Experimental Biology and Medicine最新文献

Emerging clinical evidence underscores a bidirectional epidemiological linkage between sepsis and type 2 diabetes mellitus (T2DM). This study mechanistically investigates the underlying pathogenesis of this comorbidity, specifically focusing on the role of ferroptosis-related genes in its pathogenesis. A total of 1204 shared genes between sepsis and T2DM were screened using datasets from sepsis (GSE65682) and T2DM (GSE76894). GO and KEGG enrichment analyses, combined with WGCNA, were performed to identify key pathways and hub genes. Three signaling pathways-MAPK, adherens junction, and peroxisome-were significantly associated with the sepsis-T2DM interaction. Subsequent Pearson correlation analysis implicated ferroptosis as a critically involved process. Five core ferroptosis-related genes, including CDC25B, DPP7, FBXO31, PTCD3, and CNPY2, were were identified and experimentally validated using qRT-PCR. Furthermore, based on cMAP, we screened eight candidate drugs targeting these genes. Echinacea and Ibudilast were predicted to possess the greatest preclinical potential among them. This study provides a deeper insight into the shared pathogenesis of sepsis and T2DM, highlighting the pivotal role of ferroptosis in the development and progression of this comorbidity. Our findings offer preliminary insights into the sepsis-T2DM comorbidity, highlighting ferroptosis as a potential key pathological mechanism and identifying candidate targets for future therapeutic exploration.

Burkitt's lymphoma (BL) is an aggressive subtype of B-cell non-Hodgkin's lymphoma, known for its rapid tumor growth and poor prognosis. Transforming growth factor beta-inhibited membrane-associated protein (TIMAP) is a regulatory subunit of protein phosphatase 1 catalytic subunit, enriched in lymphoid tissues, and upregulated in various cancers. Despite suggestions that TIMAP promotes lymphomagenesis in a c-myc-driven model, its precise role remains unclear. This study aimed to investigate the contribution of TIMAP to B-cell lymphomagenesis by examining transcriptomic changes upon TIMAP downregulation in BL cells. Raji BL cells were transfected with 2'Fluoro Arabinonucleic acid (FANA)-antisense oligonucleotides (ASO) targeting TIMAP (FANA-ASO-TIMAP) or a scramble control (FANA-ASO-Scramble). TIMAP expression was significantly reduced at the mRNA (0.70 ± 0.04, p = 0.001) and protein levels (median = 0.73, IQR = 0.13, p = 0.002). RNA sequencing identified 2,368 differentially expressed genes (DEGs), of which 1,326 were upregulated, and 1,042 were downregulated. Gene Ontology analysis revealed that the DEGs were primarily involved in cellular processes, DNA replication, intracellular signal transduction, and apoptosis. Pathways related to lymphoma progression, such as B-cell receptor signaling, p53 signaling, and mTOR signaling, were notably affected. Key genes such as PAK3, LINC00487, AID, PURPL, and BCL2 were among the most dysregulated, highlighting TIMAP's role in critical oncogenic pathways in B-cell Lymphoma. These findings suggest that TIMAP is a key regulator of gene expression and signaling pathways in B-cell lymphomagenesis and could serve as a potential therapeutic target for novel treatments.

Many studies reported that glaucoma is associated with cardiovascular disease (CVD). This study aims to investigate the potential causal relationship between glaucoma and CVD using a bidirectional two-sample Mendelian randomization (MR) analysis. The genome-wide association studies (GWAS) of glaucoma and CVD were downloaded from the IEU OpenGWAS project. The CVD included unstable angina pectoris (UAP), coronary artery disease (CAD), high blood pressure (HBP), myocardial infarct (MI), heart failure (HF), ischemic stroke (IS), atrial fibrillation (AF), and pulmonary embolism (PE). The inverse variance weighting (IVW) analysis was the primary method in MR analysis. Meanwhile, sensitivity analysis and statistical power tests were performed. The random effects IVW method showed a causal relationship between glaucoma and a decreased risk of MI (Odds ratio (OR): 0.94, 95% confidence interval (CI): 0.89-0.99; P = 0.012). In the reverse MR analysis, genetic susceptibility of UAP (OR: 1.12, 95% CI: 1.02-1.23; P = 0.022), CAD (OR: 1.1, 95% CI: 1-1.21; P = 0.041), and HBP (OR: 1.83, 95% CI: 1.25-2.67; P = 0.002) was significantly linked to an increased risk of glaucoma. MR-Egger (P = 0.005) and IVW (P = 0.005) methods found that HBP presented different degrees of heterogeneity. The random effects IVW method also demonstrated that HBP is the risk factor for glaucoma (P = 0.0017). Although reverse MR initially suggested a potential association between CAD and glaucoma, MVMR showed no causal relationship after adjusting for obesity and BMI. The MR analysis found that glaucoma serves as a protective factor for MI, while UAP and HBP were risk factors for glaucoma in the European population, which may contribute to preventing and managing glaucoma and CVD.

Irritable bowel syndrome with diarrhea (IBS-D), associated with the traditional Chinese medicine (TCM) pattern of liver hyperactivity with spleen deficiency pattern, lacks effective Western treatments. The modern biological relevance of the "intestine-liver-bile acid" axis aligns with this TCM concept, and interactions between intestinal microbiota and diarrhea remain unclear. Network pharmacology, molecular docking, and molecular dynamics were applied to elucidate the mechanisms and compound-target stability of Tongxie Yaofang. An IBS-D mouse model was established using Senna alexandrina Mill. combined with confinement stress. Histopathological changes in the liver and spleen were assessed by hematoxylin-eosin (HE) staining, and enzyme-linked immunosorbent assay (ELISA) was performed to quantify total bile acid levels in serum and liver. Ultimately, 16S rRNA high-throughput sequencing was employed to identify predominant and distinctive bacterial species. Network pharmacology and molecular docking revealed that Tongxie Yaofang acts primarily through the TNF-α and IL-17 pathways. Molecular dynamics confirmed strong binding affinities between active compounds (naringenin, divaricatol, and kaempferol) and target proteins. In vivo, Tongxie Yaofang alleviated colonic inflammation, increased serum bile acid levels, reduced hepatic bile acid concentrations, and increased intestinal microbial diversity and abundance. The therapeutic effects of Tongxie Yaofang on IBS-D are mechanistically linked to its multi-target actions, including suppression of inflammatory responses, inhibition of pathogenic bacterial overgrowth, restoration of immune homeostasis, and modulation of intestinal microbiota composition toward a probiotic-enriched community.

Depression has been increasingly associated with immune system dysregulation. This study investigates the potential of CD3 Gamma Subunit of T-Cell Receptor Complex (CD3G) as a diagnostic marker for depression, while also examining its role across various cancer types. Comparative analyses of immune cell infiltration and pathway activities were conducted using single-sample Gene Set Enrichment Analysis (ssGSEA) on datasets GSE98793. Depression patients were defined based on clinical diagnoses and compared to healthy controls (HC) without any psychiatric disorders. Differentially expressed genes (DEGs) were identified, followed by weighted gene co-expression network analysis (WGCNA), least absolute shrinkage and selection operator (LASSO) and logistic regression to pinpoint independent diagnostic markers. Functional enrichment analyses were performed to explore the biological implications of CD3G expression in depression. Pan-cancer analyses were also conducted to investigate CD3G's role in cancer. Depression patients exhibited significant decreases in CD8 T cells, cytotoxic cells, T cells, T helper cells, Tgd, and Th2 cells, with increased levels of dendritic cells and neutrophils compared to HC. Immune pathway activities showed increased antimicrobial, chemokine, cytokine, and TNF family member activities, with decreased TCR signaling activity in depression patients. CD3G was identified as a key immune-related gene and independent diagnostic marker for depression, validated by GSE76826 dataset. Low CD3G expression in depression was associated with enhanced immune response and inflammatory pathways. In pan-cancer analysis, CD3G was upregulated in numerous cancers and correlated with immune cell infiltration and oncogenic pathways. The study highlights significant dysregulation in immune cell infiltration and pathway activities in depression, with CD3G emerging as a critical immune-related gene and potential diagnostic marker. CD3G's role in immune modulation and cancer underscores its relevance in both depression and oncology, suggesting potential therapeutic targets and prognostic indicators.

The burgeoning clinical demand for patient-specific cardiac modeling encounters significant challenges. The current clinical cardiac models are either difficult to manufacture or lack of detailed geometric structures and hence, often fail to incorporate important patient-specific characteristics. Moreover, most 3D-printable soft materials, such as Thermoplastic Poly-Urethane (TPU) or elastic resins, exhibit insufficient flexibility and biocompatibility to accurately mimic cardiac tissues, therefore limiting their ability to truly replicate patient-specific cardiac conditions. To address these limitations, we propose an innovative method for patient-specific cardiac substructure reconstruction based on the integration of Artificial Intelligence (AI) and embedded 3D printing. First, by combining medical imaging data (CT scan) with AI-driven high-precision 3D reconstruction algorithms, the new method segments the patient-specific cardiac structure into 10 substructures. The average Dice coefficient across the ten substructures is 0.87. Second, it uses an embedded 3D printing technique which utilizes silicone rubber matrix as supporting structure and uses diluted catalyst ink to extrude onto the supporting matrix. Through precise regulation of the matrix composition, material deposition rate and curing time, it can fabricate high-fidelity, complex 3D patient-specific silicone heart models with the average dimensional error less than 0.5 mm. The proposed method can substantially reduce manual intervention and post-processing time. The fabricated models provide valuable morphological insights for cardiovascular diagnosis and treatment planning. It is believed that many clinic applications will follow.

Chronic liver disease (CLD) is a widespread condition and liver fibrosis is a common hallmark. The COVID-19 pandemic has drawn awareness over emerging pathogens that pose severe risks for chronic disease patients, whose management is complicated because most drugs can overload liver metabolism, therefore therapeutic alternatives are needed. Aims: based on the difficulty of treating CLD patients during respiratory infections, this study focused on the therapeutic evaluation of adipose-derived mesenchymal stromal cell (ASC) secretome. Methods: the effects of ASC secretome were evaluated in a preclinical murine model of liver fibrosis induced by thioacetamide (TAA) and acute lung injury induced by lipopolysaccharide, using histological and cytokine profile analyses. ASC secretome exhibited therapeutic effects alleviating fibrogenesis and inflammation, decreasing plasmatic inflammatory markers (cytokines IL-6, IL-17A and TNF-α), and restoring immune homeostasis. The secretome reduced liver collagen accumulation and IL-6 levels and restored lung cytoarchitecture, decreasing levels of CD68 and TNF-α. These results provide a preclinical basis for potential clinical use of the ASC secretome and its products, advancing the concept of cell-free, systemically active interventions for complex tissue injuries, and reinforcing the potential of its paracrine factors to modify pathological responses and promote tissue regeneration in combined chronic-acute diseases.

Follicular dendritic cell secreted protein (FDCSP) is highly expressed in various cancers and has been implicated in tumor migration and invasion, yet its role in triple-negative breast cancer (TNBC) remains poorly understood. Our findings revealed that FDCSP expression was significantly elevated in TNBC compared to normal breast tissue, whereas its expression was significantly reduced in non-TNBC. In TNBC, high FDCSP expression was associated with an increased mutation rate of TP53 and influenced the infiltration of B cells and macrophages. Single-cell transcriptome analysis demonstrated that FDCSP was predominantly highly expressed in basal cells but exhibited low expression in luminal epithelial cells. This observation was further corroborated by spatial transcriptome (ST) analysis. Immunohistochemistry (IHC) assay also confirmed the distinct expression patterns of FDCSP. Cell-cell interaction and receptor-ligand pair analyses indicated that macrophages could interact with the receptor epidermal growth factor receptor (EGFR) in FDCSP highly expressed basal cells by secreting transforming growth factor-β1 (TGF-β1). Then, the co-localization of FDCSP and EGFR in TNBC basal cells was verified by IHC and immunofluorescence (IF) assay. Additionally, we discovered that FDCSP possesses strong predictive capabilities for distinguishing between responders and non-responders to Immune checkpoint blockade (ICB) treatment. Finally, leveraging the CARE database, we identified 14 potential FDCSP-related target drugs. These findings highlight the unique expression pattern of FDCSP in breast cancer, revealing FDCSP as a promising target for therapeutic strategies in TNBC.

Peripheral nerve injuries (PNIs) pose a significant clinical challenge, often leading to incomplete functional recovery despite current treatments. Platelet-rich plasma (PRP), which contains high levels of growth factors and bioactive molecules, has emerged as a promising regenerative therapy for nerve repair and restoring function. This review consolidates current evidence on PRP applications in treating peripheral nerve injuries, examining molecular mechanisms, clinical outcomes, and therapeutic potential. PRP markedly enhances nerve regeneration, improves recovery of sensory and motor functions, and alleviates neuropathic pain across various nerve injuries. It promotes axonal growth, reduces scar formation, stimulates Schwann cell proliferation, and modulates inflammation through the release of neurotrophic factors, including PDGF, VEGF, TGF-β, and IGF-1. Combining PRP with surgical techniques and biomaterial scaffolds yields better therapeutic results. Key factors influencing efficacy include platelet concentration, leukocyte content, activation methods, and patient-specific variables. PRP is a safe and effective option for peripheral nerve injury repair. However, challenges persist in standardizing preparation protocols, optimizing treatment timing, and fully understanding molecular mechanisms. Future research should focus on personalized PRP formulations, combination therapies, and large-scale randomized controlled trials to develop definitive clinical guidelines.

Autophagy of myocardial cells involves the interaction of multiple molecular signaling pathways, and regulatory factors, while existing methods are difficult to handle. This study utilized the variational autoencoder (VAE) model to reveal the characteristic distribution of myocardial cell energy autophagy under different exercise conditions. First, this paper is based on mass spectrometry analysis, enzyme-linked immunosorbent assay ELISA (Enzyme-Linked Immunosorbent Assay) to determine the cardiomyocyte metabolite concentration data, and RNA-Seq (Ribonucleic Acid-Sequencing) to collect genes related to cardiomyocyte energy metabolism and autophagy expression data; in the VAE model, this paper utilizes the full connectivity layer to encode the data into potential representations, and reconstructs the numerical data through the numerical data decoder. The loss function is defined as the data reconstruction error and KL (Kullback-Leibler) scatter, and Adam is used to optimize the training process; the features are analyzed and the classification performance is verified under different motion conditions based on RF (Random Forest); the relationship between the features and metabolite concentration and gene expression is analyzed by LASSO (Least Absolute Shrinkage and Selection Operator) regression model to analyze the relationship between features and metabolite concentration and gene expression; the features in the latent space are downscaled using t-SNE (t-distributed Stochastic Neighbor Embedding) to visualize the feature distribution; finally, CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-Cas9) knockdown experiments to reveal the importance of AMPK, PGC1A, CPT1B, and SIRT1 in cardiomyocyte autophagy and energy metabolism, which provide potential targets for future gene-based therapies.