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Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 2.0

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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: closed (28 February 2022) | Viewed by 27213

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Prof. Dr. Seung-Yup Ku

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Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul National University College of Medicine, 28 Yonkeun-dong, Chongno-gu, Seoul 110-744, Republic of Korea
Interests: RNA; ovarian; uterus
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Reproduction is a very critical scientific phenomenon, tied to the origin of mankind. Successful or failed pregnancy, menstrual dysfunction, and the tumorigenesis of female reproductive organs currently offer numerous challenges for meeting clinically unmet needs, and often require advanced therapeutic strategies.

There has been exciting progress in understanding the molecular pathophysiology of various uterine and ovarian diseases and dysfunction in recent years. Genetic or epigenetic alterations represent novel diagnostic and prognostic molecular markers and therapeutic targets for these diseases and dysfunction. To date, specific biomarkers, as well as genetic or epigenetic alterations, have been identified.

This Special Issue of IJMS is searching for answers to some of the above-mentioned questions, in an attempt to provide reproductive biomedical scientists and clinicians with novel answers that should lead to a better understanding of these prevalent and serious universal diseases and dysfunction. Studies using clinical samples, and animal or cell culture models to investigate the molecular pathophysiology of uterine and ovarian diseases and dysfunction will be published.

IJMS looks forward to receiving excellent contributions from all types of investigators of female reproductive tract dysfunction and diseases.

Prof. Dr. Seung-Yup Ku
Guest Editor

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Keywords

uterine tumor
ovarian tumor
hormonal dysfunction
polycystic ovary syndrome
endometriosis
menopause
infertility
pregnancy
abortion
assisted reproduction
pluripotent stem cell
tissue engineering

Published Papers (9 papers)

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Research

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12 pages, 1913 KiB

Open AccessArticle

Autoimmunity to the Follicle-Stimulating Hormone Receptor (FSHR) and Luteinizing Hormone Receptor (LHR) in Polycystic Ovarian Syndrome

by Hanna A. Schniewind, Lisa-Marie Sattler, Christoph W. Haudum, Julia Münzker, Waldemar B. Minich, Barbara Obermayer-Pietsch and Lutz Schomburg

Int. J. Mol. Sci. 2021, 22(24), 13667; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413667 - 20 Dec 2021

Cited by 7 | Viewed by 2948

Abstract

Hyperandrogenemia and ovulatory dysfunction are hallmarks of polycystic ovary syndrome (PCOS), pointing to a deranged hypothalamus-pituitary-ovarian (HPO) axis. An autoimmune etiology of PCOS is suspected in a subset of patients due to the relatively high concordance of PCOS with common autoimmune diseases. For this reason, we tested the hypothesis that natural autoantibodies (aAb) to the follicle-stimulating hormone receptor (FSHR) or luteinizing hormone receptor (LHR) are prevalent in PCOS. To this end, new luminometric assays for quantifying aAb to the FSHR (FSHR-aAb) or LHR (LHR-aAb) were developed using full-length recombinant human receptors as fusion proteins with luciferase as reporter. Prevalence of FSHR-aAb and LHR-aAb was determined in serum samples from healthy controls and PCOS patients. Steroid hormone profiles were compared between patients with and without FSHR-aAb or LHR-aAb. Signal linearity and detection ranges were characterized and both methods passed basic performance quality checks. The analysis revealed a relatively low prevalence, with 4 out of 430 samples positive for FSHR-aAb in the control versus 11 out of 550 samples in the PCOS group, i.e., 0.9% versus 2.0%, respectively. Similarly, there were only 5 samples positive for LHR-aAb in the control versus 2 samples in the PCOS group, i.e., 1.2% versus 0.4%, respectively. Samples positive for FSHR-aAb displayed steroid hormones in the typical range of PCOS patients, whereas the two samples positive for LHR-aAb showed relatively elevated free testosterone in relation to total testosterone concentrations with unclear significance. We conclude that the FSHR and LHR constitute potential autoantigens in human subjects. However, the prevalence of specific autoantibodies to these receptors is relatively low, both in control subjects and in women with PCOS. It is therefore unlikely that autoimmunity to the LHR or FSHR constitutes a frequent cause of hyperandrogenemia or ovulatory dysfunction in PCOS. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 2.0)

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20 pages, 21782 KiB

Open AccessArticle

Transcriptome Analyses Identify Potential Key microRNAs and Their Target Genes Contributing to Ovarian Reserve

by Yoon-Young Kim, Kwang-Soo Kim, Yong-Jin Kim, Sung-Woo Kim, Hoon Kim and Seung-Yup Ku

Int. J. Mol. Sci. 2021, 22(19), 10819; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910819 - 06 Oct 2021

Cited by 1 | Viewed by 2339

Abstract

Female endocrinological symptoms, such as premature ovarian inefficiency (POI) are caused by diminished ovarian reserve and chemotherapy. The etiology of POI remains unknown, but this can lead to infertility. This has accelerated the search for master regulator genes or other molecules that contribute as enhancers or silencers. The impact of regulatory microRNAs (miRNAs) on POI has gained attention; however, their regulatory function in this condition is not well known. RNA sequencing was performed at four stages, 2-(2 W), 6-(6 W), 15-(15 W), and 20-(20 W) weeks, on ovarian tissue samples and 5058 differentially expressed genes (DEGs) were identified. Gene expression and enrichment were analyzed based on the gene ontology and KEGG databases, and their association with other proteins was assessed using the STRING database. Gene set enrichment analysis was performed to identify the key target genes. The DEGs were most highly enriched in 6 W and 15 W groups. Figla, GDF9, Nobox, and Pou51 were significantly in-creased at 2 W compared with levels at 6 W and 20 W, whereas the expression of Foxo1, Inha, and Taf4b was significantly de-creased at 20 W. Ccnd2 and Igf1 expression was maintained at similar levels in each stage. In total, 27 genes were upregulated and 26 genes interacted with miRNAs; moreover, stage-specific upregulated and downregulated interactions were demonstrated. Increased and decreased miRNAs were identified at each stage in the ovaries. The constitutively expressed genes, Ccnd2 and Igf1, were identified as the major targets of many miRNAs (p < 0.05), and Fshr and Foxo3 interacted with miRNAs, namely mmu-miR-670-3p and mmu-miR-153-3p. miR-26a-5p interacted with Piwil2, and its target genes were downregulated in the 20 W mouse ovary. In this study, we aimed to identify key miRNAs and their target genes encompassing the reproductive span of mouse ovaries using mRNA and miRNA sequencing. These results indicated that gene sets are regulated in the reproductive stage-specific manner via interaction with miRNAs. Furthermore, consistent expression of Ccnd2 and Igf1 is considered crucial for the ovarian reserve and is regulated by many interactive miRNAs. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 2.0)

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12 pages, 3012 KiB

Open AccessArticle

Influence of Vitamin D on the Vasoactive Effect of Estradiol in a Rat Model of Polycystic Ovary Syndrome

by Róbert Tarszabó, Bálint Bányai, Éva Ruisanchez, Borbála Péterffy, Ágnes Korsós-Novák, Krisztina Lajtai, Réka Eszter Sziva, Dóra Gerszi, Ádám Hosszú, Rita Benkő, Zoltán Benyó, Eszter Mária Horváth, Gabriella Masszi and Szabolcs Várbíró

Int. J. Mol. Sci. 2021, 22(17), 9404; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179404 - 30 Aug 2021

Cited by 2 | Viewed by 2314

Abstract

We examined the vasoactive effect of estradiol in a rat model of early PCOS and the influence of vitamin D deficiency (VDD). We created a model of chronic hyperandrogenism and VDD in adolescent female Wistar rats (N = 46) with four experimental groups: vitamin D supplemented (T-D+), VDD (T-D-), hyperandrogenic and vitamin D supplemented (T+D+), and hyperandrogenic and VDD (T+D-). T+ groups received an 8-week-long transdermal Androgel treatment, D-animals were on vitamin D-reduced diet and D+ rats were supplemented orally with vitamin D3. Estrogen-induced vasorelaxation of thoracic aorta segments were measured with a wire myograph system with or without the inhibition of endothelial nitric oxide synthase (eNOS) or cyclooxygenase-2 (COX-2). The distribution of estrogen receptor (ER), eNOS and COX-2 in the aortic wall was assessed by immunohistochemistry. VDD aortas showed significantly lower estradiol-induced relaxation independently of androgenic status that was further decreased by COX-2 inhibition. COX-2 inhibition failed to alter vessel function in D+ rats. Inhibition of eNOS abolished the estradiol-induced relaxation in all groups. Changes in vascular function in VDD were accompanied by significantly decreased ER and eNOS staining. Short-term chronic hyperandrogenism failed to, but VDD induced vascular dysfunction, compromised estrogen-dependent vasodilatation and changes in ER and eNOS immunostaining. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 2.0)

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23 pages, 3768 KiB

Open AccessArticle

Molecular Characterisation of Uterine Endometrial Proteins during Early Stages of Pregnancy in Pigs by MALDI TOF/TOF

by Dorota Pierzchała, Kamila Liput, Agnieszka Korwin-Kossakowska, Magdalena Ogłuszka, Ewa Poławska, Agata Nawrocka, Paweł Urbański, Aleksandra Ciepłoch, Edyta Juszczuk-Kubiak, Adam Lepczyński, Brygida Ślaska, Krzysztof Kowal, Marinus F. W. te Pas, Magdalena Śmiech, Paweł Leszczyński, Hiroaki Taniguchi, Leyland Fraser, Przemysław Sobiech, Mateusz Sachajko, Magdalena Herudzinska, Chandra S. Pareek and Mariusz Pierzchała Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(13), 6720; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136720 - 23 Jun 2021

Cited by 7 | Viewed by 2766

Abstract

The molecular mechanism underlying embryonic implantation is vital to understand the correct communications between endometrium and developing conceptus during early stages of pregnancy. This study’s objective was to determine molecular changes in the uterine endometrial proteome during the preimplantation and peri-implantation between 9 days (9D), 12 days (12D), and 16 days (16D) of pregnant Polish Large White (PLW) gilts. 2DE-MALDI-TOF/TOF and ClueGO^TM approaches were employed to analyse the biological networks and molecular changes in porcine endometrial proteome during maternal recognition of pregnancy. A total of sixteen differentially expressed proteins (DEPs) were identified using 2-DE gels and MALDI-TOF/TOF mass spectrometry. Comparison between 9D and 12D of pregnancy identified APOA1, CAPZB, LDHB, CCT5, ANXA4, CFB, TTR upregulated DEPs, and ANXA5, SMS downregulated DEPs. Comparison between 9D and 16D of pregnancy identified HP, APOA1, ACTB, CCT5, ANXA4, CFB upregulated DEPs and ANXA5, SMS, LDHB, ACTR3, HP, ENO3, OAT downregulated DEPs. However, a comparison between 12D and 16D of pregnancy identified HP, ACTB upregulated DEPs, and CRYM, ANXA4, ANXA5, CAPZB, LDHB, ACTR3, CCT5, ENO3, OAT, TTR down-regulated DEPs. Outcomes of this study revealed key proteins and their interactions with metabolic pathways involved in the recognition and establishment of early pregnancy in PLW gilts. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 2.0)

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11 pages, 1334 KiB

Open AccessArticle

Changes in the Expression of TBP-2 in Response to Histone Deacetylase Inhibitor Treatment in Human Endometrial Cells

by Hye In Kim, Seok Kyo Seo, Seung Joo Chon, Ga Hee Kim, Inha Lee and Bo Hyon Yun

Int. J. Mol. Sci. 2021, 22(3), 1427; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031427 - 31 Jan 2021

Cited by 13 | Viewed by 1960

Abstract

Histone deacetylase inhibitors (HDACi) induce apoptosis preferentially in cancer cells by caspase pathway activation and reactive oxygen species (ROS) accumulation. Suberoylanilide hydroxamic acid (SAHA), a HDACi, increases apoptosis via altering intracellular oxidative stress through thioredoxin (TRX) and TRX binding protein-2 (TBP-2). Because ROS accumulation, as well as the redox status determined by TBP-2 and TRX, are suggested as possible mechanisms for endometriosis, we queried whether SAHA induces apoptosis of human endometrial cells via the TRX–TBP-2 system in endometriosis. Eutopic endometrium from participants without endometriosis, and ectopic endometrium from patients with endometriosis, was obtained surgically. Human endometrial stromal cells (HESCs) and Ishikawa cells were treated with SAHA and cell proliferation was assessed using the CCK-8 assay. Real-time PCR and Western blotting were used to quantify TRX and TBP-2 mRNA and protein expression. After inducing oxidative stress, SAHA was applied. Short-interfering TRX (SiTRX) transfection was performed to see the changes after TRX inhibition. The mRNA and protein expression of TBP-2 was increased with SAHA concentrations in HESCs significantly. The mRNA TBP-2 expression was decreased after oxidative stress, upregulated by adding 2.5 μM of SAHA. The TRX/TBP-2 ratio decreased, apoptosis increased significantly, and SiTRX transfection decreased with SAHA. In conclusion, SAHA induces apoptosis by modulating the TRX/TBP-2 system, suggesting its potential as a therapeutic agent for endometriosis. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 2.0)

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13 pages, 2621 KiB

Open AccessArticle

Consecutive Low Doses of Streptozotocin Induce Polycystic Ovary Syndrome Features in Mice

by Youngjae Ryu, Yong Jin Kim, Yoon Young Kim, Jungwoo Kim, Sung Woo Kim, Hoon Kim and Seung Yup Ku

Int. J. Mol. Sci. 2021, 22(3), 1299; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031299 - 28 Jan 2021

Cited by 4 | Viewed by 5260

Abstract

Polycystic ovarian syndrome (PCOS) is a common reproductive endocrine disorder in reproductive-age women. Due to its various pathophysiological properties and clinical heterophenotypes, the mechanism of PCOS pathogenesis is still unclear. Several animal models have been used to study PCOS and allow the exploration of the specific mechanism underlying PCOS. We focused on streptozotocin (STZ) to develop a non-steroidal and non-diabetic PCOS model. We administered multiple STZ injections to female C57BL/6 mice (3–4 weeks old) at different concentrations: STZ-15 (15 mg/kg), STZ-30 (30 mg/kg), and STZ-60 (60 mg/kg) treatments. During the experimental period, we analyzed body weight, blood glucose levels, and estrous cycle pattern. Furthermore, five weeks after STZ administration, we examined hormone levels and the morphology of ovarian tissues. Mice in the STZ-15 group did not show differences in body weights, blood glucose level, insulin level, and insulin tolerance compared to wild-type and control groups whereas those in the STZ-60 group presented a typical diabetes phenotype. In the case of the STZ-30 group, only increased blood glucose level was observed. Total testosterone levels were significantly elevated in STZ-15 and STZ-30 groups. Luteinizing hormone (LH) and estradiol levels were not significantly changed in the STZ-treated groups. The number of ovarian antral follicles and atretic follicles significantly increased in the ovary of mice in the STZ-15 and STZ-30 groups. All STZ-treated groups manifested irregular estrus cycles. However, the patterns of estrous cycles were different between mice treated with different STZ concentrations. We found that PI3K-AKT and IRS-1 signaling in the ovary was enhanced by low doses of STZ treatment. Taken together, our finding indicates that multiple injections of STZ at low doses induce PCOS features in mice without induction of diabetes features. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 2.0)

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Review

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20 pages, 1447 KiB

Open AccessReview

Epigenetic Regulation in Uterine Fibroids—The Role of Ten-Eleven Translocation Enzymes and Their Potential Therapeutic Application

by Marta Włodarczyk, Grażyna Nowicka, Michał Ciebiera, Mohamed Ali, Qiwei Yang and Ayman Al-Hendy

Int. J. Mol. Sci. 2022, 23(5), 2720; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052720 - 28 Feb 2022

Cited by 4 | Viewed by 2634

Abstract

Uterine fibroids (UFs) are monoclonal, benign tumors that contain abnormal smooth muscle cells and the accumulation of extracellular matrix (ECM). Although benign, UFs are a major source of gynecologic and reproductive dysfunction, ranging from menorrhagia and pelvic pain to infertility, recurrent miscarriage, and preterm labor. Many risk factors are involved in the pathogenesis of UFs via genetic and epigenetic mechanisms. The latter involving DNA methylation and demethylation reactions provide specific DNA methylation patterns that regulate gene expression. Active DNA demethylation reactions mediated by ten-eleven translocation proteins (TETs) and elevated levels of 5-hydroxymethylcytosine have been suggested to be involved in UF formation. This review paper summarizes the main findings regarding the function of TET enzymes and their activity dysregulation that may trigger the development of UFs. Understanding the role that epigenetics plays in the pathogenesis of UFs may possibly lead to a new type of pharmacological fertility-sparing treatment method. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 2.0)

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19 pages, 1423 KiB

Open AccessReview

Epigenetic Regulation of Cardiomyocyte Differentiation from Embryonic and Induced Pluripotent Stem Cells

by Yong-Jin Kim, Amin Tamadon, Yoon-Young Kim, Byeong-Cheol Kang and Seung-Yup Ku

Int. J. Mol. Sci. 2021, 22(16), 8599; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168599 - 10 Aug 2021

Cited by 4 | Viewed by 3949

Abstract

With the intent to achieve the best modalities for myocardial cell therapy, different cell types are being evaluated as potent sources for differentiation into cardiomyocytes. Embryonic stem cells and induced pluripotent stem cells have great potential for future progress in the treatment of myocardial diseases. We reviewed aspects of epigenetic mechanisms that play a role in the differentiation of these cells into cardiomyocytes. Cardiomyocytes proliferate during fetal life, and after birth, they undergo permanent terminal differentiation. Upregulation of cardiac-specific genes in adults induces hypertrophy due to terminal differentiation. The repression or expression of these genes is controlled by chromatin structural and epigenetic changes. However, few studies have reviewed and analyzed the epigenetic aspects of the differentiation of embryonic stem cells and induced pluripotent stem cells into cardiac lineage cells. In this review, we focus on the current knowledge of epigenetic regulation of cardiomyocyte proliferation and differentiation from embryonic and induced pluripotent stem cells through histone modification and microRNAs, the maintenance of pluripotency, and its alteration during cardiac lineage differentiation. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 2.0)

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Other

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9 pages, 2576 KiB

Open AccessCase Report

Association of Anti-EGFR Antibody and MEK Inhibitor in Gynecological Cancer Harboring RAS Mutation: A Case Series

by Julie Niogret, Valentin Derangère, Corentin Richard, Lisa Nuttin, François Ghiringhelli, Laure Favier, Leila Bengrine Lefevre, Anthony Bergeron, Laurent Arnould and Romain Boidot

Int. J. Mol. Sci. 2022, 23(6), 3343; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063343 - 19 Mar 2022

Cited by 1 | Viewed by 1971

Abstract

Low-grade serous carcinoma represents a minority of serous carcinoma. Although they have better prognosis than high-grade serous carcinoma, they respond poorly to chemotherapy. Thus, it appears necessary to find other treatments such as targeted therapies. Since RAS or RAF mutations occur frequently in low-grade serous carcinoma and lead to constitutively activated MAPK cascade, MEK inhibition should be effective in the treatment of low-grade serous carcinoma. So, we wanted to evaluate the clinical benefit of MEK inhibitors in the management of advanced-stage low-grade serous carcinoma harboring KRAS or NRAS mutation. We report a case series of three women with advanced-stage low-grade serous carcinoma harboring RAS mutation who had stabilization of their disease during several months under targeted therapy combining anti-EGFR antibody and MEK inhibitor. We performed in vitro experiments, confirming the effectiveness of MEK inhibitor on the KRAS-mutated OVCAR-5 cell line, and the constitutively activation of MAPK cascade in RAS-mutated carcinoma. However, it seems that the anti-EGFR antibody does not provide any additional benefit. After whole exome analysis is carried out on the patient with the shortest response, we observed the appearance of RB1 loss-of-function mutation that could be a mechanism of resistance to MEK inhibitors in RAS- of RAF-mutated cancers. The MEK inhibitor is effective in the advanced stages of low-grade serous carcinoma harboring RAS mutation with acceptable tolerance. RB1 loss could be a mechanism of resistance to MEK inhibitors in RAS-mutated low-grade serous carcinoma. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 2.0)

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