Journal of Biomedical Research最新文献

Lung cancer in smokers (LCIS) and lung cancer in never-smokers (LCINS) are different entities with distinct molecular features. However, their cellular heterogeneity still requires further investigation. Through an integrated analysis of single-cell RNA sequencing (scRNA-seq) and bulk sequencing data, we identified cell subpopulations associated with smoking and non-smoking patients. Downstream transcriptomic analyses were then performed to reveal differences in cell function and tumor microenvironment. We observed that smoking-associated cancer cells exhibited a higher degree of aggressiveness, which may correlate with an adverse prognosis in smoking patients. Additionally, immunosuppressive CXCL10+ macrophages may be involved in their tumorigenesis in smokers, and the immunoregulatory LGALS9-HAVCR2 axis could be a potential immunotherapeutic target. In non-smokers, the inflammatory microenvironment may be involved in their tumor formation. Moreover, the decreased anti-tumor cytotoxicity could be associated with their suboptimal immunotherapeutic response. Our study uncovered differences in oncogenic and immune escape mechanisms between LCIS and LCINS patients and suggests potential immunotherapy strategies.

Cervical cancer represents a considerable global health challenge, mainly because of ineffective screening programs in middle-income countries. The current study aimed to forecast cervical cancer incidence by analyzing behavioral risk factors through logistic regression, employing feature engineering techniques such as principal component analysis (PCA). PCA successfully condensed the dataset into ten principal components, capturing 89% of the variance, while stratified K-fold cross-validation ensured a balanced representation of classes. With the application of L1 regularization, the logistic regression model achieved an accuracy of 97.2%, an AUC of 98.1%, an F1 score of 97.2%, a specificity of 96.1%, and a log loss of 0.17. The performance of models was comparatively evaluated, and the results revealed that the logistic regression model achieved the highest accuracy of 97.2% in comparison with decision trees at 93.33%, random forest at 93.33%, XGBoost at 93.33%, Naive Bayes at 91.67%, and non-regularized logistic regression at 87.55%. This research underscores the importance of early prediction of cervical cancer based on behavioral risk factors and suggests a robust, easily implementable workflow to improve classification accuracy. Future research should concentrate on refining these predictive tools to overcome social and behavioral barriers to prevention, particularly within underserved populations.

Ranked as the most prevalent cause of death worldwide, ischemic stroke urgently requires innovative therapeutic strategies. The present study demonstrates the therapeutic potential of human umbilical cord-derived mesenchymal stem cell-derived exosomes (hUMSC-Exos) in ameliorating hypoxia-induced cerebrovascular endothelial dysfunction through modulation of the AMPK/NLRP3 signaling pathway. Bioinformatics analysis of DisGeNET and exosomal cargo databases revealed 283 overlapping cerebral ischemia-related genes, implicating hUMSC-Exos in inflammatory regulation. In vitro experiments showed that hUMSC-Exos rescued oxygen-glucose deprivation (OGD)-induced endothelial dysfunction in bEnd.3 mouse brain endothelial cells, restoring viability, migration, and mitochondrial integrity. Mechanistically, hUMSC-Exos reversed OGD-induced AMPK inactivation while suppressing NLRP3 inflammasome activation, caspase-1 cleavage, and gasdermin D (GSDMD)-mediated pyroptosis. Molecular docking revealed DL-3-n-butylphthalide as a dual-target ligand for AMPK/NLRP3, synergizing with hUMSC-Exos to enhance endothelial protection. In vivo, combined therapy in the transient middle cerebral artery occlusion mouse model reduced cerebral infarction and improved neurological outcomes, accompanied by NLRP3/GSDMD downregulation and hippocampal neuron preservation. These findings establish hUMSC-Exos as regulators of AMPK/NLRP3-mediated pyroptosis and propose a translatable combinatorial regimen for ischemic stroke therapy.

Diabetic retinopathy (DR), a common complication of diabetes, is characterized by retinal angiogenesis and inflammation. The role of hepatoma-derived growth factor (HDGF) in mediating inflammation during DR remains unclear. We measured HDGF levels in the aqueous humor and found that HDGF was increased in DR but decreased after anti-angiogenesis treatment. Using public single-cell RNA sequencing datasets, we found that elevated HDGF in DR was mainly produced by Müller cells and targeted microglia. Additionally, integrin beta 2 ( Itgb2), a target gene of HDGF that induces microglial activation, was significantly upregulated in DR. To verify these results, we performed enzyme-linked immunosorbent assays, quantitative reverse transcription-PCR, Western blotting, and fluorescence immunostaining in cultured Müller and microglial cells treated with HDGF or anti-HDGF, as well as in DR mice receiving intravitreal injections of HDGF or its antibody. Exogenous HDGF further promoted microglial activation, migration, and secretion of pro-inflammatory cytokines, while neutralization of HDGF suppressed these effects caused by high glucose. Furthermore, the HDGF receptor nucleolin was overexpressed in microglia under high glucose stimulation. Therefore, blocking HDGF from Müller cells in DR reduced the excessive inflammatory response in microglia, highlighting HDGF as a potential therapeutic target.

Activation of neutrophil membrane receptors initiates intracellular signal transduction cascades that orchestrate the cell's effector functions, including phagocytosis, production of reactive oxygen and halogen species, degranulation, and NETosis (formation of neutrophil extracellular traps (NETs). NETs, which contain antimicrobial compounds such as myeloperoxidase (MPO), represent a strategy to combat infection. However, excessive production of NETs promotes thrombosis, diabetes mellitus, and other diseases. Therefore, investigations into the mechanisms of NETosis and the identification of modulators of this process are critical for developing strategies to address NETosis-related disorders. Here, we identified a novel NETosis inducer, human serum albumin (HSA) modified by the MPO product hypochlorous acid (HSA _HOCl), whose accumulation in vivo was correlated with inflammatory processes. Using human blood neutrophils, we investigated HSA _HOCl-induced NETosis and detected NET formation by flow cytometry. The results showed that the mechanism of HSA _HOCl-induced NETosis involved MPO, NADPH oxidase and phosphatidylinositol 3-kinases, and that HSA _HOCl activated a reactive oxygen species-dependent suicidal type of NETosis. Moreover, HSA _HOCl-induced NETosis was inhibited by an anti-HSA _HOCl monoclonal antibody. Thus, our findings may facilitate the development of strategies to modulate NETosis in inflammation correlated with elevated MPO activity.

PIWI-interacting RNAs (piRNAs) are a class of noncoding RNAs primarily found in germ cells. While piRNAs are known to be involved in various cancers, their specific roles in colorectal cancer (CRC) remain unclear. To elucidate the role of piRNAs in CRC, we first analyzed their expression characteristics by sequencing 10 pairs of tumor and adjacent normal tissues. Subsequently, differentially expressed piRNAs were identified through two-stage qRT-PCR validation using 20 and 114 pairs of samples. Subcellular localization was assessed through nucleoplasmic separation and immunofluorescence staining assays. RNA pull-down mass spectrometry was employed to identify piRNA-interacting proteins. We identified piR-61298as a piRNA significantly upregulated in CRC. Functional assays showed that piR-61298promoted cell proliferation and migration, inhibited apoptosis, and promoted tumor growth. Mechanistically, piR-61298bound to USP10 in the cytoplasm, impairing its deubiquitinating activity toward p53, thereby leading to p53 ubiquitination and degradation. These findings suggest that piR-61298plays a critical role in CRC progression by disrupting the USP10-p53 axis. Collectively, our study highlights piR-61298as a potential therapeutic target, offering a novel approach for CRC treatment by targeting piRNA-mediated regulation.

The effect of prenatal exposure to ambient particulate matter (PM) on birth weight varies considerably across studies, and the findings remain inconclusive. In this study, we conducted a meta-analysis to assess the associations between exposure to PM _2.5 and PM ₁₀ and birth weight. A total of 74 studies were identified through searches in Web of Science, PubMed, Embase, and Ovid Medline, as well as manual searches, up to October 2024. We found that for each 10 μg/m³ increase in PM _2.5, the risk of low birth weight (LBW) increased significantly during the entire pregnancy (odds ratio [OR] = 2.41, 95% confidence interval [CI]: 1.99-2.91) and in all trimesters. Similarly, for every 10 μg/m³ increase in PM ₁₀ concentration, the risk of LBW increased significantly during the entire pregnancy (OR = 1.46, 95% CI: 1.16-1.84). Subgroup analysis by maternal age for PM _2.5 showed that mothers aged 30 and above had a significantly higher risk of LBW (OR = 3.69, 95% CI: 2.81-4.84), compared with those under 30. In conclusion, maternal exposure to PM _2.5 and PM ₁₀ is associated with an increased risk of LBW across all trimesters. Additionally, mothers aged 30 and above are at a higher risk of LBW, compared with younger mothers. Further research is needed to clarify the biological mechanisms by which PM pollution may contribute to LBW.