Upregulation of NF-κB by USP24 aggravates ferroptosis in diabetic cardiomyopathy.

BACKGROUND: Recent investigations have proposed a potential causal association between the occurrence of ferroptosis, nuclear factor kappa B (NF-κB) and ubiquitin-specific protease 24 (USP24). Nevertheless, the mechanism of USP24 and NF-κB regulation of ferroptosis in the context of diabetic cardiomyopathy (DCM) remain unclear. METHODS: In this study, a high-fat diet and a streptozotocin-induced mouse DCM model were established, and high glucose and palmitic acid treatment of H9c2 cells and neonatal mouse primary cardiomyocytes (NMPCs) was used as an in vitro DCM models. Utilizing both the in vivo and in vitro DCM models, we assessed of USP24, NF-κB, and ferroptosis levels, and explored the relationship among them. RESULTS: In in vivo and in vitro DCM models, increased expression of USP24, NF-κB, phosphorylated NF-κB (p-NF-κB) and fatty acid-CoA ligase 4 (FACL4) were detected, along with accumulated iron, as well as reduced ferritin heavy chain 1 (FTH1), solute carrier family 7 member 11 (SLC7A11) and antioxidant capacity. Knockdown of USP24 resulted in a reduction of NF-κB levels, while knockdown of NF-κB did not lead to a decrease in USP24 expression. Moreover, in H9c2 cells, knockdown of USP24 and NF-κB separately resulted in reduced levels of FACL4, increased levels of SLC7A11 and FTH1, as well as improved antioxidant capacity and cell viability. In shUSP24 knockdown H9c2 cells, administration of phorbol 12-myristate 13-acetate (PMA) activated NF-κB, subsequently reversing the previously observed effect caused by USP24 knockdown. CONCLUSIONS: These findings show that USP24 upregulates NF-κB to promote ferroptosis in DCM.

Differentiating Origins of Outflow Tract Ventricular Arrhythmias: The Correction of Transitional Zone Index Is Not Superior to the Original One.

INTRODUCTION: Our team once proposed a correction of transitional zone index (CTZI) based on the transitional zone index (TZI) in view of achieving a more precise prediction of outflow tract ventricular arrhythmia (OTVA). The predictive accuracy of these two electrocardiogram (ECG) algorithms has not been validated and compared. The purpose of this study was to compare the predictive accuracy of TZI and CTZI in a much larger population with idiopathic OTVA. METHODS: The predictive accuracy of TZI and CTZI was compared in 695 individuals with idiopathic premature ventricular complex or ventricular tachycardia which exhibited a left bundle branch block pattern and inferior axis QRS morphology. Receiver operating characteristic curve analysis, decision curve analysis, and calibration curve were used to compare the predictive accuracy of TZI and CTZI. RESULTS: TZI and CTZI manifested the similar area under the curve. While a TZI of <0 predicted a left ventricular outflow tract (LVOT) origin with a high specificity of 88.2% but a low sensitivity of 67.1%, a CTZI of <0 yielded a high sensitivity of 84.3% but a low specificity of 59.5% in the overall analysis. Similar results were yielded in the sub-analysis of participants with a precordial transition occurring at lead V3. In the sub-analysis of participants with a TZI = 0, CTZI demonstrated a bit higher but not satisfactory predictive accuracy than TZI. CONCLUSION: Based on the scientific spirit of self-criticism and seeking truth from facts, our team disproves the correction of TZI proposed previously.

Genetic and immunological insights into COVID-19 with acute myocardial infarction: integrated analysis of mendelian randomization, transcriptomics, and clinical samples.

Background: Globally, most deaths result from cardiovascular diseases, particularly ischemic heart disease. COVID-19 affects the heart, worsening existing heart conditions and causing myocardial injury. The mechanistic link between COVID-19 and acute myocardial infarction (AMI) is still being investigated to elucidate the underlying molecular perspectives. Methods: Genetic risk assessment was conducted using two-sample Mendelian randomization (TSMR) to determine the causality between COVID-19 and AMI. Weighted gene co-expression network analysis (WGCNA) and machine learning were used to discover and validate shared hub genes for the two diseases using bulk RNA sequencing (RNA-seq) datasets. Additionally, gene set enrichment analysis (GSEA) and single-cell RNA-seq (scRNA-seq) analyses were performed to characterize immune cell infiltration, communication, and immune correlation of the hub genes. To validate the findings, the expression patterns of hub genes were confirmed in clinical blood samples collected from COVID-19 patients with AMI. Results: TSMR did not find evidence supporting a causal association between COVID-19 or severe COVID-19 and AMI. In the bulk RNA-seq discovery cohorts for both COVID-19 and AMI, WGCNA's intersection analysis and machine learning identified TLR4 and ABCA1 as significant hub genes, demonstrating high diagnostic and predictive value in the RNA-seq validation cohort. Single-gene GSEA and single-sample GSEA (ssGSEA) revealed immune and inflammatory roles for TLR4 and ABCA1, linked to various immune cell infiltrations. Furthermore, scRNA-seq analysis unveiled significant immune dysregulation in COVID-19 patients, characterized by altered immune cell proportions, phenotypic shifts, enhanced cell-cell communication, and elevated TLR4 and ABCA1 in CD16 monocytes. Lastly, the increased expression of TLR4, but not ABCA1, was validated in clinical blood samples from COVID-19 patients with AMI. Conclusion: No genetic causal link between COVID-19 and AMI and dysregulated TLR4 and ABCA1 may be responsible for the development of immune and inflammatory responses in COVID-19 patients with AMI.

6-Gingerol Alleviates Ferroptosis and Inflammation of Diabetic Cardiomyopathy via the Nrf2/HO-1 Pathway.

Background: Diabetes mellitus (DM) can induce cardiomyocyte injury and lead to diabetic cardiomyopathy (DCM) which presently has no specific treatments and consequently increase risk of mortality. Objective: To characterize the therapeutic effect of 6-gingerol (6-G) on DCM and identify its potential mechanism. Methods: In vivo streptozotocin- (STZ-) induced DM model was established by using a high-fat diet and STZ, followed by low-dose (25 mg/kg) and high-dose (75 mg/kg) 6-G intervention. For an in vitro DCM model, H9c2 rat cardiomyoblast cells were stimulated with high glucose (glucose = 33 mM) and palmitic acid (100 µM) and then treated with 6-G (100 µM). Histological and echocardiographic analyses were used to assess the effect of 6-G on cardiac structure and function in DCM. Western blotting, ELISA, and real-time qPCR were used to assess the expression of ferroptosis, inflammation, and the Nrf2/HO-1 pathway-related proteins and RNAs. Protein expression of collagen I and collagen III was assessed by immunohistochemistry, and kits were used to assay SOD, MDA, and iron levels. Results: The results showed that 6-G decreased cardiac injury in both mouse and cell models of DCM. The cardiomyocyte hypertrophy and interstitial fibrosis were attenuated by 6-G treatment in vivo and resulted in an improved heart function. 6-G inhibited the expression of ferroptosis-related protein FACL4 and the content of iron and enhanced the expression of anti-ferroptosis-related protein GPX4. In addition, 6-G also diminished the secretion of inflammatory cytokines, including IL-1ß, IL-6, and TNF-α. 6-G treatment activated the Nrf2/HO-1 pathway, enhanced antioxidative stress capacity proved by increased activity of SOD, and decreased MDA production. Compared with in vivo, 6-G treatment of H9c2 cells treated with high glucose and palmitic acid could produce a similar effect. Conclusion: These findings suggest that 6-G could protect against DCM by the mechanism of ferroptosis inhibition and inflammation reduction via enhancing the Nrf2/HO-1 pathway.

Psychological symptoms in Chinese nurses may be associated with predisposition to chronic disease: a cross-sectional study of suboptimal health status.

Background: Suboptimal health status (SHS) is a reversible state between ideal health and illness and it can be effectively reversed by risk prediction, disease prevention, and personalized medicine under the global background of predictive, preventive, and personalized medicine (PPPM) concepts. More and more Chinese nurses have been troubled by psychological symptoms (PS). The correlation between PS and SHS is unclear in nurses. The purpose of current study is to investigate the prevalence of SHS and PS in Chinese nurses and the relationship between SHS and PS along with predisposing factors as well as to discuss the feasibility of improving health status and preventing diseases according to PPPM concepts in Chinese nurses. Methods: A cross-sectional study was conducted with the cluster sampling method among 9793 registered nurses in Foshan city, China. SHS was evaluated with the Suboptimal Health Status Questionnaire-25 (SHSQ-25). Meanwhile, the PS of depression and anxiety were evaluated with Self-Rating Depression Scale (SDS) and Self-Rating Anxiety Scale (SAS) self-assessment questionnaires. The relationship between PS and SHS in Chinese nurses was subsequently analyzed. Results: Among the 9793 participants, 6107 nurses were included in the final analysis. The prevalence of SHS in the participants was 74.21% (4532/6107) while the symptoms of depression and anxiety were 47.62% (2908/6107) and 24.59% (1502/6107) respectively. The prevalence of SHS in the participants with depression and anxiety was significantly higher than those without the symptoms of depression (83.3% vs 16.7%, P < 0.001) and anxiety (94.2% vs 5.8%, P < 0.0001). The ratio of exercise habit was significantly lower than that of non-exercise habit (68.8% vs 78.4%, P < 0.001) in SHS group. Conclusions: There is a high prevalence of SHS and PS in Chinese nurses. PS in Chinese nurses are associated with SHS. Physical exercise is a protective factor for SHS and PS so that the exercise should be strongly recommended as a valuable preventive measure well in the agreement with PPPM philosophy. Along with SDS and SAS, SHSQ-25 should also be highly recommended and applied as a novel predictive/preventive tool for the health measures from the perspectives of PPPM in view of susceptible population and individual screening, the predisposition to chronic disease preventing, personalization of intervention, and the ideal health state restoring.