Experimental Biology and Medicine最新文献

Head and neck squamous cell carcinomas (HNSC) are associated with alterations in redox metabolism. This study aims to identify differentially expressed genes (DEGs) related to redox metabolism in HNSC and assess their prognostic values. We utilized the limma package for identifying redox metabolism-related DEGs and performed univariate and multivariate Cox regression analyses to evaluate their prognostic significance. Gene set variation analysis (GSVA), immune cell infiltration analysis, and single-cell RNA sequencing were utilized to explore the relationships between gene expression and tumor processes. Chemotherapy sensitivity was assessed based on ERP44 expression levels. Additionally, pan-cancer analysis was conducted to evaluate ERP44 expression and its prognostic value across different cancer types. The analysis identified several DEGs with significant prognostic value, including ERP44, which was significantly associated with poor prognosis in HNSC patients. High ERP44 expression correlated with reduced overall survival, disease-specific survival, and progression-free interval. ERP44 was notably overexpressed in tumor tissues and associated with key oncogenic pathways and immune cell infiltration patterns. Chemotherapeutic drug sensitivity analysis revealed that high ERP44 expression increased sensitivity to Paclitaxel, Vinblastine, and Sorafenib but decreased sensitivity to Rapamycin. Pan-cancer analysis indicated that ERP44 is differentially expressed and prognostic across multiple cancer types. Our findings highlight the crucial role of redox metabolism-related DEGs, particularly ERP44, in HNSC progression and prognosis. ERP44 serves as a potential biomarker for prognosis and therapeutic response, warranting further research into its biological functions and potential as a therapeutic target.

Open burning and open detonation (OB/OD) of explosive and hazardous wastes creates various toxic waste products, including particulate matter, that is released into the atmosphere and capable of generating significant health impacts upon exposure. The last commercially run OB/OD thermal treatment facility in operation in the United States is located near the rural community of Colfax in central Louisiana. To evaluate the community's concerns about the potential health impacts from air pollution due to the facility's regular open burning of explosive and hazardous wastes, we examined the disease burden in Colfax compared to the surrounding parish and state. In a cross-sectional study, we analyzed hospitalizations and mortality (2000-2018) where a primary or secondary disease code was associated with cardiovascular, respiratory, thyroid and skin disease. After adjusting for age, sex and race, morbidity and mortality due to cardiovascular and respiratory diseases were significantly higher in Colfax compared to the surrounding areas. In addition, comparing age-adjusted rates across geographies, stratified by race and sex, revealed place-based differences within sub-populations. The higher estimated prevalence of disease conditions is consistent with long-term particulate matter exposure and suggests a need for comprehensive exposure studies within the community. Our data further stress the need for enhanced epidemiological studies and tailored statistical methods to address exposures and environmental health impacts in rural populations, with fewer than 2,500 individuals, like Colfax.

Ranolazine (RAN) is an acetanilide and piperazine derivative that selectively blocks the late sodium current in cardiac cells and is prescribed in adults as an add-on medication for the symptomatic management of patients with stable angina pectoris who are insufficiently managed or intolerant of first-line antianginal treatments. RAN was first approved by the U.S. Food and Drug Administration (FDA) in 2006 and the European Medicine Agency in 2008 for the treatment of chronic stable angina. RAN has no substantial effect on hemodynamic indicators, including heart rate and blood pressure. RAN also slows fatty acid oxidation, which increases glucose oxidation, lowers lactic acid generation, and optimizes heart performance. Besides its antianginal effect, RAN has recently revealed additional pharmacological properties such as neuroprotective, hepatoprotective, renal protective, cardioprotective, and antidiabetic effects and other beneficial pharmacological activities. We choose to write this current review paper to address the many hidden pharmacological and therapeutic potentials of RAN beyond its antianginal activity.

RNA-binding proteins (RBPs) are crucial in disease as they regulate the biological functions of RNA. However, their role in coronary artery disease (CAD) progression remains unclear. RNA-seq from peripheral blood of CAD patients and no-CAD controls was analyzed to compare differentially expressed genes (DEGs) and explore their potential functions. The distribution of immune cells was assessed by CIBERSORT algorithm. Alternative splicing (AS) pattern was quantified by SUVA. Immune-related AS events (ASEs) were screened via ImmPort database. Co-expression network of ASEs, differentially expressed RBPs (DERBPs), mitochondrion and apoptosis genes, and immune cells was constructed to clarify their potential functions. A total of 1521 DEGs were detected, including 99 DERBPs, which were mainly downregulated and enriched in mRNA processing, RNA splicing, mRNA transport, and innate immune response pathways in CAD. Seven DERBPs (ANG, C4BPA, DDX60, IFIH1, IPO7, MATR3, OTUD4) were associated with immune function. Analysis of the immune cell fraction demonstrated significant increase in macrophage M0 and CD8 T cells and decrease in resting dendritic cells and activated memory CD4 T cells. Immune-related ASEs correlated with atherosclerotic stenosis were mainly the complex "alt3p/alt5p" splicing types. DERBP-AS's co-expression identified a key A5'SS event of CTSB gene. Co-expression of this event with TST and SYNCRIP may lead to a change in the proportion of macrophage M0 and CD8 T cells, respectively. The mitochondrion and apoptosis genes were also dysregulated in CAD and correlated with four DERBPs. In conclusion, RBPs have potential regulatory role in the progression of CAD by regulating the ASEs of immune-related genes and mediating immune cells composition. These findings highlight RBPs as potential therapeutic targets for CAD.

Sodium valproate (SV) has been shown to induce autism in animal models. In this study, the SV method was used to establish a mouse model of autism, and anxiety-like behaviours and learning memory performance were evaluated by behavioural tests. The effects of SV on metabolic profiles and gut microbiota were assessed by integrating gas chromatography-mass spectrometry and 16S ribosomal RNA gene sequencing. Correlations between metabolites and gut microbiota were determined using Spearman correlation coefficient. Behavioral tests, including the three-chambered social assay, repetitive behaviors, open field test, elevated plus-maze test, and novel object recognition test, demonstrated that SV treatment exacerbated anxiety-like behaviors and impeded spatial learning and memory in mice. SV disrupted metabolic pathways in hippocampus, cortex, intestine, and serum, affecting primarily valine, leucine and isoleucine biosynthesis, glycerophospholipid metabolism and glutathione metabolism and so on. SV also altered gut microbiota at the genus level, decreasing the abundances of Dubosiella, Faecalibaculum, Clostridia_UCG-014, Bifidobacterium, and Alloprevotella, while increase the abundances of Lactobacillus, Alistipes, and Lachnospiraceae in intestine. The results of correlation analysis showed that in hippocampus, Bifidobacterium was positively correlated with serine and glycine, while Alistipes was negatively correlated with them. These findings suggested that SV may contribute to the development of autism progression by altering the gut microbiota abundances and metabolite profiles. This may provide new direction for the management of autism.

Microvesicles (MV) isolated from septic individuals were observed to impact systemic hemodynamics and cardiac function. The aim of this in vitro study was to analyze the effects of TNFα-induced endothelial MV (TMV) and MV from septic patients (SMV) on beating frequency and Ca²⁺ transient kinetics of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). MV were isolated from supernatants of TNFα-stimulated primary human pulmonary microvascular endothelial cells (HPMEC) and plasma from 20 sepsis patients by ultracentrifugation and quantified using flow cytometry. Spontaneous Ca²⁺ transients were measured in hiPSC-CM using the Ca²⁺-sensitive ratiometric indicator fura-2 at different time points of incubation with different MV concentrations. At 16 h of incubation, higher MV concentrations showed significant differences, especially regarding decay and beating frequency. Despite high variability, at 10 × 10⁶ MV/mL and 16 h of incubation, TMV significantly decreased frequency compared to control MV (CMV). SMV from septic patients did not reveal any significant effects on Ca²⁺ transients under these experimental settings. MV isolated from control or TNFα-treated HPMEC affected Ca²⁺ handling and spontaneous activity of hiPSC-CM, however, the measured effects were not consistent throughout the different conditions. Further refinement of the experiment conditions is needed to specify the exact conditions for crosstalk between endothelium-derived MV and cardiomyocytes.

The relationship between the systemic immune-inflammation index (SII) and the risk of developing cardiovascular disease (CVD) over the next 10 years in the United States is largely unknown. The aim of this study is to assess the association between SII and 10-year CVD risk. This population-based cross-sectional study included 9901 participants aged between 30 and 74 from the National Health and Nutrition Examination Survey (NHANES) 1999-2018. The 10-year CVD risk was calculated using the Framingham cardiovascular risk score (FRS). The Pearson test, generalized linear model (GLM) and restricted cubic splines (RCS) were used to analyze the associations between SII and the FRS. Based on the total population, the Pearson test and GLM revealed that there were positive relationships between Ln-transformed SII (Ln (SII)) and the FRS. After adjusting for confounding factors, the odds ratio (OR) for the FRS was 1.52 (95% confidence interval [CI]: 1.12-2.06) per unit increment in Ln (SII) (P = 0.009). Compared to the lowest quartile (Q1) of Ln (SII), the OR for the FRS in the highest quartile (Q4) was 1.89 (95% CI: 1.20-2.98; P = 0.007). RCS revealed that there was a linear association between Ln (SII) and the FRS (P for non-linearity = 0.972). As Ln (SII) increased, the value of FRS rose gradually (P for overall trend <0.001). However, the relationship between Ln (SII) and FRS showed ethnic heterogeneity. In conclusion, SII exhibits significant associations with 10-year CVD risk as assessed by the FRS. However, this association varies across ethnic groups, necessitating cautious application and further validation.

The potential of mesenchymal stromal cells (MSCs) in the treatment of hemorrhagic stroke has been demonstrated; however, their clinical efficacy remains inconsistent and further comprehensive studies on their mechanism of action are warranted. In this study, the intracerebral hemorrhage (ICH) rat model was used for intravenous infusion of adipose-derived mesenchymal stromal cells (AD-MSCs) 24 h after modeling. Histopathological techniques and single cell transcriptome sequencing techniques were used to study the mechanism of AD-MSCs promoting the repair of damaged brain tissue. The results indicated that AD-MSCs markedly promote the repair of damaged brain tissues and restored neural function. Single-cell transcriptome sequencing further revealed that this therapeutic effect is specifically through the inhibition of monocyte infiltration in injured brain tissue, promotion of resident microglia proliferation and signaling pathways linked to immune response and neuroprotection. These processes are closely tied to the Csf1⁺ subgroup of AD-MSCs. For acute hemorrhagic stroke, Csf1⁺ AD-MSCs promote the repair of damaged brain tissue by activating resident microglia and inhibiting monocyte infiltration. This study offers novel insights into the mechanisms underlying MSC-based stroke treatment and supports the potential for stable and efficacious MSC therapies.

Open burn/open detonation (OB/OD) disposes of explosive waste via uncontrolled combustion, releasing harmful pollutants like toxic gases and particulate matter. Colfax, Louisiana, houses the nation's only commercially OB/OD thermal treatment (TT) facility, raising concerns about environmental and public health impacts due to its emissions. In this exploratory pilot study, we investigated metabolic alterations indicative of potential health impacts from exposure to emissions from a TT facility through an untargeted metabolomics analysis of urine samples obtained from local residents. Urine samples were collected from 51 residents living within a 30-km radius of the facility, with proximity, race, and sex as key variables. Samples were analyzed using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS) to identify metabolic alterations and potential biomarkers of exposure. A total of 217 metabolites were identified, with significant differences in abundance based on proximity to the facility. Key metabolic pathways affected included energy metabolism, amino acid metabolism, and oxidative stress-related pathways. Metabolites associated with oxidative stress, such as glutathione sulfonamide (GSA), were elevated in individuals residing closer to the facility, indicating increased oxidative stress. Alterations in the glutathione/glutathione disulfide (GSH/GSSG) ratio further highlighted redox imbalances. Pathway enrichment analyses revealed perturbations in glycolysis, citric acid cycle, sulfur metabolism, and nucleotide metabolism, which are linked to critical biological functions like energy production and DNA repair. Notable differences in metabolite profiles were also observed between sexes and racial groups, pointing to the interplay of intrinsic biological and environmental factors. These findings demonstrate that exposure to emissions from the TT facility may have significant impacts on human health, including disruptions in cellular metabolism and increased oxidative stress. Further research is crucial to understand the long-term health implications of these metabolic alterations and to develop strategies to mitigate the environmental and health risks associated with this facility.

Natural Killer (NK) cells are integral components of the innate immune system, recognizing and eliminating virus-infected cells. They may play a crucial role in the immune response and contribute to the complications associated with Single Ventricle/Hypoplastic Left Heart Syndrome (SV/HLHS). Utilizing single-cell RNA sequencing (scRNA-seq), NK cells from peripheral blood mononuclear cells (PBMCs) were analyzed in three de-identified SV/HLHS cases and three healthy controls. This study identified two novel NK cell subpopulations that could not be detected by conventional scRNA-seq pipelines or traditional flow cytometry. These subpopulations exhibit distinct gene expression profiles linked to the heterogeneity of immune responsiveness and stress adaptation in NK cells. In SV/HLHS patients, one cluster showed a significant upregulation of androgen response and downregulation of heme metabolism compared to healthy controls. Our study offers new insights into the fine-tuning of immune modulation that could help mitigate complications in SV/HLHS. It suggests that while NK cells in SV/HLHS adapt to support survival in a challenging physiological environment, these adaptations may compromise their ability to effectively respond to additional stresses, such as infections and inflammation.