Exploring Ferroptosis-Associated Gene Signatures as Diagnostic and Therapeutic Targets for Sepsis-Induced Cardiomyopathy.

BACKGROUND: Sepsis-induced cardiomyopathy (SICM) is a severe complication of sepsis associated with high mortality rates. Despite its significance, the molecular mechanisms underlying SICM remain poorly understood, particularly the role of ferroptosis - a form of iron-dependent programmed cell death. METHODOLOGY: This study analyzed the GSE79962 dataset from the Gene Expression Omnibus, containing cardiac gene expression profiles from SICM patients and controls. A list of ferroptosis-related genes (FRGs) was retrieved from the FerrDb. We used the limma package in R for differential expression analysis, setting an adjusted P-value cutoff of <0.05 and a log2-fold change threshold of ±1 to identify differentially expressed ferroptosis-related genes (DE-FRGs). We applied machine learning algorithms for biomarker identification, including least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine with recursive feature elimination (SVM-RFE), implemented via the glmnet and e1071 packages in R, respectively. Gene set enrichment analysis (GSEA) was conducted using the GSEA package to investigate the biological pathways related to key DE-FRGs. RESULTS: After differential expression analysis, we identified 145 DE-FRGs. Functional enrichment analyses underscored the involvement of these genes in critical biological processes and pathways, such as lipid metabolism and insulin resistance. Machine learning approaches pinpointed five key DE-FRGs (NCOA4, GABARAPL1, GJA1, CISD1, CP), with strong predictive potential for SICM. Further analyses, including the construction of a ceRNA network, revealed intricate post-transcriptional regulatory mechanisms that may influence the expression of these key genes. CONCLUSIONS: Our findings highlight the central role of ferroptosis in SICM and identify potential biomarkers and therapeutic targets that could help refine diagnostic and treatment strategies. This study advances our understanding of the molecular underpinnings of SICM and sets the stage for future research aimed at mitigating this severe sepsis complication.

Association of urinary bisphenol A levels with heart failure risk in U.S. adults from the NHANES (2003-2016).

Introduction: Although heart failure (HF) has been linked to bisphenol A (BPA), few studies have investigated the cut-off values for the effects of urinary BPA levels on heart failure risk. The association between urinary BPA levels and HF prognosis has not been investigated. Methods: This study included 11,849 adults over 20 years old using information from the National Health and Nutrition Examination Survey (NHANES), which was conducted from 2003 to 2016. The relationship between urinary BPA levels and the risk of HF was determined via a multivariable logistic regression model, and restricted cubic spline (RCS) methods were used to determine the cut-off for the effect of BPA levels on HF risk. Based on the available NT-proBNP concentration data from the NHANES (2003-2004), multivariable linear regression was applied to determine the linear association between the NT-proBNP concentration and urinary BPA concentration. Results: The results revealed a positive correlation between a urinary BPA concentration in the fourth quartile and the occurrence of heart failure [OR 1.49, 95% CI (1.09, 2.04), p = 0.012]. A one-unit increase (1 ng/mg creatinine) in the ln-transformed BPA concentration was linked to a 15% increase in the incidence of HF [OR 1.15, 95% CI (1.03, 1.29), p = 0.014]. The cut-off urinary BPA concentration for HF risk was 1.51 ng/mg creatinine. There was a positive correlation between urinary BPA and NT-proBNP concentrations [ß = 0.093, 95% CI (0.014, 0.171), p = 0.02] in males, but there was no linear association [ß = 0.040, 95% CI (-0.033, 0.113), p = 0.283] in females. Discussion: Increased urinary BPA levels are linked to an increased risk of heart failure and poor prognosis. There is a significant increase in the risk of heart failure if the urinary concentration of BPA exceeds 1.51 ng/mg creatinine.

ITGAM: A Pivotal Regulator in Macrophage Dynamics and Cardiac Function During Sepsis-Induced Cardiomyopathy.

BACKGROUND: Sepsis-induced cardiomyopathy (SIC) is a critical complication arising from sepsis characterized by reversible myocardial dysfunction. Despite the increasing attention to SIC in research, the underlying molecular mechanisms remain poorly comprehended. METHODS: In this study, we utilized bioinformatics to analyze RNA-sequencing (RNA-seq) and single-cell RNA-sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database to identify key immune cell populations and molecular markers associated with SIC. Our experimental approach combined in vitro and in vivo studies to investigate the roles of integrin alpha M (ITGAM) and intracellular adhesion molecule-1 (ICAM-1) in macrophage recruitment and phenotypic polarization, as well as their impact on cardiac function during SIC. RESULTS: The bioinformatics analysis disclosed significant alterations in gene expression and immune cell composition within the cardiac tissue during SIC, where macrophages emerged as the predominant immune cell type. Notably, ITGAM was identified as a key regulatory molecule that modulates macrophage function, driving the pathogenesis of SIC through its influence on the recruitment and functional reprogramming of these cells. In vitro experiments revealed that lipopolysaccharide (LPS) stimulation triggered an upregulation of ITGAM in macrophages and ICAM-1 in endothelial cells, underscoring their critical roles in immune cell mobilization and intercellular communication. The strategic administration of ITGAM-neutralizing antibodies to SIC mice resulted in a marked decrease in macrophage infiltration within the cardiac tissue, which was initially associated with an improvement in cardiac function. However, this intervention paradoxically resulted in an increased mortality rate during the later phases of SIC, underscoring the complex and dualistic function of ITGAM. CONCLUSION: This study provides new insights into the complex dynamics of immune cells within the cardiac environment during SIC, with a particular emphasis on the modulatory role of ITGAM in shaping macrophage behavior. The findings shed light on the reversible nature of myocardial dysfunction in SIC and emphasize the importance of targeted therapeutic strategies for the effective management of SIC.

Intestinal microbial community well explain larval growth than feed types.

Black soldier fly larvae (BSFL) are considered a sustainable ingredient in livestock feed. However, addressing issues related to feed substrate and intestinal microbiota is essential to ensure optimal larval development. The aim of this study was to assess and elucidate the contribution of substrate nutrients and intestinal microbes to protein and fat synthesis in BSFL. The results showed that larvae that were fed high-quality feed (chicken feed) had high fat biomass, while larvae that were fed medium-quality feed (wheat bran) had high protein biomass. These results indicate that the original nutritional content of the feed cannot fully explain larval growth and nutrient utilization. However, the phenomenon could be explained by the functional metabolism of intestinal microbes. Chicken feed enhanced the fatty acid metabolism of middle intestine microorganisms in larvae within 0-7 days. This process facilitated larval fat synthesis. In contrast, wheat bran stimulated the amino acid metabolism in posterior intestine microorganisms in larvae within 4-7 days, leading to better protein synthesis. The findings of this study highlight the importance of the microbial functional potential in the intestine in regulating protein and lipid synthesis in BSFL, which is also influenced by the type of feed. In conclusion, our study suggests that both feed type and intestinal microbes play a crucial role in efficiently converting organic waste into high-quality insect protein and fat. Additionally, a mixed culture of chicken feed and wheat bran was found to be effective in promoting larval biomass while reducing feed costs. KEY POINTS: • Intestinal microbes explain BSFL growth better than feed substrates. • Chicken feed promotes fatty acid synthesis in the middle intestine • Wheat bran promotes amino acid synthesis in the posterior intestine.