Journal of Cellular and Molecular Medicine最新文献

Understanding intracellular signalling pathways is crucial since they regulate essential functional activities. Bivariate relationships have been useful in delineating these pathways in clinical samples. In our previous studies, we have found many linear associations between pathway components, and we have interpreted these correlations as rheostatic regulators. Increases in an upstream component are correlated with a commensurate downstream increase. Here, we report a quantitative analysis of molecules in the STING pathway by assessing the variance in human peripheral blood mononuclear cell-type-specific molecular expression from patients with atherosclerotic coronary artery disease. The induction of the type I interferon track by this pathway is dependent on the expression levels of STING in T cells and monocytes and the expression levels of phospho-STING in B cells. This relationship in T cells and monocytes demonstrates definitive linearity, indicating that it is regulated as a rheostat. In B cells the relationships are logarithmic, indicating an on-off mechanism of regulation. The STING pathway-dependent stimulation of the NFκB track is also controlled by on-off mechanisms that are modelled by nonlinear bivariate relationships. These on-off switches occur at the bifurcation of the two branches involving phospho-STING, phospho-TBK1 and phospho-RelA. Whereas linear bivariate associations are readily captured by an evaluation of the correlation matrix, significant nonlinear relationships are not. Nonlinear correlations modelled logarithmically or exponentially are easily discerned by the assessment of a natural log-transformed versus non-transformed correlation matrix.

DMRTA2 is a member of the evolutionarily conserved transcription factor family involved in various developmental processes including neurogenesis. However, the roles of DMRTA2 in human development and disease are not fully characterised. Single cell RNA-seq data analysis showed that DMRTA2 is robustly expressed in neural progenitors, in particular radial glial (RG) cells, in the human fetal brain. Knockout of the DMRTA2 gene in human embryonic stem cell (hESC)-derived cerebral organoids led to smaller organoid size and fewer RG cells. We also found that DMRTA2 is highly and specifically expressed in diffuse hemispheric gliomas, H3G34-mutant (DHG-H3G34), a malignant subtype of paediatric brain tumour. Loss of DMRTA2 resulted in enhanced neuronal differentiation, fewer RG-like glioma cells and impaired tumorigenicity, suggesting its important role in both normal brain development and the formation of malignant brain tumours.

The rising levels of chemical pollutants in aquatic ecosystems threaten biodiversity and demand improved methods for assessing ecological risk. Recent deep learning methods advance molecular toxicity prediction but still suffer from limited generalisation, interpretability and robustness under data scarcity. To address these issues, we propose ADFC-ATP, a framework that integrates dual-view molecular graph fusion with contrastive topology learning based on NT-Xent loss. Our approach uses structural graph augmentations during pretraining to enhance robustness, while a graph attention encoder learns hierarchical substructure patterns through masked feature reconstruction. For downstream aquatic toxicity prediction, an adaptive attention-based fusion mechanism dynamically combines pretrained graph embeddings and fingerprint similarity metrics, enabling more accurate and robust toxicity assessment. Experimental results show that on four fish toxicity datasets, the AUC of ADFC-ATP achieves an average relative improvement of approximately 10.2% compared to two classic graph neural network baseline models: single-task graph convolutional network (GCN-ST) and multi-task graph convolutional network (GCN-MT). Ablation and attention weight visualisation confirm the critical roles of scaffold preservation and contrastive regularisation, and highlight our model's ability to identify toxicoph ores consistent with QSAR principles. ADFC-ATP thus provides a robust, interpretable, and computationally efficient tool for predicting toxicity of emerging aquatic contaminants, offering a valuable complement to traditional laboratory testing. ADFC-ATP is freely available at https://github.com/zhaoqi106/ADFC-ATP.

Clinical manifestations of 1p36.33 duplications vary depending on duplication size. This region is prone to copy number variants associated with diverse phenotypes. We report a novel 1p36.33p36.32 duplication in a patient with developmental delay and facial dysmorphism. The causative duplication was detected by whole-genome Oligo-array CGH and confirmed by real-time PCR. Integrative bioinformatic analyses-including network analysis, phenotype-driven gene prioritisation, and dosage sensitivity assessment-were performed to explore the molecular basis of the phenotype; we used integrative bioinformatic analyses, including network analysis, phenotype-driven gene prioritisation, and dosage sensitivity assessment. Assessment of a child with tonic seizures, developmental delay, and dysmorphic facial traits revealed a 2.3 MB gain in the 1p36.33p36.32 region (nucleotide 898,721 to 3,153,945) through array CGH. Bioinformatic analyses identified several candidate genes, including GABRD, DVL1, and GNB1, which are implicated in neurodevelopmental and congenital disorders. Pathway enrichment analysis revealed significant involvement of the '1P36 Copy Number Variation Syndrome' pathway. This case expands the phenotypic spectrum of 1p36 duplications and highlights the importance of integrating clinical, genomic, and bioinformatic data for accurate interpretation.

This research explored the potential of a synthesised pyrazoline derivative 5-ethoxy 5-hydroxy 3-methyls 4, 5-dihydro 1Hpyrazol 1 yl (pyridine 4 yl) methanone [5-E-5-H-PD], against arthritis using a Complete Freund's Adjuvant (CFA)-induced arthritis in a rat model. Sprague-Dawley rats were used to induce arthritis via subplantar injection of CFA (0.1 mL) into their right hind paw. Animals were divided into 6 groups (n = 4): normal, arthritis, standard drug (methotrexate 1 mg/kg intraperitoneally), and 3 treatment groups receiving 5-E-5-H-PD, 10, 20 and 40 mg/kg orally for 21 days. Clinical signs (paw volume and arthritis score), pro-inflammatory cytokines, and histopathological alterations were evaluated. The 5-E-5-H-PD groups showed a reduction in paw edema in a dose-dependent manner. On day 21, paw volume in the 40 mg/kg dose animals decreased significantly to 2.31 ± 0.12 mm compared to 4.82 ± 0.14 mm in the disease animals (p < 0.001). Arthritis scores reduced from 3.8 ± 0.2 (control) to 1.5 ± 0.3 in the high-dose treatment group. Serum IL-10, TNF-α, and NF-κB levels were significantly reduced to 66.75 ± 3.0 pg/mL, 34.50 ± 1.8 pg/mL and 9.50 ± 0.6 pg/mL respectively, compared to the arthritis induced rats 129.8 ± 2.0 pg/mL, 77.75 ± 1.5 pg/mL and 28.50 ± 1.3 pg/mL respectively, compared to the arthritis induced rats (112.3 ± 5.5, 96.8 ± 4.3, 123.1 ± 6.2 pg/mL, p < 0.001). Histopathology analysis confirmed reduced synovial hyperplasia and inflammatory infiltration in treated joints. The pyrazoline derivative, 5-E-5-H-PD, demonstrated significant anti-arthritic effects in the CFA-induced rat model by reducing inflammation, cytokine expression and joint destruction. These findings support further investigation into pyrazoline-based compounds as promising therapeutic agents for RA.

Cervical cancer ranks as the second most prevalent cancer among women worldwide, and the primary treatment for advanced cases involves cisplatin-based chemotherapy. However, the duration of cisplatin treatment is typically short, with a median survival rate of approximately 1 year. This highlights the urgent need to enhance our understanding of cisplatin's mechanism of action in cervical cancer treatment. Our findings demonstrate that p53 induces the nuclear translocation of IFI16, leading to activation of the NF-κB signalling pathway. This activation plays a crucial role in protecting cervical cancer cells against cisplatin-induced apoptosis. The activation of NF-κB is independent of STING, which is a downstream molecule of IFI16. STING signalling activation by cisplatin may not be associated with cisplatin-induced apoptosis. To further validate this tumour-promoting effect of IFI16 during cisplatin therapy, we established a subcutaneous implantation tumour model using mouse cervical cancer (U14) cells and conducted additional in vitro experiments. We examined the role and mechanism of IFI16 in cisplatin treatment of cervical cancer. The role of IFI16 in cervical cancer progression deserves further study. Targeted inhibition of IFI16 may be a new way to increase cisplatin sensitivity of cervical cancer cells.

Ischemia-reperfusion injury remains a major challenge in free flap surgery, contributing to oxidative stress, inflammation, and cell death that impair tissue viability and outcomes. Remote ischemic preconditioning (RIPC) has emerged as a potential protective strategy by modulating cellular stress responses, but its molecular mechanisms in free flaps remain incompletely understood. We prospectively enrolled 36 female patients undergoing autologous breast reconstruction with mainly deep inferior epigastric perforator (DIEP) free flaps, randomised into three groups: No RIPC, Early RIPC (24 h preconditioning), and Late RIPC (1 h preconditioning). Tissue samples were collected pre-ischemia and post-reperfusion for immunohistochemical and multiplex protein analyses. RIPC did not reduce oxidative stress markers, as 4-hydroxynonenal (4-HNE) levels were comparable across groups, while 3-nitrotyrosine levels paradoxically increased after RIPC. Early RIPC selectively modulated cell death pathways, with decreased expression of mitochondrial apoptotic marker caspase 9 and reduced necroptotic activation of mixed lineage kinase domain-like protein (MLKL) after reperfusion. Caspase 8 showed a transient modulation, suggesting effects on apoptosis-necroptosis crosstalk. Cyclophilin A levels were elevated after reperfusion in RIPC groups, indicating an adaptive stress response. These findings suggest that early RIPC exerts selective protection by modulating apoptosis and necroptosis, rather than broadly reducing oxidative stress. RIPC may represent a targeted strategy to improve free flap survival in reconstructive surgery.

Abdominal aortic aneurysm (AAA) is the most prevalent and lethal form of arterial aneurysm, frequently manifesting asymptomatically until a catastrophic rupture occurs. While various diagnostic imaging tools and several potential biomarkers have been explored for the purpose of early AAA screening, the usage of liquid biopsy such as extracellular vesicles (EVs)-carried protein for the early diagnosis of AAA is still being overlooked. In this study, we enrolled 18 AAA patients and nine healthy normal controls, including data from the National Drug Clinical Trial Organisation-Vascular Surgery (NDCTO) (in-house cohort) and the Second Clinical Medical College, Jinan University (Shenzhen People's Hospital) (external cohort). We employed Olink's proximity extension assay (PEA) technology based on the plasma EV proteins and first comprehensively characterised the proteomics landscape in circulating EV underlying AAA disease development. A complex profile of differential EV proteins and EV protein-protein interactions network in AAA patients was identified. The differentially expressed EV proteins in AAA patients were found to be significantly associated with several enriched pathways, including the cellular response to cytokine stimuli, inflammatory response, and the regulation of the glucocorticoid receptor (GR) pathway. Moreover, five hub proteins were identified as being of particular significance: these were Interleukin-4, Interleukin-6, MCP-1, Neurturin, and Oncostatin-M. The Olink proteomics technique was utilised in order to identify these proteins. The significance of these proteins was further validated through Western blotting and enzyme-linked immunosorbent assay (ELISA) in the external cohort. The five EV proteins displayed reliable performance and robustness for distinguishing AAA from healthy people, revealing high accuracy with AUC values of 0.760, 0.840, 0.800, 0.840, and 0.900, respectively. The present study has revealed the plasma EV proteins landscape within AAA and further uncovered their potential roles in the pathogenesis of the disease. This presents a new direction for clinical diagnosis and management of AAA. Consequently, these five EV proteins have the potential to serve as useful biomarkers for the diagnosis and prediction of AAA. Further research is warranted to explore their potential as therapeutic targets.

Obesity increases the likelihood of metabolic diseases and can affect stem cell function negatively. Here, we aimed to elucidate the mechanisms involved in the loss of stem cell function induced by obesity by assessing levels of oxidative stress (OS) and endoplasmic reticulum stress (ERS) in bone marrow-derived mesenchymal stromal cells (BM-MSCs) from healthy donors with a body mass index (BMI) of 25-30 (obese) and BMI > 30 (morbid obese). We assessed base levels of OS and ERS, activation of cellular response mechanisms, and the effects of Melatonin (MT), which is known to decrease OS, and TUDCA, which is known to decrease ERS. Loss of BM-MSC differentiation was correlated with the degree of obesity and associated with upregulation of OS and ERS. Increased BMI was accompanied by elevated intracellular ROS and accelerated senescence of BM-MSCs. Although treatment with MT and TUDCA was able to decrease OS and ERS in BM-MSCs from obese donors, cellular stress in BM-MSCs from morbid obese donors was irreversible. Therefore, it is imperative to treat and prevent obesity before the negative effects on stem cells become permanent and irreversible. Early treatment of obesity may not only prevent metabolic diseases; it may also protect tissue resident stem cells.

Breast cancer (BRCA) is characterised by complex cellular heterogeneity and differentiation hierarchies, which play a crucial role in bone metastasis and therapeutic resistance. However, existing classification systems remain inadequate in capturing these complexities, limiting their effectiveness in guiding treatment strategies. To address this gap, we integrated single-cell RNA-seq profiles, spatial transcriptomes, along with 1097 bulk RNA-seq profiles of TCGA-BRCA cohort to dissect the molecular landscape of BRCA. By performing UMAP analysis, we identified nine tumour clusters and three spatially distinct spot types (immune, stromal and malignant spots) and further delineated 11 differentiation states from 2493 malignant spots. Through clustering, monocle 2 pseudo-time and prognostic analyses, we identified the prognostic BRCA cell fate-related genes, then constructed a novel BRCA stratification system (four subtypes) with differential prognosis, biological plausibility and clinical significance. Also, least absolute shrinkage and selection operator (LASSO) regression analysis was performed for the BRCA cell fate-related genes in constructing a prognostic model. The model has modest accuracy and accordance (AUC = 0.708), which could distinguish BRCA patients into high-risk or low groups. With correlation analysis, regulation networks were constructed for different subtypes based on the key cell fate-related genes, transcription factors, metastasis-related pathways, immune components and so on, to investigate the regulatory relationships between primary BRCA and BRCA bone metastasis. Afterwards, we identified the most significant inhibitors (puromycin, MS-275, megestrol, aesculetin) for bone metastatic BRCA, which might have potential translational significance. In all, we developed a novel molecular stratification system for BRCA based on the cell fate-related markers of malignant cells, which offered strong translational potential for diagnosis, prognosis and personalised therapeutic interventions.