Quercetin antagonized advanced glycated end products induced apoptosis and functional inhibition of fibroblasts from the prolapsed uterosacral ligament.

The altered behaviors and functions of pelvic floor fibroblasts are pathophysiological changes of pelvic organ prolapse (POP). Our previous study showed that advanced glycated end products (AGEs) accumulated in the pelvic tissues of POP and induced fibroblast apoptosis. The study was designed to investigate whether quercetin antagonize AGEs-induced apoptosis and functional inhibition of fibroblasts. The uptake of 5-ethynyl-2'-deoxyuridine (EdU) was evaluated for cell proliferation. Flow cytometric analysis was applied for cell apoptosis. Intracellular reactive oxygen species (ROS) content was determined by the fluorescence of dichlorofluorescein (DCF). The contractility of fibroblasts was measured by collagen gel contraction assay. The expressions of extracellular matrix (ECM) related genes and the expression of miR-4429 and caspase-3 were quantified by qPCR. The expressions of phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), serine-threonine kinase (Akt), and phosphorylated Akt (p-Akt) were analyzed by Western Blot. The down-regulation of miR-4429 was achieved by cell transfection. Quercetin antagonized AGEs-induced apoptosis, proliferation inhibition, and ROS increase in fibroblasts. Quercetin did not alleviate AGEs-induced contractile impairment of fibroblasts. Quercetin reduced the gene expressions of lysyl oxidase like protein 1 (LOXL1)and matrix metallopeptidase 1 (MMP1), and increased the gene expressions of lysyl oxidase (LOX) and fibrillin 2 (FBN2) in fibroblasts. Quercetin reversed AGEs-induced upregulation of PTEN and downregulation of PI3K, P-Akt, and miR-4429 in fibroblasts. The inhibitory effect of quercetin on AGEs-induced fibroblast apoptosis was inhibited by downregulating the expression of miR-4429. In conclusion, quercetin antagonized AGEs-induced apoptosis and functional inhibition of fibroblasts from the prolapsed uterosacral ligament. And inhibiting AGEs-induced down-regulation of miR-4429/PTEN/PI3K/Akt pathway was the mechanism underlying the antagonistic effect of quercetin on AGEs-induced apoptosis.

Exosomes derived from mesenchymal stromal cells: a promising treatment for pelvic floor dysfunction.

Pelvic floor dysfunction (PFDs), which include pelvic organ prolapse (POP), stress urinary incontinence (SUI) and anal incontinence (AI), are common degenerative diseases in women that have dramatic effects on quality of life. The pathology of PFDs is based on impaired pelvic connective tissue supportive strength due to an imbalance in extracellular matrix (ECM) metabolism, the loss of a variety of cell types, such as fibroblasts, muscle cells, peripheral nerve cells, and oxidative stress and inflammation in the pelvic environment. Fortunately, exosomes, which are one of the major secretions of mesenchymal stromal cells (MSCs), are involved in intercellular communication and the modulation of molecular activities in recipient cells via their contents, which are bioactive proteins and genetic factors such as mRNAs and miRNAs. These components modify fibroblast activation and secretion, facilitate ECM modelling, and promote cell proliferation to enhance pelvic tissue regeneration. In this review, we focus on the molecular mechanisms and future directions of exosomes derived from MSCs that are of great value in the treatment of PFD.

Transvaginal single-port versus multi-port laparoscopic sacrocolpopexy: a retrospective cohort study.

BACKGROUND: Sacrocolpopexy is the gold standard treatment for apical prolapse. With the development of minimally invasive surgical techniques, the new approach of transvaginal single-port laparoscopic sacrocolpopexy (TS-LSC) has become available. However, its therapeutic effects remain unclear. The aim of this study is to compare the middle-term clinical outcomes of transvaginal single-port laparoscopic sacrocolpopexy with multi-port laparoscopic sacrocolpopexy (LSC) for apical prolapse. METHODS: We conducted a retrospective cohort study. Patients with advanced apical prolapse who underwent either TS-LSC or LSC between May 2017 to June 2019 were enrolled. Baseline demographics, perioperative results, perioperative and postoperative complications, pelvic organ prolapse quantification (POPQ) scores, pelvic floor distress inventory (PFDI-20) score and pelvic organ prolapse/urinary incontinence sexual function questionnaire (PISQ-12) score were collected at 2 years. RESULTS: 89 subjects were analyzed: 46 in TS-LSC and 43 in LSC group. Follow-up time was 38.67 ± 7.46 vs 41.81 ± 7.13 months, respectively. Baseline characteristics and perioperative outcomes were similar except that pain score was lower (2.37 ± 0.90 vs 3.74 ± 1.05) and cosmetic score was higher (9.02 ± 0.75 vs 7.21 ± 0.89) in TS-LSC group (P < 0.05). Complication rates did not differ between groups. 3 mesh exposure in each group were noted. Recurrence rate was 2.17% in TS-LSC and 6.98% in LSC, no apical recurrence occurred. Constipation was the most common postoperative symptom. Besides, patients in TS-LSC group had better POP-Q C point (- 6.83 ± 0.54 vs - 6.39 ± 0.62, P < 0.05), and similar Aa, Ap and TVL values. Bladder and pelvic symptoms were improved in both groups, but colorectal symptoms were not relieved. There were no differences of PISQ-12 scores between groups. CONCLUSION: TS-LSC was not inferior to LSC at 2 years. Patients may benefit from its mild pain, better cosmetic effect and better apical support as well as good safety and efficacy. TS-LSC is a promising considerable choice for advanced vaginal apical prolapse. Trial registration ChiCTR2000032334, 2020-4-26 (retrospectively registered).

MSC-based therapy in female pelvic floor disorders.

Mesenchymal stem cells (MSCs), also referred to as multipotent stromal cells or mesenchymal stromal cells, are present in multiple tissues and capable of differentiating into diverse cell lineages, holding a great promise in developing cell-based therapy for a wide range of conditions. Pelvic floor disorders (PFDs) is a common degenerative disease in women and may diminish a woman's quality of life at any age. Since the treatments for this disease are limited by the high rates of recurrence and surgical complications, seeking an ideal therapy in the restoration of pelvic floor function is an urgent issue at present. Herein, we summarize the cell sources of MSCs used for PFDs and discuss the potential mechanisms of MSCs in treating PFDs. Specifically, we also provide a comprehensive review of current preclinical and clinical trials dedicated to investigating MSC-based therapy for PFDs. The novel therapy has presented promising therapeutic effects which include relieving the symptoms of urinary or fecal incontinence, improving the biological properties of implanted meshes and promoting the injured tissue repair. Nevertheless, MSC-based therapies for PFDs are still experimental and the unstated issues on their safety and efficacy should be carefully addressed before their clinical applications.

The cytotoxicity of advanced glycation end products was attenuated by UCMSCs in human vaginal wall fibroblasts by inhibition of an inflammatory response and activation of PI3K/AKT/PTEN.

Pelvic organ prolapse (POP) occurs when the pelvic organs (bladder, bowel or uterus) herniate into the vagina, causing incontinence, voiding, and bowel and sexual dysfunction, negatively impacting upon a woman's quality of life. Intermediate intermolecular cross-links and advanced glycation cross-links increase in prolapsed tissue. Stem cells are able to participate in tissue repair due to their ability to differentiate into multiple lineages, and thus into various types of connective tissue cells, so they therefore hold great promise for treating pelvic floor dysfunction. The current study found that advanced glycation end products (AGEs) inhibited the viability and proliferation of human vaginal wall fibroblasts (VWFs), were cytotoxic to VWFs, and also induced the apoptosis of VWFs. In contrast, umbilical cord-derived mesenchymal stem cells (UCMSCs) secreted anti-inflammation cytokines to protect against the cytotoxic effects of fibroblasts induced by AGEs and attenuated the cytotoxic effect of AGE on fibroblasts by activation of the PI3K/Akt-PTEN pathway. This study demonstrated that UCMSCs inhibited the cytotoxic effect of AGE in cells from patients with POP by inducing an anti-inflammatory reaction and activating the PI3K/AKT/PTEN signaling pathway. The current results provide important insights into use of stem cells to treat POP.

New thoughts in exploring the pathogenesis, diagnosis, and treatment of threatened abortion.

Threatened abortion is a common complication of pregnancy. Since the underlying mechanisms behind this condition are complicated, predicting and treating threatened abortion is a challenge for clinicians. Interestingly, a recent article in Bioscience Trends (Biosci Trends 2019; DOI: 10.5582/bst.2019.01111) revealed a higher, not lower, level of ꞵ-human chorionic gonadotropin (hCG) and estrogen during the first 6 weeks of pregnancy, suggesting a novel association between ꞵ-hCG, estrogen, and threatened abortion. Unfortunately, this study was limited by its small sample size, unconvincing trial design, and inadequate exploration of the underlying mechanisms. This low-quality evidence indicates that a higher level of ꞵ- hCG and estrogen is associated with threatened abortion. However, that work provided some new insights for further studies of threatened abortion.