Atherosclerosis (AS) is a chronic inflammatory disease associated with lipid deposition in the vascular intima. Copper is a vital trace element implicated in the onset and progression of AS. Excessive intracellular copper accumulation induces a unique form of cell death termed “cuproptosis.” The emergence of the concept of cuproptosis has highlighted the potential role of copper in AS. This review explores the regulatory mechanisms of copper metabolism and cuproptosis, summarizes recent findings on the link between copper excess and AS, and examines how cuproptosis may influence AS progression. The goal is to propose novel diagnostic and therapeutic strategies for AS through the lens of cuproptosis.

Exploring the link between gut microbiota and chronic gastritis (CG), and assessing the potential mediating influence of blood metabolites. Using aggregated data from genome-wide association studies (GWAS), we performed a two-sample Mendelian randomization (MR) analysis to explore the genetic links between gut microbiota (412 types) and CG (623,822 cases). Furthermore, we utilized a two-step MR approach to measure the extent to which blood metabolites (1,400 types) mediate the impact of gut microbiota on CG. Through MR, we identified that three genetically predicted gut microbiota increased the risk of CG: the ubiquinol-8 biosynthesis pathway (OR 1.149, 95%CI 1.022–1.291), Odoribacter from the Porphyromonadaceae family (OR 1.260, 95%CI 1.044–1.523), and Coprococcus from the Lachnospiraceae family (OR 1.125, 95%CI 1.010–1.253). Currently, there is no evidence to suggest that genetically predicted CG affects the risk of gut microbiota. Four blood metabolites mediated the proportionate changes in genetically predicted gut microbiota: levels of 4-hydroxyphenylacetate levels by 14.9% (95% CI −0.559%, 30.3%), palmitoleate (16:1n7) levels, and the phosphate to alanine ratio together mediated the same microbiota by 6.97% (95% CI −1.61%, 15.6%) and 7.91% (95% CI −1.67%, 17.5%), while the phosphate to alanine ratio and X-12839 levels together mediated the same microbiota by 8.48% (95% CI −2.87%, 19.8%) and 10.7% (95% CI 0.353%, 21.1%). In conclusion, our research has confirmed a causal link between gut microbiota, blood metabolites, and CG. Metabolites such as 4-hydroxyphenylacetate levels, palmitoleate (16:1n7) levels, the phosphate to alanine ratio, and X-12839 levels have relatively significant mediating roles between gut microbiota and CG. These metabolites may influence the occurrence and development of CG by regulating inflammatory responses, energy metabolism, and gut barrier function. However, the majority of the influence of gut microbiota on CG remains unclear, necessitating further research into other potential mediating risk factors. Clinically, it is crucial to focus on patients suffering from CG who exhibit dysbiosis of gut microbiota. IMPORTANCE: The results indicate that interactions between particular gut microbiota and blood metabolites may significantly contribute to the onset and progression of CG. These findings offer new insights and potential targets for early diagnosis, personalized treatment, and prevention of CG.

Background: Myocardial ischemia-reperfusion injury (MIRI) contributes to myocardial injury following reperfusion and adversely affects clinical outcomes. Endoplasmic reticulum stress (ERS), as a crucial cellular stress response mechanism, plays a central regulatory role in the development of MIRI. Currently, the molecular pathways and cellular phenotypic characteristics of ERS-related core genes regulating MIRI remain incompletely elucidated. Targeted research in this area could provide a solid theoretical foundation for developing novel myocardial protection strategies. Methods: In the present study, two microarray gene expression datasets (GSE100499 and GSE108940) were obtained from the Gene Expression Omnibus (GEO) database. Simultaneously, ERS-related genes were collected from the GeneCards and Molecular Signatures Database (MSigDB) databases. Differentially expressed genes (DEGs) were identified using the limma package, and key module genes were selected through weighted gene co-expression network analysis (WGCNA). An intersection analysis was performed among DEGs, genes from the selected WGCNA module, and ERS-related genes. Three machine learning algorithms [least absolute shrinkage and selection operator (LASSO), Random Forest (RF) and Support Vector Machine (SVM)] were employed to identify core ERS genes; functional association analysis was performed to explore potential relationships among the core genes. Concurrently, single-nucleus RNA sequencing analysis was performed to investigate the functional mechanisms of core genes at the single-cell level. Furthermore, the pathological roles of these core genes in MIRI were validated by constructing rat MIRI models and H9c2 cell hypoxia-reoxygenation models, where 4-phenylbutyrate was used to inhibit ERS. Results: ERS-related DEGs were predominantly enriched in tumor necrosis factor (TNF) signaling pathway, lipid metabolism and atherosclerosis, and leukocyte transendothelial migration pathways, which are all critical pathological pathways in the progression of MIRI. Four ERS-related genes (Bcl2, Thbs1, Cebpb and Calr) performed best in Lasso, RF and SVM analyses. All four genes showed significant interactions with pathways associated with MIRI and ERS, including ERS activation, inflammatory response, cardiomyocyte apoptosis and inflammatory cell migration. In the single-cell transcriptome of MIRI cardiac tissue, among the 12 cell types, the aforementioned four genes were primarily upregulated in cardiomyocytes, vascular endothelial cells and cardiac macrophages. Notably, cardiomyocytes and cardiac macrophages exhibited a pronounced pro-inflammatory state and the highest levels of pyroptosis. This suggests that they may be the primary effectors of the four key genes mediating MIRI-related injury. Conclusions: Collectively, Bcl2, Thbs1, Cebpb, and Calr may serve as potential ERS-associated biomarkers and therapeutic targets for MIRI, providing novel insights into ERS-mediated molecular mechanisms underlying myocardial injury.