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Molecular Research in Uterine Biology and Pathophysiology, 2nd Edition

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 31 May 2025 | Viewed by 12593

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Prof. Dr. Andrea Tinelli

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Department of Obstetrics and Gynecology and CERICSAL (CEntro di RIcerca Clinico SALentino), "Veris delli Ponti Hospital", 73020 Scorrano, Italy
Interests: uterine fibroids; reproductive surgery; uterine biology
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Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of the 2022 Special Issue “Molecular Research in Uterine Biology and Pathophysiology”.

Uterine biology is a fascinating world that belongs to the field of reproduction, pelvic statics, sexual activity, oncology. For years, scholars of uterine biology have been searching for answers to dozens of queries on the uterine pathophysiology. Biological studies involve macro and microscopic morphological anatomy, vascularization and innervation, endometrial and myometrial biochemistry, the physiology of the cervix and smooth muscle of the myometrium, studies on embryonic implantation and implant pathologies, functionality and the endocrine impact on the uterus. To this are added the studies on the malignant pathology of the endometrium and myometrium and cervix. Molecular Research is fully part of this overview, which allows the study of the biological processes that regulate and impact uterine functionality at the molecular level. Molecular studies involve many biological processes, including the Cellular and Tissue Mechanisms of Uterine Endometrial and Myometrial Functionality, Estrogen and Progesteron receptors on uterine biology, molecular biology and genetics of endometrial and myometrial cancer, uterine endocrine receptor modulation, neuropeptides and neurotransmitters impact on uterine biology, Analysis of Proteins Secreted by the Human Endometrium InVivo and InVitro, Implantation Associated Changes in reproduction. In this area of molecular research, basic molecular research is promoted, with the aim of translating research into clinical practice.

Prof. Dr. Andrea Tinelli
Guest Editor

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Keywords

human reproduction
fertility
endometrial and myometrial functionality
estrogen and progesteron receptors
sex hormones
endometrial hyperplasia
endometrial cancer and uterine sarcoma
embryo implantation
pregnancy

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Published Papers (7 papers)

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Research

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16 pages, 4245 KiB

Open AccessArticle

JEG-3 Trophoblast Cells Influence ILC-like Transformation of NK Cells In Vitro

by Valentina Mikhailova, Polina Grebenkina, Sergey Selkov and Dmitry Sokolov

Int. J. Mol. Sci. 2025, 26(8), 3687; https://doi.org/10.3390/ijms26083687 - 14 Apr 2025

Viewed by 261

Abstract

The uterine decidua contains NK cells differing in their characteristics from classical NK cells, as well as other populations of innate lymphoid cells (ILCs). ILC differentiation depends on the active transcription factors: ILC1 is characterized by T-bet expression, ILC2 is defined by RORα and GATA3, ILC3 expresses RORγt and AhR. We analyzed in vitro the expression of transcription factors by NK cells in the presence of trophoblast cells and cytokines and changes in NK cell cytotoxic activity. We used NK-92 and JEG-3 cell lines, which we cocultured in the presence of IFNγ, IL-10, IL-15, and TGFβ. Then, cells were treated with antibodies to AhR, Eomes, GATA-3, RORα, RORγt, and T-bet and were analyzed. We determined NK cell cytotoxicity towards K562 cells. To characterize the functional state of trophoblast cells, we estimated their secretion of TGFβ and βhCG. We showed that in the presence of trophoblasts, the expression of the classical NK cell transcription factors—Eomes, T-bet, as well as RORα, regulating ILC2 differentiation, and AhR, participating in NCR+ ILC3 formation—decreased in NK cells. RORγt expression typical for NCR- ILC3 remained unchanged. IFNγ inhibited AhR expression. IL-10 stimulated an increase in the number of T-bet+ ILC1-like cells. Both IL-10 and IFNγ suppressed RORα expression by NK cells and stimulated TGFβ secretion by trophoblasts. After coculture with trophoblast cells, NK cells reduced their cytotoxicity. These results indicated trophoblast cell influence on the acquisition of ILC1 and ILC3 characteristics by NK cells. Full article

(This article belongs to the Special Issue Molecular Research in Uterine Biology and Pathophysiology, 2nd Edition)

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17 pages, 6616 KiB

Open AccessArticle

Evaluation of Thrombomodulin, hsa-miR-18a-5p, and hsa-miR-18b-5p as Potential Prognostic Biomarkers in Uterine Corpus Endometrial Carcinoma

by Enes Karaman, Ergul Bayram and Durmus Ayan

Int. J. Mol. Sci. 2025, 26(8), 3649; https://doi.org/10.3390/ijms26083649 - 12 Apr 2025

Viewed by 157

Abstract

Thrombomodulin (THBD), hsa-miR-18a-5p, and hsa-miR-18b-5p have been frequently mentioned in numerous cancer-related research studies; however, their specific functions in uterine corpus endometrial carcinoma (UCEC) are not well understood. This study aimed to investigate the roles of THBD, hsa-miR-18a-5p, and hsa-miR-18b-5p within a UCEC cohort. We utilized various web-based tools, including GEPIA2, UALCAN, Human Protein Atlas (HPA), TNM Plot, STRING, TargetScan, and ENCORI for our analysis. The expression level of the THBD gene was found to be significantly downregulated (p < 0.05) in UCEC tissue compared to adjacent normal tissue. In contrast, hsa-miR-18a-5p and hsa-miR-18b-5p were both upregulated in UCEC tissue (p < 0.05). Additionally, THBD exhibited a significant hypermethylation level in UCEC tissue (p < 0.05). The elevated expression of hsa-miR-18a-5p was linked to a shorter overall survival (OS) (p = 0.025), while THBD and hsa-miR-18b-5p showed no association with OS (p = 0.87 and p = 0.56, respectively). Notably, THBD expression was significantly negatively correlated with hsa-miR-18a-5p (p = 0.00407), whereas no significant correlation was found between THBD and hsa-miR-18b-5p (p = 0.25). Thus, it can be concluded that increased levels of miR-18a-5p in the UCEC cohort may serve as a negative prognostic marker and a potential therapeutic target. However, further studies are necessary to validate the implications of decreased THBD and increased miR-18b-5p expression levels on the clinical outcomes of these patients. Full article

(This article belongs to the Special Issue Molecular Research in Uterine Biology and Pathophysiology, 2nd Edition)

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14 pages, 5195 KiB

Open AccessArticle

Determining Sex-Specific Gene Expression Differences in Human Chorion Trophoblast Cells

by Daphne D. Arena Goncharov, Ryan C. V. Lintao, Rheanna Urrabaz-Garza, Enkhtuya Radnaa, Ananth K. Kammala, Lauren S. Richardson and Ramkumar Menon

Int. J. Mol. Sci. 2025, 26(5), 2239; https://doi.org/10.3390/ijms26052239 - 2 Mar 2025

Viewed by 808

Abstract

Differences in male (M) and female (F) neonates’ premature birth outcomes and placental trophoblast inflammation have been observed but are unknown to occur within the fetal membrane trophoblast layer (chorion trophoblasts [CTC]). This study examined whether sex-based differences in gene expression and inflammatory marker expression can be observed in CTCs under control or infectious inflammatory conditions modeling preterm birth. CTCs from six different patient-derived fetal membrane samples (3M/3F) were cultured and divided into experimental (Lipopolysaccharide [LPS]) and control groups for 6, 12, or 24 h. RNA from CTCs was subjected to RNA-seq, while cytokine multiplex or ELISA detected pro-/anti-inflammatory cytokines, progesterone, and soluble HLA-G in cell supernatants. CTC-M and CTC-F showed sex, time, and stimulant-dependent differential gene expression profiles. Cytokine analysis demonstrated a significantly lower IL-6 production in control CTC-M than in CTC-F. No sex-dependent responses were observed after LPS treatment regarding cytokines. CTC-M produced significantly lower progesterone than CTC-F. The theories of sexual dimorphism linked to placental inflammation may not extend to CTCs. This study supports that the chorion acts as a “great wall” protecting the fetus by being refractory to insults. Further examination into the weaknesses of the chorion barrier and sex-dependent responses of fetal membranes is needed. Full article

(This article belongs to the Special Issue Molecular Research in Uterine Biology and Pathophysiology, 2nd Edition)

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10 pages, 3553 KiB

Open AccessCommunication

The Immunohistochemical Expression of Epithelial–Mesenchymal Transition Markers in Precancerous Lesions and Cervical Cancer

by Aneta Popiel-Kopaczyk, Aleksandra Piotrowska, Patrycja Sputa-Grzegrzolka, Beata Smolarz, Hanna Romanowicz, Piotr Dziegiel, Marzenna Podhorska-Okolow and Christopher Kobierzycki

Int. J. Mol. Sci. 2023, 24(9), 8063; https://doi.org/10.3390/ijms24098063 - 29 Apr 2023

Cited by 5 | Viewed by 2184

Abstract

In the epithelial–mesenchymal transition (EMT) process, cells lose their epithelial phenotype and gain mesenchymal features. This phenomenon was observed in the metastatic phase of neoplastic diseases, e.g., cervical cancer. There are specific markers that are expressed in the EMT. The aim of this study was to determine the localization of and associations between the immunohistochemical (IHC) expression of TWIST, SNAIL, and SLUG proteins in precancerous lesions and cervical cancer. The IHC analysis disclosed higher expressions of EMT markers in precancerous lesions and cervical cancer than in the control group. Moreover, stronger expression of TWIST, SNAIL, and SLUG was observed in cervical intraepithelial neoplasia grade 3 (CIN3) vs. CIN1, CIN3 vs. CIN2, and CIN2 vs. CIN1 cases (p < 0.05). In cervical cancer, IHC reactions demonstrated differences in TWIST, SNAIL, and SLUG expression in grade 1 (G1) vs. grade 2 (G2) (p < 0.0011; p < 0.0017; p < 0.0001, respectively) and in G1 vs. grade 3 (G3) (p < 0.0029; p < 0.0005; p < 0.0001, respectively). The results of our study clearly showed that existing differences in the expression of the tested markers in precancerous vs. cancerous lesions may be utilized in the diagnosis of cervical cancer. Further studies on bigger populations, as well as in comparison with well-known markers, may improve our outcomes. Full article

(This article belongs to the Special Issue Molecular Research in Uterine Biology and Pathophysiology, 2nd Edition)

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16 pages, 1194 KiB

Open AccessArticle

Role of Noradrenaline and Adrenoreceptors in Regulating Prostaglandin E2 Synthesis Cascade in Inflamed Endometrium of Pigs

by Barbara Jana, Jarosław Całka, Michał Bulc and Krzysztof Witek

Int. J. Mol. Sci. 2023, 24(6), 5856; https://doi.org/10.3390/ijms24065856 - 20 Mar 2023

Cited by 2 | Viewed by 2294

Abstract

In the inflamed uterus, the production and secretion of prostaglandins (PGs) and noradrenergic innervation pattern are changed. Receptor-based control of prostaglandin E2 (PGE2) production and secretion by noradrenaline during uterine inflammation is unknown. The aim of this study was to determine the role of α1-, α2- and β-adrenoreceptors (ARs) in noradrenaline-influenced PG-endoperoxidase synthase-2 (PTGS-2) and microsomal PTGE synthase-1 (mPTGES-1) protein levels in the inflamed pig endometrium, and in the secretion of PGE2 from this tissue. E. coli suspension (E. coli group) or saline (CON group) was injected into the uterine horns. Eight days later, severe acute endometritis developed in the E. coli group. Endometrial explants were incubated with noradrenaline and/or α1-, α2- and β-AR antagonists. In the CON group, noradrenaline did not significantly change PTGS-2 and mPTGES-1 protein expression and increased PGE2 secretion compared to the control values (untreated tissue). In the E. coli group, both enzyme expression and PGE2 release were stimulated by noradrenaline, and these values were higher versus the CON group. The antagonists of α1- and α2-AR isoforms and β-AR subtypes do not significantly alter the noradrenaline effect on PTGS-2 and mPTGES-1 protein levels in the CON group, compared to noradrenaline action alone. In this group, α1A-, α2B- and β2-AR antagonists partly eliminated noradrenaline-stimulated PGE2 release. Compared to the noradrenaline effect alone, α1A-, α1B-, α2A-, α2B-, β1-, β2- and β3-AR antagonists together with noradrenaline reduced PTGS-2 protein expression in the E. coli group. Such effects were also exerted in this group by α1A-, α1D-, α2A-, β2- and β3-AR antagonists with noradrenaline on mPTGES-1 protein levels. In the E. coli group, the antagonists of all isoforms of α1-ARs and subtypes of β-ARs as well as α2A-ARs together with noradrenaline decreased PGE2 secretion versus noradrenaline action alone. Summarizing, in the inflamed pig endometrium, α1(A, B)-, α2(A, B)- and β(1, 2, 3)-ARs mediate the noradrenaline stimulatory effect on PTGE-2 protein expression, while noradrenaline via α1(A, D)-, α2A- and β(2, 3)-ARs increases mPTGES-1 protein expression and α1(A, B, D)-, α2A- and β(1, 2, 3)-ARs are involved in PGE2 release. Data suggest that noradrenaline may indirectly affect the processes regulated by PGE2 by influencing its production. Pharmacological modulation of particular AR isoforms/subtypes can be used to change PGE2 synthesis/secretion to alleviate inflammation and improve uterine function. Full article

(This article belongs to the Special Issue Molecular Research in Uterine Biology and Pathophysiology, 2nd Edition)

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12 pages, 1356 KiB

Open AccessArticle

Prolonged Dystocic Labor in Neuraxial Analgesia and the Role of Enkephalin Neurotransmitters: An Experimental Study

by Antonio Malvasi, Ettore Cicinelli, Giorgio Maria Baldini, Antonella Vimercati, Renata Beck, Miriam Dellino, Gianluca Raffaello Damiani, Gerardo Cazzato, Eliano Cascardi and Andrea Tinelli

Int. J. Mol. Sci. 2023, 24(4), 3767; https://doi.org/10.3390/ijms24043767 - 13 Feb 2023

Cited by 17 | Viewed by 2312

Abstract

The investigation studied the enkephalinergic neuro fibers (En) contained in the Lower Uterine Segment (LUS) during the prolonged dystocic labor (PDL) with Labor Neuraxial Analgesia (LNA). PDL is generally caused by fetal head malpositions in the Occiput Posterior Position (OPP), Persistent Occiput Posterior Position (POPP), in a transverse position (OTP), and asynclitism (A), and it is detected by Intrapartum Ultrasonography (IU). The En were detected in the LUS samples picked up during cesarean section (CS) of 38 patients undergoing urgent CS in PDL, compared to 37 patients submitted to elective CS. Results were statistically evaluated to understand the differences in En morphological analysis by scanning electron microscopy (SEM) and by fluorescence microscopy (FM). The LUS samples analysis showed an important reduction in En in LUS of CS for the PDL group, in comparison with the elective CS group. The LUS overdistension, by fetal head malpositions (OPP, OTP, A) and malrotations, lead to dystocia, modification of vascularization, and En reduction. The En reduction in PDL suggests that drugs used during the LNA, usually local anesthetics and opioids, cannot control the “dystocic pain”, that differs from normal labor pain. The IU administration in labor and the consequent diagnosis of dystocia suggest stopping the numerous and ineffective top-up drug administration during LNA, and to shift the labor to operative vaginal delivery or CS. Full article

(This article belongs to the Special Issue Molecular Research in Uterine Biology and Pathophysiology, 2nd Edition)

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Review

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16 pages, 779 KiB

Open AccessReview

COVID-19—The Shift of Homeostasis into Oncopathology or Chronic Fibrosis in Terms of Female Reproductive System Involvement

by Elena Petersen, Daria Chudakova, Daiana Erdyneeva, Dulamsuren Zorigt, Evgeniya Shabalina, Denis Gudkov, Pavel Karalkin, Igor Reshetov and Ospan A. Mynbaev

Int. J. Mol. Sci. 2023, 24(10), 8579; https://doi.org/10.3390/ijms24108579 - 11 May 2023

Cited by 1 | Viewed by 3564

Abstract

The COVID-19 pandemic caused by the SARS-CoV-2 coronavirus remains a global public health concern due to the systemic nature of the infection and its long-term consequences, many of which remain to be elucidated. SARS-CoV-2 targets endothelial cells and blood vessels, altering the tissue microenvironment, its secretion, immune-cell subpopulations, the extracellular matrix, and the molecular composition and mechanical properties. The female reproductive system has high regenerative potential, but can accumulate damage, including due to SARS-CoV-2. COVID-19 is profibrotic and can change the tissue microenvironment toward an oncogenic niche. This makes COVID-19 and its consequences one of the potential regulators of a homeostasis shift toward oncopathology and fibrosis in the tissues of the female reproductive system. We are looking at SARS-CoV-2-induced changes at all levels in the female reproductive system. Full article

(This article belongs to the Special Issue Molecular Research in Uterine Biology and Pathophysiology, 2nd Edition)

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