Using 17ß-estradiol heparin-poloxamer thermosensitive hydrogel to enhance the endometrial regeneration and functional recovery of intrauterine adhesions in a rat model.

Mechanical damage or infection to the endometrium can lead to the formation of adhesions in the uterine cavity, which may result in reduced reproductive outcome and/or pregnancy complications. The prognosis of this disease is poor due to few effective treatments and the complex environment of endometrium. Heparin-Poloxamer Hydrogel (HP hydrogel) is a nontoxic and biodegradable biomaterial, which has been commonly used as a sustained-release delivery system. In this study, we applied a mini-endometrial curette to scrape the endometrium of rats to mimic the process of curettage in patients. After the establishment of IUA model in rats, we injected the thermo-sensitive hydrogel(E2-HP hydrogel) into the injured uterine cavity and evaluated the therapeutic effect of E2-HP hydrogel on the recovery of IUA. Our results showed that E2-HP hydrogel can significantly facilitate the regeneration of injured endometrium along with inhibiting the cell apoptosis in IUA model. Furthermore, we revealed that E2-HP hydrogel on the recovery of IUA was closely associated with the upregulation of kisspeptin through activating the ERK1/2 and MAPKs p38 pathways. In conclusion, E2-HP hydrogel can effectively transfer E2 into the injured endometrium and it can be considered as a promising therapeutic method for the women with intrauterine adhesions.

Ureteral injuries in colorectal surgery and the impact of laparoscopic and robotic-assisted approaches.

BACKGROUND: Ureteral injury is a feared complication in colorectal surgery that has been increasing over the past decade. Some have attributed this to an increased adoption of minimally invasive surgery (MIS), but the literature is hardly conclusive. In this study we aim to further assess the overall trend of ureteral injuries in colorectal surgery, and investigate propensity adjusted contributions from open and MIS to include robotic-assisted surgery. METHODS: This is a retrospective analysis of colorectal surgeries from 2006 to 2016 using the Nationwide Inpatient Sample (NIS) database. Multivariable logistic regression was performed to identify predisposing and protective factors. Demographics, hospital factors, and case-mix differences for open and MIS were accounted for via propensity analysis. The NIS coding structure changed in 2015, which could introduce a potential source of incongruity in complication rates over time. As a result, all statistical analyses included only the first nine years of data, or were conducted before and after the change for comparison. RESULTS: Of 514,162 colorectal surgeries identified there were 1598 ureteral injuries (0.31%). Ureteral injuries were found to be increasing through 2015 (2.3/1000 vs 3.3/1000; p < 0.001) and through the coding transition to 2016 (4.8/1000; p < 0.001). This trend was entirely accounted for by injuries made during open surgery, with decreasing injury rates for MIS over time. Adjusted odds ratio (OR) for ureteral injury with all MIS vs. open cases was 0.81 (95% CI 0.70-0.93, p = 0.003) and for robotic-assisted surgery alone versus open cases was 0.50 (95% CI 0.33-0.77, p = 0.001). CONCLUSIONS: The incidence rate of ureteral injuries during open colorectal surgery is increasing over time, but have been stable or decreasing for MIS cases. These findings hold even after using propensity score analysis. More research is needed to further delineate the impact of MIS and robotic-assisted surgery on ureteral injuries.

Ovarian cyst elevation using a metreurynter for laparoscopic cystectomy of a benign ovarian cyst during pregnancy.

BACKGROUND: A uterine manipulator cannot be used to elevate the ovary in benign ovarian surgery during pregnancy. This report describes our method of elevation of the ovary using a metreurynter with the success rate of the procedure and a comparison of surgical results and pregnancy outcomes between the successful and unsuccessful cases. METHODS: Between August 2003 and February 2020, 11 pregnant patients with a tumor found sunk in the Cul-de-sac underwent laparoscopic cystectomy for a benign ovarian cyst with a metreurynter. The surgical results, success and failure of the elevation by a metreurynter, pregnancy outcomes, and fetal status at delivery were evaluated. RESULTS: Elevation of ovarian tumors with a metreurynter was successful in nine cases. However, it was unsuccessful in the remaining two cases wherein the ovary was lifted with forceps while the uterus was in a compressed state. The operative time was also longer in these cases. The pregnancy prognosis, however, was good for both, successful and unsuccessful cases. CONCLUSIONS: The metreurynter is an inexpensive and practical obstetric device, and its optimal use allows the performance of a procedure with minimal burden on a pregnant uterus. Therefore, we recommend the appropriate use of this method to enable effective laparoscopic cystectomy of ovarian tumors during pregnancy.

The Activation of Cannabinoid Type-2 Receptor with JWH-133 Protects Uterine Ischemia/Reperfusion-Induced Damage.

INTRODUCTION: Uterus transplantation is a complex surgical procedure. Uterine ischemia/reperfusion (IR) damage occurring in this process may cause loss of function in the uterus. Cell damage must be prevented for a healthy uterine function and successful transplantation. Cannabinoids, with their increasing clinical use, are substances with strong anti-inflammatory and antioxidative effects and have a role in immune system regulation. However, their efficacy in uterine IR damage is still unknown. This study provides information on the potential applications cannabinoids agonist JWH-133 in uterine IR damage and, hence, in the transplant process. METHODS: Rats were divided into 4 groups (n = 8), performed uterine IR, and treated 2 groups with JWH-133. After anesthesia, ischemia was applied for 1 h to the uterus while reperfusion was applied for 3 h. After the experiment, malondialdehyde (MDA) levels and phosphorylated nuclear factor-kappa B (p-NF-κB) expression were examined in the tissue samples. Also, cell damage was evaluated by histopathological imaging and TUNEL staining. RESULTS: In the uterine IR group, NF-κB expression and MDA levels were detected at high levels. Histopathological examinations and TUNEL staining revealed extensive cell damage. On the other hand, in groups treated with JWH-133, dose-dependent NF-κB expression and MDA levels decreased (p < 0.05). Depending on the dose, the rate of surviving cells increased in TUNEL staining results. CONCLUSION: The results showed that JWH-133 was effective in reducing uterine IR damage. Cannabinoids may be a new alternative that may be used in the transplantation process in the future.

Looking beyond the ovary for oncofertility care in women: uterine injury as a potential target for fertility-preserving treatments.

Treatment for cancer has the potential to significantly diminish fertility and, further, to negatively impact the obstetrical outcomes of pregnancies that do occur. Cancer survivors have decreased rates of fertility and increased rates of pregnancy complications, such as preterm birth and low birth weight, after exposure to chemotherapy. To date, research on the impact of chemotherapy and radiotherapy on fertility and pregnancy outcomes has focused largely on the gonadotoxic effect of cancer treatments on ovaries, while the uterus and endometrium have not been extensively studied. It is intuitive, however, that decreased fertility and poorer obstetrical outcomes may be substantially mediated through injury to a highly mitotic tissue like the endometrium, which is also central to embryo implantation and utero-placental exchange. Pregnancy complications in cancer survivors might be due to compromised blood supply to the endometrium and myometrium affecting placentation or altered remodeling of the pregnant uterus secondary to radiation fibrosis. Alterations in endometrial receptivity at the molecular level could affect pregnancy implantation and early pregnancy loss, but later complications also can occur. This review focuses on understanding the unintended effects of chemotherapy and radiotherapy on uterine function in female cancer survivors and the impact on pregnancy, and summarizes mechanisms to protect and treat the uterus before and after cancer chemotherapy and radiotherapy.

Leukemia inhibitory factor promotes the regeneration of rat uterine horns with full-thickness injury.

Severe uterine injuries may lead to infertility or pregnancy complications. There is a lack of effective methods to restore the structure and function of seriously injured uteri. Leukemia inhibitory factor (LIF), which plays a crucial role in blastocyst implantation, promotes the process of regeneration after injury in several different tissues. In this study, we explored the effect of LIF on the regeneration of rat uterine horns following full-thickness injury. One hundred and twenty four female Sprague-Dawley rats were assigned to three groups, including a sham-operated group (n = 34 uterine horns), a PBS/collagen group (n = 90 uterine horns), and a LIF/collagen group (n = 124 uterine horns). The regenerated uterine horns were collected at 1, 2, 4, 8, or 12 weeks after the surgery. The results showed that LIF/collagen scaffolds increased the number of endometrial cells and neovascularization 2 weeks after uterine full-thickness defect in excision sites (p < 0.001 vs PBS/collagen). Eight weeks after the surgery, the number of endometrial glands was dramatically higher in the LIF/collagen scaffolds group (35.2 ± 4.1/field) than in the PBS/collagen scaffolds (15.1 ± 1.4/field). The percentage of a-smooth muscle actin (a-SMA)-positive areas in the LIF/collagen scaffolds (88.8% ± 9.8%) was also significantly higher than that in the PBS/collagen group (52.9% ± 3.7%). Moreover, LIF improved the pregnancy rate and fetus number. We also found that LIF inhibited the infiltration of inflammatory cells and down-regulated the pro-inflammatory cytokine IL-12 expression while up-regulating the anti-inflammatory cytokine IL-10 expression in the injured part of the uterine horns. Our results indicate that LIF promotes regeneration of the uterus after injury, and this is at least partially due to its immunomodulatory properties. In addition, it is worth to explore further the possibility for LIF/collagen to be an alternative therapeutic approach for uterine damage in the clinic in near future.

Successful removal of an intrauterine device perforating the uterus and the bladder with the aid of a transurethral nephroscope.

AIM: An IUD perforating the uterus and bladder and creating a nidus for stone formation is a rare complication. We aim to demonstrate with a video a novel surgical technique that involves transcervically extracting a perforating IUD with a transurethral nephroscope after removal of the bladder stone on the IUD. METHODS: A 57-year-old woman was referred to our department 4 months ago following a 2-year history of suprapubic pain at the end of urination. Ultrasound and X-ray examination confirmed an IUD perforating the uterus and the bladder. The patient underwent transurethral holmium laser lithotripsy and transcervical removal of the IUD with the aid of a transurethral nephroscope. RESULTS: The stone on the perforating ectopic IUD was successfully removed and the IUD was extracted without complications. CONCLUSION: This video demonstrates a rare case of an IUD that perforated both the bladder and the uterine walls and created a nidus for stone formation in the bladder. The surgical technique involved in removing the stone and extracting the IUD is a new approach to treating this problem. It is suspected that this specific surgical intervention may also help to minimize the formation of a larger vesico-uterine fistula by decreasing the extent of trauma potentially created when extracting the IUD. However, this supposition merits further study.

Smooth Muscle Cells in Pelvic Washings at Time of Benign Hysterectomy.

STUDY OBJECTIVE: To evaluate if smooth muscle cells can be detected in pelvic washings at the time of intact hysterectomy. DESIGN: A multicentered pilot cohort study (Canadian Task Force classification II-2). SETTING: Two academically affiliated tertiary referral centers. PATIENTS: Patients undergoing total hysterectomy for benign indications without morcellation by minimally invasive gynecologic surgeons were enrolled from January 2018 to July 2018. INTERVENTIONS: Pelvic washings were collected at 2 times during surgery: after abdominal entry and after vaginal cuff closure. Cell blocks were generated, and slides were stained using hematoxylin and eosin, smooth muscle actin, and desmin and interpreted by 1 expert pathologist at each institution. MEASUREMENTS AND MAIN RESULTS: Thirty-eight subjects were recruited; 3 subjects were excluded because of unplanned morcellation. Smooth muscle uterine cells were detected in 1 prewash specimen and 2 postwash specimens. The group with positive washings was noted to have longer procedure times (136 vs 114 minutes), lower blood loss (25 vs 86 mL), and higher uterine weight (242 vs 234 g) compared with negative washings group. CONCLUSION: Tissue dissemination of uterine cells may be possible at the time of hysterectomy. Larger prospective studies are needed to better describe the incidence of and risk factors for tissue dissemination.

Adverse Maternal Outcomes Associated with Uterine Extensions at the Time of Cesarean Delivery.

OBJECTIVE: We sought to compare adverse maternal outcomes between women with and without a uterine extension at the time of cesarean. STUDY DESIGN: We conducted a retrospective cohort study of women with and without a uterine extension during a primary low transverse cesarean of a full-term singleton gestation. The primary outcomes were (1) estimated blood loss (EBL) and (2) composite maternal morbidity (defined as ≥ 1 of the following: blood transfusion, endometritis, or readmission). Pearson's chi-square or Fisher's exact test was used to compare categorical data; Student's t-test or Mann-Whitney's U-tests was used for continuous data. Linear and logistic regressions were used to adjust for confounding factors. RESULTS: There were 252 women included (126 with extension and 126 without an extension). Women with extensions had a higher EBL (1,038 vs. 832 mL, p < 0.001) and higher rate of the composite maternal morbidity (19.1 vs. 5.6%, p = 0.001). Additionally, women with extensions had an increased risk of postpartum hemorrhage ≥ 1 L (53.2 vs. 23.8%, p < 0.001) and 1.5 L (12.7 vs. 0%, p < 0.001) and were associated with prolonged length of hospital stay (29 vs. 17%, p = 0.04). CONCLUSION: Uterine extensions are associated with adverse maternal outcomes including higher EBL and increase in maternal morbidity.

Copper nanoparticle-induced uterine injury in female rats.

Copper nanoparticles (Cu-NPs) have been used increasingly in various products and applications. Although recent studies have reported that exposure to Cu-NPs leads to organ accumulation and obvious toxicity, it remains unclear whether Cu-NPs can be translocated to and cause damage in the uterus. In this study, we investigated the potential for uterine injury and gene expression patterns in female rats exposed to 3.12, 6.25, or 12.5 mg/kg/d Cu-NPs via intraperitoneal injection for 14 consecutive days. The results indicated that exposure to Cu-NPs led to significant decreases in the relative uterine weight coefficients and increases in inflammatory cell infiltration, mitochondrial swelling and vacuolization, shortened and reduced endometrial epithelial cell microvilli, and apoptosis. Furthermore, exposure to Cu-NPs increased malondialdehyde (MDA) accumulation and decreased superoxide dismutase (SOD) levels. Signal transduction mechanism studies indicated that exposure to Cu-NPs activated caspases 3, 8, and 9 and BH3 interacting domain death agonist (tBid), reduced B cell leukemia/lymphoma 2 (Bcl-2) expression, and increased the expression of apoptotic peptidase activating factor 1 (Apaf-1), BCL2-associated X, apoptosis regulator (Bax), and cytochrome c. A microarray analysis revealed significant alterations in the expression of 963 genes; of these, 622 were upregulated and 341 were downregulated. The results of further evaluations of some altered genes, including matrix metallopeptidase 12 (Mmp12), using quantitative RT-PCR agreed with the microarray findings. These results provide strong evidence that Cu-NPs can trigger both intrinsic and extrinsic apoptotic pathways to mediate uterine injury, resulting in oxidative stress-related changes in gene expression.

Transplant of insulin-like growth factor-1 expressing bone marrow stem cells improves functional regeneration of injured rat uterus by NF-κB pathway.

To investigate the potential beneficial effect of insulin-like growth factor-1 (IGF-1) in BMSC transplantation therapy of uterus injury and the underlying molecular mechanisms, rat BMSCs were isolated and cultured. The relative expressions of IGF-1 and IL-10 were determined by RT-PCR and immunoblotting. The secretory IL-10 and released E2 were measured using ELISA kits. The relative vWF and α-SMA expressions were determined by immunohistochemistry. The direct binding of NF-κB subunit p50 with IL-10 promoter was analysed by chromatin immunoprecipitation assay. The regulation of IL-10 expression by p50 was interrogated by luciferase reporter assay. Our data demonstrated that IGF-1 expression in BMSCs induced IL-10 expression and secretion, which was further enhanced by E2-PLGA. IGF-1 overexpression improved BMSCs transplantation therapy in rat uterus injury. We further demonstrated that both inhibition and knockdown of p50 abolished IGF-1-induced expression and secretion of IL-10 in BMSCs, which consequently compromised the IGF-1 conferred therapeutic benefits against uterus injury. Furthermore, we elucidated that p50 regulated IL-10 expression via direct association with its promoter. Our data suggested that transplantation of IGF-1 overexpressing BMSCs improved functional regeneration of injured uterus by inducing IL-10 expression and secretion via activation of NF-κB signalling.

Intrauterine Manipulator Use During Minimally Invasive Hysterectomy and Risk of Lymphovascular Space Invasion in Endometrial Cancer.

OBJECTIVE: This study aimed to examine an association between intrauterine manipulator (IUM) use and frequency of lymphovascular space invasion (LVSI) in women with endometrial cancer undergoing minimally invasive hysterectomy. METHODS: A retrospective case-control study was conducted among stage I-IV endometrial cancer patients who underwent hysterectomy between 2008 and 2015. Medical records were reviewed for patient demographics, surgical details, and tumor characteristics. Women who underwent total laparoscopic hysterectomy (TLH) with IUM use were compared with women who underwent total abdominal hysterectomy (TAH). Review of archived medical record for data collection and propensity score matching were performed to adjust for background differences between TLH-IUM and TAH groups. A systematic literature review with pooled analysis was performed to examine frequency of LVSI. RESULTS: There were 687 women who underwent hysterectomy for endometrial cancer. Of those, 419 women underwent TLH with IUM use and 194 women underwent TAH. The most common type of IUM was VCare (89.5%). There was no statistically significant difference in the frequency of LVSI between the 2 groups: 15.1% for TLH-IUM vs 19.9% for TAH (P = 0.14). After propensity score matching, frequencies of LVSI were similar between the 2 groups: 21.2% for TLH-IUM vs 19.6% for TAH (P = 0.78). Systematic literature review identified 1371 cases of TLH-IUM and 1246 cases of TAH performed for endometrial cancer, and frequencies of LVSI were similar between the 2 groups (15.0% vs 13.6%, P = 0.31). CONCLUSION: Our study suggests that IUM use during TLH for endometrial cancer is not associated with increased frequency of LVSI.

Successful management of acquired uterine arteriovenous malformation.

Uterine arteriovenous malformation (UAVM) is uncommon. They are usually acquired, due to previous intra uterine trauma. We report a case of acquired UAVM in a 28-years-old patient after a medical abortion, diagnosed with ultrasonography and successfully managed with uterine artery embolization.

Altered defaecatory behaviour and faecal incontinence in a video-tracked animal model of pudendal neuropathy.

AIM: The aim was to develop a behavioural animal model of faecal continence and assess the effect of retro-uterine balloon inflation (RBI) injury. RBI in the rat causes pudendal neuropathy, a risk factor for obstetric related faecal incontinence in humans. METHOD: Video-tracking of healthy rats (n = 12) in a cage containing a latrine box was used to monitor their defaecatory behaviour index (DBI) over 2 weeks. The DBI (range 0-1) was devised by dividing the defaecation rate (pellets per hour) outside the latrine by that of the whole cage. A score of 0 indicates all pellets were deposited in the latrine. Subsequently, the effects of RBI (n = 19), sham surgery (n = 4) and colostomy (n = 2) were determined by monitoring the DBI for 2 weeks preoperatively and 3 weeks postoperatively. RESULTS: The DBI for healthy rats was 0.1 ± 0.03 with no significant change over 2 weeks (P = 0.71). In the RBI group, 13 of 19 rats (68%) showed no significant change in DBI postoperatively (0.08 ±  -0.05 vs 0.11 ±  -0.07) while in six rats the DBI increased from 0.16 ±  -0.09 to 0.46 ± 0.23. The negative control, sham surgery, did not significantly affect the DBI (0.09 ± 0.06 vs 0.08 ± 0.04, P = 0.14). The positive control, colostomy, increased the DBI from 0.26 ± 0.03 to 0.86 ± 0.08. CONCLUSIONS: This is the first study showing a quantifiable change in defaecatory behaviour following injury in an animal model. This model of pudendal neuropathy affects continence in 32% of rats and provides a basis for research on interventions for incontinence.

[COMPLICATIONS OF DIAGNOSTIC AND OPERATIVE HYSTEROSCOPY--REVIEW].

Hysteroscopy is a diagnostic or surgical mini-Invasive gynecologic operating procedure. The complications of this standard procedure are relatively rare. According to retrospective studies they are 0.95-13.6%. They occur more often by an operative rather than a diagnostic hysteroscopy. These complications could be divided into two groups of an approximately equal occurrence--due to a dilation and passing through the cervix uteri (cervical laceration, creative a false cervix uteri, perforation, bleeding, impossibility to pass through the inner orifice of the cervical canal, insufficiency of the cervix uteri) and due to the operative technique itself (uterine perforation, fluid overload, thermal or mechanical trauma of the inner urinaiy and gastrointestinal tract, infection, rupture of the uterus during a subsequent pregnancy). The most occurring complication is namely the uterine perforation--1-9%, the most severe could indeed be the fluid overload--0.01-11%. The gynecologist performing the hysteroscopy should be well grounded in the typical complications. Unveiling and performing a quick intervention of the latter could prevent unwanted consequences for the patient and the legal issues that could follow occur.

Blood flow to the scarred gravid uterus at 22-24 weeks of gestation.

OBJECTIVE: To compare uterine artery volume blood flow (Q(uta)), vascular resistance (R(uta)), pulsatility index (Uta PI), and the fraction of maternal cardiac output (CO) distributed to the uteroplacental circulation in pregnant women with and without a previous caesarean section. DESIGN: Cross-sectional observational study. SETTING: University hospital in Norway. POPULATION: Thirty-two pregnant women with previous caesarean section and 32 matched controls. METHODS: Ultrasonography was used to measure uterine artery diameter and blood flow velocity between 22(+0) and 23(+6) weeks of gestation. Impedance cardiography was used to assess maternal haemodynamics. MAIN OUTCOME MEASURES: Q(uta), R(uta), Uta PI, and the fraction of maternal CO distributed to the uteroplacental circulation. RESULTS: The mean Q(uta) was 356.26 ± 213.72 ml/minute in cases and 456.41 ± 209.70 ml/minute in controls (P = 0.038). R(uta) was significantly (P = 0.026) higher among cases compared with controls (0.32 ± 0.20 versus 0.22 ± 0.14 mmHg/ml/minute), but the Uta PI did not differ between the groups (0.93 ± 0.23 versus 0.92 ± 0.47; P = 0.929). The fraction of maternal CO distributed to the uteroplacental circulation was 5.75 ± 3.68% in cases and 8.45 ± 5.02% in controls (P = 0.014). CONCLUSIONS: Uterine artery volume blood flow and the fraction of maternal cardiac output distributed to the uteroplacental circulation are lower, and uterine vascular resistance (but not Uta PI) is higher, in women with previous caesarean section compared with the control group.

A matched cohort study comparing the outcome of intrauterine adhesiolysis for Asherman's syndrome after uterine artery embolization or surgical trauma.

STUDY OBJECTIVE: To compare the outcome of hysteroscopic adhesiolysis in women who had Asherman's syndrome after uterine artery embolization (UAE) with those who had Asherman's syndrome caused by surgical trauma. DESIGN: A retrospective cohort study matched for age and intrauterine adhesion score (Canadian Task Force classification II-2). SETTING: A tertiary hysteroscopic center in a teaching hospital. PATIENTS: Nineteen women with Asherman's syndrome after UAE and 57 women with Asherman's syndrome caused by surgical trauma. INTERVENTIONS: Hysteroscopic adhesiolysis was followed by a second-look hysteroscopy 1 month later. The scoring system proposed by the American Fertility Society was used to evaluate intrauterine adhesion during hysteroscopy. MEASUREMENTS AND MAIN RESULTS: In the UAE group, only 42.1% of women experienced improvement in menstruation defined as a subjective increase in menstrual flow after surgery, which was significantly lower than that of 86.0% observed in the non-UAE group. In the UAE group, the reduction of the American Fertility Society (AFS) score after intrauterine adhesiolysis was 30%, which was significantly lower than that of 80% in the non-UAE group. The pregnancy rate and live birth rate in the UAE group (5% and 0%, respectively) were significantly lower than the corresponding rates in the non-UAE group (33% and 25%, respectively). CONCLUSION: The outcome of hysteroscopic adhesiolysis in women with Asherman's syndrome after UAE was worse than in women with Asherman's syndrome caused by surgical trauma.

[Uterine scar after caeserean section- predicting the risk of uterine rupture and decision on the way of delivery].

The Cesarean section rate in University Maternity Hospital 'Maichin dom' is 46 to 48%. The rate of repeated Cesarean section is also increasing. However there is an increasing number of women wishing to deliver vaginally after having had a Cesarean section for their first baby. On the other hand, with postponing pregnancy, increasing number of woman nowadays experience surgeries on their uterus prior to giving birth. With regards to the above-mentioned, pregnancy in scarred uterus is a common thing. Examining the uterine scar gives valuable information for the risk of uterine rupture during pregnancy and the decision making on the safest way of delivery. The current article shows ultrasound pics of uterine scar in pregnant and non-pregnant uterus. Gives recommendations for the timing of the US examination and the reference range for thickness of the uterine scar (residual myometrial thickness) in the view of the risk of rupture and the safest way of delivery. All this information is based on the most recent clinical trials.

miR-340-3p-modified bone marrow mesenchymal stem cell-derived exosomes inhibit ferroptosis through METTL3-mediated m6A modification of HMOX1 to promote recovery of injured rat uterus.

BACKGROUND: Ferroptosis is associated with the pathological progression of hemorrhagic injury and ischemia-reperfusion injury. According to our previous study, exosomes formed through bone marrow mesenchymal stem cells modified with miR-340-3p (MB-exos) can restore damaged endometrium. However, the involvement of ferroptosis in endometrial injury and the effect of MB-exos on ferroptosis remain elusive. METHODS: The endometrial injury rat model was developed. Exosomes were obtained from the supernatants of bone marrow mesenchymal stromal cells (BMSCs) and miR-340/BMSCs through differential centrifugation. We conducted RNA-seq analysis on endometrial tissues obtained from the PBS and MB-exos groups. Ferroptosis was induced in endometrial stromal cells (ESCs) by treating them with erastin or RSL3, followed by treatment with B-exos or MB-exos. We assessed the endometrial total m6A modification level after injury and subsequent treatment with B-exos or MB-exos by methylation quantification assay. We performed meRIP-qPCR to analyze m6A modification-regulated endogenous mRNAs. RESULTS: We reveal that MB-exos facilitate the injured endometrium to recover by suppressing ferroptosis in endometrial stromal cells. The injured endometrium showed significantly upregulated N6-methyladenosine (m6A) modification levels; these levels were attenuated by MB-exos through downregulation of the methylase METTL3. Intriguingly, METTL3 downregulation appears to repress ferroptosis by stabilizing HMOX1 mRNA, thereby potentially elucidating the mechanism through which MB-exos inhibit ferroptosis in ESCs. We identified YTHDF2 as a critical m6A reader protein that contributes to HMOX1 mRNA degradation. YTHDF2 facilitates HMOX1 mRNA degradation by identifying the m6A binding site in the 3'-untranslated regions of HMOX1. In a rat model, treatment with MB-exos ameliorated endometrial injury-induced fibrosis by inhibiting ferroptosis in ESCs. Moreover, METTL3 short hairpin RNA-mediated inhibition of m6A modification enhanced the inhibitory effect of MB-exos on ferroptosis in endometrial injury. CONCLUSIONS: Thus, these observations provide new insights regarding the molecular mechanisms responsible for endometrial recovery promotion by MB-exos and highlight m6A modification-dependent ferroptosis inhibition as a prospective therapeutic target to attenuate endometrial injury.

Creation of a female rabbit model for intrauterine adhesions using mechanical and infectious injury.

BACKGROUND: Intrauterine adhesions (IUA) are associated with secondary amenorrhea, infertility, and recurrent pregnancy loss. An IUA animal model would contribute to research on the pathogenesis and pathologic changes of IUA and the exploration of new treatments. MATERIALS AND METHODS: Eighty female rabbits were randomly divided into five groups: mechanical injury (16), infectious injury (16), dual injury (16), experimental control (16), and normal (16). Three methods were applied to establish the model: uterine curettage, uterine cavity left alone, lipopolysaccharide surgical suture in place for 48 h, and suture retention for 48 h after curettage. A sterile surgical suture was left in the uterine cavity for 48 h in the experimental control group. Histologic changes were monitored at 0, 24, 48, and 72 h and 7, 14, and 28 d after operation. RESULTS: The experiments revealed that endometrium injured by simple curettage or infection could be repaired. Although endometrial regeneration was severely impaired by dual injury, the ratio of the area with endometrial stromal fibrosis to total endometrial area significantly increased (P < 0.01), and the number of endometrial glands was significantly reduced (P < 0.01). CONCLUSIONS: The method of dual injury can establish a stable rabbit IUA model.