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A Molecular Perspective on Reproductive Health

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 20 May 2024 | Viewed by 6611

Special Issue Editor

Department of Animal Medicine and Surgery, Veterinary School, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
Interests: amniotic fluid; semen analysis; embryos; theriogenology; cryopreservation; reproductive biology; semen preservation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

I am very pleased to invite you to submit your contributions to this Special Issue of the International Journal of Molecular Science, which is focused on a molecular perspective of reproductive health. Reproduction, as with any other physiological function, is molecular based, and its comprehension will result in a better understanding of the mechanisms behind it. A better understanding of its molecular functioning may supply tools that could be useful in the diagnosis, treatment, and prognosis of reproductive pathologies, thus improving the clinical approach and, in turn, providing better solutions to the patients.

Dr. Maria Montserrat Rivera Del Álamo
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • reproductive function
  • molecular bases
  • male
  • female
  • reproductive pathology
  • reproductive physiology

Published Papers (8 papers)

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Research

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14 pages, 4279 KiB  
Article
YTHDF2 as a Mediator in BDNF-Induced Proliferation of Porcine Follicular Granulosa Cells
by Kening Liu, Xu Zhou, Chunjin Li, Caomeihui Shen, Guitian He, Tong Chen, Maosheng Cao, Xue Chen, Boqi Zhang and Lu Chen
Int. J. Mol. Sci. 2024, 25(4), 2343; https://doi.org/10.3390/ijms25042343 - 16 Feb 2024
Viewed by 592
Abstract
In female mammals, the proliferation and apoptosis of granulosa cells (GCs) are critical in determining the fate of follicles and are influenced by various factors, including brain-derived neurotrophic factor (BDNF). Previous research has shown that BDNF primarily regulates GC proliferation through the PI3K/AKT, [...] Read more.
In female mammals, the proliferation and apoptosis of granulosa cells (GCs) are critical in determining the fate of follicles and are influenced by various factors, including brain-derived neurotrophic factor (BDNF). Previous research has shown that BDNF primarily regulates GC proliferation through the PI3K/AKT, NF-kB, and CREB tumour pathways; however, the role of other molecular mechanisms in mediating BDNF-induced GC proliferation remains unclear. In this study, we investigated the involvement of the m6A reader YTH domain-containing family member 2 (YTHDF2) in BDNF-stimulated GC proliferation and its underlying mechanism. GCs were cultured in DMEM medium supplemented with varying BDNF concentrations (0, 10, 30, 75, and 150 ng/mL) for 24 h. The viability, number, and cell cycle of GCs were assessed using the CCK-8 assay, cell counting, and flow cytometry, respectively. Further exploration into YTHDF2’s role in BDNF-stimulated GC proliferation was conducted using RT-qPCR, Western blotting, and sequencing. Our findings indicate that YTHDF2 mediates the effect of BDNF on GC proliferation. Additionally, this study suggests for the first time that BDNF promotes YTHDF2 expression by increasing the phosphorylation level of the ERK1/2 signalling pathway. This study offers a new perspective and foundation for further elucidating the mechanism by which BDNF regulates GC proliferation. Full article
(This article belongs to the Special Issue A Molecular Perspective on Reproductive Health)
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11 pages, 1635 KiB  
Article
Serum Lipocalin-2 Levels as a Biomarker in Pre- and Post-Pubertal Klinefelter Syndrome Patients: A Pilot Study
by Roberto Paparella, Giampiero Ferraguti, Marco Fiore, Michela Menghi, Ginevra Micangeli, Francesca Tarani, Aurora Ligotino, Marisa Patrizia Messina, Mauro Ceccanti, Antonio Minni, Christian Barbato, Marco Lucarelli, Luigi Tarani and Carla Petrella
Int. J. Mol. Sci. 2024, 25(4), 2214; https://doi.org/10.3390/ijms25042214 - 12 Feb 2024
Viewed by 481
Abstract
Klinefelter syndrome (KS) is a male genetic disease caused by the presence of an extra X chromosome, causing endocrine disorders mainly responsible for a high rate of infertility and metabolic disorders in adulthood. Scientific research is interested in identifying new biomarkers that can [...] Read more.
Klinefelter syndrome (KS) is a male genetic disease caused by the presence of an extra X chromosome, causing endocrine disorders mainly responsible for a high rate of infertility and metabolic disorders in adulthood. Scientific research is interested in identifying new biomarkers that can be predictive or prognostic of alterations strictly connected to KS. Lipocalin-2 (LCN-2, also known as NGAL) is a small protein initially identified within neutrophils as a protein related to innate immunity. Serum LCN-2 estimation seems to be a useful tool in predicting the metabolic complications caused by several pathological conditions. However, little is known about its potential role in infertility conditions. The present pilot study aims to investigate the presence of LCN-2 in the serum of a group of pre-pubertal and post-pubertal children affected by KS, compared to healthy controls. We demonstrated for the first time the presence of elevated levels of LCN-2 in the serum of KS patients, compared to controls. This increase was accompanied, in pre-pubertal KS patients, by the loss of correlation with LH and HDL, which instead was present in the healthy individuals. Moreover, in all KS individuals, a positive correlation between LCN-2 and inhibin B serum concentration was found. Despite the limited size of the sample analyzed, our preliminary data encourage further studies to confirm the findings and to extend the study to KS adult patients, to verify the predictive/prognostic value of LCN-2 as new biomarker for metabolic diseases and infertility associated with the pathology. Full article
(This article belongs to the Special Issue A Molecular Perspective on Reproductive Health)
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14 pages, 1000 KiB  
Article
Quantitative Analysis of the Human Semen Phosphorometabolome by 31P-NMR
by Rebeca Serrano, David Martin-Hidalgo, Jon Bilbao, Ganeko Bernardo-Seisdedos, Oscar Millet, Luis J. Garcia-Marin and Maria Julia Bragado
Int. J. Mol. Sci. 2024, 25(3), 1682; https://doi.org/10.3390/ijms25031682 - 30 Jan 2024
Viewed by 482
Abstract
Phosphorus-containing metabolites occupy a prominent position in cell pathways. The phosphorometabolomic approach in human sperm samples will deliver valuable information as new male fertility biomarkers could emerge. This study analyzed, by 31P-NMR, seminal plasma and whole semen from asthenozoospermic and normozoospermic samples [...] Read more.
Phosphorus-containing metabolites occupy a prominent position in cell pathways. The phosphorometabolomic approach in human sperm samples will deliver valuable information as new male fertility biomarkers could emerge. This study analyzed, by 31P-NMR, seminal plasma and whole semen from asthenozoospermic and normozoospermic samples (71% vs. 27% and 45% vs. 17%, total and progressive sperm motility, respectively), and also ejaculates from healthy donors. At least 16 phosphorus-containing metabolites involved in central energy metabolism and phospholipid, nucleotide, and nicotinamide metabolic pathways were assigned and different abundances between the samples with distinct sperm quality was detected. Specifically, higher levels of phosphocholine, glucose-1-phosphate, and to a lesser degree, acetyl phosphate were found in the asthenozoospermic seminal plasma. Notably, the phosphorometabolites implicated in lipid metabolism were highlighted in the seminal plasma, while those associated with carbohydrate metabolism were more abundant in the spermatozoa. Higher levels of phosphocholine, glucose-1-phosphate, and acetyl phosphate in the seminal plasma with poor quality suggest their crucial role in supporting sperm motility through energy metabolic pathways. In the seminal plasma, phosphorometabolites related to lipid metabolism were prominent; however, spermatozoa metabolism is more dependent on carbohydrate-related energy pathways. Understanding the presence and function of sperm phosphorylated metabolites will enhance our knowledge of the metabolic profile of healthy human sperm, improving assessment and differential diagnosis. Full article
(This article belongs to the Special Issue A Molecular Perspective on Reproductive Health)
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15 pages, 1221 KiB  
Article
Programmed Death-Ligand (PD-L1), Epidermal Growth Factor (EGF), Relaxin, and Matrix Metalloproteinase-3 (MMP3): Potential Biomarkers of Malignancy in Canine Mammary Neoplasia
by Makchit Galadima, Mariana Teles, Josep Pastor, Javier Hernández-Losa, Joan Enric Rodríguez-Gil and Maria Montserrat Rivera del Alamo
Int. J. Mol. Sci. 2024, 25(2), 1170; https://doi.org/10.3390/ijms25021170 - 18 Jan 2024
Viewed by 719
Abstract
Gene expression has been suggested as a putative tool for prognosis and diagnosis in canine mammary neoplasia (CMNs). In the present study, 58 formalin-fixed paraffin-embedded (FFPE) paraffined canine mammary neoplasias from 27 different bitches were included. Thirty-seven tumours were classified as benign, whereas [...] Read more.
Gene expression has been suggested as a putative tool for prognosis and diagnosis in canine mammary neoplasia (CMNs). In the present study, 58 formalin-fixed paraffin-embedded (FFPE) paraffined canine mammary neoplasias from 27 different bitches were included. Thirty-seven tumours were classified as benign, whereas thirty-one were classified as different types of canine carcinoma. In addition, mammary samples from three healthy bitches were also included. The gene expression for vascular endothelial growth factor-α (VEGFα), CD20, progesterone receptor (PGR), hyaluronidase-1 (HYAL-1), programmed death-ligand 1 (PD-L1), epidermal growth factor (EGF), relaxin (RLN2), and matrix metalloproteinase-3 (MMP3) was assessed through RT-qPCR. All the assessed genes yielded a higher expression in neoplastic mammary tissue than in healthy tissue. All the evaluated genes were overexpressed in neoplastic mammary tissue, suggesting a role in the process of tumorigenesis. Moreover, PD-L1, EGF, relaxin, and MMP3 were significantly overexpressed in malignant CMNs compared to benign CMNs, suggesting they may be useful as malignancy biomarkers. Full article
(This article belongs to the Special Issue A Molecular Perspective on Reproductive Health)
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21 pages, 5140 KiB  
Article
Bromodomain-Containing Protein 9 Regulates Signaling Pathways and Reprograms the Epigenome in Immortalized Human Uterine Fibroid Cells
by Qiwei Yang, Somayeh Vafaei, Ali Falahati, Azad Khosh, Maria Victoria Bariani, Mervat M. Omran, Tao Bai, Hiba Siblini, Mohamed Ali, Chuan He, Thomas G. Boyer and Ayman Al-Hendy
Int. J. Mol. Sci. 2024, 25(2), 905; https://doi.org/10.3390/ijms25020905 - 11 Jan 2024
Viewed by 921
Abstract
Bromodomain-containing proteins (BRDs) are involved in many biological processes, most notably epigenetic regulation of transcription, and BRD dysfunction has been linked to many diseases, including tumorigenesis. However, the role of BRDs in the pathogenesis of uterine fibroids (UFs) is entirely unknown. The present [...] Read more.
Bromodomain-containing proteins (BRDs) are involved in many biological processes, most notably epigenetic regulation of transcription, and BRD dysfunction has been linked to many diseases, including tumorigenesis. However, the role of BRDs in the pathogenesis of uterine fibroids (UFs) is entirely unknown. The present study aimed to determine the expression pattern of BRD9 in UFs and matched myometrium and further assess the impact of a BRD9 inhibitor on UF phenotype and epigenetic/epitranscriptomic changes. Our studies demonstrated that the levels of BRD9 were significantly upregulated in UFs compared to matched myometrium, suggesting that the aberrant BRD expression may contribute to the pathogenesis of UFs. We then evaluated the potential roles of BRD9 using its specific inhibitor, I-BRD9. Targeted inhibition of BRD9 suppressed UF tumorigenesis with increased apoptosis and cell cycle arrest, decreased cell proliferation, and extracellular matrix deposition in UF cells. The latter is the key hallmark of UFs. Unbiased transcriptomic profiling coupled with downstream bioinformatics analysis further and extensively demonstrated that targeted inhibition of BRD9 impacted the cell cycle- and ECM-related biological pathways and reprogrammed the UF cell epigenome and epitranscriptome in UFs. Taken together, our studies support the critical role of BRD9 in UF cells and the strong interconnection between BRD9 and other pathways controlling the UF progression. Targeted inhibition of BRDs might provide a non-hormonal treatment option for this most common benign tumor in women of reproductive age. Full article
(This article belongs to the Special Issue A Molecular Perspective on Reproductive Health)
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10 pages, 741 KiB  
Communication
Immune Checkpoints in Recurrent Pregnancy Loss: New Insights into a Detrimental and Elusive Disorder
by Luca Marozio, Anna Maria Nuzzo, Eugenio Gullo, Laura Moretti, Emilie M. Canuto, Annalisa Tancredi, Margherita Goia, Stefano Cosma, Alberto Revelli, Alessandro Rolfo and Chiara Benedetto
Int. J. Mol. Sci. 2023, 24(17), 13071; https://doi.org/10.3390/ijms241713071 - 22 Aug 2023
Cited by 2 | Viewed by 947
Abstract
Recurrent pregnancy loss (RPL) refers to two or more miscarriages before 20 weeks gestation. Its prevalence is 1–2%; its pathogenesis remains unexplained in more than 50% of cases, in which the cause is thought to be abnormal immune activity during placentation leading to [...] Read more.
Recurrent pregnancy loss (RPL) refers to two or more miscarriages before 20 weeks gestation. Its prevalence is 1–2%; its pathogenesis remains unexplained in more than 50% of cases, in which the cause is thought to be abnormal immune activity during placentation leading to a lack of pregnancy-induced immune tolerance. It is unknown whether immune activity is deranged in the endometrium of women with RPL. We studied the gene expression and the quantitative tissue protein levels of three immune checkpoints (CD276, which enhances cytotoxic T-cell activity, cytotoxic T-lymphocyte-associated antigen-4 [CTL-4], which reduces Th1 cytokine production, and lymphocyte activation gene-3 [LAG-3], which shows suppressive activity on Tregs and CD4+ T-cells) in endometrial samples from 27 women with unexplained RPL and in 29 women with dysfunctional uterine bleeding and previous uneventful pregnancies as controls. RNA isolation, real-time PCR, protein isolation, and ELISA were performed. CD276 gene expression and protein tissue levels were significantly lower in the endometrium of the RPL group than in the controls, whereas both CTL-4 and LAG-3 were significantly higher. This difference suggests defective endometrial immune regulation and overactivation of immune response in women with a history of RPL, at least in relation to controls with dysfunctional uterine bleeding and previous normal reproductive history. Full article
(This article belongs to the Special Issue A Molecular Perspective on Reproductive Health)
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Review

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29 pages, 1205 KiB  
Review
Phospholipase C Zeta in Human Spermatozoa: A Systematic Review on Current Development and Clinical Application
by Alessandra Parrella, Llanos Medrano, Jon Aizpurua and María José Gómez-Torres
Int. J. Mol. Sci. 2024, 25(2), 1344; https://doi.org/10.3390/ijms25021344 - 22 Jan 2024
Viewed by 649
Abstract
During fertilization, the fusion of the spermatozoa with the oocytes causes the release of calcium from the oocyte endoplasmatic reticulum. This, in turn, triggers a series of calcium ion (Ca2+) oscillations, a process known as oocyte activation. The sperm-specific factor responsible [...] Read more.
During fertilization, the fusion of the spermatozoa with the oocytes causes the release of calcium from the oocyte endoplasmatic reticulum. This, in turn, triggers a series of calcium ion (Ca2+) oscillations, a process known as oocyte activation. The sperm-specific factor responsible for oocyte activation is phospholipase C zeta (PLCζ). Men undergoing intracytoplasmic sperm injection (ICSI) with their spermatozoa lacking PLCζ are incapable of generating Ca2+ oscillation, leading to fertilization failure. The immunofluorescence assay is the most used technique to assess the expression and localization of PLCζ and to diagnose patients with reduced/absent ability to activate the oocytes. In these patients, the use of assisted oocyte activation (AOA) technique can help to yield successful ICSI results and shorten the time of pregnancy. However, the production of a stable PLCζ recombinant protein represents a new powerful therapeutic approach to treating individuals with this condition. We aim to conduct a systematic review focusing on the expression, level, and localization of PLCζ, discussing the novel genetic mutation associated with its impairment. In addition, we highlight the benefits of AOA, looking at new and less invasive methods to diagnose and treat cases with PLCζ dysfunction. Full article
(This article belongs to the Special Issue A Molecular Perspective on Reproductive Health)
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14 pages, 718 KiB  
Review
Human Papillomavirus and Male Infertility: What Do We Know?
by Arianna Sucato, Michela Buttà, Liana Bosco, Leonardo Di Gregorio, Antonio Perino and Giuseppina Capra
Int. J. Mol. Sci. 2023, 24(24), 17562; https://doi.org/10.3390/ijms242417562 - 16 Dec 2023
Viewed by 1052
Abstract
In recent years, increasing attention has been paid to understanding the causes of infertility, which is being recognized as a growing health problem affecting large numbers of couples worldwide. Male infertility is a contributing factor in approximately 30–40% of cases, and one of [...] Read more.
In recent years, increasing attention has been paid to understanding the causes of infertility, which is being recognized as a growing health problem affecting large numbers of couples worldwide. Male infertility is a contributing factor in approximately 30–40% of cases, and one of its etiological causes is sexually transmitted infections (STIs). Among sexually transmitted pathogens, human papillomavirus (HPV) can contribute in various ways to the failure of spontaneous and assisted reproduction, acting in the different phases of conception, especially in the early ones. In particular, HPV infection can affect sperm DNA integrity, sperm motility, count, viability, and morphology and can induce the production of anti-sperm antibodies (ASAs). In this narrative review, we aimed to provide an overview of existing research on the potential adverse effects of HPV infection on male reproductive health. Furthermore, we analyzed how limiting the spread of the infection, particularly with gender-neutral vaccination, could be a possible therapeutic tool to counteract male and female fertility problems. Full article
(This article belongs to the Special Issue A Molecular Perspective on Reproductive Health)
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