Background: The emerging epitranscriptome plays an essential role in female fertility. As the most prevalent internal mRNA modification, N6-methyladenine (m⁶A) methylation regulate mRNA fate and translational efficiency. However, whether m⁶A methylation was involved in the aging-related ovarian reserve decline has not been investigated. Herein, we performed m⁶A transcriptome-wide profiling in the ovarian granulosa cells of younger women (younger group) and older women (older group).Results: m⁶A methylation distribution was highly conserved and enriched in the CDS and 3’UTR region. Besides, an increased number of m⁶A methylated genes were identified in the older group. Bioinformatics analysis indicated that m⁶A methylated genes were enriched in the FoxO signaling pathway, adherens junction, and regulation of actin cytoskeleton. A total of 435 genes were differently expressed in the older group, moreover, 58 of them were modified by m⁶A. Several specific genes, including BUB1B, PHC2, TOP2A, DDR2, KLF13, and RYR2 which were differently expressed and modified by m⁶A, were validated using qRT-PCR and might be involved in the decreased ovarian functions in the aging ovary.Conclusions: Hence, our finding revealed the transcriptional significance of m⁶A modifications and provide potential therapeutic targets to promote fertility reservation for aging women.

Women with hereditary breast cancer factors are more likely to be infertile and tend to receive fertility treatments. The safety of fertility treatments that contain hormone-related medications for ovarian stimulation has gained wide attention; however, evidence of the safety of fertility treatments is limited. This study aims to assess the association between fertility treatments and the incidence rate of breast cancer in women with a family history of breast cancer or BRCA mutations. A literature search was conducted in PubMed, Cochrane Library, and Embase. Studies concerning the effect of fertility treatments on breast cancer risk in genetically susceptible women were included. The fixed and random effects models were used to estimate the summary effects. Risk Of Bias In Non-randomized Studies - of Interventions instrument was used to assess the risk of bias in the included studies. A total of 5,282 studies were screened. Five cohort studies and three case-control studies were included. Breast cancer risk was not significantly increased by fertility treatments in general genetically susceptible women [pooled odds ratio (OR) 1.18, 95% confidence interval (CI) 0.96–1.45], women with a family history of breast cancer (pooled OR 1.35, 95% CI 0.97–1.89), or women with BRCA mutations (pooled OR 1.02, 95% CI 0.74–1.4). In subgroup analyses, there was no significant increase in breast cancer risk whether in BRCA1 mutation carriers (pooled OR 1.18, 95% CI 0.81–1.72), BRCA2 mutation carriers (pooled OR 0.54, 95% CI 0.09–3.34), or in the women treated with in vitro fertilization (pooled OR 0.75, 95% CI 0.51–1.1), clomiphene citrate (pooled OR 1.07, 95% CI 0.78–1.45) or gonadotropins (pooled OR 1.32, 95% CI 0.8–2.18). This is the first meta-analysis concerning the impact of fertility treatments on breast cancer risk in genetically susceptible women. Despite the finding that fertility treatment did not significantly increase breast cancer risk in genetically susceptible women, large prospective cohorts with more detailed information are required. Further investigations are needed to explore subtypes of breast cancer, genetic background of hormone-related breast cancer, and the association between BRCA mutations and the incidence of hormone receptor-positive breast cancer. Registration number: PROSPERO(CRD42021281336).

In this study, we aimed to investigate the molecular mechanisms of RNA N6-methyladenosine (m6A) modification and how its associated proteins affect granulosa cell aging. A granulosa cell senescence model was constructed to detect the differences in total RNA m6A modification levels and the expression of related enzymes. Changes in downstream molecular expression and the effects on the cellular senescence phenotype were explored by repeatedly knocking down and overexpressing the key genes fat mass and obesity-associated protein (FTO), YT521-B homology domain family member 2 (YTHDF2), and matrix metalloproteinase-2 (MMP2). There was an increased total RNA m6A modification and decreased expression of the demethylase FTO and target gene MMP2 in senescent granulosa cells. FTO and MMP2 knockdown promoted granulosa cell senescence, whereas FTO and MMP2 overexpression retarded it. YTHDF2 and FTO can bind to the messenger RNA of MMP2. The extracellular signal-regulated kinase (ERK) pathway, which is downstream of MMP2, retarded the process of granulosa cell senescence through ERK activators. In granulosa cells, FTO can regulate the expression of MMP2 in an m6A-YTHDF2-dependent manner, influencing the activation status of the ERK pathway and contributing to the aging process of granulosa cells.

Introduction: Hepatic ischemia/reperfusion (I/R) injury is common after liver surgery, particularly in patients of older age. However, an understanding of the mechanism of injury remains incomplete. In this study, we explored the molecular mechanisms underlying hepatic I/R injury and associations with age in a murine model.

Introduction: Trace elements in the environment are considered significant risk factors for chronic liver disease. However, the impact of blood metal levels on the incidence of liver fibrosis or cirrhosis has not been fully assessed. Our study investigated the correlation between metal mixture exposure and liver fibrosis/cirrhosis as well as the mediating effect between non-alcoholic fatty liver disease (NAFLD) and liver fibrosis/cirrhosis. Methods: We conducted a cross-sectional study using the National Health and Nutrition Examination Survey database from 2017 to 2020. Transient elastography was used to identify NAFLD and liver fibrosis or cirrhosis. Various statistical models have been applied to evaluate the relationship between blood metal mixtures and liver fibrosis/cirrhosis. The role of metal mixtures in NAFLD-associated liver fibrosis/cirrhosis was explored using a mediation analysis. Results: In the fully adjusted logistic models, selenium was negatively correlated with liver fibrosis [odds ratio (OR) = 0.219, P = 0.039) and cirrhosis (OR = 0.007, P = 0.003). In the weighted quantile sum and quantile-based g-computation models, selenium showed the highest contribution to liver fibrosis (0.544 and 0.578) and cirrhosis (0.538 and 0.630, respectively). Bayesian kernel machine regression and restricted cubic splines models indicated an L-shaped association between selenium and liver fibrosis/cirrhosis. Selenium negatively mediated the relationship between NAFLD and liver fibrosis/cirrhosis according to the mediation analysis (−3.4% and −13.3%). Conclusions: Selenium shows an L-shaped relationship with liver fibrosis and cirrhosis and plays a negative mediating role in the association between NAFLD and liver fibrosis/cirrhosis. Blood selenium is a promising biomarker for chronic liver diseases, and supplemental selenium intake might contribute to the prevention and management of liver fibrosis/cirrhosis.