Trophoblasts are significant components of the placenta and play crucial roles in maternal-fetal crosstalk. Adequate trophoblast migration and invasion are essential for embryo implantation and healthy pregnancy. Ubiquitin-specific protease 7 (USP7), a member of the deubiquitinating enzyme family, regulates the processes of migration and invasion in multiple tumor cells. However, the effects of USP7 on trophoblasts and its possible mechanism in the development of recurrent spontaneous abortion (RSA) are still unclear. In this study, we analyzed the expression of USP7 in villous tissues obtained from RSA patients and healthy controls, and then GNE-6776 (a USP7-specific inhibitor) and USP7 siRNA were used in a trophoblast cell line, HTR-8/SVneo, to further assess the effect of USP7 on the biological function of trophoblasts. Our results provide convincing evidence that USP7 is downregulated in the placental villous tissues of RSA patients. USP7 was found to have a crucial role in the proliferation, apoptosis, migration, invasion, and epithelial-mesenchymal transition (EMT) process of trophoblast cells. Further experiments revealed that USP7 directly interacted with the enhancer of zeste homolog 2 (EZH2) and regulated the Wnt/β-catenin signaling pathway in trophoblasts. Taken together, these findings indicate the vital role of USP7 in regulating trophoblast proliferation, migration and invasion, thus affecting the pathogenesis of RSA, providing new insights into the important role of USP7 in the maternal-fetal interface.

Summary Sentence

In conclusion, USP7 prevents recurrent spontaneous abortion by targeting EZH2 to regulate trophoblast proliferation, apoptosis, migration, and invasion through the Wnt/β-catenin pathway.

Graphical Abstract

Endometriosis is a chronic inflammatory disease distinguished by ectopic endometrium and fibrosis. NLRP3 inflammasome and pyroptosis are present in endometriosis. Aberrant increase of Long noncoding (Lnc)-metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a vital role in endometriosis. However, the relationship between lnc-MALAT1, pyroptosis, and fibrosis is not completely known. In the present study, we found that the pyroptosis levels in ectopic endometrium of patients with endometriosis were significantly increased, consistent with fibrosis levels. Lipopolysaccharide (LPS) + ATP could induce pyroptosis of primary endometrial stromal cells (ESCs), thereby releasing interleukin (IL)-1β and stimulating transforming growth factor (TGF)-β1-mediated fibrosis. NLRP3 inhibitor MCC950 had the same effect as TGFβ1 inhibitor SB-431542 in suppressing the fibrosis-inducing effect of LPS + ATP in vivo and in vitro. The abnormal increase of lnc-MALAT1 in ectopic endometrium was connected with NLRP3-mediated pyroptosis and fibrosis. Leveraging bioinformatic prediction and luciferase assays combined with western blotting and quantitative reverse transcriptase-polymerase chain reaction, we validated that lnc-MALAT1 sponges miR-141-3p to promote NLRP3 expression. Silencing lnc-MALAT1 in HESCs ameliorated NLRP3-mediated pyroptosis and IL-1β release, thereby relieving TGF-β1-mediated fibrosis. Consequently, our findings suggest that lnc-MALAT1 is critical for NLRP3-induced pyroptosis and fibrosis in endometriosis through sponging miR-141-3p, which may indicate a new therapeutic target of endometriosis treatment.

Summary Sentence

Lnc-MALAT1 sponges miR-141-3p to deregulate its inhibitory effect on NLRP3, thus promoting endometrial stromal cell pyroptosis and exacerbating the progressive fibrosis of ectopic lesions.

Graphical Abstract

Insulin-like growth factor 1 (Igf1) is known to promote ovarian maturation by interacting with other hormones. However, the limited research on the role of Igf1 in the energy metabolism supply of gonads has hindered further exploration. To explore the role of Igf1 in gonadal development of silver pomfret, we analyzed the expression levels and the localization of igf1 mRNA and protein during testicular and ovarian development of silver pomfret. The results of the study showed upregulation of Igf1 in the critical period of vitellogenesis and sperm meiosis, which was found to be mainly expressed in the somatic cells of the gonads. Upon adding E2 and Igf1 to cultured gonadal tissues, the expression of energy-related genes was significantly increased, along with the E2-enhanced effect of Igf1 in the testis. Importantly, stimulation of both ovaries and testes with E2 and Igf1 led to a remarkable increase in the expression of vitellogenesis and meiosis-related genes. Therefore, we conclude that Igf1 promotes vitellogenesis and sperm meiosis by regulating gonadal energy production. Moreover, the expression of Igf1 in gonads is significantly regulated by E2. These findings provide new insights for the research of Igf1 in fish breeding, thus allowing the regulation of energy metabolism between growth and reproduction for successful reproductive outcomes.

Summary Sentence

Igf1 regulates gonadal energy metabolism to promote vitellogenesis and sperm meiosis, and its role in the gonad is modulated by E2.

Graphical Abstract

The present study aimed to investigate the regulation of placentas and uterus remodeling and involvement of estradiol in gestational diabetes mellitus. To achieve this, we established in vitro and in vivo models for gestational diabetes mellitus placentas by culturing human placental choriocarcinoma cells (BeWo) under hyperglycemic concentration and treating pregnant rats with streptozotocin. We evaluated the expression of angiogenesis-related proteins. The expression of the anti-angiogenic factor, excess placental soluble fms-like tyrosine kinase 1 was increased in our in vitro gestational diabetes mellitus model compared with the control. Moreover, the expressions of placental soluble fms-like tyrosine kinase 1 and the von Willebrand factor were also significantly elevated in the placenta of streptozotocin-treated rats. These data indicate the disruption of angiogenesis in the gestational diabetes mellitus placentas. The expression levels of connexin 43, a component of the gap junction and collagen type I alpha 2 chain, a component of the extracellular matrix, were decreased in the gestational diabetes mellitus uterus. These results suggest that uterus decidualization and placental angiogenesis are inhibited in gestational diabetes mellitus rats. Our results also showed upregulation of the expression of genes regulating estradiol synthesis as well as estrogen receptors in vivo models. Accordingly, the concentration of estradiol measured in the culture medium under hyperglycemic conditions, as well as in the serum and placenta of the streptozotocin-treated rats, was significantly elevated compared with the control groups. These results suggest that the dysregulated remodeling of the placenta and uterus may result in the elevation of estradiol and its signaling pathway in the gestational diabetes mellitus animal model to maintain pregnancy.

Summary Sentence

In this study, we suggest that regulation of uterus and placenta remodeling gestational diabetes mellitus models.

Graphical Abstract

Endometrial decidualization is critical to successful uterine receptivity and embryo implantation. Dysfunction of decidualization is associated with some pregnancy-related disorders, including miscarriage. Protein glycosylation is involved in many physiological and pathological processes. Protein O-fucosyltransferase 1 (poFUT1) is a key enzyme responsible for O-fucosylation biosynthesis on glycoproteins. Bone morphogenetic protein 1 (BMP1) is an essential glycoprotein in reproduction. However, the role and molecular mechanism of fucosylated BMP1 in endometrial stromal cell decidualization are still unknown. In the current study, we found that BMP1 contains a potential O-fucosylation site. Moreover, poFUT1 and BMP1 levels in the secretory phase are higher than those in the proliferative phase, and the highest level was observed in the human uterine tissues of early pregnancy, while a decrease of poFUT1 and BMP1 in the decidua was observed in miscarriage patients. Using human endometrial stromal cells (hESCs), we demonstrated that O-fucosylation of BMP1 was elevated after induced decidualization. Moreover, the increase of BMP1 O-fucosylation by poFUT1 promoted BMP1 secretion to the extracellular matrix, and more actively binds to CHRD. The binding of BMP1 and CHRD further released BMP4 originally bound to CHRD, and activated BMP/Smad signaling pathway, thereby accelerating the decidualization of human endometrial stromal cells. In summary, these results suggest that BMP1 O-fucosylation by poFUT1 could be a potential diagnostic and therapeutic target to predict miscarriage in early pregnancy examinations.

Summary Sentence

BMP1 O-fucosylation promotes decidualization.

Graphical Abstract

The fallopian tubes (FTs) are part of the female upper genital tract. The healthy FT provides the biological environment for successful fertilization and facilitates the subsequent movement of the conceptus to the endometrial cavity. However, when the FT is damaged, as with salpingitis, pyosalpinx, and hydrosalpinx, it may increase the risk of an ectopic pregnancy, a life-threatening condition. Decidualization refers to a multifactorial process by which the endometrium changes to permit blastocyst implantation. The decidualization reaction is vital for endometrial receptivity during the window of implantation. To date, no comprehensive review that collates evidence on decidualization in the human FT has been conducted. Therefore, the aim of this review is to compile the current evidence on cellular decidualization occurring in the healthy and pathological FT in women of reproductive age. A literature search was conducted using five databases and identified 746 articles, 24 of which were analyzed based on inclusion and exclusion criteria. The available evidence indicates that the FT are able to undergo decidual changes under specific circumstances; however, the exact mechanism by which this occurs is poorly understood. Further research is needed to elucidate the mechanism by which decidualization can occur in the FT.

Summary Sentence

Under certain circumstances, the fallopian tubes exhibit molecular changes consistent with decidualization.

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The development of oocytes occurs over a broad time frame, starting at the earliest stages of embryogenesis and continuing into adulthood. Conditional knockout technologies such as the Cre/loxP recombination system are useful for analyzing oocyte development at specific stages, but not every time frame has appropriate Cre drivers, for instance, during oocyte meiotic initiation through early prophase I in the embryo. Here, we generated a novel knockin mouse line that produces a bicistronic transcript from the endogenous Stra8 locus that includes a “self-cleaving” 2A peptide upstream of cre. This allows for high efficiency cleavage and production of both proteins individually and results in expression of cre in both male and female gonads at the biologically relevant stage. Fluorescent reporter analysis confirms that this line recapitulates endogenous Stra8 expression in both sexes and does not affect fertility of heterozygous nor homozygous mice. This line, named Stra8^P2Acre, adds to the repertoire of germ-cell specific cre driver lines and, importantly, allows for deletion of target genes during key embryonic oocyte developmental stages, including early events in meiosis.

Summary Sentence

Generation of a novel cre recombinase knockin to the Stra8 locus allows production of Stra8 and cre without affecting fertility.

Graphical Abstract

In human spermatozoa, the electrochemical potentials across the mitochondrial and plasma membranes are related to sperm functionality and fertility, but the exact role of each potential has yet to be clarified. Impairing sperm mitochondrial function has been considered as an approach to creating male or unisex contraceptives, but it has yet to be shown whether this approach would ultimately block the ability of sperm to reach or fertilize an egg. To investigate whether the mitochondrial and plasma membrane potentials are necessary for sperm fertility, human sperm were treated with two small-molecule mitochondrial uncouplers (niclosamide ethanolamine and BAM15) that depolarize membranes by inducing passive proton flow, and evaluated the effects on a variety of sperm physiological processes. BAM15 specifically uncoupled human sperm mitochondria while niclosamide ethanolamine induced proton current in the plasma membrane in addition to depolarizing the mitochondria. In addition, both compounds significantly decreased sperm progressive motility with niclosamide ethanolamine having a more robust effect. However, these uncouplers did not reduce sperm adenosine triphosphate (ATP) content or impair other physiological processes, suggesting that human sperm can rely on glycolysis for ATP production if mitochondria are impaired. Thus, systemically delivered contraceptives that target sperm mitochondria to reduce their ATP production would likely need to be paired with sperm-specific glycolysis inhibitors. However, since niclosamide ethanolamine impairs sperm motility through an ATP-independent mechanism, and niclosamide is FDA approved and not absorbed through mucosal membranes, it could be a useful ingredient in on-demand, vaginally applied contraceptives.

Summary Statement: Here we find that human sperm can maintain their ATP levels without mitochondrial oxidative phosphorylation, and we improve the subcellular localization of Adenosine Nucleotide Translocator 4; these findings will help focus future development of sperm-targeted contraceptives.

Sperm development, maturation, and successful fertilization within the female reproductive tract are intricate and orderly processes that involve protein translation and post-translational modifications. Among these modifications, sialylation plays a crucial role. Any disruptions occurring throughout the sperm's life cycle can result in male infertility, yet our current understanding of this process remains limited. Conventional semen analysis often fails to diagnose some infertility cases associated with sperm sialylation, emphasizing the need to comprehend and investigate the characteristics of sperm sialylation. This review reanalyzes the significance of sialylation in sperm development and fertilization and evaluates the impact of sialylation damage on male fertility under pathological conditions. Sialylation serves a vital role in the life journey of sperm, providing a negatively charged glycocalyx and enriching the molecular structure of the sperm surface, which is beneficial to sperm reversible recognition and immune interaction. These characteristics are particularly crucial during sperm maturation and fertilization within the female reproductive tract. Moreover, enhancing the understanding of the mechanism underlying sperm sialylation can promote the development of relevant clinical indicators for infertility detection and treatment.

Summary Sentence

Sialic acids exhibit three pivotal characteristics that render them essential factors in determining the fate decision of mammalian sperm: their negative charge, reversible recognition function, and immune recognition.

Graphical Abstract