Cell Proliferation最新文献

Cell size is an important component of cell morphological characteristics. It reflects the characteristics of the cell type, nutritional status, growth stage and physiological function. The cell size of cells of the same type tends to be homogeneous and stable. However, in tumour cells, mutations in cell cycle genes and cytoskeletal genes and overexpression of the corresponding signalling pathways often lead to large variations in tumour cell size. Tumour cells regulate cell size and growth and proliferation through multiple signalling pathways, such as PI3K/Akt/mTOR, Myc and Hippo pathways, which work together to regulate cell size and proliferation. This allows tumour cells to adapt to different survival environments. Alterations in cell size also cause tumours to perform different functions, leading to alterations in tumour stemness, invasive migration and anti-tumour immunity by affecting immune cells in the tumour immune microenvironment. In this review, we describe the endogenous and exogenous factors affecting tumour cell size, analyse the mechanisms by which tumour cells regulate cell size and the effects of cell size on tumour malignancy and tumour immunity, summarise the potential therapeutic targets for cell size, and look forward to possible future research directions and clinical applications.

The inflammatory storm is a hallmark of acute respiratory distress syndrome (ARDS), yet effective therapies remain unavailable. FK506-binding protein 51 (FKBP5) has emerged as a regulator of inflammatory responses. In this study, FKBP5 expression was markedly increased in patients with sepsis and correlated with both cytokine levels and disease severity. Using sepsis-induced ARDS models in Fkbp5^−/− and bone marrow chimeric mice, this study demonstrated that non-haematopoietic FKBP5 mitigates inflammatory injury. Single-cell transcriptomic analysis identified fibroblasts and epithelial cells as the primary sources of non-haematopoietic FKBP5 in the lung injury. Conditional deletion of FKBP5 in fibroblasts (Col1a2-iCre Fkbp5^flox/flox) confirmed the essential role of fibroblast FKBP5 in the inflammatory response during ARDS. Mechanistically, FKBP5-mediated necroptosis of alveolar fibroblasts triggered NF-κB activation, proinflammatory cytokine release, neutrophil recruitment, and the establishment of an inflammatory microenvironment in alveolar epithelial tissue. These findings suggest a potential therapeutic strategy targeting fibroblast FKBP5 and provide a foundation for future clinical investigation in ARDS management.

With the continuous increase of the elderly population and the deepening of population ageing in China, osteoporosis has gradually become one of the significant public health problems. Elucidating the pathophysiological mechanisms that induce osteoporosis and identifying more effective therapeutic targets is of great clinical significance. In this study, in vitro experiments demonstrated that endothelial cell exosomes (EC-EXOs) promoted osteogenic and inhibited adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Aged and ovariectomy (OVX)-induced osteoporosis mice models injected with EC-EXOs confirmed that EC-EXOs delayed bone loss. Proteomic analysis revealed a key protein regulating the differentiation of BMSCs. Expression of THBS3 was significantly higher in EC-EXOs than in Human microvascular endothelial cells (HMEC-1). In vitro and in vivo experiments further validated that THBS3 promoted BMSCs' osteogenic differentiation, inhibited their adipogenic differentiation, and retarded bone loss. Computational biology analysis found that CD47 is a downstream target and potentially functional receptor in BMSCs that bind to THBS3. THBS3 treatment of BMSCs down-regulated the expression of CD47 in in vitro experiments. The aged/OVX models further confirmed that EC-EXOs can regulate the differentiation of BMSCs and delay the process of bone loss via the THBS3–CD47 axis. CD47 antibody may be a potential therapeutic agent for treating ageing-associated bone loss.

Neurodevelopmental impairment due to hypoxic–ischemic brain damage (HIBD) lacks effective biomarkers and therapeutic targets. Based on some cues from published papers, extracellular serine/threonine protein kinase FAM20C was speculated to play a crucial role in the neurodevelopmental impairment of HIBD. In this study, FAM20C was found suppressed in the ischemic hippocampal tissue of HIBD. The inhibition of FAM20C caused by HIBD affected cell differentiation and subsequently caused cognitive impairment. KAP1 was identified as a kinase substrate of FAM20C in the central nervous system. The regulation of the YTHDC1-NCL-KAP1-LINE1 RNA complex by FAM20C was mediated through KAP1 phosphorylation and LINE1 RNA m6A. These alterations consequently modulated the establishment of the H3K9me3 modification on LINE1 DNA, thereby resulting in neuronal differentiation. Furthermore, E2F4, identified as a transcription factor, regulated FAM20C in HIBD. This research has clarified the novel association between FAM20C and HIBD, laying the foundation for innovative diagnostic and therapeutic strategies to counteract neurodevelopmental disruptions arising from neonatal hypoxic–ischemic encephalopathy (HIE).

Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options. Ferritinophagy, an autophagy-dependent process regulating iron metabolism, has emerged as a key contributor to ferroptosis and tumour progression. This study hypothesised that the ferritinophagy-related gene FTH1 drives HCC pathogenesis by modulating tryptophan metabolism and reactive oxygen species (ROS)-dependent ferroptosis. To test this, we first analysed TCGA data to identify prognostic ferritinophagy genes, revealing FTH1 as a critical risk factor. Functional experiments using FTH1-knockdown/−overexpressing HCC cell lines and xenograft models demonstrated that FTH1 enhances proliferation, migration, and tumour growth by upregulating CYP1A1/CYP1A2 in the tryptophan pathway, thereby increasing the synthesis of 6-hydroxymelatonin (6-HMT). Mechanistically, 6-HMT suppressed ROS and ferroptosis by inhibiting cytochrome P450 oxidoreductase (POR). Concurrently, intracellular tryptophan levels were found to inhibit NCOA4-mediated selective autophagy of FTH1, stabilising FTH1 levels and promoting tumour survival. Collectively, our findings establish FTH1 as a central regulator of ferritinophagy in HCC and reveal its dual role in linking tryptophan metabolism to redox homeostasis. This result provides a hint of how FTH1 influences HCC pathogenesis and positions the tryptophan metabolism pathway as a promising therapeutic target.

Histone deacetylase(HDAC) is Zn²⁺-dependent histone deacetylases that regulate the key signalling pathways involved in gene transcription. 11 isoforms have been identified. Recent in vitro and in vivo studies have shown that HDACs are involved in the pathophysiology of cardiovascular diseases (CVDs) and play important roles in cell proliferation, differentiation and mitochondrial metabolism. In terms of physiological mechanisms, HDAC1–6 may play important roles in normal cardiac development and physiological function, while HDAC7 regulates angiogenesis. In pathological processes, class I HDACs function as pro-hypertrophic mediators, whereas class II HDACs act as anti-hypertrophic mediators. HDAC1–3, 6, 9, and 11 participate in lipid cell formation, oxidative stress and endothelial cell injury through multiple signalling pathways, contributing to the pathogenesis of atherosclerosis. In addition, HDACs also play a role in CVDs such as heart failure, myocardial fibrosis, pulmonary hypertension and diabetic cardiomyopathy. In view of this, we reviewed the regulatory pathways and molecular targets of HDACs in the pathogenesis of CVD. In addition, we summarise the current discovery of inhibitors targeting HDACs. HDAC inhibitors have shown promising therapeutic progress in animal experiments, but clinical trials to demonstrate their efficacy in humans are still lacking. A better understanding of the role of HDACs in CVD provides a new direction for the development of therapeutic interventions and holds significant research value.

RING finger protein 219 (RNF219) is a co-factor for the CCR4-NOT deadenylase complex in mammals. Here, we found that mutations within the C3HC4 scaffold of the RING finger domain in RNF219 are capable of forming condensates via liquid–liquid phase separation (LLPS), though the wild-type RING finger domain intrinsically suppresses LLPS. We further demonstrated that the adjacent coiled-coil 1 (CC1) domain promotes the potential of RNF219 to form condensates. Moreover, the mutant RNF219 condensates are able to encapsulate the CCR4-NOT complex, inhibiting the RNA deadenylation activity of CCR4-NOT. Additionally, we observed that RNF219 mutations could promote cell proliferation. These findings suggest a pathogenic mechanism whereby RNF219 mutations could induce CCR4-NOT condensate formation, inhibit deadenylation-dependent mRNA decay and drive cell proliferation.

Colorectal cancer (CRC) is one of the most common malignant tumours and is the second leading cause of cancer-related mortality worldwide. Despite the availability of preventative, diagnostic and treatment methods including endoscopic treatment, surgical intervention, radiotherapy, biologics, salvage therapy and immunotherapy, the mortality rate associated with CRC remains alarming. Consequently, there is a pressing need to search for medicines for the treatment of CRC. Phytomedicines have been shown to suppress the proliferation and metastasis of CRC through various mechanisms, including immune regulation, modulation of gut microbiota, targeting of stem cells, macrophage polarisation, glycolysis, ferroptosis induction, modulation of extracellular vesicles, activation of mitochondria-induced apoptosis, inflammation reduction, oxidative stress management and intervention of autophagy. Furthermore, numerous studies have reported the anti-cancer and anti-metastatic effects of various phytomedicines, including curcumin, resveratrol, berberine, shikonin, dihydroartemisinin, fucoidan, luteolin, andrographolide, piperine, kaempferol, emodin, cannabidiol, tanshinone IIA and evodiamine. In this review, we sort out the effects and mechanisms of phytomedicines on CRC and outline the major phytomedicines commonly used in CRC treatment. We hope that these phytomedicines may serve as promising drugs or important lead compounds for the management of CRC.

In recent years, a growing number of studies have disclosed the substantial role of macrophages—key immune cells—in the pathological process of intervertebral disc degeneration. Researchers have categorised macrophage phenotypes into M1 and M2 polarisation, associating these polarisations with intervertebral disc degeneration. Essentially, macrophage phenotypes can be classified as either pro-inflammatory or anti-inflammatory. Induced by diverse factors, these distinct polarisation states exert contrary effects on disc injury and repair. Although numerous studies focus on the polarisation of macrophages and the cytokines they secrete in relation to intervertebral disc degeneration, these studies frequently neglect the relationship between the efferocytosis of macrophages and the progression of intervertebral disc degeneration. Efferocytosis is a specialised procedure in which phagocytes, such as macrophages, engulf and eliminate apoptotic cells. This process is crucial for maintaining tissue homeostasis and resolving inflammation. By effectively clearing these dying cells, efferocytosis helps prevent the release of potentially detrimental cellular contents, thereby facilitating healing and the resolution of inflammation. Simultaneously, macrophages digest the engulfed cell debris and release various cytokines that participate in tissue self-repair. Therefore, this article presents an overview of the molecular mechanisms connecting macrophages and their efferocytosis activity to intervertebral disc degeneration, explores new directions for the utilisation of macrophages in the treatment of intervertebral disc degeneration, and discusses the future prospects for the development of therapeutic targets.

Metabolic disorders could cause dysregulated glucose and lipid at the systemic level, but how inter-tissue/organ communications contribute to glucolipotoxicity is difficult to dissect in animal models. To solve this problem, myocardium and nerve tissues were modelled by 3D engineered heart tissues (EHTs) and neural organoids (NOs), which were co-cultured in a generalised medium with normal or elevated glucose/fatty acid contents. Morphology, gene expression, cell death and functional assessments detected no apparent alterations of EHTs and NOs in co-culture under normal conditions. By contrast, NOs significantly ameliorated glucolipotoxicity in EHTs. Transcriptomic and protein secretion assays identified the extracellular matrix protein versican as a key molecule that was transferred from NOs into EHTs in the high-glucose/fatty acid condition. Recombinant versican protein treatment was sufficient to reduce glucolipotoxicity in EHTs. Adeno-associated virus-delivered versican overexpression was sufficient to ameliorate cardiac dysfunction in a murine model of diabetic cardiomyopathy. These data provide the proof-of-concept evidence that inter-tissue/organ communications exist in the co-culture of engineered tissues and organoids, which could be systemically studied to explore potential pathological mechanisms and therapeutic strategies for multi-organ diseases in vitro.