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Our study probed the differences in ion channel gene expression in the endometrium of women with Recurrent Implantation Failure (RIF) compared to fertile women. We analyzed the relative expression of genes coding for T-type Ca2+, ENaC, CFTR, and KCNQ1 channels in endometrial samples from 20 RIF-affected and 10 control women, aged 22–35, via microarray analysis and quantitative real-time PCR. Additionally, we examined DNA methylation in the regulatory region of KCNQ1 using ChIP real-time PCR. The bioinformatics component of our research included Gene Ontology analysis, protein–protein interaction networks, and signaling pathway mapping to identify key biological processes and pathways implicated in RIF. This led to the discovery of significant alterations in the expression of ion channel genes in RIF women’s endometrium, most notably an overexpression of CFTR and reduced expression of SCNN1A, SCNN1B, SCNN1G, CACNA1H, and KCNQ1. A higher DNA methylation level of KCNQ1’s regulatory region was also observed in RIF patients. Gene-set enrichment analysis highlighted a significant presence of genes involved with ion transport and membrane potential regulation, particularly in sodium and calcium channel complexes, which are vital for cation movement across cell membranes. Genes were also enriched in broader ion channel and transmembrane transporter complexes, underscoring their potential extensive role in cellular ion homeostasis and signaling. These findings suggest a potential involvement of ion channels in the pathology of implantation failure, offering new insights into the mechanisms behind RIF and possible therapeutic targets.

Endometriosis is a prevalent women's health disorder that lacks a definitive cure. Numerous studies have been conducted to identify the underlying causes of this disease and select the most effective pharmaceutical intervention. ISL LIM homeobox 2 (ISL2) plays a significant role in promoting angiogenesis. Contemporary investigations strongly suggest that inhibiting angiogenesis could lead to the modulation of endometriosis and reduce associated symptoms. This study aims to repurpose drugs to target ISL2 for endometriosis treatment. In this computational study, we sought to confirm that ISL2 is an appropriate target for this study by evaluating its expression in the endometrial tissues of patients diagnosed with endometriosis, as well as in tissues from a control group of healthy women. Subsequently, we used computational techniques to select the best inhibitor for ISL2 from among select food and drug administration (FDA)-approved drugs. There was a significant increase gene expression in the tissues of women with endometriosis. Therefore, we selected the ISL2 protein as a target for drug repurposing. Initial docking results revealed that, out of 2471 FDAapproved drugs, six (Dactinomycin, Paritaprevir, Ivermectin, Ergotamine, Alectinib, and Simeprevir) exhibited the most favourable binding energy (ΔG ≤-8 kcal/mol) with ISL2. Molecular dynamics (MD) simulations of these six complexes showed that Ivermectin displayed the lowest root mean square fluctuation (RMSF) and root mean square deviation (RMSD), as well as the highest count of hydrogen bonds and number of contacts, which indicated a more stable formation of this complex with ISL2. Although these six drugs appear to be promising candidates for modulating endometriosis, Ivermectin is more likely to effectively inhibit ISL2.

Endometriosis is major gynecological disease that affects over 10% of women worldwide and 30%-50% of these women have pelvic pain, abnormal uterine bleeding and infertility. The cause of endometriosis is unknown and there is no definite cure mainly because of our limited knowledge about its pathophysiology at the cellular and molecular levels. Therefore, demystifying the molecular mechanisms that underlie endometriosis is essential to develop advanced therapies for this disease. In this regard, HOX genes are remarkable because of their critical role in endometrial development and receptivity during implantation, which is attributed to their ability to mediate some of the sex steroid functions during the reproductive period. Access to the expression profiles of these genes would provide the necessary information to uncover new genes for endometriosis and assist with disease diagnosis and treatment. In this study we demonstrate an altered expression pattern for the HOX clusters (A-D) and their cofactors in both eutopic and ectopic conditions compared to control tissue biopsies. Remarkably, most of the intensive changes occurred in eutopic samples from endometriosis patients compared to control tissue biopsies. Pathway analysis revealed the involvement of differentially expressed genes in cancer that correlate with an association between endometriosis and cancer. Our results suggest critical roles for the HOX cluster and their cofactors in endometriosis pathophysiology.

Genomic imprinting is an epigenetic phenomenon that plays a critical role in normal development of embryo. Using exogenous hormones during assisted reproductive technology (ART) can change an organism hormonal profile and subsequently affect epigenetic events. Ovarian stimulation changes gene expression and epigenetic pattern of imprinted genes in the organs of mouse fetus. For this experimental study, expression of three imprinted genes (Insulin-like growth factor 2) and (Cyclin-dependent kinase inhibitor 1C), which have important roles in development of placenta and embryo, and the epigenetic profile of their regulatory region in some tissues of 19-days-old female fetuses, from female mice subjected to ovarian stimulation, were evaluated by quantitative reverse-transcription PCR (qRT-PCR) and Chromatin immunoprecipitation (ChIP) methods. gene was significantly lower in heart (P<0.05), liver (P<0.05), lung (P<0.01), placenta (P<0.01) and ovary (P<0.01). It was significantly higher in kidney of ovarian stimulation group compared to control fetuses (P<0.05). expression was significantly higher in brain (P<0.05) and kidney (P<0.05), while it was significantly lower in lung of experimental group fetuses in comparison with control fetuses (P<0.05). expression was significantly higher in lung (P<0.05). It was significantly decreased in placenta of experimental group fetuses rather than the control fetuses (P<0.05). Histone modification data and DNA methylation data were in accordance to the gene expression profiles. Results showed altered gene expressions in line with changes in epigenetic pattern of their promoters in the ovarian stimulation group, compared to normal cycle.

Activator of CREM in the testis (ACT) is a tissue specific transcription factor which activates cAMP responsive element modulator (CREM), a key transcription factor in differentiation of round spermatids into mature spermatozoa. They bind to CRE region in the promoters of transition protein genes ( ) and protamine genes ( and ), which are essential for sperm chromatin compaction, and regulates their transcription. This study was conducted to consider the expression of ACT and CREM and their regulatory roles on the expression of and genes in testis tissues of infertile men. In this case-control study, testicular biopsies were collected from 40 infertile men and classified into three groups: obstructive azoospermia (OA, n=10, positive control), round spermatid maturation arrest (SMA, n=20), Sertoli cell-only syndrome (SCOS, n=10, negative control group). Using quantitative real-time polymerase chain reaction (PCR), the expression profile of and genes were assessed in testicular samples and incorporation of ACT and CREM proteins on the promoters of and genes were also evaluated by ChIP-real time PCR. Our results demonstrated significant decrease in the expression levels of ACT, CREM and in their incorporations on their target genes in SMA group in comparison to control groups (P≤0.05). These data confirm that there is low expression and incorporation of ACT and CREM and of their target genes in infertilities which are associated with post-meiotic arrest.

Bromodomain testis associated (BRDT), a testis-specific member of the Bromo- and Extra-Terrminal domain (BET) protein family, is involved in spermatogenesis and, more specifically, chromatin remodeling. In the post-meiotic spermatogenic cells, BRDT protein binds to the hyperacetylated histones and facilitates their replacement with transition proteins (TPs), particularly protamines, which are essential for chromatin condensation. The current research was conducted to assess the expression and epigenetic profile of in the testis tissues of infertile men. In this case-control study, three groups were included: positive control group: obstructive azoospermia (OA, n=10), round spermatid maturation arrest group (SMA, n=10) and negative control group: sertoli cellonly syndrome (SCOS, n=10). Using quantitative real-time polymerase chain reaction (PCR), the expression profile of BRDT was generated. Also, ChIP-real time PCR was used to measure the following histone marks: H3K9ac, H3K9me3, H3K4me3, H3K27me3 on the promoter region of . Our data indicated that expression decreased in the SMA group in comparison with the positive control group and this finding is in line with the ChIP results obtained in this group. Based on these data, we postulate that gene has a vital role in the spermatogenesis and its decreased expression due to an aberrant epigenetic signaling might be associated with male infertility.

Preeclampsia (PE) is a pregnancy related disorder with prevalence of 6-7%. Insufficient trophoblastic invasion leads to incomplete remodeling of spiral arteries and consequent decrease in feto-placental perfusion. Altered placental expression of tissue inhibitors of matrix metalloproteinase (TIMPs) is considered to be involved in this process while the balance between matrix metalloproteinases (MMPs) and TIMPs contributes to remodeling of the placenta and uterine arteries by degradation and refurbishing of extracellular matrix (ECM). Therefore, TIMPs, fetal expression pattern was evaluated with the aim of its potential to be used as a determinant for the (early) detection of PE. In this case-control study, cell free fetal RNA (cffRNA) released by placenta into the maternal blood was used to determine expression patterns of 1, 2, 3 and 4 in the severe preeclamptic women in comparison with the normal pregnant women. Whole blood from 20 preeclamptic and 20 normal pregnant women in their 28-32 weeks of gestational age was collected. The second control group consisted of 20 normal pregnant women in either 14 or 28 weeks of gestation (each 10). cffRNA was extracted from plasma and real-time polymerase chain reaction (PCR) was done to determine the expression levels of 1, 2, 3 and 4 genes. Statistical analysis of the results showed significant higher expression of 1-4 in the preeclamptic women in comparison with the control group (P=0.029, 0.037, 0.037 and 0.049, respectively). Also, an increased level of expression was observed by comparing 14 to 28 weeks of gestational age in the normal pregnant women in the second control group. An increased cffRNA expression level of may be correlated with the intensity of placental vascular defect and may be used as a determinant of complicated pregnancies with severe preeclampsia.

The diminished ovarian reserve (DOR) is a condition characterized by a reduction in the number and/or quality of oocytes. This primary infertility disorder is usually accompanied with an increase in the follicle-stimulating hormone (FSH) levels and regular menses. Although there are many factors contributing to the DOR situation, it is likely that many of idiopathic cases have genetic/epigenetic bases. The association between the FMR1 premutation (50-200 CGG repeats) and the premature ovarian failure (POF) suggests that epigenetic disorders of FMR1 can act as a risk factor for the DOR as well. The aim of this study was to analyze the mRNA expression and epigenetic alteration (histone acetylation/methylation) of the FMR1 gene in blood and granulosa cells of 20 infertile women. In this case-control study, these women were referred to the Royan Institute, having been clinically diagnosed as DOR patients. Our control group consisted of 20 women with normal antral follicle numbers and serum FSH level. All these women had normal karyotype and no history of genetic disorders. The number of CGG triplet repeats in the exon 1 of the FMR1 gene was analyzed in all samples. Results clearly demonstrated significantly higher expression of the FMR1 gene in blood and granulosa cells of the DOR patients with the FMR1 premutation compared to the control group. In addition, epigenetic marks of histone 3 lysine 9 acetylation (H3K9ac) and di-metylation (H3K9me2) showed significantly higher incorporations in the regulatory regions of the FMR1 gene, including the promoter and the exon 1, whereas tri-metylation (H3K9me3) mark showed no significant difference between two groups. Our data demonstrates, for the first time, the dynamicity of gene expression and histone modification pattern in regulation of FMR1 gene, and implies the key role played by epigenetics in the development of the ovarian function.

Identification of molecular markers which can predict the outcome of sperm retrieval non-invasively in patients with non-obstructive azoospermia (NOA) are valuable in clinical andrology. Jumonji domain-containing 1a (JMJD1A) is a significant epigenetic regulator during spermatogenesis, which plays an important role in the differentiation of post-meiotic germ cells into mature spermatozoa. We therefore aimed to examine the potential association between JMJD1A expression and the outcome of sperm retrieval in patients with NOA. Testicular biopsy specimens from 50 NOA patients with either successful sperm retrieval (sperm+, n=22) or failed sperm retrieval (sperm-, n=28) were collected and then examined for JMJD1A expression by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, conventional clinical parameters including luteinizing hormone, follicle-stimulating hormone, testosterone, age, and testicular volume were compared between the two NOA groups. The expression of JMJD1A in the sperm+ group was significantly higher than in the sperm- group (P<0.001), however, no significant difference was observed between the two groups in clinical parameters. The receiver operating characteristic (ROC) curve of JMJD1A expression in predicting the sperm retrieval outcome showed a sensitivity of 90.91% and a specificity of 89.29% with significant discriminatory ability between the sperm+ and sperm- groups [area under the ROC curve (AUC)= 0.91]. This study demonstrates a significant association between the expression of JMJD1A and the success of sperm recovery in patients with NOA, and thus suggests that JMJD1A expression quantification in testicular biopsies may be a valuable biomarker along with conventional parameters in predicting the presence of spermatozoa.

Background: Endometriosis is a common, chronic inflammatory disease which is defined as an overgrowth of endometrial tissue outside the uterine cavity. The etiology of this disease is complex and multifactorial but there is a strong evidence that supports the presence of endometrial stem cells and their possible involvement in endometriosis. Objective: In this study, we analyzed the mRNA expression of REX-1 stemness gene and reconsidered three other stemness genes SOX-2, NANOG, OCT-4 in women with endometriosis compared to normal endometrium. Materials and Methods: Ten ectopic and ten eutopic tissue samples along with 23 normal endometrium specimens were recruited in this study. The expression levels of OCT-4, NANOG, SOX-2, and REX-1 genes were evaluated by the quantitative real-time polymerase chain reaction. Results: The transcription levels of OCT-4, NANOG, and SOX-2 mRNA were significantly increased in ectopic lesions compared with eutopic and control group (p = 0.041, p = 0.035, p = 0.048), although the REX-1 mRNA increase was not significant between endometriosis and control groups. Also, there were differences in the expression level of these genes in normal endometrium during the menstrual cycles (p = 0.031, p = 0.047, p = 0.031). Conclusion: Based on our data, we confirm the dynamic role of stemness genes in proliferation and growth of normal endometrium during the menstrual cycle and conclude that differential expression n levels of these genes may contribute to the pathophysiology of endometriosis. Key words: Endometriosis, Stemness genes.