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AIM Endometrial cell proliferation plays a critical role in adenomyosis. It has been reported that MIR22HG and miR-2861 play similar roles in regulating endometrial cell proliferation, indicating their involvement in adenomyosis. This study aimed to investigate the potential involvement of MIR22HG and miR-2861 in adenomyosis. METHODS Endometrial biopsy was collected from both adenomyosis (n = 45) and the healthy controls (n = 45). The expression of MIR22HG and miR-2861 in biopsies were determined by quantitative reverse transcription polymerase chain reaction (RT-qPCR). The relationship between MIR22HG and miR-2861 in endometrial cells was analyzed by RT-qPCR. Methylation-specific PCR (MSP) was performed to analyze the effects of overexpression of MIR22HG on the expression of miR-2861. Western-blot assays were performed to illustrate the effect of MIR22HG, miR-2861, STAT3, and MMP2 on adenomyosis. Luciferase report assay was performed to analyze the interactions among miR-2861, STAT3, and MMP2. The role of MIR22HG and miR-2861 in regulating the proliferation of endometrial cells was analyzed by cell proliferation assay. RESULTS The expression of MIR22HG and miR-2861 in adenomyosis did not change with menstrual cycle. MIR22HG and miR-2861 were significantly downregulated in adenomyosis and they were significantly and positively correlated with each other. In endometrial cells, overexpression of MIR22HG upregulated the expression of miR-2861 and decreased methylation of miR-2861 gene. MIR22HG and miR-2861 downregulated STAT3 and MMP2 to inhibit the proliferation of endometrial cells. In addition, overexpression of both MIR22HG and miR-2861 showed stronger effects. CONCLUSION MIR22HG is downregulated in adenomyosis and upregulates miR-2861 through demethylation to inhibit endometrial cell proliferation.

Couples are delaying childbearing in recent decades. While women experience a notable decrease in oocyte production in their late thirties, the effect of advanced paternal age on reproduction is incompletely understood. Herein, we observed that numerous miRNAs, including miR-574, increased in the sperm of aging males, as indicated by high-throughput sequencing. We demonstrated that miR-574 was upregulated in the sperm of two aging mouse models and was related to inferior sperm motility as an adverse predictor. Moreover, we proved that miR-574 suppressed mitochondrial function and reduced cellular ATP production in GC2 cells. Mechanistically, we demonstrated that miR-574 regulated mitochondrial function by directly targeting mt-ND5. Our study revealed an important role of miR-574 in sperm function in aging males and provided a fresh view to comprehend the aging process in sperm.

An increasing number of men are fathering children at an older age than in the past. While advanced maternal age has long been recognized as a risk factor for adverse reproductive outcomes, the influence of paternal age on reproduction is incompletely comprehended. Herein, we found that miR‐125a‐5p was upregulated in the sperm of aging males and was related to inferior sperm DNA integrity as an adverse predictor. Moreover, we demonstrated that miR‐125a‐5p suppressed mitochondrial function and increased cellular DNA damage in GC2 cells. We also found that miR‐125a‐5p perturbed embryo development at specific morula/blastocyst stages. Mechanistically, we confirmed that miR‐125a‐5p disturbed the mitochondrial function by targeting Rbm38 and activating the p53 damage response pathway, and induced a developmental delay in a p21‐dependent manner. Our study revealed an important role of miR‐125a‐5p in sperm function and early embryo development of aging males, and provided a fresh view to comprehend the aging process in sperm., miR‐125a‐5p was increased in the sperm of aging males. miR‐125a‐5p suppressed mitochondrial function and increased cellular DNA damage by targeting Rbm38 and activating p53 damage response pathway. miR‐125a‐5p perturbed embryo development at specific morula/blastocyst stages in a p21‐dependent manner.

Seminal plasma (SP), particularly SP exosomes (sExos), alters with age and can affect female mouse uterine immune microenvironment. However, the relationship between fertility decline in reproductively older males, and SP and sExos age-related changes, which may compromise the uterine immune microenvironment, remains unclear. The present study demonstrated that the implantation rate of female mice treated with SP from reproductively older male mice (aged-SP group) was lower than that of those treated with SP from younger male mice (young-SP group). RNA-sequencing analysis revealed altered levels of dendritic cell (DC)-related cytokines and chemokines in the uteri of the former group compared with those of the latter group. In vivo and in vitro experiments demonstrated a weaker inhibitory effect of aged SP on DC maturation than of young SP upon stimulation. After isolating and characterizing sExos from young and advanced-age male mice, we discovered that insemination of a subset of the aged-SP group with sExos from young male mice partially recovered the implantation rate decline. Additional in vivo and in vitro experiments revealed that sExos extracted from age male mice exerted a similar effect on DC maturation as SP of aged mice, indicating an age-related sExos inhibitory effect. In conclusion, our study demonstrated that age-related alterations of sExos may be partially responsible for lower implantation rates in the aged-SP group compared with those in the young-SP group, which were mediated by uterine immunomodulation. These findings provide new insights for clinical seminal adjuvant therapy.

Endometrial receptivity is crucial for successful embryo implantation. It is regulated by multiple factors which include ovarian steroid hormones and the immune microenvironment among others. Nod-Like Receptor Pyrins-3 (NLRP3) is a key intracellular pattern-recognition receptor and a critical component of the inflammasome, which plays an essential role in the development of inflammation and of immune responses. However, the physiological functions of NLRP3 in the endometrium remain largely unclear. This study investigated the physiological and pathological significance of NLRP3 in human endometrial epithelial cell during the implantation window. NLRP3 is highly expressed during the mid-proliferative and mid-secretory phases of the human endometrium and transcriptionally up-regulated by estradiol (E2) through estrogen receptor β (ERβ). In addition, NLRP3 promotes embryo implantation and enhances epithelial-mesenchymal transition (EMT) of Ishikawa (IK) cells via both inflammasome-dependent and inflammasome-independent pathways, which might provide a novel insight into endometrial receptivity and embryo implantation. Our findings suggest that NLRP3, which is transcriptionally regulated by E2, induces epithelial–mesenchymal transition of endometrial epithelial cells and promotes embryo adhesion.