摘要: Maternal age has been reported to impair oocyte quality. However, the molecular mechanisms underlying the age-related decrease in oocyte competence remain poorly understood. Cumulus cells establish direct contact with the oocyte through gap junctions, facilitating the provision of crucial nutrients necessary for oocyte development. In this study, we obtained the proteomic and metabolomic profiles of cumulus cells from both young and old mice. We found that fatty acid beta-oxidation and nucleotide metabolism, markedly active in aged cumulus cells, may serve as a compensatory mechanism for energy provision. Tryptophan undergoes two principal metabolic pathways, including the serotonin (5-HT) synthesis and kynurenine catabolism. Notably, we discovered that kynurenine catabolism is reduced in aged cumulus cells compared to young cells, whereas 5-HT synthesis exhibited a significant decrease. Furthermore, the supplement of 5-HT during cumulus-oocyte complexes (COCs) culture significantly ameliorated the metabolic dysfunction and meiotic defects in old oocytes. In sum, our data provide a comprehensive multiple omics resource, offering potential insights for improving oocyte quality and promoting fertility in aged females.

摘要: The E3 ubiquitin ligase RNF187, also known as RING domain AP1 coactivator-1, is a member of the RING finger family. RNF187 is indispensable for the proliferation and migration of GC-1 cells derived from mouse spermatogonia and GC-2 cells derived from spermatocytes. However, it remains unclear whether RNF187 plays a crucial role in the self-renewal and migration of human spermatogonial stem cells (SSCs). In this study, we observed a positive correlation between RNF187 expression and the proliferation and migration of human SSCs. Through co-immunoprecipitation and mass spectrometry analyses, we identified WD repeat-containing protein 77 (WDR77) as an interacting partner of RNF187. Specifically, RNF187 recognises the K118 site of WDR77 through lysine 48-linked polyubiquitination, subsequently mediating its degradation via the ubiquitin-proteasome system (UPS). Further studies have revealed that decreased expression of WDR77 diminishes the symmetric dimethylation at H4R3 (H4R3me2s) catalysed by its interacting protein, the arginine methyltransferase PRMT5. This, in turn, relieves the transcriptional repression of early growth response protein 1 (EGR1), a positive regulator for human SSC maintenance. In conclusion, this study has unveiled a pivotal role for RNF187 in the proliferation and migration of human SSCs. This may provide a promising strategy for addressing non-obstructive azoospermia (NOA) caused by SSC dysfunction.

摘要: The function of super-enhancers (SEs) in pulmonary hypertension (PH), especially in the proliferation of pulmonary artery smooth muscle cells (PASMCs), is currently unknown. We identified SEs-targeted genes in PASMCs with chromatin immunoprecipitation (ChIP)-sequence by H3K27ac antibody and proved that CBP/p300-interacting transactivator with Glu/Asp-rich C-terminal domain, 2 (CITED2) is an SEs-targeted gene through bioinformatics prediction, ChIP-PCR, dual-luciferase reporter gene assays and other experimental methods. We also found that the expression of CITED2 and the transcription factor Forkhead Box J3 (FOXJ3) was reduced in hypoxic mouse PASMCs. In addition, the expression of CITED2 and FOXJ3 also decreased in both the patients with idiopathic pulmonary arterial hypertension (iPAH) and the human PASMCs exposed to hypoxia. The decreased expression of CITED2 was reversed by co-transfection of FOXJ3 and SEs plasmids. Overexpressing of CITED2 attenuated the PASMCs proliferation induced by hypoxia. Lentiviral overexpression of CITED2 also reversed hypoxia-induced pulmonary hypertension mice model. Mechanically, the expression of CITED2 by affecting by FOXJ3, which binding with three SEs located in the about 2000 bp of TSS. In conclusion, we first identified that CITED2 is a kind of SEs-targeted gene, modulated by FOXJ3. The FOXJ3/SEs/CITED2 axis may become a new therapeutic target of PH.

摘要: The global increase in the aging population has led to a concurrent rise in the incidence of age-related diseases, posing substantial challenges to healthcare systems and affecting the well-being of the elderly. Identifying and securing effective treatments has become an urgent priority. In this context, mesenchymal stem cell-derived exosomes (MSC-Exos) have emerged as a promising and innovative modality in the field of anti-aging medicine, offering a multifaceted therapeutic approach. MSC-Exos demonstrate significant potential due to their immunomodulatory and anti-inflammatory properties, their ability to inhibit oxidative stress, and their reparative effects on senescent tissues. These attributes make them valuable in combating a range of conditions associated with aging, such as cardiovascular diseases, neurodegeneration, skin aging, and osteoarthritis. The integration of exosomes with membrane-penetrating peptides introduces a novel strategy for the delivery of biomolecules, surmounting traditional cellular barriers and enhancing therapeutic efficacy. This review provides a comprehensive synthesis of the current understanding of MSC-Exos, underscoring their role as a novel and potent therapeutic strategy against the intricate challenges of age-related diseases.

摘要: Ageing of the endometrium is a critical factor that affects reproductive health, yet its intricate mechanisms remain poorly explored. In this study, we performed transcriptome profiling and experimental verification of endometrium and endometrial organoids from young and advanced age females, to elucidate the underlying mechanisms and to explore novel treatment strategies for endometrial ageing. First, we found that age-associated decline in endometrial functions including fibrosis and diminished receptivity, already exists in reproductive age. Subsequently, based on RNA-seq analysis, we identified several changes in molecular processes affected by age, including fibrosis, imbalanced inflammatory status including Th1 bias in secretory phase, cellular senescence and abnormal signalling transduction in key pathways, with all processes been further validated by molecular experiments. Finally, we uncovered for the first time that PI3K-AKT-FOXO1 signalling pathway is overactivated in ageing endometrium and is closely correlated with fibrosis and impaired receptivity characteristics of ageing endometrium. Blocking or activation of PI3K by LY294002 or 740Y-P could attenuate the effect of ageing or accelerate dysfunction of endometrial organoids. This discovery is expected to bring new breakthroughs for understanding the pathophysiological processes associated with endometrial ageing, as well as treatment strategies to improve reproductive outcomes in women of advanced reproductive age.