Guangwei Zeng

The association between obesity and atrial fibrillation (AF) has garnered increasing attention. Obesity is a significant risk factor for cardiovascular diseases and promotes the occurrence of AF through multiple mechanisms. This study aims to explore the molecular mechanisms of obesity-induced AF using GLP-1R/GIPR dual-target agonist fusion protein (Fc) loaded into adipose-derived mesenchymal stem cell (ADSC) exosome-liposome hybrid nanoparticles (LE@Fc NPs). We successfully constructed and purified the Fc, verifying its purity and functional activity through SDS-PAGE and UV absorption spectroscopy. The fusion protein was then loaded into nanovesicles, and their morphology, size, and stability were assessed using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and dynamic light scattering (DLS). In vitro experiments demonstrated that LE@Fc NPs exhibit high fusion efficiency and targeted delivery capability. In vivo experimental results show that LE@Fc NPs significantly inhibit ferroptosis in the epicardial adipose tissue (EAT) of obese mice (iron content: 3.69 ± 0.36 vs. 0.88 ± 0.09), by restoring GSH levels (0.45 ± 0.08 vs. 0.87 ± 0.08) and Gpx4 expression (0.32 ± 0.06 vs. 1.01 ± 0.16), and reducing ROS (12.01 ± 0.95 vs. 2.68 ± 0.17), MDA (3.17 ± 0.29 vs. 0.95 ± 0.09), and 4-HNE (3.74 ± 0.51 vs. 0.91 ± 0.09) levels. Furthermore, LE@Fc NPs treatment significantly improved the inflammatory response (IL-1β: 44.08 ± 3.74 vs. 12.07 ± 0.65, IL-6: 515.59 ± 47.70 vs. 288.43 ± 16.81, MCP-1: 1401.04 ± 194.88 vs. 600.28 ± 45.54, TNF-α: 39.96 ± 2.48 vs. 18.01 ± 0.85). LE@Fc NPs also reduced atrial fibrosis, thereby effectively lowering the incidence of AF. Echocardiography and electrocardiogram monitoring revealed that LE@Fc NPs treatment significantly improved atrial remodeling and reduced the occurrence of AF in obese mice. In addition, LE@Fc NPs significantly improved obesity-induced systemic inflammation and metabolic disorders. In conclusion, LE@Fc NPs show great potential for the treatment of obesity-related AF. Graphical abstract Mechanism of LE NPs in Treating AF.

LIM‐domain proteins have been shown to be associated with heart development and diseases. Systematic studies of LIM family members at the genome‐wide level, which are crucial to further understand their functions in cardiac hypertrophy, are currently lacking. Here, 70 LIM genes were identified and characterised in mice. The expression patterns of LIM genes differ greatly during cardiac development and in the case of hypertrophy. Both Crip2 and Xirp2 are differentially expressed in cardiac hypertrophy and during heart failure. In addition, the hypertrophic state of cardiomyocytes is controlled by the relative expression levels of Crip2 and Xirp2. This study provides a foundation for further understanding of the special roles of LIM proteins in mammalian cardiac development and hypertrophy.

Cardiomyocyte apoptosis is a major cause of myocardial ischemia/reperfusion (MI/R) injury, in which the activation of the signal transducer and activator of transcription 1 (STAT1) plays an important role. The E3-ubiquitin ligase TRIM6 has been implicated in regulating STAT1 activity, however, whether it is associated with MI/R injury and the underlying mechanism are not determined. In this study, by investigating a mouse MI/R injury model, we show that TRIM6 expression is induced in mouse heart following MI/R injury. Additionally, TRIM6 depletion reduces and its overexpression increases myocardial infarct size, serum creatine phosphokinase (CPK) level and cardiomyocyte apoptosis in mice subjected to MI/R injury, indicating that TRIM6 functions to aggravate MI/R injury. Mechanistically, TRIM6 promotes IKKε-dependent STAT1 activation, and the inhibition of IKKε or STAT1 with the specific inhibitor, CAY10576 or fludarabine, abolishes TRIM6 effects on cardiomyocyte apoptosis and MI/R injury. Similarly, TRIM6 mutant lacking the ability to ubiquitinate IKKε and induce IKKε/STAT1 activation also fails to promote cardiomyocyte apoptosis and MI/R injury. Thus, these results suggest that TRIM6 aggravates MI/R injury through promoting IKKε/STAT1 activation-dependent cardiomyocyte apoptosis, and that TRIM6 might represent a novel therapeutic target for alleviating MI/R injury.

Summary: Gastric cancer accounts for a sizeable proportion of global cancer mortality with high morbidity and poor prognosis. Kinesin superfamily proteins (KIFs) are microtubule‐dependent motor proteins that function as oncogenes in cancer cells, it has been discovered in recent years. Kinesin family member 2a (KIF2A), a member of the KIFs, has received attention for its role in carcinogenesis and its prognostic value in several human cancers such as breast cancer, colorectal cancer, and squamous cell carcinoma. However, the role of KIF2A in human gastric cancer remains unknown. In this study we aimed to explore the expression and biological functions of KIF2A in human gastric cancer cells, as well as to reveal its potential action mechanism. First, we found that KIF2A was markedly increased in gastric cancer cells (MKN‐28, MKN‐45, NCI‐N87 and SGC‐7901) compared to normal gastric mucosa epithelial cells (GES‐1). Then KIF2A was successfully silenced in MKN‐45 and SGC‐7901 cells to facilitate further research into its function. We discovered that KIF2A silencing can significantly inhibit the growth and invasion of MKN‐45 and SGC‐7901 cells in a time‐independent manner, accompanying a decreased expression of Membrane type 1‐matrix metalloproteinase (MT1‐MMP). When MT1‐MMP was reintroduced into MKN‐45 and SGC‐7901 cells in the KIF2A‐siRNA group, only invasion inhibition effects on MKN‐45 and SGC‐7901 cells induced by KIF2A silencing can be reversed. In conclusion, our study reveals that down‐regulation of KIF2A can inhibit gastric cancer cell invasion by suppressing MT1‐MMP.