Asiaticoside ameliorates uterine injury induced by zearalenone in mice by reversing endometrial barrier disruption, oxidative stress and apoptosis.

Zearalenone (ZEA) is a mycotoxin produced by Fusarium fungi that has been shown to have adverse effects on human and animal health, particularly on the fertility of females. As a saponin derived from the medicinal plant Centella asiatica, asiaticoside (AS) has multiple bioactivities. This study aimed to investigate the protective effects of AS on ZEA-induced uterine injury and the underlying mechanism. In the present study, we demonstrated that AS could rescue ZEA-induced uterine histopathological damage and modulate the secretion of sex hormones, including progesterone (P4), luteinizing hormone (LH), and estradiol (E2), in ZEA-treated mice. Moreover, AS alleviated ZEA-induced damage to endometrial barrier function by upregulating the expression of tight junction proteins (ZO-1, occludin, and claudin-3). Further mechanistic investigations indicated that ZEA reduces the antioxidant capacity of uterine tissues, whereas AS improves the antioxidant capacity through activating the Nrf2 signaling pathway. Most notably, the protective effect of AS was blocked in Nrf2 gene knockout (Nrf2-/-) mice. Moreover, the p38/ERK MAPK pathway has been implicated in regulating ZEA toxicity and the beneficial effect of AS. Additionally, an Nrf2 inhibitor (ML385) weaken the suppressive effect of AS on the oxidative stress and MAPK pathway. AS also inhibits ZEA-induced apoptosis in uterine tissues via the PI3K/Akt signaling pathway. However, when the PI3K small molecule inhibitor LY294002 was co-administered, the ability of AS to suppress the expression of apoptosis-related proteins and inhibit ZEA-induced apoptosis decreased. Collectively, these findings reveal the involvement of multiple pathways and targets in the protective effect of AS against ZEA-induced uterine injury, providing a new perspective for the application of AS and the development of a ZEA antidote.

Use of statins and risks of ovarian, uterine, and cervical diseases: a cohort study in the UK Biobank.

PURPOSE: To examine the associations between use of statins and risks of various ovarian, uterine, and cervical diseases, including ovarian cancer, endometrial cancer, cervical cancer, ovarian cyst, polycystic ovarian syndrome, endometriosis, endometrial hyperplasia, endometrial polyp, and cervical polyp. METHODS: We conducted a cohort study among female participants in the UK Biobank. Information on the use of statins was collected through verbal interview. Outcome information was obtained by linking to national cancer registry data and hospital inpatient data. We used Cox proportional hazards regression to examine the associations. RESULTS: A total of 180,855 female participants (18,403 statin users and 162,452 non-users) were included. Use of statins was significantly associated with increased risks of cervical cancer (adjusted hazard ratio (HR), 1.55; 95% confidence interval (95% CI), 1.05-2.30) and polycystic ovarian syndrome (adjusted HR, 4.39; 95% CI, 1.68-11.49). However, we observed no significant association between use of statins and risk of ovarian cancer, endometrial cancer, ovarian cyst, endometriosis, endometrial hyperplasia, endometrial polyp, or cervical polyp. CONCLUSION: Our findings suggest that use of statins is associated with increased risks of cervical cancer and polycystic ovarian syndrome, but is not associated with increased or decreased risk of ovarian cancer, endometrial cancer, ovarian cyst, endometriosis, endometrial polyp, or cervical polyp.

Expression of SOX2, NANOG and OCT4 in a mouse model of lipopolysaccharide-induced acute uterine injury and intrauterine adhesions.

BACKGROUND: Activation of inflammation-mediated endometrial injury is suggested to play a decisive role in pathogenesis of intrauterine adhesion (IUA). The stem cell theory of endometrial diseases has been given a hotspot, in that human endometrial stem cells have been isolated from the endometrium. Three transcription factors that play key roles in maintaining pluripotency and self-renewal in stem cells are sex-determining region Y-box2 (SOX2), Nanog homebox (NANOG), and octamer-binding protein (OCT4), which may be responsible for the damage or repair process of uterine endometrium. We aim to investigate the expression of SOX2, NANOG and OCT4 in a mouse model of acute uterine injury induced by peritoneal injection of lipopolysaccharide (LPS) and also analyze their changes in endometrium of women with IUA. METHODS: The mouse uterine horns were collected at 0 h, 6 h, 12 h, 18 h or 24 h after a single dose of LPS or PBS injection. Meanwhile, we recruited 19 women with IUA diagnosed by hysteroscopy and 16 disease-free women as control group. Endometrial tissue samples were collected. SOX2, NANOG, and OCT4 expression were analyzed with Quantitative Real-time Polymerase Chain Reaction and Western blotting assay. RESULTS: In a mouse model of acute uterine injury, there was significant upregulation of NANOG at 6 h, SOX2 and OCT4 at 12 h compared with the values before injection or PBS injection. NANOG expression reached a peak at 6 h, while SOX2 and OCT4 peaked later at 12 h after LPS treatment. NANOG mRNA and protein expressions were significantly higher in endometrium of IUA patients compared to those of the control group. CONCLUSIONS: Expression of pluripotency factors SOX2, NANOG and OCT4 increased in a mouse model of LPS-induced acute uterine injury. NANOG peaked earlier followed by the other two factors before returning to baseline levels. NANOG but not SOX2 and OCT4 expression was overexpressed in the endometrium of women with IUA. They may be involved in the formation or restoration of IUA, and their roles in pathogenesis of IUA need to be further studied.

Intrauterine inflammation induces sex-specific effects on neuroinflammation, white matter, and behavior.

Exposure to inflammation during pregnancy has been linked to adverse neurodevelopmental consequences for the offspring. One common route through which a developing fetus is exposed to inflammation is with intrauterine inflammation. To that end, we utilized an animal model of intrauterine inflammation (IUI; intrauterine lipopolysaccharide (LPS) administration, 50µg, E15) to assess placental and fetal brain inflammatory responses, white matter integrity, anxiety-related behaviors (elevated zero maze, light dark box, open field), microglial counts, and the CNS cytokine response to an acute injection of LPS in both males and females. These studies revealed that for multiple endpoints (fetal brain cytokine levels, cytokine response to adult LPS challenge) male IUI offspring were uniquely affected by intrauterine inflammation, while for other endpoints (behavior, microglial number) both sexes were similarly affected. These data advance our understanding of sex-specific effects of early life exposure to inflammation in a translationally- relevant model.

Endometrial breakdown with sustained progesterone release involves NF-κB-mediated functional progesterone withdrawal in a mouse implant model.

Irregular uterine bleeding is a major side effect of long-acting progestogen-only contraceptives in women, and is the primary reason women discontinue their use. In this study, a mouse model of endometrial breakdown was established using a subcutaneous progesterone implant to understand how irregular bleeding begins. Although progestogens sustained decidualization, endometrial breakdown was still observed in this model. We, therefore, hypothesized that endometrial breakdown might involve functional progesterone withdrawal. Using co-immunoprecipitation assays, we observed the constitutive activation of nuclear factor kappa-b (NF-κB) p65 and its interaction with the progesterone receptor (PGR); moreover, transcriptional activity of the PGR was also repressed by NF-κB activity in primary mouse and human decidual stromal cells that mimic progesterone maintenance. Yet the ratio of PGR-B to PGR-A was not increased in the mouse model. In vivo comparison of endometrial breakdown induced by progesterone withdrawal to that seen during sustained progesterone exposure, in the presence of NF-κB inhibitors, revealed that NF-κB-mediated functional progesterone withdrawal is involved in endometrial breakdown in this implant model. These data prompt further studies to determine the homology of this functional progesterone withdrawal mechanism in human endometrium. Mol. Reprod. Dev. 83: 780-791, 2016 © 2016 Wiley Periodicals, Inc.

Acute uterine irritation provokes colonic motility via transient receptor potential A(1)-dependent spinal NR2B phosphorylation in rats.

BACKGROUND: Patients with inflammatory gynecological/obstetrical problems often complain of irritable bowel syndrome. The authors examined whether acute uterus irritation reflexively provokes colonic motility in rat preparations. METHODS: A modified colon manometry and striated abdominal muscle electromyogram activity in response to mustard oil (MO) instillation into the uterine horn were continuously recorded in anesthetized rats. The lumbosacral (L6-S1) dorsal horn was dissected to assess the level and the cellular location of phosphorylated NR2B subunit using Western blotting and immunofluorescence analysis, respectively. Finally, the uterine transient receptor potential A1 or spinal NR2B subunit was pharmacologically blocked to elucidate its roles. RESULTS: MO (0.1%, 0.2 ml) injected into the lower uterine horn dramatically provoked colonic hypermotility characterized by rhythmic colonic contractions (about 3-4 contractions per 10 min, n = 7) accompanied by synchronized electromyogram firing in the abdominal muscle (about 4-5 folds of control, n = 7). In addition to provoking colonic hypermotility, MO administration also up-regulated phosphorylated (about 2-3 folds of control, n = 7), but not total, NR2B expression in the dorsal horn neurons. Both intrathecal Ro 25-6981 (a selective NR2B subunit antagonist; 10 µM, 10 µl) and intrauterine HC-030031 (a selective transient receptor potential A1 receptor antagonist; 30 mg/kg, 0.2 ml) injected before the MO instillation attenuated the MO-induced colonic hypermotility and spinal NR2B phosphorylation. CONCLUSION: The comorbidity of gynecological/obstetrical and gastrointestinal problems is not coincidental but rather causal in nature, and clinicians should investigate for gynecological/urological diseases in the setting of bowel problems with no known pathological etiology.

Estrogen decreases the expression of claudin-5 in vascular endothelial cells in the murine uterus.

Vascular endothelial (VE)-cadherin and claudin-5 are major components of the adherens and tight junctions of vascular endothelial cells, respectively, and decreases in their expression are associated with increases in endothelial paracellular permeability. In the uterus, estrogen induces endometrial edema. However, the in vivo effect of estrogen on endothelial paracellular permeability is unknown. Therefore, we studied the expression of VE-cadherin and claudin-5 in vascular endothelial cells in murine uteri stimulated by estrogen or progesterone. Ovariectomized mature mice were injected with estradiol-17ß (1 µg/mouse) or progesterone (1 mg/mouse) at intervals of 24 hours for 6 days. The frozen transverse sections of the uteri of these mice and untreated mice were stained for CD31 (vascular endothelial cell marker) plus VE-cadherin or claudin-5 using a double-immunofluorescence method. Then, the percentages of VE-cadherin- or claudin-5-positive vessels among CD31-positive vessels were examined in the uterine endometria. VE-cadherin and claudin-5 were expressed in most CD31-positive vessels in the endometria of the untreated mice. Progesterone did not affect the expression of both VE-cadherin and claudin-5 and estradiol-17ß also did not affect the VE-cadherin expression, but estradiol-17ß significantly decreased the claudin-5 expression. This decreasing effect of estradiol-17ß was detected from 24 hours later when the water content per a uterus significantly increased. The present study indicates that estrogen, but not progesterone, decreases the expression of claudin-5 in vascular endothelial cells in the murine uterine endometrium from 24 hours later, suggesting that the decrease in the claudin-5 expression contributes to the endometrial edema late after the estrogen stimulation.

Effect of estradiol valerate on endometrium thickness during clomiphene citrate-stimulated ovulation.

AIM: The aim of this study was to examine the effects of estradiol valerate (EV) on the thickness of clomiphene citrate (CC)-stimulated endometrium. MATERIAL AND METHODS: Thirty-four normal ovulatory women were randomized double-blindly into two groups to receive CC 100 mg/day on day 2-6 of the treatment cycle, and either vitamin B (placebo) or EV 6 mg/day on day 10-14 of the cycle. The endometrial thickness, endometrial pattern, numbers of mature follicles, and maximal diameters of preovulatory follicles were evaluated by transvaginal sonographic examination. RESULTS: Thirty women completed both treatment cycles. Two other participants dropped out during the treatment due to side-effects (headache). The average endometrial thickness of the group treated with CC + placebo became slightly thinner when compared to the thickness at the baseline (9.04 vs 9.52 mm; P = 0.24). The CC + placebo and the CC + EV resulted in similar endometrial pattern, ovulation day, numbers of mature follicles, and sizes of the leading follicles before ovulation. However, an addition of EV into the CC cycle significantly increased the average endometrial thickness (10.7 mm vs 9.04 mm; P < 0.001). CONCLUSIONS: We concluded that the addition of 6 mg/day EV following the CC treatment can prevent the endometrial thinning without perturbing folliculogenesis and ovulation.

Dehydroepiandrosterone induces ovarian and uterine hyperfibrosis in female rats.

STUDY QUESTION: Do dehydroepiandrosterone (DHEA)-treated rats with polycystic ovary syndrome (PCOS) demonstrate a high level of fibrosis in ovarian and uterine tissues? SUMMARY ANSWER: DHEA induces ovarian and uterine hyperfibrosis in rats, probably involving a transforming growth factor-ß (TGF-ß)-dependent mechanism. WHAT IS KNOWN ALREADY: Chronic inflammation is the typical cause of fibrosis and is involved in the pathophysiological process of PCOS. Patients with PCOS are reported to have a higher serum level of TGF-ß, a well-characterized key pro-fibrotic factor. Fibrillin-3, a protein capable of interacting with TGF-ß, has been reported to be partially responsible for the fetal origin of PCOS. STUDY DESIGN, SIZE, DURATION: Female Sprague-Dawley rats were treated with a vehicle control or DHEA for 35 days, with subsequent analyses of changes in morphology and gene expression in ovarian and uterine tissues. Rescue groups treated with metformin or simvastatin and their corresponding controls were also analyzed. A total of 80 rats were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: The PCOS model was induced by daily administration of DHEA s.c. to 3-week-old female rats, and the rescue groups were injected daily with either metformin or simvastatin in addition to DHEA. Serum steroid hormone levels were measured by enzyme-linked immunosorbent assay. Samples were stained with hematoxylin and eosin for histological morphology, and Sirius Red and immunohistochemistry for revealing collagens. The expression of fibrosis-related genes was analyzed both at mRNA (real-time RT-PCR) and protein (western blot) levels. MAIN RESULTS AND THE ROLE OF CHANCE: DHEA-induced rats with PCOS exhibited significantly higher levels of fibrosis (collagen IV) in both ovarian and uterine tissues. In ovarian tissue, the expression of connective tissue growth factor (CTGF) increased following DHEA treatment at both mRNA and protein levels (P < 0.05, P < 0.001 versus controls, respectively). Similar results versus controls were obtained at a protein level for TGF-ß (P < 0.01) and mRNA level for fibronectin (P < 0.05) and angiotensin-II (P < 0.05). Likewise, in uterine tissue, the protein levels of both CTGF and TGF-ß were higher than controls following DHEA treatment (P < 0.05). Treatment with either metformin or simvastatin attenuated the fibrosis progression induced by DHEA exposure, as evidenced by a reduction of TGF-ß, plus CTGF or not, in both ovarian and uterine tissues. LIMITATIONS, REASONS FOR CAUTION: The particular mechanism involved in the DHEA-induced fibrosis was not fully revealed. WIDER IMPLICATIONS OF THE FINDINGS: Ovarian and uterine hyperfibrosis may occur in patients with PCOS and result in anovulation or other PCOS-related phenotypes. Anti-fibrotic therapy, for example metformin treatment, may be beneficial for patients with PCOS. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Natural Science Foundation of China (81170541) and the Natural Basic Research Program of China (973 program 2010CB945103). The authors declare no conflicts of interest.

Ovarian stimulation leads to a severe implantation defect in mice.

The aim of the present study was to evaluate whether ovarian stimulation could induce embryo implantation dysfunction in mice and to explore the possible mechanisms involved. Ovarian stimulation was performed with intraperitoneal injections of 0, 2.5, 5.0, 7.5 and 10.0 IU pregnant mare serum gonadotrophin followed by the same dose of human chorionic gonadotrophin 48h later. A dose-dependent implantation defect in stimulated mice was demonstrated, which can be mainly explained by premature luteolysis and secondary endometrial changes induced by an imbalance in oestradiol and progesterone.

ACE inhibitors and angiotensin receptor blockers could promote the onset of endometrial polyps in hypertensive women.

OBJECTIVE: To investigate whether anti-hypertensive therapy is a risk factor for the onset of endometrial polyps in hypertensive women. METHODS: A sample of 305 hypertensive patients was analyzed. By applying multivariable logistic regression analysis, the odds of developing endometrial polyps relative to the known risk factors for endometrial polyps and to the class of anti-hypertensive drugs were calculated. RESULTS: The variables reaching significance after multivariable logistic regression analysis included the following: hypertension not-in-therapy (odds ratio 2.544; 95% confidence intervals 1.249 - 5.182; p = 0.010); ACE inhibitor therapy (odds ratio 2.400; 95% confidence intervals 1.248 - 4.614; p = 0.009); angiotensin receptor blockers (odds ratio 2.091; 95% confidence intervals 1.044 - 4.187; p = 0.037); and fasting glucose level (odds ratio 1.018; 95% confidence intervals 1.007 - 1.030; p = 0.001). CONCLUSIONS: Although the results should be interpreted carefully, it appears that ACE inhibitors and, to a lesser extent, angiotensin receptor blockers may promote the onset of endometrial polyps in hypertensive patients.

[Tamoxifen and endometrial disease in patients with breast cancer]. / Tamoxifeno y afecciones endometriales en pacientes con cáncer de mama.

The objectives were to evaluate prevalence of endometrial disease in patients treated with tamoxifen (TAM) and analyze the epidemiological, sonographic, hysteroscopic and histopathological findings. From January 1999 to December 2008, 152 breast cancer patients treated with TAM (20 mg/day), symptomatic (with bleeding) or asymptomatic, pre-and postmenopausal, were included consecutively in a prospective and observational follow-up study. Diagnostic methods were (TV) transvaginal ultrasound, hysteroscopy and curettage biopsy. TV ultrasound was performed every 12 months for 12 to 60 months. The patients' age were 62.76 years ± 10.24 the TAM-time: 36.24 ± 19. Adenocarcinoma was observed in 3/87 patients (3.45%) with risk factors and in 1/65 (1.54%) without them (RA 1.91, IC 95% 1.88-1.94). We found benign disease in 148 patients (97.37%) and adenocarcinomas in 4 (2.63%), one within a polyp. The 4 adenocarcinomas were detected in postmenopausal women (2 asymptomatic) with endometrial thicknesses equal or greater than 16 mm. The cancer risk was significantly increased in symptomatic (2.36 versus 0.42 in asymptomatic). Three adenocarcinomas were observed between 24 and 48 months of treatment. In conclusion, we suggest an adequate transvaginal ultrasound monitoring of asymptomatic patients treated with TAM, with removal of polyps, because atypia can be present hidden within, considering risk factors and exposure time. We suggest as an acceptable cut-off = 10 mm in asymptomatic postmenopausal patients.

TT-10 may elevate YAP and repair mouse uterine damage resulting from the inhibition effect of ibuprofen on COX2-PGE2 and YAP.

Ibuprofen (IBU) is an emerging environmental contaminant that, in high doses, can damage reproductive organs in humans and other mammals. Recently, its effects on the uterus have been investigated. It is known that the COX2-PGE2 pathway and Yes-associated protein (YAP) are involved in female reproductive organ development and form a COX2-PGE2-EP2-Gas-ß-catenin-YAP-COX2 positive feedback loop, in addition, TT-10, a pharmacological product, has been found to increase YAP. In this study, IBU was orally administrated to female mice for 7 d at doses of 0, 50, 100, and 200 mg/kg·bw/day (control, low, medium, and high doses, respectively). In addition, 0, 50, 100, and 200 µmol/L IBU was added in vitro to cultured uterine cells for 7 d at control, low, medium, and high doses, respectively; then, 0, 5, 10, and 20 µmol/L TT-10 were given to the in vitro uterine culture containing 100 µmol/L IBU to observe the effect of YAP activation. The results showed that medium and high doses of IBU inhibited the COX2-PGE2 pathway, decreasing YAP and increasing pYAP, leading to reduced circPVT1, elevated miR-149, and increased apoptosis, ultimately damaging the uterus. Conversely, 10 µmol/L TT-10 maximally enhanced YAP, which regulated COX2-PGE2 pathway activation, increased circPVT1, and decreased miR-149, and promoted cell proliferation, preventing uterine damage. This suggests that IBU may cause uterine damage by inhibiting the COX2-PGE2 pathway and YAP, and that appropriate doses of TT-10 may repair this damage by elevating YAP and stimulating COX2 via the feedback loop.

Evaluation of endometrium by transvaginal ultrasonography and Doppler in tamoxifen-treated women with breast cancer.

PURPOSE: The purpose of this study was to investigate the discriminative role of transvaginal ultrasonography and Doppler measurements on the detection of endometrial pathologies in tamoxifen-treated breast cancer patients. METHODS: Tamoxifen-treated breast cancer patients were included in this prospective study between February 2009 and June 2010. The subjects were assessed by gynecologic examination and transvaginal gray-scale and Doppler sonography. The patients whose endometrial thicknesses were more than 6 mm underwent endocervical/endometrial curettage for histopathological examination. RESULTS: There were 98 tamoxifen-treated patients with breast cancer enrolled in the study, providing 141 ultrasound evaluations. Uterine artery pulsatility index was significantly lower in postmenopausal than premenopausal patients (p: 0.013). Endocervical and endometrial curettage was performed in 52 patients. It was more prevalent that the endometrial strip was > or = 6 mm in women with abnormal endometrial histopathology (p: 0.020). However the women with abnormal endometrial histopathology presented lower vascular indices; the only significant difference was in myometrial pulsatility index (p: 0.036). CONCLUSION: The most evident tool for evaluating the endometrium in tamoxifen-treated breast cancer patients is still the transvaginal measurement of its thickness. It exists that Doppler ultrasonographic assessment of uterine, radial and spiral vasculature has no additional benefit for detection of endometrial pathology.

Maternal/fetal mortality and fetal growth restriction: role of nitric oxide and virulence factors in intrauterine infection in rats.

OBJECTIVE: The mechanism of infection-related deaths of pregnant rats and intrauterine growth restriction are not understood. We assessed whether nitric oxide (NO) has differential effects on infection with Escherichia coli Dr/Afa mutants that lack either AfaE or AfaD invasins. STUDY DESIGN: Sprague-Dawley rats were infected intrauterinally with the clinical strain of E coli AfaE(+)D(+) or 1 of its isogenic mutants in the presence or absence of the NO synthesis inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Maternal/fetal mortality rates, fetoplacental weight, and infection rates were evaluated. RESULTS: Maternal and/or fetal death was associated with the presence of at least 1 virulence factor (AfaE(+)D(+)>AfaE(+)D(-)>AfaE(-)D(+)) and was increased by L-NAME treatment. The fetal and placental weights were lower than controls and were further reduced by L-NAME treatment. CONCLUSION: These results demonstrate that NO enhanced AfaE- and AfaD-mediated virulence and plays an important role in Dr/Afa(+)E coli gestational tropism.

Intrauterine Adhesions After Chlamydia Infection With a Levonorgestrel-Releasing Intrauterine Device in Place.

BACKGROUND: Little is known about the long-term reproductive effects of pelvic infection when a levonorgestrel-releasing intrauterine device (LNG-IUD) is in situ. Society guidelines do not recommend removing an LNG-IUD during pelvic infection. CASE: A 37-year-old woman presented with primary infertility, and the only contributing factor was intrauterine adhesions in the shape of an IUD. She was known to previously have an LNG-IUD and was treated for asymptomatic chlamydia infection while the IUD was in place. After lysis of adhesions, she successfully conceived spontaneously. CONCLUSION: Data on long-term reproductive effects of pelvic infection with an LNG-IUD in situ are not available, and there may be consequences affecting the intrauterine milieu requiring further studies and potential counseling.

Protective effect of Coenzyme Q10 on oxidative ovarian and uterine damage induced by methotrexate in rats.

Methotrexate (MTX) has toxic effects on the uterus and ovaries via oxidative stress. Coenzyme Q10 (CoQ10) is an important component in electron transport in the mitochondria and an antioxidant in cellular metabolism through the inhibition of lipid peroxidation. The aim of this study was to investigate the preventive effects of CoQ10 on MTX-induced utero-ovarian damage and oxidative stress in rats.In this experimental study, 30 albino Wistar female rats were divided randomly into three groups. Once a day for a month, 10 mg/kg of CoQ10 was orally administered to the rats in the MTX+CoQ10 group, while the same volume of olive oil was administered orally to the other two groups. One hour thereafter, 20 mg/kg of MTX was injected intraperitoneally into the rats in the MTX and MTX+CoQ10 groups; the remaining group was the control. At the end of the month, biochemical and histopathologic examinations were performed on the extracted uteri and ovaries. In the uterine ovarian tissues of the animals in the MTX group, there was an increase in oxidative stress mediators and a decrease in antioxidant and anti-inflammatory mediators, but these trends were reversed in the MTX+CoQ10 group, demonstrating the antioxidant effects of CoQ10. MTX leads to oxidative stress-related ovarian and uterine injury, and CoQ10 may be useful for protecting ovarian and uterine tissue from such injury.

WJ­MSCs intervention may relieve intrauterine adhesions in female rats via TGF­β1­mediated Rho/ROCK signaling inhibition.

Estrogen is a commonly used hormone in the adjuvant treatment of intrauterine adhesion (IUA), which can promote endometrial growth. Stem cell transplantation has also been reported to promote endometrial regeneration in IUA due to its potential differentiative capacity. Human Wharton's jelly mesenchymal stem cells (WJ­MSCs) are isolated from the umbilical cord, possess strong self­renewal and proliferative abilities, and are hypo­immunogenic and non­tumorigenic. Therefore, the present study aimed to investigate the therapeutic effects and underlying mechanism of WJ­MSCs transplantation with estrogen treatment, separately or as a combined therapy, on IUA. The IUA model was established using the ethanol damage method. A total of 50 Sprague­Dawley female rats were randomly divided into the control, IUA model, WJ­MSCs treatment, estrogen treatment and WJ­MSCs+ estrogen treatment groups (n=10/group). WJ­MSCs were injected three times at 5­day intervals. IUA rats in the estrogen group received 0.2 mg/kg estrogen through intragastric administration, once every 2 days for 8 weeks. Morphological changes were evaluated by hematoxylin­eosin staining. Immunohistochemical evaluations of pan­keratin, vimentin, transforming growth factor (TGF)­ß1, RhoA, RhoB, RhoC, Rho­associated coiled­coil­containing protein kinase (ROCK)I, and ROCKII expression were performed in uterine tissue. After treatment, the uterine specimens were observed to have increased uterine thickness and gland numbers in all treatment groups compared with the IUA group; however, the degree of restoration in the independent WJ­MSCs and estrogen treatment groups was better than in the combined treatment group. Immunohistochemical analysis demonstrated that pan­keratin expression was increased, and RhoA, ROCKI and TGF­ß1 expression was significantly inhibited in the WJ­MSCs and WJ­MSCs + estrogen treatment groups compared with the IUA group; however, the expression levels of these proteins were similar among all treatment groups. No change in vimentin expression was detected in any treatment group. The expression levels of RhoB, RhoC and ROCKII were clearly not affected by WJ­MSCs intervention alone. In conclusion, transplantation of WJ­MSCs may repair endometrial damage in IUA rats via TGF­ß1­mediated inhibition of RhoA/ROCKI signaling.

Effect of Gloriosa superba linn (EEGS) on mPT and monosodium glutamate-induced proliferative disorder using rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: Hyperplasia, Tumors and cancers are various forms of proliferative disorders affecting humans. Surgery is the main treatment approach while other options are also associated with adverse effects. There is therefore a need for the development of better alternative therapy that is cost effective and readily available with little or no adverse effect. Some bioactive agents in medicinal plants exhibit their anti-proliferative potential by induction of mitochondrial permeability transition pore (mPT) opening. Gloriosa superba, a medicinal plant, is folklorically used in the treatment of tumors and cancers. AIM OF THE STUDY: This study therefore aimed at investigating the effect of ethanol leaf extract of Gloriosa superba (EEGS) on mPT and monosodium glutamate-induced proliferative disorder in some specific tissues using rat model. MATERIALS AND METHODS: Isolated rat liver mitochondria were exposed to different concentrations (10, 30, 50, 70 and 90 µg/ml) of EEGS. The mPT pore opening, cytochrome c release, mitochondrial ATPase activity and lipid peroxidation were assessed spectrophotometrically. Caspases 9 and 3 activities were carried out using ELISA technique. Histological assessment of the liver, prostate and uterus of normal and monosodium glutamate (MSG)-treated rats were carried out. RESULTS: The results showed significant induction of mPT pore opening, release of cytochrome c, enhancement of mitochondrial ATPase activity, inhibition of lipid peroxidation and activation of caspases 9 and 3 activities by EEGS. The histological assessment revealed the presence of MSG-induced hepato-cellular damage, benign prostate hyperplasia and uterine hyperplasia which were ameliorated by EEGS co-administration. CONCLUSIONS: These findings suggest that EEGS contains putative agents that can induce apoptosis via induction of mPT pore opening and as well protect against MSG-induced hepato-cellular damage and proliferative disorder in prostate and uterus.

Endometrial effects of exemestane compared to tamoxifen within the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) trial: results of a prospective gynecological ultrasound substudy.

OBJECTIVES: This study prospectively assessed the effects of exemestane and tamoxifen on the endometrium in patients receiving adjuvant treatment for postmenopausal hormone receptor-positive breast cancer within the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) trial. METHODS: Patients were randomized to receive tamoxifen or exemestane. In a prespecified trial subprotocol, patients underwent transvaginal ultrasound to assess endometrial thickness at baseline and during a 1- to 3-year treatment period. RESULTS: Among 143 evaluable patients, there were no cases of endometrial thickness >10 mm with exemestane, vs. 11 cases with tamoxifen (p < 0.0003). There was a significant difference between the treatment groups regarding time to endometrial thickness >10mm, in favour of exemestane (p < 0.0001). Time to endometrial thickness > 5 mm was significantly longer for exemestane than for tamoxifen (p < 0.0001). Median time to endometrial thickness > 5 mm or censoring was 583 days in the exemestane group versus 315 days in the tamoxifen group. There were also significantly fewer incidences of endometrial thickness > 5 mm at month 6 and month 12 with exemestane compared to tamoxifen (tamoxifen: 6% and 2%; exemestane: 29% and 39%, respectively). After 12 months, mean increases in endometrial thickness from baseline were 2.64 mm and 6.0mm in the exemestane and tamoxifen groups, respectively (p < 0.0006). Moreover, 17 histologically confirmed endometrial changes were observed in the tamoxifen group, vs. one in the exemestane group. CONCLUSIONS: Exemestane was associated with significantly less endometrial thickening than tamoxifen during adjuvant endocrine therapy for postmenopausal hormone receptor-positive breast cancer.