Science China Life Sciences最新文献

Ovarian aging poses significant challenges to female fertility and overall health. While whole-grain black rice diet (BRD) has emerged as a promising anti-aging intervention, its translational potential for ovarian health remains underexplored. This study systematically evaluated BRD's effects on ovarian functional decline through single-cell profiling and phenotypic validation. We demonstrated that BRD intervention effectively delays ovarian aging by preserving the ovarian reserve and maintaining hormonal balance, with granulosa cells (GCs) exhibiting the most pronounced responsiveness. Notably, BRD counteracts age-associated reductions in the GCs population and restores ovarian functional capacity. These findings highlight BRD's ability to rejuvenate the ovarian cellular landscape and stabilize aging-related tran-scriptional profiles. Our study provides actionable insights for developing BRD-based nutritional strategies to combat female reproductive aging, paving the way for clinically translatable dietary interventions and functional food innovations targeting the extension of women's healthspan.

Dysregulation of low-density lipoprotein (LDL) cholesterol is strongly correlated with the risk of metabolic dysfunction-associated steatotic liver disease. Endogenous molecules targeting LDL clearance play crucial roles in the progression of liver steatosis. Human cathelicidin LL-37 can form complexes with lipoproteins, but whether these complexes regulate lipoprotein-driven cholesterol metabolism is not clear. Here, we find that cathelicidin LL-37 binds to LDL via apolipoprotein (Apo)B-100 domains, enhancing the solubility of ApoB-100 and inhibiting the modifications and aggregation of LDL. LL-37-LDL interaction promotes LDL uptake through LDL receptor (LDLR) both in hepatocytes and macrophages. This interaction also promotes LDL cholesterol clearance by facilitating cholesterol excretion and cholesterol efflux. In Apoe^-/- mice with hypercholesterolemia, the murine homolog cathelicidin Cramp similarly accelerates cholesterol clearance by activating cholesterol excretion and preventing hepatic lipid accumulation. This study identifies LL-37 as an endogenous regulator of LDL that promotes LDL cholesterol clearance.

Chromatin accessibility is a key determinant of transcriptional regulation across eukaryotes, yet its organization and functional significance in ciliated protists remain poorly defined. Here, we optimized ATAC-seq to delineate the chromatin landscape in the transcriptionally active macronucleus of Tetrahymena thermophila. Our analyses reveal that accessible chromatin is predominantly enriched upstream of transcription start sites (TSSs), in stark contrast to the promoter-proximal accessibility observed in human embryonic stem cells. Dynamic profiling across different life cycle stages of T. thermophila (vegetative growth, starvation, conjugation, and refeeding) uncovers coordinated shifts in chromatin architecture that closely mirror extensive transcriptional reprogramming. Moreover, transcriptional inhibition by flavopiridol reduces chromatin openness upstream of TSSs while enhancing nucleosome organization downstream of TSSs, underscoring the direct impact of transcription on shaping chromatin structure. Comparative analyses across 13 eukaryotic species further indicate that upstream-biased accessibility is an ancestral trait in unicellular eukaryotes, whereas higher vertebrates have evolved more complex promoter architectures. These findings not only establish T. thermophila as a powerful model for dissecting chromatin-dependent gene regulation but also provide novel insights into the evolutionary divergence of chromatin organization across the eukaryotic lineage.

Vesicles, with closed membrane structures containing nucleic acids, proteins, lipids, and metabolites, play a vital role in cell crosstalk. And bone, the important center of cellular information exchange, is where abundant vesicle-based cellular crosstalk occurs. This review explores the composition, functions, and clinical applications of vesicles derived from bone-related cells. Extracellular vesicles, including exosomes, microvesicles, apoptotic bodies, and newly identified structures such as migrasomes, exhibit heterogeneity in size, origin, biogenesis, and components. These vesicles facilitate complex cellular interactions, influencing bone formation, resorption, and immune responses. Extracellular vesicles hold significant promise as diagnostic biomarkers and therapeutic tools in bone-related diseases. Despite advancements, challenges remain in addressing vesicle heterogeneity, standardizing isolation techniques, and translating vesicle-based therapies into clinical practice. We summarize the latest advances in vesicle research related to bone, aiming to draw the attention of the academic community to newly identified vesicle structures, and may provide insights for studying vesicle-based interactions in other systemic organs.

Dehydroepiandrosterone (DHEA), a steroid hormone critical to reproductive health, is widely used to improve outcomes in assisted reproductive technologies, though its molecular targets and mechanisms remain incompletely defined. In our previous studies, we identified DHEA as a ligand for the male reproductive-related receptor ADGRG2 and elucidated the recognition mechanism between DHEA and ADGRG2 using Cryo-EM structure of ADGRG2 in complex with DHEA and Gs. However, it remains unclear whether DHEA acts as a physiological ligand for ADGRG2 to regulate its functions. Using ADGRG2-deficient mice and in vitro reconstitution assays, we demonstrated that DHEA activated the Gs signaling pathways of ADGRG2 in efferent ductal cells, which facilitated synergistic coupling with cystic fibrosis transmembrane conduction regulator (CFTR) to regulate chlorine homeostasis. Strikingly, ADGRG2 is selectively expressed in X chromosome-bearing (X) sperm, where DHEA enhances motility via a Gs-cAMP signaling axis. This functional bias enables efficient enrichment of X sperm through DHEA-induced motility enhancement, achieving 80.5% XX embryos in in vitro fertilization (IVF). These findings reveal ADGRG2-dependent mechanisms underlying male reproductive physiology and position DHEA-ADGRG2 axis as a promising therapeutic target for precision management of infertility and sex-controlled reproductive technologies.

Ubiquitin-specific protease 7 (USP7), a deubiquitinase, is involved in tumor progression. However, its roles in pancreatic neuroendocrine neoplasms (pNENs) remain unclear. The main objective of this study was therefore to investigate the molecular mechanism of how USP7 promoted pNEN progression. Proteomics and ubiquitin-omics were used to identify the substrates for USP7. We investigated the roles of USP7 and histone H1.2 in DNA repair in pNEN cells using comet assays and γ-H2AX immunofluorescence. The synergistic effects of cisplatin and the USP7 inhibitor, P005091, were evaluated using CCK-8, colony formation, and EdU assays. Western blot analysis was conducted to characterize the PI3K/AKT/mTOR signaling pathway. In vivo, the efficacy of the combination therapy was tested in xenograft models. The results showed a significant increase in USP7 levels in the tissues and cells of pNENs. Furthermore, USP7 was found to promote the proliferation, migration, and invasion of pNENs both in vitro and in vivo. Mechanistically, USP7 facilitated DNA repair through its interaction with histone H1.2 and the activation of the PI3K/AKT/mTOR pathway. The combination of cisplatin and P005091, a USP7 inhibitor, synergistically inhibited tumor growth and DNA repair in both in vitro and in vivo models, without exhibiting significant toxicity. In conclusion, USP7 was a key regulator of DNA repair in pNENs. The combination of cisplatin and P005091 therefore holds promise as a therapeutic strategy for pNENs.