Bibliometric analysis of studies on stress urinary incontinence surgery.

Background: Stress urinary incontinence (SUI) is characterized by the involuntary leakage of urine during activities that increase abdominal pressure. In recent years, a considerable number of studies on SUI surgery have been published. However, there has been a lack of systematic quantification and comprehensive summarization of these studies. Bibliometrics is a discipline that utilizes measurement methods to quantify scientific literature. Thus, this study utilized publications from the Web of Science (WOS) as a data source and conducted a comprehensive analysis and visualization of studies related to SUI surgery in recent years using bibliometric techniques. Methods: We conducted a search and retrieved information on 988 studies related to SUI surgery in the WOS Core Collection. The data covered ten years from September 7, 2013, to September 7, 2023. We employed VOSviewer software, CiteSpace software, and Bibliometrix for analysis and visualization. Results: Over the ten years, the number of publications exhibited a fluctuating trend, initially decreasing and then increasing. The United States emerged as the leading contributor in terms of both publication volume and quality. The University of Alabama Birmingham ranked as the institution with the highest number of publications, while the International Urogynecology Journal featured the most publications among journals. Conclusions: This paper presents a bibliometric analysis of publications related to SUI surgery from 2013 to 2023. The aim is to offer researchers a concise overview of the field and inspire future research directions.

Microneedle systems: cell, exosome, and nucleic acid based strategies.

Cells, exosomes, and nucleic acids play crucial roles in biomedical engineering, holding substantial clinical potential. However, their utility is often hindered by various drawbacks, including cellular immunogenicity, and instability of exosomes and nucleic acids. In recent years, microneedle (MN) technology has revolutionized drug delivery by offering minimal invasiveness and remarkable versatility. MN has emerged as an ideal platform for the extraction, storage, and delivery of these biological components. This review presents a comprehensive overview of the historical progression and recent advances in the field of MN. Specifically, it highlights the current applications of cell-, exosome-, and nucleic acid-based MN systems, while presenting prevailing research challenges. Additionally, the review provides insights into the prospects of MN in this area, aiming to provide new ideas for researchers and facilitate the clinical translation of MN technology.

Chitin-based hydrogel loaded with bFGF and SDF-1 for inducing endogenous mesenchymal stem cells homing to improve stress urinary incontinence.

Nonoperative treatments for Stress Urinary Incontinence (SUI) represent an ideal treatment method. Mesenchymal stem cell (MSCs) treatment is a new modality, but there is a lack of research in the field of gynecological pelvic floor and no good method to induce internal MSC homing to improve SUI. Herein, we develop an injectable and self-healing hydrogel derived from ß-chitin which consists of an amino group of quaternized ß-chitin (QC) and an aldehyde group of oxidized dextran (OD) between the dynamic Schiff base linkage.it can carry bFGF and SDF-1a and be injected into the vaginal forearm of mice in a non-invasive manner. It provides sling-like physical support to the anterior vaginal wall in the early stages. In the later stage, it slowly releasing factors and promoting the homing of MSCs in vivo, which can improve the local microenvironment, increase collagen deposition, repair the tissue around urethra and finally improve SUI (Scheme 1). This is the first bold attempt in the field of pelvic floor using hydrogel mechanical support combined with MSCs homing and the first application of chitin hydrogel in gynecology. We think the regenerative medicine approach based on bFGF/SDF-1/chitin hydrogel may be an effective non-surgical approach to combat clinical SUI.

Ferrostatin-1 alleviates the damage of C2C12 myoblast and mouse pelvic floor muscle induced by mechanical trauma.

Ferroptosis is a special form of regulated cell death, which is reported to play an important role in a variety of traumatic diseases by promoting lipid peroxidation and devastating cell membrane structure. Pelvic floor dysfunction (PFD) is a kind of disease affecting the quality and health of many women's lives, which is closely related to the injury of the pelvic floor muscle. Clinical findings have discovered that there is anomalous oxidative damage to the pelvic floor muscle in women with PFD caused by mechanical trauma, but the specific mechanism is still unclear. In this study, we explored the role of ferroptosis-associated oxidative mechanisms in mechanical stretching-induced pelvic floor muscle injury, and whether obesity predisposed pelvic floor muscle to ferroptosis from mechanical injury. Our results, in vitro, showed that mechanical stretch could induce oxidative damage to myoblasts and trigger ferroptosis. In addition, glutathione peroxidase 4 (GPX4) down-regulation and 15-lipoxygenase 1(15LOX-1) up-regulation exhibited the same variational characteristics as ferroptosis, which was much more pronounced in palmitic acid (PA)-treated myoblasts. Furthermore, ferroptosis induced by mechanical stretch could be rescued by ferroptosis inhibitor (ferrostatin-1). More importantly, in vivo, we found that the mitochondria of pelvic floor muscle shrank, which were consistent with the mitochondrial morphology of ferroptosis, and GPX4 and 15LOX-1 showed the same change observed in cells. In conclusion, our data suggest ferroptosis is involved in the injury of the pelvic floor muscle caused by mechanical stretching, and provide a novel insight for PFD therapy.

Collagen type â -loaded methacrylamide hyaluronic acid hydrogel microneedles alleviate stress urinary incontinence in mice: A novel treatment and prevention strategy.

Stress urinary incontinence (SUI), a chronic disease with widespread effects and an overall prevalence of up to 46% in adult women, is associated with a heavy disease burden. The clinical treatment for mild to moderate SUI is conservative, such as electrical stimulation and Kegel exercises, but the therapeutic effect is unsatisfactory, so it is imperative to seek new treatment modalities. Hydrogel microneedles (MNs) have been widely used in transdermal drug delivery because of their minimally invasive and highly biocompatible characteristics. Therefore, for the first time, we combined collagen type I with MN technology for the treatment and prevention of mild to moderate SUI.

Purvalanol A induces apoptosis and reverses cisplatin resistance in ovarian cancer.

Cisplatin (DDP) resistance limits therapeutic efficacy in patients diagnosed with ovarian cancer. Purvalanol A (Pur) is a novel cyclin-dependent kinase (CDK) inhibitor that has been demonstrated to induce apoptosis in various cancer cells. The present study investigated the effect of the combination treatment of Pur and DDP, and the potential anticancer mechanisms in epithelial ovarian cancer (EOC) cells in vitro and in vivo . We found that Pur enhanced the anti-tumor efficacy of cisplatin in EOC cells. The combination of Pur and DDP had more significant effects on apoptosis induction in EOC cells compared with the individual-treatment groups and the control group. We further demonstrated that the combination of Pur and DDP may trigger apoptosis and autophagy in EOC cells by inducing reactive oxygen species (ROS). And the ROS/Akt/mammalian target of rapamycin signaling pathway as a potential mechanism for the initiation of autophagy induced by combination therapy. Similar results were observed in vivo . These results demonstrated that Pur sensitized the response of EOC cells to cisplatin in vitro and in vivo , reversing the resistance to cisplatin in ovarian cancer.

Corrigendum: Development and validation of a prognostic nomogram based on DNA methylation-driven genes for patients with ovarian cancer.

[This corrects the article DOI: 10.3389/fgene.2021.675197.].

Targeting purine metabolism in ovarian cancer.

Purine, an abundant substrate in organisms, is a critical raw material for cell proliferation and an important factor for immune regulation. The purine de novo pathway and salvage pathway are tightly regulated by multiple enzymes, and dysfunction in these enzymes leads to excessive cell proliferation and immune imbalance that result in tumor progression. Maintaining the homeostasis of purine pools is an effective way to control cell growth and tumor evolution, and exploiting purine metabolism to suppress tumors suggests interesting directions for future research. In this review, we describe the process of purine metabolism and summarize the role and potential therapeutic effects of the major purine-metabolizing enzymes in ovarian cancer, including CD39, CD73, adenosine deaminase, adenylate kinase, hypoxanthine guanine phosphoribosyltransferase, inosine monophosphate dehydrogenase, purine nucleoside phosphorylase, dihydrofolate reductase and 5,10-methylenetetrahydrofolate reductase. Purinergic signaling is also described. We then provide an overview of the application of purine antimetabolites, comprising 6-thioguanine, 6-mercaptopurine, methotrexate, fludarabine and clopidogrel. Finally, we discuss the current challenges and future opportunities for targeting purine metabolism in the treatment-relevant cellular mechanisms of ovarian cancer.

Application of estrogen for the treatment of stress urinary incontinence in mice.

BACKGROUND: Stress urinary incontinence (SUI) is a pervasive health tissue among women, which seriously affects the quality of life. The etiology of SUI is complex and diverse in women, with past studies having demonstrated that estrogen deficiency plays an important role in pelvic floor muscle atrophy and urethral degeneration. We comprehensively investigated the effects of estrogen in the treatment of SUI in female mice at cellular and animal levels. METHODS: L929 fibroblasts mechanical injury model was established by four-point bending device, and SUI mouse model was established by vaginal dilation method commonly used to simulate labor injury. After estrogen treatment, the expressions of Collagen I, Collagen III, Elastin, TIMP-1, TIMP-2, MMP-2, and MMP-9 were detected, the leak point pressure (LPP) and abdominal leak point pressure (ALPP) of mice in each group were detected, and both the effect of estrogen on extracellular matrix remodeling of mouse urethra and anterior vaginal wall was observed from the histological level. RESULTS: The results revealed that an appropriate amount of estrogen can promote the expression of Collagen I, Collagen III, Elastin, TIMP-1, and TIMP-2, decrease the expression of MMP-2 and MMP-9, and maintain the dynamic balance of MMPs/TIMPs at both cellular and animal levels. Meanwhile, we determined that estrogen can increase the LPP and ALPP values of SUI mice. The collagen fibers' content in the mice treated with estrogen was significantly greater than in the control group mice. CONCLUSIONS: The estrogen may alleviate the symptoms of SUI by reconstituting ECM, thus laying a solid foundation for further exploration of estrogen therapy.

Dimethyl fumarate ameliorates stress urinary incontinence by reversing ECM remodeling via the Nrf2-TGF-ß1/Smad3 pathway in mice.

INTRODUCTION AND HYPOTHESIS: Mechanical trauma and oxidative injury are involved in the pathogenesis of stress urinary incontinence (SUI), and oxidative stress (OS) is considered a potential therapeutic target. The antioxidant properties of dimethyl fumarate (DMF), a potent activator of Nrf2, have been highlighted recently. We therefore predicted that DMF might have therapeutic effects on mechanical trauma-induced SUI. METHODS: The SUI mice model was established by vaginal distension (VD). Leak point pressure (LPP), serum OS biomarkers, cell proliferation and apoptosis, collagen, elastin, matrix metalloproteinases (MMP), Nrf2, the TGF-ß1/Smad3 signaling pathway, and the associated tissue growth factors in the anterior vaginal wall were measured in either wild-type or Nrf2-knockout (Nrf2-/-) female C57BL/6 mice. RESULTS: The results showed that DMF improved the VD-induced LPP reduction, alleviated oxidative injury, stimulated cell proliferation and inhibited apoptosis in the anterior vaginal wall tissue of mice. Moreover, DMF treatment reduced the hydrolysis of ECM proteins by MMP2 and MMP9. The above effects may be mediated by a series of tissue growth factors, including α-SMA, PAI-1, and TIMP-2, with the TGF-ß1/Smad3 signaling pathway as the core regulatory mechanism. In further study, Nrf2-/- mice were used to replicate the SUI model. And the difference is that DMF failed to reactivate the TGF-ß1/Smad3 pathway, nor did it improve LPP. CONCLUSIONS: Dimethyl fumarate can ameliorate urethra closure dysfunction in the VD-induced SUI mice model, and the therapeutic effect of DMF is mediated by the Nrf2-dominated antioxidant system and its downstream TGF-ß1/Smad3 signaling pathway.

Tumor Immune Microenvironment Related Gene-Based Model to Predict Prognosis and Response to Compounds in Ovarian Cancer.

BACKGROUND: The tumor immune microenvironment (TIME) has been recognized to be an imperative factor facilitating the acquisition of many cancer-related hallmarks and is a critical target for targeted biological therapy. This research intended to construct a risk score model premised on TIME-associated genes for prediction of survival and identification of potential drugs for ovarian cancer (OC) patients. METHODS AND RESULTS: The stromal and immune scores were computed utilizing the ESTIMATE algorithm in OC patient samples from The Cancer Genome Atlas (TCGA) database. Weighted gene co-expression network and differentially expressed genes analyses were utilized to detect stromal-and immune-related genes. The Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression was utilized for additional gene selection. The genes that were selected were utilized as the input for a stepwise regression to construct a TIME-related risk score (TIMErisk), which was then validated in Gene Expression Omnibus (GEO) database. For the evaluation of the protein expression levels of TIME regulators, the Human Protein Atlas (HPA) dataset was utilized, and for their biological functions, the TIMER and CIBERSORT algorithm, immunoreactivity, and Immune Cell Abundance Identifier (ImmuCellAI) were used. Possible OC medications were forecasted utilizing the Genomics of Drug Sensitivity in Cancer (GDSC) database and connectivity map (CMap). TIMErisk was developed based on ALPK2, CPA3, PTGER3, CTHRC1, PLA2G2D, CXCL11, and ZNF683. High TIMErisk was recognized as a poor factor for survival in the GEO and TCGA databases; subgroup analysis with FIGO stage, grade, lymphatic and venous invasion, debulking, and tumor site also indicated similar results. Functional immune cells corresponded to more incisive immune reactions, including secretion of chemokines and interleukins, natural killer cell cytotoxicity, TNF signaling pathway, and infiltration of activated NK cells, eosinophils, and neutrophils in patients with low TIMErisk. Several small molecular medications which may enhance the prognosis of patients in the TIMErisk subgroup were identified. Lastly, an enhanced predictive performance nomogram was constructed by compounding TIMErisk with the FIGO stage and debulking. CONCLUSION: These findings may offer a valuable indicator for clinical stratification management and personalized therapeutic options for OC patients and may be a foundation for future mechanistic research of their association.

Development and Validation of a Prognostic Nomogram Based on DNA Methylation-Driven Genes for Patients With Ovarian Cancer.

Background: DNA methylation affects the development, progression, and prognosis of various cancers. This study aimed to identify DNA methylated-differentially expressed genes (DEGs) and develop a methylation-driven gene model to evaluate the prognosis of ovarian cancer (OC). Methods: DNA methylation and mRNA expression profiles of OC patients were downloaded from The Cancer Genome Atlas, Genotype-Tissue Expression, and Gene Expression Omnibus databases. We used the R package MethylMix to identify DNA methylation-regulated DEGs and built a prognostic signature using LASSO Cox regression. A quantitative nomogram was then drawn based on the risk score and clinicopathological features. Results: We identified 56 methylation-related DEGs and constructed a prognostic risk signature with four genes according to the LASSO Cox regression algorithm. A higher risk score not only predicted poor prognosis, but also was an independent poor prognostic indicator, which was validated by receiver operating characteristic (ROC) curves and the validation cohort. A nomogram consisting of the risk score, age, FIGO stage, and tumor status was generated to predict 3- and 5-year overall survival (OS) in the training cohort. The joint survival analysis of DNA methylation and mRNA expression demonstrated that the two genes may serve as independent prognostic biomarkers for OS in OC. Conclusion: The established qualitative risk score model was found to be robust for evaluating individualized prognosis of OC and in guiding therapy.

MnO2 nanosheets anchored with polypyrrole nanoparticles as a multifunctional platform for combined photothermal/photodynamic therapy of tumors.

Herein, PPy@MnO2 nanocomposites were first harvested by anchoring MnO2 nanosheets on polypyrrole (PPy) nanoparticles via an in situ redox reaction, then polyethylene glycol (PEG) modifier and methylene blue (MB) photosensitizer were linked through electrostatic interactions to obtain PPy@MnO2-PEG-MB nanoarchitectures. PPy nanoparticles ensure photothermal therapy (PTT) ability and MnO2 nanosheets ameliorate tumor hypoxia for enhanced photodynamic therapy (PDT). Therefore, a multifunctional nanotherapeutic system was constructed for the combined PTT/PDT of tumors. For extracellular photothermal properties, the optimal temperature elevation was 52.6 °C with 54.4% photothermal conversion efficiency. The extracellular PDT ability was measured by detecting 1O2 generation; more 1O2 was produced under acidic conditions in the presence of H2O2 (a simulated tumor microenvironment). The effective cellular uptake of the nanotherapeutic system in HeLa cells was observed by confocal laser scanning microscopy (CLSM). CLSM also indicated that more 1O2 was generated by the nanotherapeutic system as compared to free MB in HeLa cells, confirming the amelioration of tumor hypoxia by MnO2 nanosheets. MTT assays demonstrated that the nanotherapeutic system possessed superior biocompatibility without laser irradiation, and the lowest cell viabilities for single PTT and PDT groups were 13.78%, 38.82% respectively, while there was only 1.29% cell viability in the combined PTT and PDT group. These results suggest that the strategy of assembling PPy with MnO2 for a multifunctional PTT and enhanced PDT nanoplatform was realized, and opens up an unimpeded approach for integrating photothermal reduction materials with MnO2 for use in synergistic PTT and PDT.

Expression of ArfGAP3 in Vaginal Anterior Wall of Patients With Pelvic Floor Organ Prolapse in Pelvic Organ Prolapse and Non-Pelvic Organ Prolapse Patients.

PURPOSE OF INVESTIGATION: The purpose of this study was to study the expression of adenosine diphosphate ribosylation factor GTPase-activating protein 3 (ArfGAP3) in the anterior vaginal wall of patients with pelvic organ prolapse (POP). MATERIALS AND METHODS: From July 2016 to July 2018, the anterior vaginal wall of 31 POP patients (pelvic organ prolapse quantification [POP-Q] II-III [n = 10] and POP-Q IV [n = 21]) with pelvic floor dysfunction-related symptoms who underwent vaginal hysterectomy were enrolled in POP group in the Department of Gynecology of Wuhan University People's Hospital. The anterior vaginal wall of 28 non-POP patients who underwent vaginal hysterectomy was selected as control group. The expression of 3 groups was determined by immunohistochemical staining, Western blotting, and quantitative real-time fluorescence polymerase chain reaction. RESULTS: The expression levels of ArfGAP3 of POP-Q II-III and POP-Q IV groups were lower than the control group (P < 0.05), and there were significant differences between POP-Q II-III and POP-Q IV groups (P < 0.05). CONCLUSIONS: The expression of ArfGAP3 in the anterior vaginal wall of POP patients decreased, which was related to the pathogenesis and clinical grading of POP.

T-type calcium channel blockade induces apoptosis in C2C12 myotubes and skeletal muscle via endoplasmic reticulum stress activation.

Loss of T-type calcium channel (TCC) function has been reported to result in decreased cell viability and impaired muscle regeneration, but the underlying mechanisms remain largely unknown. We previously found that expression of TCC is reduced in aged pelvic floor muscle of multiple vaginal delivery mice, and this is related to endoplasmic reticulum stress (ERS) activation and autophagy flux blockade. In the present work, we further investigated the effects of TCC function loss on C2C12 myotubes and skeletal muscle, which is mediated by promotion of ERS and ultimately contributes to mitochondrial-related apoptotic cell death. We found that application of a TCC inhibitor induced mitochondria-related apoptosis in a dose-dependent manner and also reduced mitochondrial transmembrane potential (MMP), induced mito-ROS generation, and enhanced expression of mitochondrial apoptosis proteins. Functional inhibition of TCC induced ERS, resulting in disorder of Ca2+ homeostasis in endoplasmic reticulum, and ultimately leading to cell apoptosis in C2C12 myotubes. Tibialis anterior muscles of T-type α1H channel knockout mice displayed a smaller skeletal muscle fiber size and elevated ERS-mediated apoptosis signaling. Our data point to a novel mechanism whereby TCC blockade leads to ERS activation and terminal mitochondrial-related apoptotic events in C2C12 myotubes and skeletal muscles.

Mechanical Stretching induces the apoptosis of parametrial ligament Fibroblasts via the Actin Cytoskeleton/Nr4a1 signalling pathway.

The anatomical positions of pelvic floor organs are maintained mainly by ligaments and muscles. Long-term excessive mechanical tension stimulation of pelvic floor tissue beyond the endurance of ligaments or muscles will lead to the occurrence of pelvic organ prolapse (POP). In addition, cytoskeletal reconstitution is a key process by which cells respond to mechanical stimulation. The aim of the present study was to investigate the protective effect of actin cytoskeleton to resist mechanical stretching (MS)-induced apoptosis in parametrial ligament fibroblasts (PLFs) and the underlying mechanisms. MS provided by a four­point bending device could significantly induce apoptosis of PLFs from non-POP patients, which exhibited an apoptosis rate close to that of PLFs from POP patients, and the apoptosis rate was higher following latrunculin A (Lat-A, a potent inhibitor of actin) treatment. In addition, Nr4a1 and Bax expression was increased while Bcl-2 and caspase-3 expression was clearly decreased after treatment with MS and Lat-A. However, the apoptosis induced by MS was reduced when the expression of Nr4a1 was downregulated by siRNA. These outcomes reveal a novel mechanism that links the actin cytoskeleton and apoptosis in PLFs by Nr4a1; this mechanism will provide insight into the clinical diagnosis and treatment of POP.

CACNA1H downregulation induces skeletal muscle atrophy involving endoplasmic reticulum stress activation and autophagy flux blockade.

Multiple vaginal delivery (MVD) is an important factor for pelvic floor muscle (PFM) function decline and pelvic floor dysfunction (PFD). PFD is common in middle-aged and elderly women, but its pathogenesis is not clear. In this study, we found that the expression of CACNA1H was lower in the PFM of old mice after MVD compared with old or adult mice. In in-vitro studies, we found that treatment with the T-type Ca2+ channel (T-channel) inhibitor NNC-55 or downregulation of the CACNA1H gene by siRNA intervention promoted myotube atrophy and apoptosis. Mechanistically, we revealed that NNC-55 increased the expression of GRP78 and DDIT3 in myotubes, indicating endoplasmic reticulum stress (ERS) activation, and that the IRE1 and PERK pathways might be involved in this effect. NNC-55 induced the formation of autophagosomes but inhibited autophagy flux. Moreover, rapamycin, an autophagy activator, did not rescue myotube atrophy or apoptosis induced by NNC-55, and the autophagy inhibitors 3-MA and HCQ accelerated this damage. Further studies showed that the ERS inhibitors 4-PBA and TUDAC relieved NNC-55-induced damage and autophagy flux blockade. Finally, we found multisite muscle atrophy and decreased muscle function in Cacna1h-/- (TH-null) mice, as well as increased autophagy inhibition and apoptotic signals in the PFM of old WT mice after MVD and TH-null mice. Taken together, our results suggest that MVD-associated PFD is partially attributed to CACNA1H downregulation-induced PFM atrophy and that ERS is a potential therapeutic target for this disease.

Knockdown of Hypoxia-Inducible Factor 1α (HIF-1α) Promotes Autophagy and Inhibits Phosphatidylinositol 3-Kinase (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) Signaling Pathway in Ovarian Cancer Cells.

BACKGROUND Ovarian cancer has the highest mortality rate among all female genital tumors because of its insidious onset and drug resistance. Hypoxia-inducible factor 1alpha (HIF-1alpha), one of the best-studied oncogenes, plays an important part in tumor adaptation to microenvironmental hypoxia and was found to be overexpressed in several malignancies, including ovarian cancer. Previous studies found that the effect of HIF-1alpha on cancers may be correlated with autophagy and some signaling pathways, such as PI3K/AKT/mTOR, in several tumors. However, the function and potential mechanism have not been clearly defined. MATERIAL AND METHODS The expression of HIF-1alpha in ovarian cancer tissues were detected by immunohistochemistry. HIF-1alpha was knocked down by siRNA transfection. Cell viability was examined by CCK8 and colony formation assay. Apoptosis and autophagy were detected with flow cytometry, transmission electron microscopy, and laser scanning confocal microscopy, respectively. The proteins related to autophagy and PI3K/AKT/mTOR were detected through Western blot analysis. RESULTS HIF-1alpha was expressed at higher levels in epithelial or metastatic ovarian cancer tissue than in normal fallopian tube tissue. When HIF-1alpha was knocked down by siRNA in A2780 and SKOV3 cells, the viability of ovarian cancer cells was weakened, but the apoptosis and autophagy were strengthened. Accordingly, autophagosome formation increased and the expression of autophagy-related proteins LC3 and P62 increased in HIF-1alpha knockdown cells. The PI3K/Akt/mTOR signaling pathway was also found to be inactivated in HIF-1alpha knockdown cells. CONCLUSIONS These findings show that knockdown of HIF-1alpha promoted autophagy and inhibited the PI3K/AKT/mTOR signaling pathway in ovarian cancer cells.

Effect of integrin ß1 in the treatment of stress urinary incontinence by electrical stimulation.

The aim of the present study was to investigate the protective effect of integrin ß1 in the treatment of stress urinary incontinence (SUI) by electrical stimulation, and the underlying mechanisms by which electrical stimulation regulates the collagen metabolism of female vaginal wall fibroblasts (FVWFs). FVWFs obtained from the vaginal wall tissue of patients with (Ingelman­Sundberg scale; grade II, n=8; grade III, n=10) or without (n=8) SUI during gynecological operations were isolated by enzymatic digestion and subsequently identified by immunocytochemistry. Following this, cultured FVWFs were treated with an inhibitor of integrin ß1, recombinant human integrin ß1 and electrical stimulation (100 mv/mm, 2 h, 20 Hz), followed by total mRNA and protein extraction. mRNA and protein expression levels of integrin ß1, transforming growth factor (TGF)­ß1 and collagen (COL) I and III in FVWFs were quantified by reverse transcription­quantitative PCR (RT­qPCR) and western blot analysis respectively. Integrin ß1, TGF­ß1 and COL I and III expression levels were decreased in patients with SUI compared with healthy controls, and the grade III group had lower levels than the grade II group. Following electrical stimulation treatment, the expression levels of TGF­ß1, COL I and III were enhanced in the grade II group, but not in the grade III group. Nevertheless, the inhibitor of integrin ß1 reduced the protective effect of electrical stimulation in the grade II group. In addition, electrical stimulation combined with recombinant human integrin ß1 could also protect cells from SUI in the grade III group. The present study provides evidence for the increased degradation of the extracellular matrix and integrin ß1 in the vaginal wall tissues of patients with SUI, and the protective effect of electrical stimulation against SUI via integrin ß1. These results provide a novel mechanism for the treatment of SUI using electrical stimulation.

Protective Role of Nuclear Factor Erythroid-2-Related Factor 2 against Mechanical Trauma-Induced Apoptosis in a Vaginal Distension-Induced Stress Urinary Incontinence Mouse Model.

Apoptosis and oxidative damage are involved in the pathogenesis and progression of stress urinary incontinence (SUI). Our previous results indicate that cell apoptosis and oxidative damage increase in a mouse model of mechanical injury-induced SUI and in fibroblasts treated with excessive mechanical strain. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a well-characterized global antioxidant gene inducer that can reduce oxidative damage and apoptosis. Therefore, we predicted that Nrf2 may have a protective role in mechanical trauma-induced SUI. To test this hypothesis, a mouse model of vaginal distension- (VD-) induced SUI was established. Leak point pressure (LPP); levels of apoptosis, apoptosis-related proteins, and peroxidation products; and the activities of antioxidative proteins in the anterior vaginal wall were measured in wild-type (Nfe2l2+/+) C57BL/6 mice and Nrf2-knockout mice (Nfe2l2-/-). The results showed that Nrf2 knockout aggravated VD-induced reduction in LPP, increase in cell apoptosis and peroxidation product levels, decrease in antioxidative protein activities, and alterations in apoptosis-related protein levels in the vaginal walls of mice. To further confirm the role of Nrf2 in mechanical trauma-induced apoptosis and SUI, VD was performed on mice overexpressing Nrf2 via in vivo transfection of LV-Nfe2l2. The results showed that Nrf2 overexpression significantly alleviated VD-induced abnormalities in the anterior vaginal wall. Taken together, our data suggested that Nrf2 is a potential protective factor in mechanical trauma-induced apoptosis in a mouse model of SUI. Antioxidative therapy may be a promising treatment for mechanical trauma-related SUI.