stress urinary incontinence by inhibiting autophagy.

Stress urinary incontinence (SUI) is defined as involuntary urinary leakage happening in exertion. Nicotinamide phosphoribosyltransferase (Nampt) is seldom researched in the pathogenesis of SUI. Accordingly, the current study set out to elucidate the role of Nampt in SUI progression. Firstly, we determined Nampt expression patterns in SUI patients and rat models. In addition, fibroblasts were obtained from the anterior vaginal wall tissues of non-SUI patients and subjected to treatment with different concentrations of interleukin-1ß (IL-1ß), followed by quantification of Nampt expressions in fibroblasts. Subsequently, an appropriate concentration of IL-1ß was selected to treat anterior vaginal wall fibroblasts. Nampt was further silenced in IL-1ß-treated fibroblasts to assess the role of Nampt in autophagy and extracellular matrix (ECM) degradation. Lastly, functional rescue assays were carried out to inhibit autophagy and evaluate the role of autophagy in the mechanism of Nampt modulating IL-1ß-treated fibroblast ECM degradation. It was found that Nampt was highly-expressed in SUI patients and rat models and IL-1ß-treated fibroblasts. On the other hand, Nampt silencing was found to suppress ECM degradation and promote SUI fibroblast autophagy. Additionally, inhibition of autophagy attenuated the inhibitory effects of Nampt silencing on SUI fibroblast ECM degradation. Collectively, our findings revealed that Nampt was over-expressed in SUI, whereas Nampt silencing enhanced SUI fibroblast autophagy, and thereby inhibited ECM degradation.

An In Vitro Study on Extracellular Vesicles From Adipose-Derived Mesenchymal Stem Cells in Protecting Stress Urinary Incontinence Through MicroRNA-93/F3 Axis.

Since the potential roles of extracellular vesicles secreted by adipose-derived mesenchymal stem cells (ADSCs) are not well understood in collagen metabolism, the purpose of this research was to evaluate the effects of ADSCs-extracellular vesicles in stress urinary incontinence and the regulatory mechanism of delivered microRNA-93 (miR-93). ADSCs were isolated and cultured, and ADSCs-extracellular vesicles were extracted and identified. Stress urinary incontinence primary fibroblasts or satellite cells were treated with ADSCs-extracellular vesicles to detect the expression of Elastin, Collagen I, and Collagen III in fibroblasts and Pax7 and MyoD in satellite cells. After transfecting ADSCs with miR-93 mimics or inhibitors, extracellular vesicles were isolated and treated with stress urinary incontinence primary fibroblasts or satellite cells to observe cell function changes. The online prediction and luciferase activity assay confirmed the targeting relationship between miR-93 and coagulation factor III (F3). The rescue experiment verified the role of ADSCs-extracellular vesicles carrying miR-93 in stress urinary incontinence primary fibroblasts and satellite cells by targeting F3. ADSCs-extracellular vesicles treatment upregulated expression of Elastin, Collagen I, and Collagen III in stress urinary incontinence primary fibroblasts and expression of Pax7 and MyoD in stress urinary incontinence primary satellite cells. miR-93 expression was increased in stress urinary incontinence primary fibroblasts or satellite cells treated with ADSCs-extracellular vesicles. Extracellular vesicles secreted by ADSCs could deliver miR-93 to fibroblasts and then negatively regulate F3 expression; ADSCs-extracellular vesicles could reverse the effect of F3 on extracellular matrix remodeling in stress urinary incontinence fibroblasts. miR-93 expression was also increased in stress urinary incontinence primary satellite cells treated by ADSCs-extracellular vesicles. Extracellular vesicles secreted by ADSCs were delivered to satellite cells through miR-93, which directly targets F3 expression and upregulates Pax7 and MyoD expression in satellite cells. Our study indicates that miR-93 delivered by ADSCs-extracellular vesicles could regulate extracellular matrix remodeling of stress urinary incontinence fibroblasts and promote activation of stress urinary incontinence satellite cells through targeting F3.

Morphogenetic Aspects of the Response of Vaginal Tissues to Polypropylene Implants as the Basis of Mesh-Associated Complications.

Morphometric and immunohistochemical examination of the vaginal mucosa before and 12 months after installation of polypropylene implants for the correction of stress urinary incontinence was performed in 20 patients with genital prolapse. The research results confirmed good biocompatibility of polypropylene and the formation of full-fledged connective tissue in the vaginal mucosa, but revealed the presence of a weak lymphocytic reaction to polypropylene 12 months after surgery. According to immunohistochemical study, increased contents of B lymphocytes and plasma cells responsible for the inductive and productive stages of the immune response were revealed in the vaginal mucosa around the implants 12 months after surgery. This reaction in the presences of provoking factors can lead to the development of inflammation and erosion, a type of mesh-associated complications.

Brain derived neurotrophic factor mediates accelerated recovery of regenerative electrical stimulation in an animal model of stress urinary incontinence.

OBJECTIVE: Stress urinary incontinence (SUI) is prevalent among older women and can result from insufficient regeneration of the pudendal nerve (PN). Electrical stimulation (ES) of the PN upregulates brain derived neurotrophic factor (BDNF) and accelerates regeneration. Using tyrosine kinase B (TrkB) to reduce the availability of free BDNF, the aim of this study was to determine if BDNF is necessary for accelerated recovery via ES in a model of SUI. METHODS: Our SUI model consists of Female Sprague-Dawley rats, whose PNs were crushed bilaterally twice for 30 s, followed by insertion of a modified Foley catheter into the vagina with balloon inflation for 4 h. These rats were divided into 4 groups: 1) Sham PN crush and sham vaginal distension without electrode implantation and with saline treatment (sham injury); 2) SUI with sham stimulation and saline treatment (SUI); 3) SUI and ES with saline treatment (SUI&ES); and 4) SUI and ES with TrkB treatment (SUI&ES&TrkB). Animals underwent ES or sham stimulation four times a week for two weeks. Four weeks after injury, animals underwent functional testing consisting of leak point pressure (LPP) with simultaneous external urethral sphincter (EUS) electromyography (EMG) and pudendal nerve recordings. Data was analyzed using ANOVA with Holm-Sidak posthoc test (p < 0.05). EUS and PN specimen were sectioned and stained to semi-quantitatively evaluate morphology, regeneration, and reinnervation. RESULTS: LPP and EUS EMG firing rate were significantly increased in the sham injury and SUI&ES groups compared to the SUI and SUI&ES&TrkB groups. EUS of SUI rats showed few innervated neuromuscular junctions compared to sham injured rats, while both treatment groups showed an increase in reinnervated neuromuscular junctions. CONCLUSION: ES accelerates functional recovery via a BDNF-mediated pathway in a model of SUI. These findings suggest ES could be used as a potential regenerative therapy for women with SUI.

Bone marrow stem cells secretome accelerates simulated birth trauma-induced stress urinary incontinence recovery in rats.

Stress urinary incontinence (SUI) is defined as involuntary urine leakage during physical activities that increase the intra-abdominal pressure on the bladder. We studied bone marrow stem cell (BMSC) secretome-induced activation of anterior vaginal wall (AVW) fibroblasts and its ability to accelerate SUI recovery following vaginal distention (VD) in a rat model of birth trauma using BMSC-conditioned medium (BMSC-CM) and concentrated conditioned medium (CCM). BMSC-CM enhanced the proliferation, migration, and collagen synthesizing abilities of fibroblasts. Differentially expressed genes in BMSC-CM-induced fibroblasts were mainly enriched for cell adhesion, extracellular fibril organization and angiogenesis. Treatment with the JAK2 inhibitor AG490 reversed BMSC-CM-induced activation of the JAK2/STAT4 pathway. Periurethral injection with BMSC-CCM markedly enhanced the abdominal leak point pressure (LPP) in rats after VD. Histological analysis revealed increased numbers of fibroblasts, improved collagen fibers arrangement and elevated collagens content in the AVW of rats receiving BMSC-CCM. These findings suggest the BMSC secretome activates AVW fibroblasts and contributes to the functional and anatomic recovery of simulated birth trauma-induced SUI in rats.

Treatment of Stress Urinary Incontinence with Muscle Stem Cells and Stem Cell Components: Chances, Challenges and Future Prospects.

Urinary incontinence (UI) is a major problem in health care and more than 400 million people worldwide suffer from involuntary loss of urine. With an increase in the aging population, UI is likely to become even more prominent over the next decades and the economic burden is substantial. Among the different subtypes of UI, stress urinary incontinence (SUI) is the most prevalent and focus of this review. The main underlying causes for SUI are pregnancy and childbirth, accidents with direct trauma to the pelvis or medical treatments that affect the pelvic floor, such as surgery or irradiation. Conservative approaches for the treatment of SUI are pelvic physiotherapy, behavioral and lifestyle changes, and the use of pessaries. Current surgical treatment options include slings, colposuspensions, bulking agents and artificial urinary sphincters. These treatments have limitations with effectiveness and bear the risk of long-term side effects. Furthermore, surgical options do not treat the underlying pathophysiological causes of SUI. Thus, there is an urgent need for alternative treatments, which are effective, minimally invasive and have only a limited risk for adverse effects. Regenerative medicine is an emerging field, focusing on the repair, replacement or regeneration of human tissues and organs using precursor cells and their components. This article critically reviews recent advances in the therapeutic strategies for the management of SUI and outlines future possibilities and challenges.

Small extracellular vesicles secreted by vaginal fibroblasts exert inhibitory effect in female stress urinary incontinence through regulating the function of fibroblasts.

Stress urinary incontinence (SUI) is a common condition in women and associated with extra-cellular matrix (ECM) reconstruction, which is mainly regulated by fibroblasts. However, the underlying mechanism remains obscure. Small extracellular vesicles (sEVs) play fundamental biological roles in various cellular functions. Some studies suggested that the sEVs were involved in the metabolism of ECM and the function of fibroblasts. The purpose of our study was to investigate the effect of sEVs secreted by vaginal fibroblasts on the pathogenesis of SUI. We showed that the fibroblasts of female anterior vaginal wall secreted sEVs. Moreover, fibroblasts of females with SUI had significantly elevated secretion of sEVs. The collagen contents, proliferation and migration capacity of fibroblasts were decreased when fibroblasts were co-cultured with fibroblasts-derived sEVs (fibroblast-sEVs) from SUI patients. Proteomic analysis revealed that fibroblast-sEVs contained various differentially expressed proteins including TIMP2, TGF-ß and ABCC4, which were involved in signaling pathways of fibroblasts regulation. Therefore, we suggested that fibroblast-sEVs contributed to the pathogenesis of SUI through various proteins including TIMP2, TGF-ß and ABCC4.

Evaluation of the In Vitro Damage Caused by Lipid Factors on Stem Cells from a Female Rat Model of Type 2 Diabetes/Obesity and Stress Urinary Incontinence.

Human stem cell therapy for type 2 diabetes/obesity (T2D/O) complications is performedwith stem cell autografts, exposed to the noxious T2D/O milieu, often with suboptimal results.We showed in the Obese Zucker (OZ) rat model of T2D/O that when their muscle-derived stemcells (MDSC) were from long-term T2D/O male rats, their repair ecacy for erectile dysfunctionwas impaired and were imprinted with abnormal gene- and miR-global transcriptional signatures(GTS). The damage was reproduced in vitro by short-term exposure of normal MDSC to dyslipidemicserum, causing altered miR-GTS, fat infiltration, apoptosis, impaired scratch healing, and myostatinoverexpression. Similar in vitro alterations occurred with their normal counterparts (ZF4-SC) fromthe T2D/O rat model for female stress urinary incontinence, and with ZL4-SC from non-T2D/O leanfemale rats. In the current work we studied the in vitro eects of cholesterol and Na palmitate aslipid factors on ZF4-SC and ZL4-SC. A damage partially resembling the one caused by the femaledyslipidemic serum was found, but diering between both lipid factors, so that each one appears tocontribute specifically to the stem cell damaging eects of dyslipidemic serum in vitro and T2D/Oin vivo, irrespective of gender. These results also confirm the miR-GTS biomarker value forMDSC damage.

ANO1 in urethral SMCs contributes to sex differences in urethral spontaneous tone.

Stress urinary incontinence (SUI) is more common in women than in men, and sex differences in anatomic structure and physiology have been suggested as causes; however, the underlying cellular and molecular mechanisms remain unclear. The spontaneous tone (STT) of the urethra has been shown to have a fundamental effect on preventing the occurrence of SUI. Here, we investigated whether the urethral STT exhibited sex differences. First, we isolated urethral smooth muscle (USM) and detected STT in female mice and women. No STT was found in male mice or men. Furthermore, caffeine induced increased contractility and intracellular Ca2+ concentration in urethrae from female mice compared with male mice. EACT [an N-aroylaminothiazole, anoctamin-1 (ANO1) activator] elicited increased intracellular Ca2+ concentration and stronger currents in female mice than in male mice. Moreover, ANO1 expression in single USM cells from women and female mice was almost twofold higher than that found in cells from men and male mice. In summary, ANO1 in USM contributes to sex differences in urethral spontaneous tone. This finding may provide new guidance for the treatment of SUI in women and men.

Delayed Treatment With Low-intensity Extracorporeal Shock Wave Therapy in an Irreversible Rat Model of Stress Urinary Incontinence.

OBJECTIVE: To determine the outcomes and mechanisms of delayed low-intensity extracorporeal shock wave therapy (Li-ESWT) in a rat model of irreversible stress urinary incontinence (SUI). MATERIALS AND METHODS: Twenty-four female Sprague-Dawley rats were randomly assigned into 3 groups: sham control, vaginal balloon dilation + ß-aminopropionitrile (BAPN; SUI group), and vaginal balloon dilation + BAPN + treatment with Li-ESWT (SUI-Li-ESWT group). An irreversible SUI model was developed by inhibiting the urethral structural recovery with BAPN daily for 5 weeks. Thereafter, in the SUI-Li-ESWT group, Li-ESWT was administered twice per week for 2 weeks. After a 1-week washout, all 24 rats were evaluated with functional and histologic studies at 17 weeks of age. Endogenous progenitor cells were detected via the EdU-labeling method. RESULTS: Functional analysis with leak point pressure testing showed that the SUI-Li-ESWT group had significantly higher leak point pressures compared with untreated rats. Increased urethral and vaginal smooth and striated muscle content and increased thickness of the vaginal wall were noted in the SUI-Li-ESWT group. The SUI group had significantly decreased neuronal nitric oxide /tyrosine hydroxylase positive nerves ratio in the smooth muscle layers of the urethra, while the SUI-Li-ESWT group had neuronal nitric oxide/tyrosine hydroxylase+ nerves ratio similar to that of the control group. The continuality of urothelial cell lining was also improved in the SUI-Li-ESWT group. In addition, there were significantly increased EdU-positive cells in the SUI-Li-ESWT group. CONCLUSION: Li-ESWT appears to increase smooth muscle content in the urethra and the vagina, increase the thickness of urethral wall, improve striated muscle content and neuromuscular junctions, restore the integrity of the urothelium, and increase the number of EdU-retaining progenitor cells in the urethral wall.

The Expression of Hormone Receptors as a Gateway toward Understanding Endocrine Actions in Female Pelvic Floor Muscles.

OBJECTIVE: To provide an overview of the hormone actions and receptors expressed in the female pelvic floor muscles, relevant for understanding the pelvic floor disorders. METHODS: We performed a literature review focused on the expression of hormone receptors mainly in the pelvic floor muscles of women and female rats and rabbits. RESULTS: The impairment of the pelvic floor muscles can lead to the onset of pelvic floor dysfunctions, including stress urinary incontinence in women. Hormone milieu is associated with the structure and function alterations of pelvic floor muscles, a notion supported by the fact that these muscles express different hormone receptors. Nuclear receptors, such as steroid receptors, are up till now the most investigated. The present review accounts for the limited studies conducted to elucidate the expression of hormone receptors in pelvic floor muscles in females. CONCLUSION: Hormone receptor expression is the cornerstone in some hormone-based therapies, which require further detailed studies on the distribution of receptors in particular pelvic floor muscles, as well as their association with muscle effectors, involved in the alterations relevant for understanding pelvic floor disorders.

LncRNA and mRNA Expression Profiling in the Periurethral Vaginal Wall Tissues of Postmenopausal Women with Stress Urinary Incontinence.

Stress urinary incontinence (SUI) is one of the major pelvic floor disorders affecting postmenopausal women. To investigate the lncRNA and mRNA expression profiling of SUI in postmenopausal women, we used a microarray analysis to examine the differentially expressed long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) in the periurethral vaginal wall of postmenopausal women with SUI. A total of 8840 lncRNAs and 7102 mRNAs were dysregulated in the two groups (absolute fold change ≥ 2 and P < 0.05). The expression levels of five randomly selected lncRNAs and mRNAs were validated by quantitative real-time PCR. A functional analysis revealed that several lncRNAs are involved in the lysosome pathway associated with extracellular matrix (ECM) remodeling. In addition, we also found several mRNAs involved in fibroblast pseudopodia formation, fibroblast growth, and the regulation of smooth muscle cell differentiation in the urinary tract. Our study offers essential data regarding differentially expressed lncRNAs and mRNAs and may provide new potential candidates for the study of SUI.

Gene expression in stress urinary incontinence: a systematic review.

INTRODUCTION: A contribution of genetic factors to the development of stress urinary incontinence (SUI) is broadly acknowledged. This study aimed to: (1) provide insight into the genetic pathogenesis of SUI by gathering and synthesizing the available data from studies evaluating differential gene expression in SUI patients and (2) identify possible novel therapeutic targets and leads. METHODS: A systematic literature search was conducted through September 2017 for the concepts of genetics and SUI. Gene networking connections and gene-set functional analyses of the identified genes as differentially expressed in SUI were performed using GeneMANIA software. RESULTS: Of 3019 studies, 4 were included in the final analysis. A total of 13 genes were identified as being differentially expressed in SUI patients. Eleven genes were overexpressed: skin-derived antileukoproteinase (SKALP/elafin), collagen type XVII alpha 1 chain (COL17A1), plakophilin 1 (PKP1), keratin 16 (KRT16), decorin (DCN), biglycan (BGN), protein bicaudal D homolog 2 (BICD2), growth factor receptor-bound protein 2 (GRB2), signal transducer and activator of transcription 3 (STAT3), apolipoprotein E (APOE), and Golgi SNAP receptor complex member 1 (GOSR1), while two genes were underexpressed: fibromodulin (FMOD) and glucocerebrosidase (GBA). GeneMANIA revealed that these genes are involved in intermediate filament cytoskeleton and extracellular matrix organization. CONCLUSION: Many genes are involved in the pathogenesis of SUI. Furthermore, whole-genome studies are warranted to identify these genetic connections. This study lays the groundwork for future research and the development of novel therapies and SUI biomarkers in clinical practice.

A Randomized-Controlled Trial Pilot Study Examining the Effect of Pelvic Floor Muscle Training on the Irisin Concentration in Overweight or Obese Elderly Women with Stress Urinary Incontinence.

OBJECTIVE: This study aimed to examine the effect of pelvic floor muscle training on the irisin (Ir) concentration in overweight or obese elderly women with stress urinary incontinence. METHODS: The number of participants included in analysis was 49: 28 women in the experimental group and 21 women in the control group. The experimental group (EG) underwent pelvic floor muscle training, whereas no therapeutic intervention was applied to the control group (CG). Irisin concentration, severity of urinary incontinence (RUIS), and body mass index (BMI) were measured in all women at the initial and final assessments. RESULTS: By comparing the initial and final assessment results we have been able to demonstrate statistically significant differences in the measured variables in the experimental group. No statistically significant differences in the measured variables were reported for the control group at the initial and final assessments. Moderate negative correlation was observed between the BMI results with the irisin concentration results in the EG at the initial assessment and no correlation at the final assessment. Weak positive correlation was observed between the BMI results with the irisin concentration in the CG at the initial and final assessment. CONCLUSION: Further studies are necessary to observe the regulation of irisin concentration and explain mechanisms underlying these effects.

The RyR-ClCa -VDCC axis contributes to spontaneous tone in urethral smooth muscle.

Current therapies including pharmaceutical intervention and surgery have limited efficacy on stress urinary incontinence (SUI). One type of SUI is due to low intraurethral pressure caused by the disabled contraction of urethral smooth muscle (USM). However, the molecular mechanisms underlying the motility of USM remain unknown. Here, we show that USM represents spontaneous tone after stretching in humans and mice. Deletion of TMEM16A in the smooth muscle of mice abolishes spontaneous urethral tone. Furthermore, ClCa currents and [Ca2+ ]i in TMEM16ASMKO mice were largely impaired. Inhibitors of ryanodine receptor (RyR), TMEM16A encoded calcium-activated chloride channel (ClCa ) and L-type voltage-dependent calcium channel (VDCC) fully prevented spontaneous tone accompanied by a significant decrease of intracellular calcium concentration ([Ca2+ ]i ). In summary, RyR-ClCa -VDCC signaling contributes to spontaneous USM tone. This finding may provide a new promising approach for women with stress SUI who reject surgery.