The innate immune molecule NLR family CARD domain-containing 5 (NLRC5) plays a significant role in endometrial carcinoma (EC) immunosurveillance. However, NLRC5 also plays a protumor role in EC ...cells. Mismatch repair gene deficiency (dMMR) can enable tumors to grow faster and also can exhibit high sensitivity to immune checkpoint inhibitors. In this study, we attempted to determine whether NLRC5-mediated protumor role in EC is via the regulation of dMMR. Our findings revealed that NLRC5 promoted the proliferation, migration, and invasion abilities of EC cells and induced the dMMR status of EC in vivo and in vitro. Furthermore, the mechanism underlying NLRC5 regulated dMMR was also verified. We first found NLRC5 could suppress nuclear factor-kappaB (NF-κB) pathway in EC cells. Then we validated that the positive effect of NLRC5 in dMMR was restricted when NF-κB was activated by lipopolysaccharides in NLRC5-overexpression EC cell lines. In conclusion, our present study confirmed the novel NLRC5/NF-κB/MMR regulatory mechanism of the protumor effect of NLRC5 on EC cells, thereby suggesting that the NLRC5-mediated protumor in EC was depend on the function of MMR.
To examine the effects of atosiban, given before transfer of frozen-thawed embryo to women with endometriosis (EMs).
A randomized, controlled clinical trial.
University hospital and IVF center.
One ...hundred twenty women with endometriosis undergoing frozen-thawed embryo transfer were randomly allocated into the atosiban treatment and the control groups. Another 120 women with infertility due to tubal factor were enrolled into a tubal factor group, to compare serum oxytocin (OT) and prostaglandin (PG)F2α levels and uterine contractions with the endometriosis group.
In the endometriosis treatment group, a single bolus (6.75 mg, 0.9 mL per vial) of atosiban was administrated before ET.
Implantation rate and pregnancy rate.
Serum OT level (1.89 ± 0.33 vs. 1.66 ± 0.32 ng/L), PGF2α (2.83 ± 0.34 vs. 2.36 ± 0.35 ng/L) level, and uterine contractions (2.5 ± 1.2 vs. 1.8 ± 1.0 waves per minute) in the endometriosis group were all significantly higher than in the tubal factor group. The clinical pregnancy rate per cycle and implantation rate per transfer were 58.3% and 41.0%, respectively, in the atosiban treatment group, significantly higher than in the control group (38.3% and 23.4%, respectively).
Women with endometriosis showed higher serum OT level, PGF2α level, and uterine contractions. Atosiban treatment before ET in endometriosis is effective in the priming of the uterus, suitable for embryo implantation. This is the first study to evaluate the effect of atosiban treatment in patients with endometriosis.
ChiCTR-IOQ-14005715.
The mechanical force between cells and the extracellular microenvironment is crucial to many physiological processes such as cancer metastasis and stem cell differentiation. Mitosis plays an ...essential role in all these processes and thus an in-depth understanding of forces during mitosis gains insight into disease diagnosis and disease treatment. Here, we develop a traction force microscope method based on monolayer fluorescent beads for measuring the weak traction force (tens of Pa) of mitotic cells in three dimensions. We quantify traction forces of human ovarian granulosa (KGN) cells exerted on the extracellular matrix throughout the entire cell cycle in three dimensions. Our measurements reveal how forces vary during the cell cycle, especially during cell division. Furthermore, we study the effect of paclitaxel (PTX) and nocodazole (NDZ) on mitotic KGN cells through the measurement of traction forces. Our results show that mitotic cells with high concentrations of PTX exert a larger force than those with high concentrations of NDZ, which proved to be caused by changes in the structure and number of microtubules. These findings reveal the key functions of microtubule in generating traction forces during cell mitosis and explain how dividing cells regulate themselves in response to anti-mitosis drugs. This work provides a powerful tool for investigating cell-matrix interactions during mitosis and may offer a potential way to new therapies for cancer.
The use of bisphenol A (BPA) has been restricted due to its endocrine-disrupting effects. As a widely used alternative to BPA today, environmental levels of bisphenol Z (BPZ) continue to rise and ...accumulate in humans. Oocyte quality is critical for a successful pregnancy. Nevertheless, the toxic impacts of BPZ on the maturation of mammalian oocytes remain unexplored. Therefore, the impacts of BPZ and BPA on oocyte meiotic maturation were compared in an in vitro mouse oocyte culture model. Exposure to 150 μM of both BPZ and BPA disrupted the assembly of the meiotic spindle and the alignment of chromosomes, and BPZ exerted stronger toxicological effects than BPA. Furthermore, BPZ resulted in aberrant expression of F-actin, preventing the formation of the actin cap. Mechanistically, BPZ exposure disrupted the mitochondrial localization pattern, reduced mitochondrial membrane potential and ATP content, leading to impaired mitochondrial function. Further studies revealed that BPZ exposure resulted in oxidative stress and altered expression of genes associated with anti-oxidative stress. Moreover, BPZ induced severe DNA damage and triggered early apoptosis in oocytes, accompanied by impaired lysosomal function. Overall, the data in this study suggest that BPZ is not a safe alternative to BPA. BPZ can trigger early apoptosis by affecting mitochondrial function and causing oxidative stress and DNA damage in oocytes. These processes disrupt cytoskeletal assembly, arrest the cell cycle, and ultimately inhibit oocyte meiotic maturation.
Display omitted
•BPZ inhibits meiotic maturation of oocytes, and its toxic effects are significantly stronger than those of BPA.•BPZ causes abnormal spindle morphology and disorganized chromosome arrangement in oocytes.•BPZ affects the construction of actin filaments in mouse oocytes.•BPZ impairs mitochondrial function and induces oxidative stress and DNA damage, leading to early apoptosis in oocytes.
Multiple morphological abnormalities of flagella (MMAF) are human reproduction disorders due to the dysplastic development of sperm flagella. The spermatozoa of men with MMAF manifest absent, short, ...coiled, bent, and/or irregular-caliber flagella. Previous studies revealed genetic contributions to human MMAF, but known MMAF-associated genes only explained approximately 50% MMAF cases. In this study, we employed human whole-exome sequencing for genetic analysis and identified biallelic mutations of CFAP251 (cilia- and flagella-associated protein 251, also known as WDR66) in three (5%) of 65 Han Chinese men with MMAF. All these CFAP251 mutations are loss-of-function. The population genome data suggested that these CFAP251 mutations are extremely rare (only heterozygous) or absent from human populations. Our functional assays of gene expression and immunofluorescence staining in a CFAP251-deficient man, together with previous experimental evidence from model organisms, suggested that CFAP251 is involved in flagellar functions. Our observations suggested that CFAP251 is associated with sperm flagellar development and human male infertility.
HMGB1 that belongs to the High Mobility Group-box superfamily, is a nonhistone chromatin associated transcription factor. It is present in the nucleus of eukaryotes and can be actively secreted or ...passively released by kinds of cells. HMGB1 is important for maintaining DNA structure by binding to DNA and histones, protecting it from damage. It also regulates the interaction between histones and DNA, affecting chromatin packaging, and can influence gene expression by promoting nucleosome sliding. And as a DAMP, HMGB1 binding to RAGE and TLRs activates NF-κB, which triggers the expression of downstream genes like IL-18, IL-1β, and TNF-α. HMGB1 is known to be involved in numerous physiological and pathological processes. Recent studies have demonstrated the significance of HMGB1 as DAMPs in the female reproductive system. These findings have shed light on the potential role of HMGB1 in the pathogenesis of diseases in female reproductive system and the possibilities of HMGB1-targeted therapies for treating them. Such therapies can help reduce inflammation and metabolic dysfunction and alleviate the symptoms of reproductive system diseases. Overall, the identification of HMGB1 as a key player in disease of the female reproductive system represents a significant breakthrough in our understanding of these conditions and presents exciting opportunities for the development of novel therapies.
Background
Asthenoteratospermia with multiple morphological abnormalities in the sperm flagella (MMAF) is a significant cause of male infertility. WDR19 is a core component in the IFT-A complex and ...has a critical role in intraflagellar transport. However, the role of
WDR19
mutations in male infertility has yet to be examined.
Methods and results
We performed whole exome sequencing (WES) for 65 asthenoteratospermia individuals and identified a proband who carried a homozygous
WDR19
(c.A3811G, p.K1271E) mutation from a consanguineous family. Systematic examinations, including CT scanning and retinal imaging, excluded previous ciliopathic syndromes in the proband. Moreover, semen analysis of this patient showed that the progressive rate decreased to zero, and the sperm flagella showed multiple morphological abnormalities. Scanning and transmission electron microscopy assays indicated that the ultrastructure of sperm flagella in the patient was completely destroyed, while immunofluorescence revealed that WDR19 was absent from the sperm neck and flagella. Moreover, IFT140 and IFT88, predicted to interact with WDR19 directly, were mis-allocated in the
WDR19
-mutated sperm. Notably, the MMAF subject harboring
WDR19
variant and his partner successfully achieved clinical pregnancy through intracytoplasmic sperm injection (ICSI).
Conclusions
We identified
WDR19
as a novel pathogenic gene for male infertility caused by asthenoteratospermia in the absence of other ciliopathic phenotypes, and that patients carrying
WDR19
variant can have favorable pregnancy outcomes following ICSI.
Purpose
To evaluate the association between the DNA methylation of specific genes and sperm DNA integrity status in human sperm samples.
Methods
A total of 166 semen samples were evaluated (86 ...controls and 80 cases with impaired sperm DNA integrity). We detected the methylation status of 257 CpG sites among two imprinted genes (
H19
and
SNRPN
) and four non-imprinted genes related to male infertility (
MTHFR
,
GSTM1
,
DAZL
, and
CREM
) by using a targeted next-generation sequencing method.
Results
Differential methylation was found in 43 CpG sites of the promoters of the six candidate genes.
H19
,
SNRPN
,
MTHFR
,
DAZL
,
GSTM1
, and
CREM
contained 22, 12, 1, 4, 0, and 4 differentially methylated CpG sites (
P
<0.05), respectively. The imprinting genes were associated with relatively higher rates of differentially methylated CpG sites (28.21% in
H19
and 41.38% in
SNRPN
) than the non-imprinting genes. One CpG site in
H19
remained significant after performing strict Bonferroni correction.
Conclusion
In this study, we found that different site-specific DNA methylation signatures were correlated with sperm DNA integrity status. Further studies are needed to investigate the specific mechanisms leading to the epigenetic modifications.
Polycystic ovary syndrome (PCOS) is a common frequent endocrine disorder among women of reproductive age. Although assisted reproductive techniques (ARTs) are used to address subfertility in PCOS ...women, their effectiveness is not clear. Our aim was to compare transcriptomic profiles of oocytes and cumulus cells (CCs) between women with and without PCOS, and assess the effectiveness of ARTs in treating PCOS patients. We collected oocytes and CCs from 16 patients with and without PCOS patients to categorize them into 6 groups according to oocyte nuclear maturation. Transcriptional gene expression of oocyte and CCs was determined via single-cell RNA sequencing. The ratio of fertilization and cleavage was higher in PCOS patients than in non-PCOS patients undergoing ARTs, and there was no difference in the number of high-quality embryos between the groups. Differentially expressed genes including PPP2R1A, PDGFRA, EGFR, GJA1, PTGS2, TNFAIP6, TGF-β1, CAV1, INHBB et al. were investigated as potential causes of PCOS oocytes and CCs disorder at early stages, but their expression returned to the normal level at the metaphase II (MII) stage via ARTs. In conclusion, ARTs can improve the quality of cumulus-oocyte complex (COC) and increase the ratio of fertilization and cleavage in PCOS women.
Infertility affects approximately one-sixth of the people of childbearing age worldwide, causing not only economic burdens of treatment for families with fertility problems but also psychological ...stress for patients and presenting challenges to societal and economic development. Premature ovarian insufficiency (POI) refers to the loss of ovarian function in women before the age of 40 due to the depletion of follicles or decreased quality of remaining follicles, constituting a significant cause of female infertility. In recent years, with the help of the rapid development in genetic sequencing technology, it has been demonstrated that genetic factors play a crucial role in the onset of POI. Among the population suffering from POI, genetic studies have revealed that genes involved in processes such as meiosis, DNA damage repair, and mitosis account for approximately 37.4% of all pathogenic and potentially pathogenic genes identified. FA complementation group M (FANCM) is a group of genes involved in the damage
PDF
