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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.

One of the most common side effects of chemotherapy is premature ovarian failure (POF) in women younger than 40. POF is linked to higher levels of gonadotropin hormones, lower levels of estradiol, and increased apoptosis and follicular atresia, all of which lower the quality of fertility and eventually make women unable to have children. There have been more and more reports since 1981 of different treatments that can protect against ovarian damage caused by chemotherapy. However, it is still challenging to find effective fertility-preserving measures for treating POF. Many of the newly proposed or developing chemotherapy treatments and radiotherapy-induced premature ovarian failure have shown limited efficacy or are associated with side effects, and their ability to fully restore ovarian function remains uncertain. However, the use of antioxidants to treat premature ovarian failure is a more effective method with fewer side effects than the recommended treatment methods. Antioxidants reduce symptoms of premature ovarian failure by affecting histone-modifying genes, especially the Sirtuin family, which function as redox environment sensors in granulosa cells and regulate the expression of downstream genes such as FOXO3a, P53, NF-κB, NRF2, and PGC-1a. This study aims to investigate how different treatments, especially antioxidants, can reactivate Sirtuin family genes to help with premature ovarian failure. It is shown that antioxidants, by increasing the expression levels of Sirtuin family genes, have the most significant impact on improving ovarian function in premature ovarian failure induced by multiple chemotherapy drugs. Graphical Abstract

Tumor necrosis factor-alpha (TNF-α) is a multifunctional pro-inflammatory cytokine, responsible for autoimmune and inflammatory disorders. In COVID-19 patients, increased TNF-α concentration may provoke inflammatory cascade and induce the initiation of cytokine storm that may result in fatal pneumonia and acute respiratory distress syndrome (ADRS). Hence, TNFα is assumed to be a promising drug target against cytokine storm in COVID-19 patients. In the present study, we focused on finding novel small molecules that can directly block TNF-α-hTNFR1 (human TNF receptor 1) interaction. In this regards, TNF-α-inhibiting capacity of natural carotenoids was investigated in terms of blocking TNF-α-hTNFR1 interaction in COVID-19 patients with the help of a combination of in silico approaches, based on virtual screening, molecular docking, and molecular dynamics (MD) simulation. A total of 125 carotenoids were selected out of 1204 natural molecules, based on their pharmacokinetics properties and they all met Lipinski’s rule of five. Among them, Sorgomol, Strigol and Orobanchol had the most favorable ΔG with the best ADME (absorption, distribution, metabolism, excretion) properties, and were selected for MD simulation studies, which explored the complex stability and the impact of ligands on protein conformation. Our results showed that Sorgomol formed the most hydrogen bonds, resulting in the highest binding energy with lowest RMSD and RMSF, which made it the most appropriate candidate as TNF-α inhibitor. In conclusion, the present study could serve to expand possibilities to develop new therapeutic small molecules against TNF-α.

Endometriosis is a common gynecological disease that occurs in between 6 and 10% of women who are at reproductive maturity. The presence of endometrial tissue outside the uterine cavity is the defining characteristic of this disease. Although the etiology of endometriosis remains controversial, there is a general consensus that multiple biological processes such as angiogenesis and vasculogenesis, oxidative stress, and inflammation contribute to its complex pathophysiology. Patients' expectations and priorities influence the treatment plan that is selected. For instance, therapy with hormone medications is inappropriate for endometriosis patients who wish to become pregnant since these medications interfere with ovulation. On the other hand, considering that the current endometriosis treatments are associated with recurrence of pain and disease despite the treatment of the disease and have many side effects, the design and application of non-hormonal drugs in this field is very necessary. Therefore, in this article, we tried to have an overview on non-hormonal treatments by considering angiogenesis, oxidative stress, and inflammation as important biological processes involved in endometriosis.

Endometriosis, a benign gynecological disorder affecting 10-15% of women during their reproductive years, is characterized by the growth of endometrial tissue outside the uterus. Despite its prevalence, the exact pathophysiology of this disease remains poorly understood. Current treatments, including surgery and hormonal therapies, often have limited efficacy and may be associated with significant side effects. In recent years, drug repurposing has emerged as a promising strategy for managing endometriosis. This approach capitalizes on the molecular similarities between endometriosis and certain cancers, particularly the role of proteins such as fibronectin. By targeting these shared molecular pathways, researchers are exploring the potential of repurposing existing drugs, especially anticancer agents, to treat endometriosis. This strategy promises to provide more effective and less invasive treatment options for patients with endometriosis. Preliminary studies have shown the potential of anticancer drugs in inhibiting disease progression and alleviating symptoms. However, further clinical trials are necessary to confirm these findings and establish the precise role of anticancer drugs in the management of endometriosis.

Laparoscopy is the gold standard for diagnosing endometriosis; however, it is an invasive and costly method. Recent studies offer a non-invasive approach based on extracellular vesicle miRNA. Despite this, no consensus diagnostic biomarker has been identified to date. For addressing this gap, we decided to investigate plasma derived extracellular vesicle associated candidate miRNAs. In order to identify candidate miRNAs, a comprehensive search was performed in PubMed database using the search terms “micro-RNA” and “endometriosis”. Then, bioinformatics analysis was performed utilizing the miRTarBase database, Enrichr, and relevant software. During the experimental phase, the presence of candidate miRNAs was assessed in blood samples of 13 women with severe endometriosis, confirmed through laparoscopy or doppler sonography, as well as in 11 endometriosis-free women, as control group. After literature review of 405 articles published between 2007 and 2023, followed by bioinformatics analysis, were identified five miRNAs (miR-451a, 148a, 23b, 100, and 154) as candidate miRNAs. Subsequently, the expression levels of miR-451a, 148a, 23b, and 100 found to exhibit differences between the case and control groups. Our study suggests to serve of these miRNAs as a potentially diagnostic biomarker panel for endometriosis, however it needs to be confirmed by future studies with large diagnostic validation.

Background Endometriosis, as chronic estrogen-dependent disease, is defined by the presence of endometrial-like tissue outside the uterus. Proliferation of endometrial tissue and neoangiogenesis are critical factors in development of endometriosis. Hence, vascular endothelial growth factor (VEGF) as well as insulin‐like growth factor 1 and 2 (IGF1, 2) may be involved as inducers of cellular proliferation or neoangiogenesis. Imprinted long noncoding RNA H19 (lncRNA H19) has been suggested to be involved in pathogenesis of endometriosis via regulation of cellular proliferation and differentiation. Epigenetic aberrations appear to play an important role in its pathogenesis. The present study was designed to elucidate VEGF, IGF1, IGF2 and H19 lncRNA genes expression and epigenetic alterations of differentially methylated region (DMR) of H19 ( H19 -DMR) regulatory region in endometrial tissues of patients with endometriosis, in comparison with control women. Methods In this case–control study, 24 women with and without endometriosis were studied for the relative expression of VEGF , IGF1 , IGF2 and H19 lncRNA genes using real-time polymerase chain reaction (PCR) technique. Occupancy of the MeCP2 on DMR region of H19 gene was assessed using chromatin immunoprecipitation (ChIP), followed by real-time PCR. Results Genes expression profile of H19 , IGF1 and IGF2 was decreased in eutopic and ectopic endometrial tissues of endometriosis group, compared to the control tissues. Decreased expression of H19 in ectopic samples was significant in comparison with the controls (P < 0.05). Gene expression of VEGF was increased in eutopic tissues of endometriosis group, compared to control group. Whereas its expression level was lower in ectopic lesions versus eutopic and control endometrial samples. ChIP analysis revealed significant and nearly significant hypomethylation of H19 -DMR region II in eutopic and ectopic samples, compared to the control group respectively. This epigenetic change was aligned with expression of IGF2 . While methylation of H19 -DMR region I was not significantly different between the eutopic, ectopic and control endometrial samples. Conclusion These data showed that VEGF , IGF1 , IGF2 and H19 lncRNA genes expression and epigenetic alterations of H19 lncRNA have dynamic role in the pathogenesis of endometriosis, specifically in the way that hypomethylation of H19 -DMR region II can be involved in IGF2 dysregulation in endometriosis.

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.

In this study, the global DNA methylation, histone acetylation and methylation levels of cumulus cells (CCs) in infertile polycystic ovary syndrome (PCOS) patients and the correlation of these epigenetic modifications with the expression of the ovarian aromatase gene (as an important marker in the etiology of PCOS) were investigated. A cross-sectional study was conducted on 24 patients (12 PCOS patients and 12 healthy women), who underwent ovarian stimulation. Nucleosome ELISA was performed, in order to identify the global occupancy level of Mecp2 (as a marker of DNA methylation) and H3K9me2/H3K9ac as histone modification markers in chromatin fractions obtained from CCs. The gene expression was measured by qRT-PCR. The level of DNA incorporation of MeCP2, histone modification markers and binding of estrogen receptor β (ERβ) to regulatory sequences were examined by ChIP-QPCR assay. The data demonstrate a significant increase in global occupancy levels of MeCP2 and H3K9ac markers and a decrease of H3K9me2 to chromatin in CCs of PCOS patients vs. control group. Furthermore, gene expression, and the incorporation of H3K9ac in PII, PI.3, and PI.4 promoters of in PCOS, were higher than those of controls. Also, significant hypomethylation of H3K9 at PII and DNA hypomethylated at PII and PI.3 promoters and differential binding of ERβ to three promoters were observed in PCOS patients ( < 0.05). Aromatase expression can be affected by epigenetic modifications and differential ERβ binding to the proximal promoters. These mechanisms may be involved in the enhanced aromatase transcription during ovarian stimulation in PCOS patients.

Background It was reported that steroid-related gene expressions in the adipose tissue (AT) of women differ between women affected with polycystic ovary syndrome (PCOS) and non-PCOS. Although association between PCOS in mother and offspring’s health is a crucial issue, there are few studies focusing on AT of pregnant women suffering from PCOS. Our objectives were to determine the differences between mRNA expression levels of key steroid-converting enzymes in abdominal subcutaneous AT of pregnant women afflicted with PCOS and non-PCOS. Methods Twelve pregnant women with PCOS (case) and thirty six non-PCOS pregnant women (control) (1:3 ratio; age- and BMI-matched) undergoing cesarean section were enrolled for the present study. Expressions of fifteen genes related to steriodogenesis in abdominal subcutaneous AT were investigated using quantitative real-time PCR. Results No significant differences were detected with respect to age, BMI (prior pregnancy and at delivery day), gestational period and parity among pregnant women with PCOS and non-PCOS. Most of the sex steroid-converting genes except 17β-Hydroxysteroid dehydrogenases2 ( 17BHSD2 ), were highly expressed on the day of delivery in subcutaneous AT. Women with PCOS showed significantly higher mRNA levels of steroidgenic acute regulator ( STAR; P  <  0.001 ), cytochrome P450 monooxygenase ( CYP11A1; P  <  0.05 ), 17α-hydroxylase ( CYP17A1; P  <  0.05 ), and 11β-Hydroxysteroid dehydrogenase ( 11BHSD1 and 11BHSD2; P  <  0.05 ). The expression of steroid 21-hydroxylase ( CYP21) in non-PCOS was fourfold higher than those of women with PCOS ( P  < 0.001). There were no significant differences between relative expression of aromatase cytochrome P450 (CYP19A1), 3β-hydroxysteroid dehydrogenase ( 3BHSD1 and 3BHSD2 ), and 17BHSD family (1, 3, 5, 7, and 12) between the two groups. Conclusion The expression levels of genes related to sex steroids metabolism were similar to age-matched and BMI- matched pregnant non-PCOS and pregnant women with PCOS at delivery day. However, the alterations in gene expressions involved in glucocorticoids and mineralocorticoids metabolism were shown. It is necessary to point out that further studies regarding functional activity are required. More attention should be given to AT of pregnant women with PCOS that was previously ignored.