Cell Proliferation最新文献

Obstructive sleep apnea (OSA) is strongly associated with an increased risk of hypertension; however, the molecular mechanisms linking these two conditions remain incompletely understood. In this study, we identified phosphodiesterase 4B (PDE4B) as a key mediator in the development of OSA-related hypertension. Using integrated bioinformatics analysis and experimental validation, we found that PDE4B expression was significantly elevated in both cell and animal models of OSA combined with pulmonary hypertension. Functional studies demonstrated that PDE4B promotes pulmonary artery smooth muscle cell (PASMC) proliferation and migration, contributing to vascular remodelling. Mechanistically, we uncovered that lactate accumulation under hypoxic conditions induces histone lactylation at the PDE4B promoter, enhancing its transcriptional activity. Furthermore, PDE4B was shown to regulate the phosphorylation and nuclear translocation of FUS, which binds to the angiotensinogen (AGT) promoter and enhances AGT expression, thereby promoting pulmonary hypertension. These findings reveal a novel PDE4B-FUS-AGT signalling axis driven by epigenetic modifications in OSA-induced hypertension, offering potential therapeutic targets for patients with this comorbidity.

Recurrent implantation failure (RIF) remains a major challenge in assisted reproductive technologies, with the underlying molecular mechanisms still largely unknown. Here, we conducted proteomic profiling and analysed publicly available single-cell RNA sequencing data, revealing a marked decrease in lactate dehydrogenase A (LDHA) expression in RIF cases. While traditionally considered a metabolic byproduct, it is now recognised to play a role in signalling and epigenetic regulation. Utilising human endometrial organoids, we demonstrated that lactate enhances human endometrial receptivity by promoting epithelial-mesenchymal transition (EMT) and upregulating histone H3 lysine 18 lactylation (H3K18la). Further multi-omics analyses identified solute carrier family 7 member 11 (SLC7A11) as an H3K18la-regulated target. Functional assays confirmed that lactate-induced H3K18la upregulates SLC7A11, thereby driving EMT and cellular migration. Notably, using a blastoid-endometrial cell implantation model, we demonstrated that SLC7A11 promotes both blastoid adhesion and expansion, highlighting its critical role in embryo-endometrial interactions. Collectively, leveraging multiple organoid systems, including endometrial organoids and blastoid-endometrial cell implantation models, our findings reveal a novel lactate-H3K18la-SLC7A11 axis that orchestrates endometrial epithelial plasticity and receptivity. In addition, this study established a robust methodological framework for investigating implantation mechanisms.

Spinal cord injury (SCI) is a devastating condition with limited therapeutic options. Although neural stem cell (NSC) transplantation shows regenerative potential, its efficacy is constrained by the hostile post-injury microenvironment. Here, we employed untargeted metabolomics to investigate metabolic reprogramming induced by NSC-loaded multichannel collagen scaffolds in a rat SCI model. NSC transplantation significantly enhanced functional recovery and structural remodelling, concomitant with elevated neurogenesis and attenuated gliosis. Metabolomic profiling identified lysophosphatidylcholine 18:0 (LPC18:0) as a key NSC-derived metabolite. Mechanistically, LPC18:0 promoted the differentiation of endogenous NSCs into neurons via the GPR55/AKT/GSK3β signalling axis, as validated by receptor-specific inhibition. In vivo administration of LPC18:0 improved motor function, axonal regeneration and recruitment of immature neurons. These findings reveal a novel metabolic mechanism underlying NSC-based therapy, positioning LPC18:0/GPR55/AKT/GSK3β signalling as a therapeutic target for SCI recovery.

Mitochondrial quality control (MQC) impairment plays a central role in driving the pathogenesis of metabolism-associated steatotic liver disease (MASLD). Specifically, this is manifested as reduced mitophagy; increased mitochondrial fission and decreased fusion; and impaired mitochondrial biogenesis. Key pathological mechanisms of MASLD, such as hepatocyte apoptosis, pyroptosis, and ferroptosis, are activated under the influence of factors including free fatty acids (FFAs), oxidative stress, NLRP3 inflammasome activation, and gut microbiota imbalance. Meanwhile, the letter also lists novel potential therapeutic strategies targeting these pathways, including autophagy enhancers, mitochondrial dynamics regulators, biogenesis promoters, and ferroptosis inhibitors.

Periodontal regeneration requires coupled angiogenesis and osteogenesis, while current strategies to promote angiogenesis face limitations such as poor cytokine stability and safety concerns. Nanosilicates (nSi), as bioactive nanomaterials with potent properties, show promise for enhancing bone regeneration via osteogenic pathways. However, their pro-angiogenic potential and precise mechanisms, particularly within the periodontal microenvironment, remain poorly understood. This study addresses this knowledge void by introducing nSi into rat periodontal defects, revealing significantly enhanced vascular network formation and bone repair in vivo. Crucially, through intervention in relevant signalling pathways, this research provides the first evidence for the molecular mechanism underlying nSi-induced angiogenesis in endothelial cells. We demonstrate that nSi regulate microtubule homeostasis via the MAPK-mediated MAP4 signalling pathway, facilitating STAT3 nuclear translocation and ultimately promoting angiogenic differentiation. This mechanistic elucidation fills a critical gap in understanding the nSi-cytoskeleton-transcriptional regulation axis. These findings offer fundamental insights to guide the rational design and optimisation of nSi-based biomaterial systems for vascularised periodontal regeneration.

A mechanistic network of ovarian aging, highlighting mitochondrial dysfunction as a central hub interconnected with genetic, metabolic, and inflammatory pathways.

The cover image is based on the article Glutaminase-1 Mediated Glutaminolysis to Glutathione Synthesis Maintains Redox Homeostasis and Modulates Ferroptosis Sensitivity in Cancer Cells by Changsen Bai et al., https://doi.org/10.1111/cpr.70036.

Circadian rhythm is an essential biological process that synchronises physiological activities with environmental light/dark cycles. However, its regulatory mechanisms in tooth development remain incompletely understood. Here, we investigated the role of the p75 neurotrophin receptor (p75NTR) in circadian rhythm regulation and daily mineralization during tooth development using immunofluorescence, circadian rhythm tracking, and genetic models. Spatiotemporal analysis of rat dental germs revealed that oscillatory expression patterns of p75NTR closely aligned with clock genes (Bmal1, Clock, Per1, Per2), mineralization-related factors, and odontogenesis-related factors. p75NTR knockout mice (p75NTR^ExIII-/-) exhibited reduced body weight, lower melatonin levels, delayed incisor eruption, decreased daily mineralization width, and downregulation of core clock genes. Mechanistically, p75NTR overexpression in immortalised stem cells from the dental apical papilla (iSCAPs) upregulated casein kinase 2 (CK2) expression, enhanced PER2 phosphorylation, and promoted nuclear p-PER2 accumulation, while CK2 inhibition partially reversed these effects. In vivo, CK2 inhibition via quinalizarin exacerbated incisor eruption defects in p75NTR^ExIII-/- mice. These findings demonstrate that p75NTR regulates circadian-driven mineralization and tooth morphogenesis, probably via the CK2/PER2 pathway, providing critical insight into the interplay between the circadian rhythm and dental development.

Cellular geometry is tightly associated with the function of a cell. During tumour progression, cancer cells undergo changes in phenotypes and biological behaviour with deformations in cellular morphology. However, whether the morphological diversity of cancer cells correlates with the cellular phenotype, and the underlying mechanism of morphology-related function in cancer cells is still unclear. Here, we simplified the cellular morphology by clustering cancer cells into three categories based on two-dimensional cellular morphological features. The silence of caveolin-1 (Cav-1), the primary constituent of membrane caveolae, reproduced the morphological evolutionary behaviour of cancer cells, which is similar to the epithelial-mesenchymal transition process. The attenuation of dorsal stress fibres, the assembly of focal adhesions and the disorder of transverse arc fibres and their regulatory signals are demonstrated as the main morphological evolutionary tools of cancer cells. Moreover, a modified vertex model theoretically reconfirmed the evolutionary process of cellular morphology. Small GTPases and focal adhesion kinase signalling were implicated in Cav-1 knockdown-induced cytoskeletal remodelling and focal adhesion assembly. Both in vitro and in vivo studies have demonstrated that Cav-1-dependent morphological changes are closely associated with the self-renewal capacity of breast cancer cells. Overall, our work highlights new insight into the morphological diversity and the correlation between cellular shape and phenotype of cancer cells, and provides evidence that Cav-1 could affect cancer cell properties such as self-renewal capacity through maintaining the morphological stability.