Cell Proliferation最新文献

Meiosis, a specialised form of cell division, is essential for sexual reproduction, which requires the proper formation of synaptonemal complex (SC) and homologous recombination (HR). However, the regulatory mechanisms underlying these processes remain incompletely understood. Here, we demonstrate that SOX30 is a key transcriptional regulator of male meiotic synapsis and recombination. In Sox30-knockout mice, zygotene spermatocytes accumulate with synapsis defects. SOX30 deficiency disrupts the SC central element components SYCE1, SYCE2, and TEX12 distribution. Furthermore, disrupted γ-H2AX distribution reveals impaired DNA double-strand break repair and the persistence of recombination proteins RAD51 and RPA2 in late spermatocytes confirms defective homologous recombination repair (HRR) which results in reduced crossover formation in Sox30-knockout mice spermatocytes. Mechanistically, SOX30 directly binds to SYCE1/SYCE2 promoters to modulate their transcription, thereby regulating SC assembly and HRR. Restoring SOX30 expression effectively rescues meiotic defects. Importantly, transcriptome co-expression analysis in non-obstructive azoospermia (NOA) testes identifies SOX30 as a central regulator of NOA transcriptional networks. Collectively, these findings underscore SOX30's crucial role in meiotic synapsis and recombination, highlighting its therapeutic potential for NOA.

Periapical periodontitis is one of the most common inflammatory bone destructive diseases. Epidemiological evidence suggests that hypoxia exposure, such as that resulting from high-altitude exposure or sleep apnea syndrome, may be a significant risk factor that exacerbates the disease process. However, its specific role and the underlying molecular mechanisms remain unclear. In this study, we established a mouse model of periapical periodontitis under conditions of chronic hypoxia to evaluate its impact on pathological bone loss using micro-computed tomography, histological staining, and serum cytokine analysis. Furthermore, we explored the potential molecular regulatory mechanisms using in vitro osteoclast differentiation models, adeno-associated virus-mediated in vivo gene knockdown, and cleavage under targets and tagmentation (CUT&Tag) sequencing. Our study revealed that hypoxia exposure significantly aggravated alveolar bone resorption, osteoclast activation, and systemic inflammation in the mouse model of periapical periodontitis compared to normoxia. At the molecular level, hypoxia-inducible factor-1α (HIF-1α) showed a rapid but transient increase under hypoxia, whereas HIF-2α displayed a progressive and sustained elevation throughout osteoclast differentiation. These dynamics indicate that HIF-2α plays a more prominent role than HIF-1α in mediating the hypoxia-accelerated osteoclastogenic response. In vivo, local knockdown of HIF-2α in the periapical region markedly attenuated bone destruction exacerbated by hypoxia exposure. Further mechanistic investigation, combining CUT&Tag sequencing and functional validation experiments, revealed that HIF-2α mediates its pro-osteoclastogenic function by directly binding to the promoter region of the calmodulin-dependent protein kinase IV (Camk4) gene and activating its transcription. This study unveils that hypoxia exposure, acting as a critical environmental risk factor, functions as a 'synergistic amplifier' to enhance pathological osteoclastic responses in periapical periodontitis through the HIF-2α-CAMK4 regulatory axis. The findings deepen our understanding of periapical periodontitis and suggest that targeting HIF-2α or downstream pathways may be an adjunctive therapeutic strategy for hypoxia-associated inflammatory bone loss.

Atherosclerosis remains a significant global health challenge, arising from the complex interactions among dysregulated lipid metabolism, chronic inflammation and immune activation. Ferroptosis, marked by lipid peroxide buildup dependent on iron, is gaining recognition as a modulator of macrophage activity in atherosclerosis. Macrophages are the pivotal orchestrators of chronic inflammation and atherosclerotic plaque formation. The marked heterogeneity and plasticity of macrophages within plaques dynamically shape the local microenvironment, contributing to phenomena such as lipid overload, cytokine overactivation, hypoxia, and programmed cell death. This review examines how dysregulated iron handling, lipid metabolism, and redox imbalances synergise to induce macrophage ferroptosis in atherosclerosis. Moreover, ferroptosis contributes to the development and progression of atherosclerosis by causing dysfunction in vascular smooth muscle cells (VSMCs), vascular endothelial cells (VECs), and macrophages, thereby promoting plaque formation and instability. Furthermore, macrophages are intricately linked to ferroptosis, with this iron-dependent cell death enhancing oxidative stress and inflammatory pathways. Macrophage ferroptosis drives plaque progression and destabilisation, ultimately heightening the risk of rupture and cardiovascular events. By inhibiting macrophage ferroptosis, it may be possible to reduce oxidative stress and inflammation, stabilise atherosclerotic plaques, and ultimately lower the risk of cardiovascular events. This review highlights the therapeutic potential of targeting macrophage ferroptosis for the treatment of atherosclerosis.

Periodontitis is a chronic inflammatory disease driven by a dysregulated host immune response, in which macrophage-mediated inflammation shifts from protective to pathological. While monocyte-derived macrophages (MDMs) are known to adopt a destructive, M1-like pro-inflammatory phenotype, the mechanisms that enable this 'runaway' polarisation by bypassing endogenous negative feedback remain elusive. Here, we identify alternative polyadenylation (APA) as a critical post-transcriptional mechanism driven by pathogens to disrupt macrophage immune control. Integrating single cell RNA sequencing with Sierra APA analysis of human gingival tissues, we uncovered a global shift toward proximal poly(A) site (PAS) usage, indicative of 3'UTR shortening, specifically within the pro-inflammatory MDM subset. This APA remodelling preferentially affected genes essential for cytokine production and inflammatory signalling. In vitro, the keystone pathogen Porphyromonas gingivalis similarly induced widespread 3'UTR shortening in macrophages. This shortening systematically eliminated inhibitory miRNA-binding sites, thereby derepressing pro-inflammatory transcripts. Mechanistically, using Selenok as a representative example, we demonstrate that P. gingivalis induced 3'UTR shortening selectively abolishes repression by miR-320-3p, a 'brake' miRNA upregulated in periodontitis, whose binding site is excised by the proximal APA event. Collectively, these findings reveal APA remodelling as a key pathogenic strategy that enables pro-inflammatory macrophages to escape miRNA-mediated suppression, leading to an uncontrolled M1-like state. This 'disruption' of the post-transcriptional braking system provides a new mechanistic rationale for the persistent, destructive inflammation in periodontitis.

LMPt enters the cell mainly through caveolin-mediated endocytosis, and then fuses with endosomes and lysosomes to deliver MPt to mitochondria and the endoplasmic reticulum to induce mitophagy based on the fusion of lysosomes and mitochondria, and endoplasmic reticulum stress and subsequent apoptosis via the Bip-PERK-eIF2α-ATF4 axis to exert an anti-breast cancer effect.

The transcriptional effector of the Hippo signalling pathway, YAP, regulates the first lineage specification in mouse preimplantation embryos. However, how YAP undergoes dephosphorylation specifically in the trophectoderm (TE) but not in the inner cell mass (ICM) remains unresolved. Here, we discovered that the serine/threonine phosphatase PPP1CC exhibits uniform distribution prior to blastocyst formation but becomes specifically localised to the TE during the blastocyst stage. Through mediating YAP dephosphorylation in the outer cells of mouse morula, PPP1CC facilitates YAP nuclear translocation, thereby ultimately driving TE lineage specification. Importantly, the spatially restricted localisation of PPP1CC in TE is achieved via its interaction with the long non-coding RNA GAS5, which localises to the subcortical region throughout early mouse embryonic development. Knockdown of GAS5 phenocopies PPP1CC deficiency, causing developmental arrest at the morula stage accompanied by impaired YAP dephosphorylation in outer cells. Moreover, overexpression of GAS5 in one blastomere of the 2-cell stage biases its descendants predominantly towards the TE fate. In summary, our study identifies the GAS5-PPP1CC-YAP axis as a central regulator of first lineage specification during mouse preimplantation development, highlighting its critical role in reversible phosphorylation during early embryogenesis.

Genomic imprinting, an epigenetic process resulting in parent-specific gene expression, is essential for normal development and growth. Disruption of imprinting leads to various developmental disorders and cancers, yet our understanding of the full repertoire of imprinted genes in humans remains incomplete. Here, we utilised androgenetic, parthenogenetic and biparental human embryonic stem cells and their neural derivatives to identify novel imprinted genes by analysing their methylome and transcriptome profiles. Our analysis revealed 12 novel putative imprinted genes distributed across four distinct loci, with six of them clustered in an uncharacterised imprinted region on chromosome 19. We identified potential imprinting control regions regulating this novel cluster, suggesting a coordinated regulatory mechanism. Notably, these imprinted genes are enriched in cancer-related pathways, with several showing isoform-specific imprinting patterns. Our analysis also revealed consistent DNA methylation aberrations in pluripotent stem cells at specific imprinted loci, highlighting potential epigenetic instability during culturing. These findings contribute to our understanding of genomic imprinting regulation in human development and highlight potential genomic regions for further investigation of imprinting-related disorders.

RETRACTION: T. Liu, X. Zhang, K. Sha, X. Liu, L. Zhang and B. Wang, “ miR-709 Up-Regulated in Hepatocellular Carcinoma, Promotes Proliferation and Invasion by Targeting GPC5,” Cell Proliferation 48, no. 3 (2015): 330–337, https://doi.org/10.1111/cpr.12181.

The above article, published online on 27 March 2015 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Qi Zhou; and John Wiley & Sons Ltd. The retraction has been agreed upon following the identification of duplicated elements between Figures 5c and 7c, which were reported to represent different experimental conditions. The authors provided some supporting data; however, it was insufficient to fully address the concerns. As a result, the editors have lost confidence in the reliability of the results. The authors did not respond when asked to agree to the final wording of the retraction.

Decreased sialic acid increases the adhesion of RBC membranes to immunoglobulins leading to an increased erythrocyte sedimentation rate (ESR). The increase in reactive oxygen species (ROS) damages the sialic acid glycosyl chains on the surface of RBC membrane proteins, causing the membrane proteins to be overexposed to the plasma environment due to the loss of sialic acid coverage. Immunoglobulins in plasma adhere to RBC membrane Band3 extracellularly exposed peptides through intermolecular interactions. The reduction of sialic acid causes a weakening of the RBC membrane negative charge barrier and the adhesion of immunoglobulins further destabilises the suspension of RBCs, resulting in a rapid addition of ESR to multiple myeloma.

Compared to classical drug screening, single-cell screening not only significantly enhances throughput but also provides richer transcriptional response information. In this study, we employed the high-throughput and high-sensitive single-nucleus sequencing platform, snHH-seq, to screen clinical drug combinations with anti-hepatocellular carcinoma (HCC) activity. Single-cell transcriptomics analysis revealed that the HY combination (HHT and YM155) exhibited the strongest suppression of tumour cell proliferation, a finding validated by both in vitro and in vivo functional assays. Further investigation suggested that HY triggers ferroptosis, as evidenced by rescue from cell death upon co-treatment with the ferroptosis inhibitor Fer-1. Subcluster analysis identified distinct tumour cell subclusters' responses to HY treatment. A gene regulatory network analysis highlighted JUN as a key regulator mediating proliferation inhibition, primarily active in the apoptotic cell subcluster. These findings illustrate how integrating high-throughput screening with mechanistic dissection can accelerate the discovery of targeted drug combination therapies, and offer a blueprint for precise interventions using pathway vulnerabilities and cellular heterogeneity in HCC.