Advanced Glycation End-Products of Follicular Fluid are Associated with Embryo Morphokinetic Parameters and ART Outcomes.

Advanced glycation end products (AGEs) can disrupt antioxidant system and steroidogenesis, resulting in detrimental effects on assisted reproductive technology (ART) outcomes. This study aimed to investigate the association of AGEs in follicular fluid (FF) with morphokinetic parameters of embryos and ART outcomes. Fifty women undergoing ART treatment were studied. AGEs, glucose, 25(OH) vitamin D, malondialdehyde (MDA) levels and catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX) activities were evaluated in FF. The expression of 3ßHSD, CYP11A1, and CYP19A1 genes were analyzed in granulosa cells (GCs) by qRT-PCR technique. Morphokinetic parameters were evaluated using time-lapse technology. The FF level of AGEs was reversely associated with CAT, SOD, and GPX activities, and total and mature oocytes number, blastocyst formation rate, and high-grade embryos number, while it showed positive correlations with the FF MDA levels, the expression of steroidogenesis genes, number of immature oocytes, morphokinetic parameters, and number of low-grade embryos. Furthermore, the level of vitamin D in FF had an inverse association with AGEs and positive correlations with ART outcomes and morphokinetic parameters. Comparison between the those with positive and negative biochemical pregnancy showed no significant differences in terms of FF factors and just the expression of 3ßHSD, CYP11A1, and CYP19A1 genes were higher in pregnant women (p < 0.05). AGEs could delay blastomere division and lead to an increase in the number of low-quality embryos, while vitamin D have an adverse effect on AGEs and a protective function against AGEs negative effects.

Engineered exosome as a biological nanoplatform for drug delivery of Rosmarinic acid to improve implantation in mice with induced endometritis.

Endometritis is an inflammatory and histopathologic disease in uterine tissues that interferes with the proper decidualization and implantation of the embryo. In this study, rosmarinic acid (RA) is used as an anti-inflammatory agent that encapsulates in exosomes and is used to attenuate lipopolysaccharide (LPS)-induced endometritis and improve implantation. For this purpose, exosomes were loaded with RA and then administrated into the animal groups, including RA, exosome, RA plus exosome (RA + Exo), and RA-loaded exosomes (RALExo) groups. The concentrations of RA or exosomes used in this study were 10 mg/kg, and the compounds were injected into the uterine horn 24 h following the induction of endometritis. Upon the presence of inflammation detected by the histopathological method, the most proper groups were mated with male mice. The effect of the treatment group on the implantation rate, progesterone levels, and gene expressions were assessed by Chicago Blue staining, enzyme-linked immunosorbent assay (ELISA), and Quantitative PCR (qPCR), respectively. Results showed RALExo10 and RA10 + Exo10 groups improved pathological alterations, enhanced progesterone levels, increased implantation rate, as well as heightened expression levels of Leukemia inhibitory factor (LIF) and Mucin-16 (MUC-16) genes. Besides, the expression levels of inflammatory cytokines, including Transforming growth factor-ß (TGF-ß), Interlukine-10 (IL-10), Interlukine-15 (IL-15), and Interlukine-18 (IL-18), were regulated. Our findings indicated that the expression of LIF, Muc-16 genes as well as IL-18, were significantly correlated with serum progesterone concentrations and the implantation rate in the treatment groups. The RALExo10 and RA10 + Exo10 groups showed ameliorated implantation rates in experimental groups.

Vitamin D and its binding protein in patients with leiomyomas.

AIM: This study examined the levels of VitD, VitD binding protein (DBP), and free VitD in leiomyomas patients and their association with the quantity, dimensions, and site of fibroid growths. Additionally, we evaluated the potentiality of employing these factors as a biomarker tool for the diagnosis and assessment of uterine fibroid progression. METHODS: This study involved the participation of 55 women with leiomyomas and 50 healthy women. We utilized commercial ELISA kits to measure the levels of total VitD and DBP in their serum. Additionally, we calculated the levels of free VitD and the ratio of VitD to DBP. Moreover, we determined the number, size, and location of the leiomyomas in the patients. RESULTS: There were no significant differences in the levels of total VitD between the groups. However, patients had significantly lower levels of free VitD and higher levels of DBP compared to the control group. The size of the largest leiomyomas showed a negative relationship with free VitD and a positive relationship with DBP. Receiver operating characteristic analyses, showed that the cut-off value for free VitD was 4.47 pg/mL, with a sensitivity of 75.6% and a specificity of 74.4%. The cut-off value for DBP was 256.2 µg/mL, with a sensitivity of 86% and a specificity of 70.3%. CONCLUSIONS: Free VitD and DBP potentially contribute to the development of leiomyomas and are linked to the size of these tumors. The measurement of serum levels of these factors could serve as additional biomarkers for the diagnosis of leiomyomas.

Association of Trophectoderm mRNAs and MicroRNAs with Chromosomal Aneuploidy of Embryo.

MicroRNAs (miRNAs) and mRNAs can serve as indicators of the chromosomal state of an embryo, with different profiles observed in euploid and aneuploid blastocysts. Examining the levels of miRNAs associated with aneuploidy and euploidy, as well as mRNAs related to implantation, can aid in predicting blastocyst chromosomal normality and improving assisted reproductive technology (ART) outcomes. This study analyzed chromosomal abnormality of 25 blastocysts using fluorescence in situ hybridization (FISH) and also the expression of genes ERBB4, SELL, ITGB3, and ITGAV, as well as miRNAs, miR-339, miR-27b, miR-661, miR-30c, miR-191, miR-345, miR-142, miR-141, miR-20a, and miR-372. We found that 17 out of 25 embryos were aneuploid. Moreover, results revealed lower expression levels of miR-30c and miR-372 in aneuploid embryos compared to euploid ones, while ITGAV and ITGB3 showed significantly higher expression in aneuploid embryos. These findings suggest that miR-372, miR-30c, ITGAV, and ITGB3 expression in trophectoderm cells can serve as biomarkers for assessing embryo health.

Programmed cell death 4: A novel player in the pathogenesis of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a pathological condition recognized by menstrual cycle irregularities, androgen excess, and polycystic ovarian morphology, affecting a significant proportion of women of childbearing age and accounting for the most prevalent cause of anovulatory sterility. In addition, PCOS is frequently accompanied by metabolic and endocrine disturbances such as obesity, dyslipidemia, insulin resistance, and hyperinsulinemia, indicating the multiplicity of mechanisms implicated in the progression of PCOS. However, the exact pathogenesis of PCOS is yet to be elucidated. Programmed cell death 4 (PDCD4) is a ubiquitously expressed protein that contributes to the regulation of various cellular processes, including gene expression, cell cycle progression, proliferation, and apoptosis. Despite some disparities concerning its exact cellular effects, PDCD4 is generally characterized as a protein that inhibits cell cycle progression and proliferation and instead drives the cell into apoptosis. The apoptosis of granulosa cells (GCs) is speculated to take a major part in the occurrence and progression of PCOS by ceasing antral follicle development and compromising oocyte competence. Given the possible involvement of GC apoptosis in the progression of PCOS, as well as the contribution of PDCD4 to the regulation of cell apoptosis and the development of metabolic diseases, the current review aimed to discuss whether or how PDCD4 can play a role in the pathogenesis of PCOS by affecting GC apoptosis.

Expression of interleukin-1ß and its receptor in human granulosa cells and their association with steroidogenesis.

This study aimed to investigate whether interleukin 1ß (IL-1ß) and soluble IL-1 receptor 2 (sIL-1R2) are expressed in human granulosa cells (GCs) and relate to ovarian steroidogenesis. Ninety-six women undergoing in vitro fertilization (IVF) were recruited. RT-PCR and immunocytochemistry were used to detect mRNAs and proteins of IL-1ß and IL-1R2, respectively. The steroidogenesis of primary cultured GCs was evaluated following treatment with either IL-1ß alone or IL-1ß and FSH in combination. There were positive correlations between serum IL-1ß and serum progesterone (r = 0.220, p = 0.032) and follicular fluid (FF) estradiol (r = 0.242, p = 0.018). Additionally, serum and FF sIL-1R2 were negatively and positively correlated with FF estradiol (r = -0.376, p = 0.005) and FF progesterone (r = 0.434, p = 0.001), respectively. The mRNA and protein expression of IL-1ß and IL-1R2 became evident in GCs. IL-1ß alone significantly increased estradiol secretion from GCs, but in the presence of FSH, it could notably promote progesterone secretion in addition to estradiol. In conclusion, IL-1ß and sIL-1R2 are expressed in human GCs and substantially contribute to ovarian steroidogenesis, suggesting that the IL-1ß system may be a potential target for optimizing ovarian hyperstimulation and steroidogenesis in IVF cycles.

Follicular fluid advanced glycation end products in assisted reproduction: A systematic review.

Follicular fluid (FF) advanced glycation end products (AGEs) have been associated with low oocyte quality and number, low fertilization rate, impaired embryonic development and low pregnancy rate. These findings are especially relevant in women undergoing in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), ie, assisted reproductive technology (ART). A systematic literature search was conducted to examine various AGEs including pentosidine, carboxymethyl-lysine (CML), methylglyoxal 5-hydro-5-methylimidazolones (MG-H1), toxic AGE (TAGE), and soluble receptor for AGE (sRAGE) with ART outcomes. Studies showed that total AGEs and sRAGE in FF were associated with the ovarian response, follicle number, retrieved oocyte number, mature (MII) oocyte number, fertilization rate, embryo number, embryo quality, and successful pregnancy. Although FF AGEs could be considered predictive biomarkers, population heterogeneity and differences in ovulation induction protocols make the findings less clear. This review highlights important role of AGEs in ART and necessity of evaluating AGEs in serum vs with FF to better predict ART outcomes.

Anticancer Effect of Enterococcus faecium, Isolated from Vaginal Fluid, on Ovarian Cancer Cells

Background: Given the association between cervicovaginal microbiota and OVC, we investigated the effect of Enterococcus faecium conditioned medium (CM) on OVC (Caov-4) cells. Methods: CM was obtained from the bacterium E. faecium isolated from the vagina of healthy women. The Caov-4 cells were treated with varying concentrations of CM that comprised co-cultured bacteria with 0.2, 0.5, 1, 1.5, and 2 OD for 12, 24, and 48 h. The apoptosis and growth of cancer cells were evaluated by 4',6-diamidino-2-phenylindole (DAPI) staining, flow cytometry, and DNA laddering assay. Moreover, the expression of PTEN, BAX, BCL2, and AKT1 genes were analyzed using real-time PCR. Results: The CM at a concentration of 0.5 OD from the cultured bacteria and incubation time of 48 h showed the highest negative effect on the viability of cancer cells. The CM treatment increased DNA fragmentation and also induced apoptosis in Caov-4 cells. Interestingly, CM could decrease the expression of proapoptotic genes were less, while antiapoptotic genes were more than fluorouracil in the presence of CM. Conclusion: CM of human-derived E. faecium could have an anticancer effect on OVC cells in a concentration- and time-dependent manner. This study demonstrated that E. faecium secretes anticancer substances into the CM, which could directly affect the viability and apoptosis of cancer cells.

Enhanced anti-inflammatory effect of Rosmarinic acid by encapsulation and combination with the exosome in mice with LPS-induced endometritis through suppressing the TLR4-NLRP3 signaling pathway.

The TLR4-NLRP3 signaling pathway plays an essential role in the development of inflammation and especially endometritis. Rosmarinic acid (RA) can have potent anti-inflammatory effects in the drug-loading system. The purpose of this was to evaluate the anti-inflammatory effects of RA loaded to exosomes (RLE) on lipopolysaccharide (LPS)-induced endometritis in mice. RA was loaded into serum-derived exosome, using sonication methods. Animals in the treatment groups were subjected to uterine horn injection of RA, exosome, RA combination with exosome (R+E), and RA loaded to exosome (RLE) in uterine horn by two dosages in each group (5 and 10 mg/kg of RA or exosome), 24 h after inducing endometritis. Histopathological analysis, MPO production, immunohistochemistry, and qPCR were used to determine whether the treatment groups were adequate in controlling inflammation. The results showed that treatment groups, and mainly RLE10 and R10 +E10 groups, could modulate pathological changes, inhibit myeloperoxidase (MPO) activity, and significantly reduce the gene and protein expression of TLR4, NLRP3, inflammatory cytokines such as IL-1ß, IL-18, and TNF-α, and lastly, GSDM-D as a pyroptosis factor. In conclusion, RA loaded and combination with exosomes at a dosage of 10 mg/kg (RLE10 and R10 +E10) improved endometritis in mice through a suppressing TLR4-NLRP3 signaling pathway.

Optimization of green and environmentally-benign synthesis of isoamyl acetate in the presence of ball-milled seashells by response surface methodology.

Ball-milled seashells, as a nano-biocomposite catalyst and natural source of CaCO3 in its aragonite microcrystalline form with fixed CO2, was optimized for the synthesis of isoamyl acetate (3-methylbutyl ethanoate) by response surface methodology with a five-level three-factor rotatable circumscribed central composite design. The seashells nano-biocomposite has proved to be an excellent heterogeneous multifunctional catalyst for the green and environmentally-benign synthesis of isoamyl acetate from acetic acid and isoamyl alcohol under solvent-free conditions. A high yield of 91% was obtained under the following optimal conditions: molar ratio of alcohol: acetic acid (1:3.7), catalyst loading (15.7 mg), the reaction temperature (98 °C), and the reaction time (219 min). The outstanding advantages of this protocol are the use of an inexpensive, naturally occurring and easily prepared nano-biocomposite material having appropriate thermal stability and without any modifications using hazardous reagents, lower catalyst loading and reaction temperature, no use of corrosive Bronsted acids as well as toxic azeotropic solvents or water adsorbents, and simplicity of the procedure.

Comparing energy system optimization models and integrated assessment models: Relevance for energy policy advice.

Background: The transition to a climate neutral society such as that envisaged in the European Union Green Deal requires careful and comprehensive planning. Integrated assessment models (IAMs) and energy system optimisation models (ESOMs) are both commonly used for policy advice and in the process of policy design. In Europe, a vast landscape of these models has emerged and both kinds of models have been part of numerous model comparison and model linking exercises. However, IAMs and ESOMs have rarely been compared or linked with one another. Methods: This study conducts an explorative comparison and identifies possible flows of information between 11 of the integrated assessment and energy system models in the European Climate and Energy Modelling Forum. The study identifies and compares regional aggregations and commonly reported variables. We define harmonised regions and a subset of shared result variables that enable the comparison of scenario results across the models. Results: The results highlight how power generation and demand development are related and driven by regional and sectoral drivers. They also show that demand developments like for hydrogen can be linked with power generation potentials such as onshore wind power. Lastly, the results show that the role of nuclear power is related to the availability of wind resources. Conclusions: This comparison and analysis of modelling results across model type boundaries provides modellers and policymakers with a better understanding of how to interpret both IAM and ESOM results. It also highlights the need for community standards for region definitions and information about reported variables to facilitate future comparisons of this kind. The comparison shows that regional aggregations might conceal differences within regions that are potentially of interest for national policy makers thereby indicating a need for national-level analysis.

Interrelation among exercise training, cardiac hypertrophy, and tissue kallikrein-kinin system in athlete and non-athlete women.

Introduction: The tissue kallikrein-kinin system is an endogenous homeostatic pathway, which its stimulation is associated with cardioprotection. The present study aimed to determine the effect of exercise training on plasma tissue kallikrein (TK) and bradykinin (BK) and their association with cardiac hypertrophy. Methods: 22 non-athlete and 22 athlete women were exposed to acute (Bruce test) and chronic (12-week swimming training) exercises. 2D echocardiography was used to evaluate morphological and functional features of the heart. Plasma concentrations of TK and BK were quantified by ELISA. Results: Athletes had significantly higher values of left ventricle end-diastolic diameter index (LVEDDI) and left ventricle mass index (LVMI) than non-athletes. Exercise intervention affected echocardiographic features in neither of the study groups. Chronic exercise training notably increased plasma levels of TK and BK, which increase was more pronounced in the athletes. Plasma TK negatively correlated with LVEDDI (r=-0.64, P=0.036 and r=-0.58, P=0.027) and LVMI (r=-0.51, P=0.032 and r=-0.63, P=0.028) in the non-athlete and athlete groups. In opposition, there was a positive correlation between plasma TK and left ventricle ejection fraction in non-athletes (r=0.39, P=0.049) and athletes (r=0.53, P=0.019). Conclusion: The upregulation of the tissue kallikrein-kinin system may be a protective mechanism against excessive cardiac hypertrophy induced by chronic exercise training.

Growth Hormone: A Potential Treatment of Patients with Refractory Thin Endometrium: A Clinical Trial Study.

BACKGROUND: Growth hormone (GH) is a potential treatment in the assisted reproductive technology (ART) to improve endometrial receptivity and thickness. In the current study, we investigated the effect of the intrauterine administration of GH on the endometrial thickness (EMT) and ART outcomes in the patients with refractory thin endometrium. MATERIALS AND METHODS: In this clinical trial study, women with a refractory thin endometrium and a history of one or more frozen embryo transfer (FET) cancellation who were referred to the infertility center of the Tabriz Al-Zahra hospital (Tabriz, Iran) and Milad Infertility Clinic (Tabriz, Iran) received intrauterine injections of GH every other day from day 14 of the menstrual cycle until the EMT reached ≥7 mm in addition to the routine endometrium preparation protocol. EMT was evaluated during the treatment and in the cases with EMT ≥7 mm, biochemical/clinical pregnancy was evaluated after embryo transfer. RESULTS: Thirty-one women aged 35.29 ± 6.21 years were included in this study. The mean amount of EMT was significantly increased following the GH treatment (7.03 ± 1.23 mm) vs. before treatment (5.14 ± 1.1 mm, P<0.001). The EMT reached ≥7 mm in the 65% patients (20/31). Also, the embryo transfer resulted in pregnancy in the patients, biochemical pregnancy: 9/20 (45%) and clinical pregnancy: 7/20 (35%). There was a positive correlation between EMT on the day 13 of cycle (before the treatment) and the maximum EMT (r=0.577 and P=0.001). The EMT was statistically different on the embryo transfer day between clinically pregnant and non-pregnant women (7.18 ± 0.56 vs. 6.21 ± 0.72 mm, P=0.007). CONCLUSION: The intrauterine administration of GH could be an appropriate therapeutic strategy for patients with refractory thin endometrium. This treatment could significantly increase the EMT as well as implantation and pregnancy rates in these patients (registration number: IRCT20210220050429N1).

microRNAs in the blastocoel fluid as accessible indicators of chromosomal normality.

MicroRNAs (miRNAs) derived from the pre-implantation blastocoel fluid (BF) have attracted interest as accessible biomarkers indicative of embryonic health in ongoing IVF cycles. Therefore, we investigated expression levels of some aneuploidy-associated miRNAs and implantation-related mRNAs as predictive markers for embryo chromosomal normality. In this study, the BF of 25 blastocysts that had been checked for aneuploidy (aneuploid=17 and euploid=8) was aspirated and the expression of 10 miRNAs (miR-20a, miR-30c, miR-661, miR-372, miR-142, miR-191, miR-345, miR-339, miR-141, and miR-27b) and four genes (ERBB4, SELL, ITGB3, ITGAV) were evaluated using real time-PCR. Results showed that the levels of miR-661 and miR-20a were significantly higher in the BF of the aneuploid embryos compared to the euploid group (p = 0.0017 and 0.004, respectively). A comparison of the mRNA levels between the aneuploid and euploid groups also demonstrated a significant difference in ITGAV (p = 0.013) and SELL (p = 0.0317) levels. In the euploid group, a negative correlation was found between ITGB3 and miR-30c (r = -0.71, p = 0.08), and in the aneuploid group, a positive correlation was found between ERBB4 and miR-345 (r = 0.71, p = 0.02). It can be suggested that miR-20a, miR-661, and ITGAV levels of BF could be used as less-invasive biomarkers to evaluate embryonic health. Moreover, aneuploidy-related miRNA levels were associated with levels of genes involved in embryo implantation.

Individual dynamics of uterine natural killer cells in natural and stimulated cycles monitored using a new endometrial dating method.

PROBLEM: It is important to evaluate the dynamics of uterine natural killer (uNK) cells in hormone replacement therapy (HRT) cycles, given their potential role in implantation and the common usage of HRT cycles with in vitro fertilization (IVF). METHOD OF STUDY: A total of 132 subfertile patients were evaluated during the secretory phase of either natural ovulation (OV) or HRT cycles, with two biopsies taken on approximately days 5 and 10 after ovulation/progesterone administration in a single menstrual cycle. Immunohistochemical Personal Endometrial Maturation Analysis (PEMA) was used to better quantify secretory-phase endometrial development, in combination with subsequent evaluation of uNK cell density. RESULTS: uNK cell density increased rapidly from the early to mid-secretory phase, with mean uNK densities of 113 and 117 per mm2 in first biopsies and 315 and 387 per mm2 in second biopsies for OV and HRT cycles, respectively. After reassessment of endometrial development with PEMA, the first and second biopsies in HRT and OV cycles were histologically dated to developmental ranges between days 15-20 (first biopsy) and days 19-25 (second biopsy). CONCLUSION: Subfertile women showed variable endometrial development in PEMA assessment, with uNK cell density correlating with the dating results. Overall, comparable levels of uNK cell density were observed in OV and HRT cycles. Importantly, uNK cell density depends on the histological maturation stage, with similar low coefficients of determination. This observation suggests that aberrant uNK cell results more likely reflect displaced endometrial maturation, rather than an intrinsic anomaly in uNK cell trafficking.

Does Anti-Müllerian hormone vary during a menstrual cycle? A systematic review and meta-analysis.

OBJECTIVE: Numerous studies have indicated that the level of the Anti-Müllerian hormone (AMH), one of the main markers for the ovarian reserve, does not fluctuate throughout a menstrual cycle, while some studies have rejected this finding. The purpose of this systematic and meta-analysis study is to consensus on all contradictory studies that have measured AMH levels throughout the menstrual cycle and to investigate the exact extent of AMH variation in a cycle. METHODS: The protocol for this meta-analysis was registered at PROSPERO before data extraction. Relevant studies were identified by systematic search in PubMed, ScienceDirect, Embase, Cochrane Library, and Google Scholar with no limitation on publication date. Longitudinal studies which have evaluated AMH levels in the follicular and luteal phases of an unstimulated (natural) menstrual cycle in healthy women without endocrinology or ovarian disorders were included. We used the JBI Critical Appraisal Checklist for assessing the quality of studies found eligible for meta-analysis. RESULTS: A total of 11 studies involving 733 women with regular menstrual cycles were included. The results showed that the AMH level in the follicular phase was significantly higher than in the luteal phase (95% Cl = 0.11 [0.01 to 0.21]; p < 0.05) and it varies about 11.5% from the luteal phase. The analysis of studies which had also examined the ovulatory phase (n = 380) showed that the serum levels of AMH in the ovulatory phase (about 2.02 ng/ml) did not significantly vary compared to follicular (95% Cl = 0.11 [-0.10 to 0.33]; p = 0.30) and luteal (95% Cl = 0.06 [-0.08 to 0.20]; p = 0.43) phases. CONCLUSIONS: According to the results of this study, AMH levels differ between follicular and luteal phases which might be due to ovarian response to the gonadotropins. It seems the phase of AMH measurement needs to be considered for interpretation of the serum AMH test.

Role of miRNAs in preimplantation embryo development and their potential as embryo selection biomarkers.

CONTEXT: MicroRNAs (miRNAs) play different roles in oocyte fertilisation, degradation of maternal transcripts, embryo development, and implantation. During in vitro fertilisation (IVF), different miRNAs are released from embryos into the spent culture media (SCM) that can potentially reflect the status of the embryo. AIMS: This study is the assessment of miRNAs, which secreted in SCM during the IVF cycles can be used as noninvasive biomarkers to predict an embryo's ability to form a blastocyst, implant, and give live birth. METHODS: Systematic literature search was conducted to review all recent studies about miRNAs as potential non-invasive biomarkers for selecting the best embryos in the assisted reproductive technology (ART) cycle. KEY RESULTS: Studies have shown that levels of some miRNAs in the SCM have an association with the implantation potential and pregnancy outcome of the embryo. CONCLUSIONS: Embryo-secreted miRNAs can be used as potential non-invasive biomarkers for selecting the best embryos in the ART cycle. Unfortunately, few human studies evaluated the association between ART outcomes and miRNAs in SCM. IMPLICATIONS: This review can pave the way for further miRNAs transcriptomic studies on human embryo culture media and introducing a specific miRNA profile as a multivariable prediction model for embryo selection in IVF cycles.

Oncostatin M and its receptor in women with polycystic ovary syndrome and association with assisted reproductive technology outcomes.

The role of adipokines in ovarian-related disorders such as polycystic ovary syndrome (PCOS) has been reported. However, the involvement of Oncostatin M (OSM), a recently identified adipokine, in ovarian function is unknown. Therefore, we investigated the association of the OSM signaling pathway with ovarian functions and PCOS pathogenesis. This case-control study enrolled 30 PCOS and 30 healthy women who underwent the intracytoplasmic sperm injection procedure. OSM and OSM receptor (OSMR) levels were evaluated in the follicular fluid (FF). Moreover, the expression of insulin receptor substrates (IRS1 and IRS2), OSM, OSMR, suppressor of cytokine signaling 3 (SOCS3), and androgen receptor (AR) genes were analyzed in the isolated cumulus cells (CCs). For the in-vitro experiment, the effect of recombinant OSM on the expression of related genes in isolated CCs was analyzed. Follicular concentrations of OSM and OSMR were significantly lower in PCOS (123.91±48.58 pg/ml and 0.93±0.35 ng/ml, respectively) compared to control women (283.53 ± 96.62 pg/ml and 1.45 ± 0.18 ng/ml, respectively; p < 0.001) and were positively correlated with the oocyte maturation (r = 0.611 and r = 0.611, respectively) and fertilization (r = 0.592 and r = 0.627, respectively) rates in the PCOS group. Furthermore, the SOCS3 expression was upregulated about eight times in PCOS patients compared to the controls (p < 0.05). The treatment of cells with recombinant OSM significantly increased SOCS3, OSMR, IRS-1, and -2 expression and decreased AR expression. The decreased levels of OSM and its receptor in PCOS patients, possibly mediated by SOCS3, could negatively affect oocyte maturation and fertilization rates.

Epithelial-mesenchymal transition process during embryo implantation.

The epithelial to mesenchymal transition (EMT) in endometrial epithelial and trophectoderm cells is essential for the progression of embryo implantation and its impairment could cause implantation failure. Therefore, EMT should be tightly regulated in both embryonic and endometrial cells during implantation. Studies reported the involvement of numerous factors in EMT regulation, including hormones, growth factors, transcription factors, microRNAs, aquaporins (AQPs), and ion channels. These factors act through different signaling pathways to affect the expression of epithelial and mesenchymal markers as well as the cellular cytoskeleton. Although the mechanisms involved in cancer cell EMT have been well studied, little is known about EMT during embryo implantation. Therefore, we comprehensively reviewed different factors that regulate the EMT, a key event required for the conceptus implantation to the endometrium.Summary sentence: Abnormal epithelial-mesenchymal transition (EMT) process within endometrial epithelial cells (EECs) or trophoblast cells can cause implantation failure. This process is regulated by various factors. Thus, the objective of this review was to summarize the effective factors on the EMT process during implantation.

Melatonin as a Therapeutic Agent for the Inhibition of Hypoxia-Induced Tumor Progression: A Description of Possible Mechanisms Involved.

Hypoxia has an important role in tumor progression via the up-regulation of growth factors and cellular adaptation genes. These changes promote cell survival, proliferation, invasion, metastasis, angiogenesis, and energy metabolism in favor of cancer development. Hypoxia also plays a central role in determining the resistance of tumors to chemotherapy. Hypoxia of the tumor microenvironment provides an opportunity to develop new therapeutic strategies that may selectively induce apoptosis of the hypoxic cancer cells. Melatonin is well known for its role in the regulation of circadian rhythms and seasonal reproduction. Numerous studies have also documented the anti-cancer properties of melatonin, including anti-proliferation, anti-angiogenesis, and apoptosis promotion. In this paper, we hypothesized that melatonin exerts anti-cancer effects by inhibiting hypoxia-induced pathways. Considering this action, co-administration of melatonin in combination with other therapeutic medications might increase the effectiveness of anti-cancer drugs. In this review, we discussed the possible signaling pathways by which melatonin inhibits hypoxia-induced cancer cell survival, invasion, migration, and metabolism, as well as tumor angiogenesis.