Synthesis and biological evaluation of 3-styrylchromone derivatives as selective monoamine oxidase B inhibitors.

A series of 3-styrylchromone derivatives was synthesized and evaluated for monoamine oxidase (MAO) A and B inhibitory activities. Most of all derivatives inhibited MAO-B selectively, except compound 21. Compound 19, which had a methoxy group at R2 on the chromone ring and chlorine at R4 on phenyl ring, potently inhibited MAO-B, with an IC50 value of 2.2 nM. Compound 1 showed the highest MAO-B selectivity, with a selectivity index of >3700. Further analysis of these compounds indicated that compounds 1 and 19 were reversible and mixed-type MAO-B inhibitors, suggesting that their mode of action may be through tight-binding inhibition to MAO-B. Quantitative structure-activity relationship (QSAR) analyses of the 3-styrylchromone derivatives were conducted using their pIC50 values, through Molecular Operating Environment (MOE) and Dragon. There were 1796 descriptors of MAO-B inhibitory activity, which showed significant correlations (P < 0.05). Further investigation of the 3-styrylchromone structures as useful scaffolds was performed through three-dimensional-QSAR studies using AutoGPA, which is based on the molecular field analysis algorithm using MOE. The MAO-B inhibitory activity model constructed using pIC50 value index exhibited a determination coefficients (R2) of 0.972 and a Leave-One-Out cross-validated determination coefficients (Q2) of 0.914. These data suggest that the 3-styrylchromone derivatives assessed herein may be suitable for the design and development of novel MAO inhibitors.

Influence of a patient education and care program on women undergoing non-assisted reproductive technology fertility treatment.

PURPOSE: To determine the influence of a patient education and care program on the quality of life (QOL) of female patients undergoing non-assisted reproductive technology (ART) fertility treatment. METHODS: Participants completed the MOS 36-Item Short-Form Health Survey and fertility QOL (FertiQoL) questionnaires at baseline and at 3, 6, and 12 months of treatment. The responses of patients who underwent three sessions of the program (at baseline, 3 months, and 6 months of treatment) were compared with those of patients who did not receive the program. RESULTS: This study compared 69 patients who received an additional care program with 104 patients in the control group, all from 13 facilities. Treatment FertiQoL responses (p = 0.004) and treatment tolerability (p = 0.043) differed between the program and control groups at 3 months using the repeated measures mixed model. The cost of treatment per pregnancy was lower in the program group than in the control group. CONCLUSION: The patient education and care program provided by reproductive fertility specialists or fertility nurses during non-ART fertility programs improves patient satisfaction.

2-Styrylchromone derivatives as potent and selective monoamine oxidase B inhibitors.

A series of eighteen 2-styrylchromone derivatives (see Chart 1) were synthesized and evaluated for their monoamine oxidase (MAO) A and B inhibitory activities. Many of the derivatives inhibited MAO-B comparable to pargyline (a positive control), and most of them inhibited MAO-B selectively. Of the eighteen derivatives, compound 9 having methoxy group at R1 and chlorine at R4 showed both the best MAO-B inhibitory activity (IC50 = 17 ±â€¯2.4 nM) and the best MAO-B selectivity (IC50 for MAO-A/IC50 for MAO-B = 1500). The mode of inhibition of compound 9 against MAO-B was competitive and reversible. Quantitative structure-activity relationship (QSAR) analyses of the 2-styrylchromone derivatives were conducted using their pIC50 values with the use of Molecular Operating Environment (MOE) and Dragon, demonstrating that the descriptors of MAO-B inhibitory activity and MAO-B selectivity were 1734 and 121, respectively, that showed significant correlations (P < 0.05). We then examined the 2-styrylchromone structures as useful scaffolds through three-dimensional-QSAR studies using AutoGPA, which is based on the molecular field analysis algorithm using MOE. The model using pIC50 value indexes for MAO-B exhibited a determination coefficient (R2) of 0.873 as well as a Leave-One-Out cross-validated determination coefficient (Q2) of 0.675. These data suggested that the 2-styrylchromone structure might be a useful scaffold for the design and development of novel MAO-B inhibitors.

Individualized management of umbilical endometriosis: a report of seven cases.

AIM: The aim of this study was to review diagnostic/therapeutic strategies of umbilical endometriosis managed in our department and evaluate the effectiveness of these strategies. METHODS: Medical records for patients with diagnosis of endometriosis managed from 1999 through 2011 in the University of Tokyo Hospital were retrospectively reviewed. Cases with diagnosis of umbilical endometriosis were identified. Clinical information of age, gravida, parity, histories of surgery and oral contraceptive (OC), management for the disease prior to the first visit, symptoms, patients' desire for pregnancy, diagnostic/therapeutic methods and prognosis were reviewed and summarized. RESULTS: During the period, 2530 patients with diagnosis of endometriosis were identified. Seven patients had diagnosis of umbilical endometriosis, giving an incidence of 0.29% of all endometriosis cases and 5.6% of extragenital endometriosis cases. A definitive diagnosis was made by histological examination following a biopsy (two cases) or a resection (three cases). A clinical diagnosis was made by empirical treatment with OC (one case) or dienogest (one case). With regard to therapy, three patients chose expectant management and did not require therapeutic intervention. Three patients began OC and symptoms were well controlled in all patients. One patient who wished to conceive chose a wide resection followed by umbilical reconstruction. She became pregnant afterwards and recurrence was not reported. CONCLUSION: There are various options of diagnostic/therapeutic strategies, such as empirical treatments and OC that can provide individualized management of umbilical endometriosis, congruent with the severity of patient symptoms, age and desire for pregnancy.

Increased risk of placenta previa is associated with endometriosis and tubal factor infertility in assisted reproductive technology pregnancy.

Although assisted reproductive technology (ART) is suspected to increase the risk of placenta previa, a life-threatening complication of pregnancy, the reason is poorly understood. We recruited consecutive 318 pregnancies conceived by ART in our clinic and examined relation of ten variables, i.e. maternal age, gravidity, parity, male or female fetus, previous abortion, previous cesarean delivery, endometriosis, ovulatory disorder, tubal disease, and male infertility, to placenta previa, by logistic regression analysis. As a result, we found that endometriosis (odds ratio = 15.1; 95% CI = 7.6-500.0) and tubal disease (odds ratio = 4.4; 95% CI = 1.1-26.3) were significantly associated with placenta previa. It would be preferable to take the increased risk of placenta previa into account in treating ART pregnancy with endometriosis and tubal disease.

A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs.

Background. Many anti-cancer drugs used in clinical practice cause adverse events such as oral mucositis, neurotoxicity, and extravascular leakage. We have reported that two 3-styrylchromone derivatives, 7-methoxy-3-[(1E)-2-phenylethenyl]-4H-1-benzopyran-4-one (Compound A) and 3-[(1E)-2-(4-hydroxyphenyl)ethenyl]-7-methoxy-4H-1-benzopyran-4-one (Compound B), showed the highest tumor-specificity against human oral squamous cell carcinoma (OSCC) cell lines among 291 related compounds. After confirming their superiority by comparing their tumor specificity with newly synthesized 65 derivatives, we investigated the neurotoxicity of these compounds in comparison with four popular anti-cancer drugs. Methods: Tumor-specificity (TSM, TSE, TSN) was evaluated as the ratio of mean CC50 for human normal oral mesenchymal (gingival fibroblast, pulp cell), oral epithelial cells (gingival epithelial progenitor), and neuronal cells (PC-12, SH-SY5Y, LY-PPB6, differentiated PC-12) to OSCC cells (Ca9-22, HSC-2), respectively. Results: Compounds A and B showed one order of magnitude higher TSM than newly synthesized derivatives, confirming its prominent tumor-specificity. Docetaxel showed one order of magnitude higher TSM, but two orders of magnitude lower TSE than Compounds A and B. Compounds A and B showed higher TSM, TSE, and TSN values than doxorubicin, 5-FU, and cisplatin, damaging OSCC cells at concentrations that do not affect the viability of normal epithelial and neuronal cells. QSAR prediction based on the Tox21 database suggested that Compounds A and B may inhibit the signaling pathway of estrogen-related receptors.

Successful pregnancy following low-dose hCG administration in addition to hMG in a patient with hypothalamic amenorrhea due to weight loss.

We describe successful ovulation induction with low-dose hCG administration in addition to hMG in a patient with refractory hypothalamic amenorrhea. A 24-year-old woman with weight loss-related amenorrhea underwent ovulation induction and intracytoplasmic sperm injection (ICSI). Administration of exogenous gonadotropins was ineffective in ovulation induction. Supplementation with low-dose hCG in order to increase luteinizing hormone (LH) activity in the late follicular phase produced late folliculogenesis and steroidogenesis, and ovulation was then successfully induced. This report reacknowledges the critical role that LH plays cooperatively with follicle-stimulating hormone in both folliculogenesis and steroidogenesis.

Singleton pregnancy outcomes after assisted and non-assisted reproductive technology in infertile patients.

PURPOSE: Singleton pregnancy after assisted reproductive technology (ART) has been associated with higher risks of adverse pregnancy outcome than naturally conceived singleton pregnancy. This study was to elucidate whether the ART procedure is responsible for abnormal pregnancy outcome comparing those after ART and non-ART in infertile patients. METHODS: We compare the singleton pregnancy outcome of infertile patients in our university hospital between 2000 and 2008 following ART (351 pregnancies) and non-ART (213 pregnancies) procedures. Pregnancy outcome parameters were incidence of pregnancy induced hypertension, placenta previa, placental abruption, cesarean delivery, preterm birth, very preterm birth, stillbirth, low birth weight and very low birth weight. RESULTS: Most of the pregnancy outcome parameters were not significantly different between the ART group and the non-ART group. Only placenta previa was significantly higher in the ART group than in the non-ART group (odds ratio 4.0; 95 % CI 1.2-13.7). CONCLUSIONS: ART procedure may itself be a risk factor for the development of placenta previa. Some of the abnormal perinatal outcomes that had been previously attributed to ART, however, may be due to the baseline characteristics of infertile patients.

TGF-ß1 induces proteinase-activated receptor 2 (PAR2) expression in endometriotic stromal cells and stimulates PAR2 activation-induced secretion of IL-6.

BACKGROUND: Proteinase-activated receptor 2 (PAR2) is a G-protein-coupled receptor that is activated by several serine proteases. PAR2 activation in endometriotic stromal cells (ESCs) has been implicated in the development of endometriosis but the regulatory mechanism of PAR2 expression in ESC is unknown. Our objective was to study the mechanism by which PAR2 expression may be regulated in endometriotic lesions. METHODS: Primary cultures of ESCs were treated with transforming growth factor-ß (TGF-ß) 1, tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), and the expression of PAR2 was examined by real-time quantitative PCR. ESCs pretreated with or without TGF-ß1 were treated with PAR2 agonist peptide (PAR2AP) and the secretion of the pro-endometriotic cytokine, IL-6, was measured using a specific enzyme-linked immunosorbent assay. Effects of TGF-ß type 1 inhibitor, SB431542, and PAR2 small interfering RNA (siRNA) on the TGF-ß1 stimulation of PAR2 gene expression and PAR2AP-induced IL-6 secretion were also evaluated. To study intracellular signaling, effects of inhibitors of mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K) and of Smad4 siRNA on the TGF-ß1-induced PAR2 gene expression were studied. RESULTS: Only TGF-ß1, but neither TNF-α nor IL-1ß, increased gene expression of PAR2. Activation of PAR2 with PAR2AP increased the secretion of IL-6 from ESCs. As expected, TGF-ß1 pretreatment dose-dependently enhanced the PAR2AP-induced increase in IL-6 secretion from ESCs. Treatment of ESCs with the TGF-ß type 1 inhibitor, SB431542, inhibited both TGF-ß1-stimulation of PAR2 gene expression and PAR2AP-induced IL-6 secretion. Transfection of ESCs with PAR2 siRNA produced a similar inhibition of IL-6 secretion. The TGF-ß1-induced increase in PAR2 gene expression was repressed by inhibition of p38 MAPK, p42/44 MAPK or PI3K, but not by knockdown of Smad4 expression. CONCLUSIONS: In view of significant roles of PAR2 and IL-6 in endometriosis, the TGF-ß1-induced increase in PAR2 expression may be an elaborate mechanism that augments the progression of the disease.

Dienogest, a new conservative strategy for extragenital endometriosis: a pilot study.

Extragenital endometriosis severely impairs the quality of life for affected women but its standard management has not yet been well established because of its relatively low incidence. As extragenital organs, intestine, followed by urinary tract, is the most common place affected by endometriosis, for which surgical treatment is sometimes difficult and accompanied by severe complications. Recently, dienogest, a novel progestin, has emerged as a new alternative for endometriosis, especially for endometriosis-associated pain. In this report, we presented four cases with rectosigmoidal and one with bladder endometriosis, treated with oral 2 mg/day dienogest for over 6 months. For all cases, the measurable extragenital lesions exhibited the reduction in their size after 10 to 11 months of use, accompanied with immediate relief of subjective symptoms related with extragenital lesions. This report suggests that dienogest can be a novel conservative alternative for extragenital endometriosis.

Progesterone decreases bone morphogenetic protein (BMP) 7 expression and BMP7 inhibits decidualization and proliferation in endometrial stromal cells.

BACKGROUND: Regulation of decidualization is decisive for proper implantation and the establishment of pregnancy. Recent studies have suggested that several bone morphogenetic proteins (BMPs) play physiological roles in reproduction. In the present study, we examined the expression of BMP7 in the endometrium and the effect of BMP7 on decidualization and proliferation of endometrial stromal cells (ESC). METHODS: The gene expression of BMP7 in endometrial tissues collected from women with regular menstrual cycles was determined and the effect of ovarian steroid hormones on BMP7 gene expression was investigated in cultured ESC. The effect of BMP7 on the decidualization of ESC was determined by measuring the gene expression and protein secretion of insulin-like growth factor binding protein 1 (IGFBP1), a marker of decidualization. The effect of BMP7 on the proliferation of ESC was examined by the bromodeoxyuridine (BrdU) incorporation assay. RESULTS: The gene expression of BMP7 in endometrial tissues was low at and after the mid-secretory phase of the menstrual cycle. Progesterone suppressed the gene expression of BMP7 in cultured ESC. Treatment with progesterone and estradiol for 12 days achieved decidualization of ESC, increasing the gene expression and protein secretion of IGFBP1. Addition of BMP7 protein to the culture almost completely inhibited these increases. BMP7 suppressed BrdU incorporation in ESC, which indicated an antiproliferative effect of BMP7 on ESC. CONCLUSIONS: Progesterone-induced suppression of BMP7 and BMP7-induced inhibition of decidualization and proliferation of ESC suggest an elaborate regulatory mechanism for decidualization through BMP7 in the endometrium.

Interleukin (IL)-1beta stimulates migration and survival of first-trimester villous cytotrophoblast cells through endometrial epithelial cell-derived IL-8.

IL-1, secreted by human embryos and trophoblast cells, is important for successful implantation and pregnancy. We previously reported that IL-1beta induced IL-8 production in human endometrial stromal cells (ESCs) and that induction was regulated by substances implicated in implantation. In the present study using human primary cells in culture, we measured IL-1beta-induced production of IL-8 from endometrial epithelial cells (EECs) and ESCs and examined effects of the endometrium-derived IL-8 on migration and number of first-trimester villous cytotrophoblast cells (vCTs). Both basal and IL-1beta-induced IL-8 levels of cell supernatants were much higher in EECs than ESCs. Addition of IL-1beta to EECs increased the chemotactic activity of the supernatants to vCTs, and this effect was suppressed by immunoneutralization with anti-IL-8 antibody. Supernatants of IL-1beta-stimulated EECs yielded significantly higher number of vCTs compared with those of untreated EECs, and the effect was inhibited by IL-8 antibody. These findings suggest that IL-1 promotes implantation by stimulating EECs to produce IL-8, which subsequently induces migration of vCTs and contributes to survival of vCTs.

Interleukin-4 stimulates proliferation of endometriotic stromal cells.

Several lines of evidence indicate that the Th2 immune response is associated with endometriosis. Although an increased concentration of interleukin (IL)-4, a typical Th2 cytokine, has been reported in endometriotic tissues, the implication of this for endometriosis has not been determined. To investigate a possible role of IL-4 in the development of endometriosis, we examined the presence of IL-4-producing cells in endometriotic tissues and the effect of IL-4 on proliferation of endometriotic stromal cells. Endometriotic stromal cells were isolated from endometriotic tissues obtained from women undergoing surgery for endometrioma. Immunohistochemistry of endometriotic tissues revealed that IL-4-positive cells were abundant in the stroma. The effect of IL-4 on proliferation of endometriotic stromal cells was studied using cell counting and BrdU incorporation assays. IL-4 (0.1 to 10 ng/ml) significantly increased cell number and BrdU incorporation in a dose-dependent manner, and the proliferative effect of IL-4 was inhibited by anti-IL-4 receptor antibody. IL-4-induced activation of mitogen-activated protein kinases in endometriotic stromal cells was examined by Western blotting. IL-4 induced phosphorylation of p38 mitogen-activated protein kinase, stress-activated protein kinase/c-Jun kinase, and p42/44 mitogen-activated protein kinase and inhibitors of these kinases suppressed IL-4-induced proliferation of endometriotic stromal cells. These findings suggest that proliferation of endometriotic stromal cells induced by locally produced IL-4 is involved in the development of endometriosis.

Tunicamycin enhances the apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand in endometriotic stromal cells.

BACKGROUND: The increase in concentration of osteoprotegerin, an antagonist of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), in the peritoneal fluid of women with endometriosis may interfere with TRAIL-induced apoptosis in endometriotic cells and promote the development of endometriosis. In the present study, the effect of tunicamycin, a possible apoptosis enhancer, on TRAIL-induced apoptosis in endometriotic stromal cells (ESC) was determined. METHODS: ESC were isolated from cyst walls of ovarian endometrioma and cultured. ESC were incubated with or without tunicamycin (2 microg/ml) for the first 16 h, and then incubated with or without TRAIL (200 ng/ml) for the following 24 h. To examine whether caspases were involved in TRAIL-induced apoptosis, z-VAD-fmk (30 microM), a general caspase inhibitor, was added 1 h before TRAIL treatment. ESC were transfected with small interfering RNA (siRNA) for DR5, a receptor of TRAIL, before tunicamycin treatment to evaluate its role in ESC. DR5 mRNA level was determined by quantitative RT-PCR. Apoptosis in ESC was evaluated by flow cytometry. RESULTS: Tunicamycin increases both DR5 mRNA (P < 0.005) and TRAIL-induced apoptosis (P < 0.0001) in ESC. The increase in TRAIL-induced apoptosis in ESC by tunicamycin was suppressed (P < 0.05) by z-VAD-fmk. Transfection with DR5 siRNA suppressed the tunicamycin-induced increase in DR5 mRNA and abrogated the up-regulation of TRAIL-induced apoptosis by tunicamycin. CONCLUSIONS: The combined treatment with tunicamycin and TRAIL may have therapeutic potential in the treatment of endometriosis.

Interleukin (IL)-17A stimulates IL-8 secretion, cyclooxygensase-2 expression, and cell proliferation of endometriotic stromal cells.

IL-17A is secreted from Th17 cells, a discovery leading to revision of the mechanism underlying the role of Th1/Th2 in the immune response. Strong evidence suggests that immune responses associated with inflammation are involved in the pathogenesis of endometriosis. In the present study, we first demonstrated that the presence of Th17 cells in peritoneal fluid of endometriotic women by flow cytometric analysis and IL-17A-positive cells in endometriotic tissues by immunohistochemistry. To investigate the role of IL-17A in the development of endometriosis, we then studied the effect of IL-17A on IL-8 production, cyclooxygensase-2 expression, and cell proliferation of cultured endometriotic stromal cells (ESCs). IL-17A enhanced IL-8 secretion from ESCs in a dose-dependent manner. The IL-17A-induced secretion of IL-8 from ESCs was suppressed by anti-IL-17 receptor A antibodies or inhibitors of p38 MAPK, p42/44 MAPK, and stress-activated protein kinase/c-Jun N-terminal kinase. Addition of TNFalpha synergistically increased IL-17A-induced IL-8 secretion from ESCs. IL-17A also enhanced the expression of cyclooxygensase-2 mRNA and proliferation of ESCs. IL-17A may play a role in the development of endometriosis by stimulating inflammatory responses and proliferation of ESCs.

Intraoperative and Postoperative Clinical Evaluation of the Hysteroscopic Morcellator System for Endometrial Polypectomy: A Prospective, Randomized, Single-blind, Parallel Group Comparison Study.

OBJECTIVE: To evaluate the TRUCLEAR™ system (Smith and Nephew Inc., London, UK), a hysteroscopic system that morcellates and aspirates masses, in terms of the operating time, surgeon's convenience, and effect on patients compared with conventional electrosurgical resection. METHODS: Patients undergoing hysteroscopic resection of endometrial polyps were randomly allocated to undergo hysteroscopic morcellation or electrosurgical resection (UMIN-CTR identifier: UMIN000019649). The primary outcome was the operating time. Secondary outcomes were the removal success, fluid deficit, convenience with the technique, insertion time, number of insertions during the operation, visibility of the operative field, recurrence of the patient's chief complaint, and adverse events. RESULTS: Sixty-seven women were randomly allocated to the morcellation arm (n = 34) or electrosurgical resection arm (n = 33) from November 2015 to November 2016. The polyps were completely removed, and no adverse events were observed in all 67 patients. The average operating time (8.3 min vs. 12.0 min, P = 0.014), insertion time (5.0 min vs. 9.0 min, P < 0.001), and number of insertions (1.0 vs. 8.2, P < 0.001) were significantly lower in the morcellation arm than in the electrosurgical resection arm. Surgeons' subjective evaluation measured on a 10-cm visual analog scale was higher in the morcellation arm than in the electrosurgical resection arm in terms of easiness of removal (8.4 vs. 6.5, P < 0.001) and visibility of the operative field (7.8 vs. 6.4, P < 0.001). CONCLUSION: Surgeons gave the hysteroscopic morcellator system a better evaluation compared than electrosurgical resection, and the system shortened the operating time.

Gene expression of Dio2 (thyroid hormone converting enzyme) in telencephalon is linked with predisposed biological motion preference in domestic chicks.

Filial imprinting leads to the formation of social attachment if training is performed during a brief sensitive period after hatching. We found that thyroid hormone (3,5,3'-triiodothyronine, T3) acts as a critical determining factor of the sensitive period in domestic chicks. Imprinting upregulates gene expression of the converting enzyme (Dio2, type 2 iodothyronine deiodinase) in the telencephalon, leading to increased brain T3 content. If systemically applied, T3 facilitates imprinting in aged chicks even after the sensitive period is over. Imprinting is also associated with the rapid development of visual perception. Exposure to motion pictures induces a predisposed preference to Johansson's biological motion (BM), and those individuals with higher BM preference are more easily imprinted. Here, we examined whether Dio2 expression is also linked with BM predisposition. Chicks were trained by a rotating red block, and tested for imprinting (experiment 1) and BM preference (experiment 2). To examine the time courses of behavioural and physiological processes, Dio2 expression in telencephalon was compared among three groups: naïve control chicks, and chicks trained for a short (0.5 h) or long period (2 h). In experiment 1, higher Dio2 expression appeared in the 2-h group than in the 0.5-h/control groups, but it was not correlated with the individual imprinting score. In experiment 2, a significant positive correlation appeared between Dio2 expression and BM preference in 2-h-trained chicks. Memory priming by T3 is therefore functionally linked to BM preference induction, leading to successful imprinting to natural objects even when they are initially exposed to artificial objects.

Metformin suppresses interleukin (IL)-1beta-induced IL-8 production, aromatase activation, and proliferation of endometriotic stromal cells.

CONTEXT: Metformin, a widely used treatment for diabetes that improves insulin sensitivity, also has both antiinflammatory properties and a modulatory effect on ovarian steroid production, two actions that have been suggested to be efficacious in therapy for endometriosis. OBJECTIVE: To determine whether metformin may be effective for the treatment of endometriosis, we evaluated the effects of this agent on inflammatory response, estradiol production, and proliferation of endometriotic stromal cells (ESCs). DESIGN: ESCs derived from ovarian endometriomas were cultured with various concentrations of metformin. MAIN OUTCOME MEASURES: IL-8 production, mRNA expression and aromatase activity, and 5-bromo-2'-deoxyuridine incorporation in ESCs were measured. RESULTS: Metformin dose-dependently suppressed IL-1beta-induced IL-8 production, cAMP-induced mRNA expression and aromatase activity, and 5-bromo-2'-deoxyuridine incorporation in ESCs. CONCLUSION: These results suggest that further investigation into the unique therapeutic potential of metformin as an antiendometriotic drug is warranted.

Selective increase in high molecular weight adiponectin concentration in serum of women with preeclampsia.

Total adiponectin concentrations have been shown to increase in serum of preeclamptic women. However, variance of concentrations of different isoforms has not been studied, despite the emerging notion that high, medium and low molecular weight adiponectin exert different functions. We have determined serum concentrations of each adiponectin isoform using a newly developed enzyme immunosorbent assay. High molecular weight (HMW) adiponectin concentrations were significantly higher in women with preeclampsia (n=14; median, 11.2 microg/ml; interquartile range, 9.2-15.8) compared to normal pregnant women (n=14; 6.8 microg/ml, 5.4-10.7; P=0.04). In contrast, medium molecular weight and low molecular weight adiponectin concentrations were substantially equal between the groups. The ratio of HMW adiponectin to total adiponectin was also markedly higher in preeclamptic women (52.3%, 49.5-58.7) than control women (43.0%; 39.8-48.0; P=0.004). Taken together with other reports our findings imply a physiological feedback response to minimize endothelial damage in preeclamptic women.

Expression of toll-like receptors 2, 3, 4, and 9 genes in the human endometrium during the menstrual cycle.

Innate immunity in the endometrium has fundamental significance for reproduction. Although toll-like receptors (TLRs) play central roles in innate immune responses, their expression in the human endometrium remains to be fully elucidated. We have examined the gene expression of TLR2, TLR3, TLR4, and TLR9 in endometrial tissues by real-time quantitative PCR and in situ hybridization. The expression levels of the four genes in endometrial tissues varied in a similar pattern during the menstrual cycle; the levels were high in the perimenstrual period and low in the periovulatory period. Expression of the four genes was detected in both epithelial cells and stromal cells throughout the menstrual cycle. Expression levels were higher in epithelial cells for TLR3 and in stromal cells for TLR4, while they were comparable in epithelial cells and stromal cells for TLR2 and TLR9. These findings imply that differential spatio-temporal expression patterns of TLRs subserve proper innate immunity of the endometrium.