Hypomethylation of IL6ST promotes development of endometriosis by activating JAK2/STAT3 signaling pathway

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(1), P. e0317569 - e0317569

Published: Jan. 16, 2025

Endometriosis is a chronic inflammatory disorder characterized by presence of endometrial tissue outside the uterine cavity. Immunohistochemical analysis (IHC) revealed markedly elevated expression IL6ST in patients with ovarian endometriosis. Level methylation diminished endometriosis, whereas level mRNA RT-PCR. Cell Counting Kit-8, Transwell, Terminal deoxynucleotidyl transferase dUTP nick end labeling assays substantiated stromal cells stably transfected 3*FLAG-IL6ST plasmid exhibited enhanced viability, augmented invasive capacity, and notable reduction apoptosis rates. Furthermore, facilitated progression endometriosis activating mitogen-activated protein kinase 9/Signal Transducer Activator Transcription 3 signaling pathway. Western blot significantly levels p-JAK2/JAK2, p-STAT3/STAT3, HIF-1α, VEGF overexpression group. Conversely, JAK2/STAT3 inhibitor WP1066 had reduced p-JAK2 p-STAT3 Inhibiting pathway mitigating effect on proliferative enhancement cells, as well inhibition induced IL6ST. These findings offer novel potential targets strategies for treatment

Language: Английский

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Gut–X axis

iMeta, Journal Year: 2025, Volume and Issue: 4(1)

Published: Feb. 1, 2025

Abstract Recent advances in understanding the modulatory functions of gut and microbiota on human diseases facilitated our focused attention contribution to pathophysiological alterations many extraintestinal organs, including liver, heart, brain, lungs, kidneys, bone, skin, reproductive, endocrine systems. In this review, we applied “gut–X axis” concept describe linkages between other organs discussed latest findings related axis,” underlying mechanisms potential clinical intervention strategies.

Language: Английский

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Impaired bone morphogenetic protein (BMP) signaling pathways disrupt decidualization in endometriosis

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: Feb. 24, 2024

Abstract Endometriosis is linked to increased infertility and pregnancy complications due defective endometrial decidualization. We hypothesized that identification of altered signaling pathways during decidualization could identify the underlying cause complications. Our study reveals transforming growth factor β (TGFβ) are impaired in endometrium individuals with endometriosis, leading Through detailed transcriptomic analyses, we discovered abnormalities TGFβ key regulators, such as SMAD4, affected individuals. also observed compromised activity bone morphogenetic proteins (BMP), a subset family, control receptivity. Using 3-dimensional models stromal epithelial assembloids, showed exogenous BMP2 improved decidual marker expression endometriosis. findings reveal dysfunction BMP/SMAD explaining defects subsequent these

Language: Английский

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Association between METTL14 gene polymorphisms and risk of ovarian endometriosis

Frontiers in Genetics, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 3, 2025

Endometriosis, a prevalent chronic gynecological condition, is frequently associated with infertility and pelvic pain. Despite numerous studies indicating correlation between epigenetic regulation endometriosis, its precise genetic etiology remains elusive. Methyltransferase-like 14 (METTL14), crucial component of the N6-methyladenosine (m6A) RNA methyltransferase complex an binding scaffold, known to play pivotal role in various human diseases. The possibility that single nucleotide polymorphisms (SNPs) METTL14 gene contribute susceptibility endometriosis has not been thoroughly investigated. We assessed genotype frequencies five potential functional SNPs (rs298982 G>A, rs62328061A>G, rs9884978G>A, rs4834698C>T, rs1064034A>T) Chinese population consisting 458 patients ovarian 462 healthy controls. employed unconditional logistic regression stratified analyses evaluate their genotypic associations risk endometriosis. Among examined, we found rs298982 A allele was significantly increased risk, whereas rs62328061 G linked decreased Individuals harboring two unfavorable genotypes demonstrated elevated (adjusted odds ratio (AOR) = 1.57, 95% confidence interval (CI) 1.16-2.13, P 0.004) compared those no genotypes. Stratified analysis revealed effect GA/AA gravidity≤1, parity≤1, rASRM stage I, II + III IVsubgroups. Haplotype showed individuals GATAA haplotype were at higher (AOR 5.54, CI 1.63-18.87, 0.006), AGTTG exhibited protective effects 0.55, 0.31-0.97, 0.039) wild-type GACAG carriers. Additionally, Bayesian false discovery probability positive report confirmed robustness significant findings. Expression quantitative trait loci association rs9884978 mRNA levels fibroblasts adrenal gland. Conversely, GA/GG reduced nucleus accumbens frontal cortex. Our results demonstrate are among women.

Language: Английский

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β-elemene, a sesquiterpene constituent from Curcuma phaeocaulis inhibits the development of endometriosis by inducing ferroptosis via the MAPK and STAT3 signaling pathways

Journal of Ethnopharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 119344 - 119344

Published: Jan. 1, 2025

Language: Английский

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Macrophages: a double-edged sword in female reproduction and disorders

Experimental & Molecular Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

Reproduction consists of sequential inflammation-like events, primarily within the endometrium, from ovulation to embryo implantation, decidualization and delivery. During reproductive cycle, endometrium repeatedly undergoes cyclic periods proliferation, differentiation, tissue breakdown repair without scarring. Owing their phagocytic activity, macrophages, key players in innate immunity, are thought play crucial roles endometrium. Endometrial macrophages actively participate various stages remodeling, particularly during pregnancy establishment. Traditionally considered simple bystanders that clear debris prevent autoimmune responses homeostasis, now recognized as main actors with broad functional plasticity allows them fine tune balance between pro- anti-inflammatory inflammation, remodeling repair. Homeostatic is determined by sum mediators produced two distinctly polarized macrophage subpopulations. The biased polarization tissue-resident may contribute pathogenesis diseases, such inflammation cancer. Thus, understanding how endometrial homeostasis for deciphering underlying mechanisms disorders. Nanomedicines using extracellular vesicles, nanoparticles noncoding RNAs have recently been applied modulate alleviate disease phenotypes. Despite these advances, functions under physiological pathophysiological conditions remain poorly understood, which complicates development targeted therapies. Here we update current homeostatic function putative contribution dysfunction disorders women, along innovative molecular therapeutics resolve this issue.

Language: Английский

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Decreased expression of miR-200a and miR-223-3p in endometriosis during the secretory phase of menstrual cycle: Insights from a case-control study on molecular biomarkers and disease-related infertility

International Journal of Reproductive BioMedicine (IJRM), Journal Year: 2025, Volume and Issue: 22(12)

Published: Feb. 3, 2025

Background: Endometriosis (EM) is a condition that causes infertility with decreasing uterine receptivity. It reported it affects about 20–25% of all infertile women. Some genetic markers play crucial role in pathogenesis and infertility. Objective: This study investigates the miR-200a miR-223-3p embryo implantation their association EM-related Materials Methods: In this case-control study, 36 women who referred to Center for Research on Reproductive Health Infertility Babol University Medical Sciences Fatemeh Al-Zahra Specialized Treatment Babol, Iran between June 2022 July 2023 were evaluated. Participants divided into 2 EM control groups (n = 18/each). Endometrial samples collected from participants 17th 24th days menstrual cycle. Histopathological examination (hematoxylin eosin periodic acid schiff) was performed confirm secretory stage, expressions analyzed by quantitative reverse transcriptase-polymerase chain reaction. Results: Histological analysis confirmed both stage. Additionally, miRNA expression results showed significant decrease levels group compared group. The level eutopic endometrial tissue notably lower than those Conclusion: Our suggest are involved pathogenesis, while other genes signaling pathways probably failure.

Language: Английский

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Analysis of inflammatory biomarkers IL-6, vascular endothelial growth factor and matrix metalloproteinases-9 expression in endometriosis

SAGE Open Medicine, Journal Year: 2025, Volume and Issue: 13

Published: Jan. 1, 2025

Special attention has been paid to genetic mechanisms that might have a significant impact on the context of risk developing endometriosis, in recent years. The study aimed analyze expression levels three inflammatory biomarkers Interleukin-6 (IL-6), vascular endothelial growth factor, and matrix metalloproteinases-9, increased incidence endometriosis. material for testing was tissue slices embedded paraffin blocks from these patients with endometriosis (I-II) (n = 24), (III-IV) control group 30) Lianyungang maternal child health hospital January 2020 December 2023. IL-6, metalloproteinases-9 genes were determined by real-time polymerase chain reaction technique. IL-6 factor gene peripheral blood peritoneal fluid not statistically lower than group. Besides, differences found between eutopic endometrial tissues group, compared group; significantly severity disease. In addition, there difference level fluid, stages III-IV, I-II. Among them, Revised American Society Reproductive Medicine classification used These showed blood, ectopic as condition worsens. research suggested determination certain value evaluating which play an important role pathogenesis be explored postoperative recurrence monitoring.

Language: Английский

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Endometriosis: A New Perspective on Epigenetics and Oxidative Stress

Journal of Reproductive Immunology, Journal Year: 2025, Volume and Issue: 169, P. 104462 - 104462

Published: Feb. 21, 2025

Language: Английский

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A novel mechanism of FTO modulating the progression of endometriosis through mediating the m6A methylation of GEF-H1 in a YTHDF1-dependent manner

Molecular Medicine, Journal Year: 2025, Volume and Issue: 31(1)

Published: Feb. 25, 2025

Abstract Background Endometriosis (EMs) is a condition characterized by the growth of endometrial tissue outside uterine cavity. Although this benign, it has cancer-like features. N6-methyladenosine (m6A) common RNA modification involved in diverse biological processes, but its role EMs remains unclear. Methods A human stromal cell line (HESCs), primary eutopic cells (Eu-ESCs), ectopic (Ec-ESCs), and clinical samples were used study. colorimetric assay was to measure methylation levels mouse samples. Functional assays (CCK-8, EdU, Transwell, wound healing) evaluate phenotypic changes. m6A immunoprecipitation sequencing (MeRIP-seq) identified downstream targets. Mechanistic studies conducted via qRT‒PCR, Western blot, (RIP), dual-luciferase reporter, stability assays. Results We detected aberrantly low within endometriotic lesions, which attributed increased expression eraser fat mass obesity-associated protein (FTO). Notably, estrogen inflammatory factors, are recognized as pathogenic agents amplify FTO while suppressing levels. In vitro experiments demonstrated that overexpression leads reduction concomitantly promotes their proliferation, migration, invasion. Furthermore, both genetic deletion Fto chemical inhibition impeded lesions vivo. By utilizing m6A-seq, we GEF-H1 (a Rho guanine nucleotide exchange factor) pivotal target FTO. Specifically, diminished at certain site 3'UTR YTH RNA-binding F1 (YTHDF1)-dependent manner, thereby activating RhoA pathway. Subsequent revealed mediates effects promoting migration Conclusions This study decreases level , increasing stability, turn activates GEF-H1-RhoA pathway promote invasion cells, inducing EMs. Our findings suggest potential therapeutic avenues for targeting alleviate progression.

Language: Английский

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