Background: Mesenchymal stem cells (MSCs) have been widely applied to treat various inflammatory diseases. Inflammatory cytokines can induce both apoptosis and autophagy in MSCs. However, whether autophagy plays a pro- or con-apoptosis effect on MSCs in an inflammatory microenvironment has not been clarified. Methods: We inhibited autophagy by constructing MSCs with lentivirus containing small hairpin RNA to knockdown Beclin-1 and applied these MSCs to a model of sepsis to evaluate therapeutic effect of MSCs. Results: Here we show that inhibition of autophagy in MSCs increases the survival rate of septic mice more than control MSCs, and autophagy promotes apoptosis of MSCs during application to septic mice. Further study demonstrated that autophagy aggravated tumor necrosis factor alpha plus interferon gamma-induced apoptosis of MSCs. Mechanically, autophagy inhibits the expression of the pro-survival gene Bcl-2 via suppressing reactive oxygen species/mitogen-activated protein kinase 1/3 pathway. Conclusions: Our findings indicate that an inflammatory microenvironment-induced autophagy promotes apoptosis of MSCs. Therefore, modulation of autophagy in MSCs would provide a novel approach to improve MSC survival during immunotherapy.

We aimed to screen out biomarkers for atrial fibrillation (AF) based on machine learning methods and evaluate the degree of immune infiltration in AF patients in detail. Two datasets (GSE41177 and GSE79768) related to AF were downloaded from Gene expression omnibus (GEO) database and merged for further analysis. Differentially expressed genes (DEGs) were screened out using “limma” package in R software. Candidate biomarkers for AF were identified using machine learning methods of the LASSO regression algorithm and SVM-RFE algorithm. Receiver operating characteristic (ROC) curve was employed to assess the diagnostic effectiveness of biomarkers, which was further validated in another independent validation dataset of GSE14975. Moreover, we used CIBERSORT to study the proportion of infiltrating immune cells in each sample, and the Spearman method was used to explore the correlation between biomarkers and immune cells. 129 DEGs were identified, and CYBB, CXCR2, and S100A4 were identified as key biomarkers of AF using LASSO regression and SVM-RFE algorithm. Both in the training dataset and the validation dataset, CYBB, CXCR2, and S100A4 showed favorable diagnostic effectiveness. Immune infiltration analysis indicated that, compared with sinus rhythm (SR), the atrial samples of patients with AF contained a higher T cells gamma delta, neutrophils and mast cells resting, whereas T cells follicular helper were relatively lower. Correlation analysis demonstrated that CYBB, CXCR2, and S100A4 were significantly correlated with the infiltrating immune cells. In conclusion, this study suggested that CYBB, CXCR2, and S100A4 are key biomarkers of AF correlated with infiltrating immune cells, and infiltrating immune cells play pivotal roles in AF.

Hydrogen sulfide (H₂S) has been highlighted as an important gasotransmitter in mammals. A growing number of studies have indicated that H₂S plays a key role in the pathophysiology of vascular diseases and physiological vascular homeostasis. Alteration in H₂S biogenesis has been reported in a variety of vascular diseases and H₂S supplementation exerts effects of vasodilation. Accumulating evidence has shown vascular potassium channels activation is involved in H₂S-induced vasodilation. This review aimed to summarize and discuss the role of H₂S in the regulation of vascular tone, especially by interaction with different vascular potassium channels and the underlying mechanisms.

Glucose fluctuation is more harmful than sustained hyperglycemia, but the effect on cardiomyocyte apoptosis have not yet been clarified. In this study, we aim to identify the effect of glucose fluctuation on cardiomyocyte apoptosis and explore the underlying mechanism. Sprague-Dawley rats were intraperitoneally injected with streptozotocin (STZ) and divided into three groups: controlled diabetic group (C-STZ); uncontrolled diabetic group (U-STZ) and glucose fluctuated diabetic group (GF-STZ). After twelve weeks, echocardiography, Hematoxylin-eosin (HE) staining, and Masson staining were adopted to assess the cardiac function and pathological changes. TUNEL staining was used to detect apoptotic cells. Expressions of apoptosis-related proteins and key molecules in the endoplasmic reticulum (ER) stress pathway were determined via western blots. Further, primary cardiomyocytes incubated in different glucose conditions were treated with the inhibitor of ER stress to explore the causative role of ER stress in glucose fluctuation-induced cardiomyocyte apoptosis. In vivo, we demonstrated that glucose fluctuation promoted cardiomyocyte apoptosis, and were more harmful to cardiomyocytes than sustained hyperglycemia. Moreover, glucose fluctuation significantly triggered ER stress signaling pathway. In vitro, primary cardiomyocyte apoptosis induced by glucose fluctuation and the activation of ER stress were significantly attenuated by 4-PBA, which is an ER stress inhibitor. Above all, glucose fluctuation can promote cardiomyocyte apoptosis through triggering the ER stress signaling pathway in diabetic rats and in primary cardiomyocytes. GRAPHICAL ABSTRACT

Background: Age is an independent risk factor of the progress and prognosis of atrial fibrillation (AF). However, ablation outcomes between elderly and younger patients with AF remain elusive. Methods: Cochrane Library, Embase, PubMed, and Web of Science were systematically searched up to 1 April 2022. Studies comparing AF ablation outcomes between elderly and younger patients and comprising outcomes of AF ablation for elderly patients were included. Trial sequential analysis (TSA) was performed to adjust for random error and lower statistical power in our meta-analysis. Subgroup analysis identified possible determinants of outcome impact for elderly patients after ablation. Moreover, linear and quadratic prediction fit plots with confidence intervals were performed, as appropriate. Results: A total of 27 studies with 113,106 AF patients were eligible. Compared with the younger group, the elderly group was significantly associated with a lower rate of freedom from AF (risk ratio [RR], 0.95; p = 0.008), as well as a higher incidence of safety outcomes (cerebrovascular events: RR, 1.64; p = 0.000; serious hemorrhage complications: RR, 1.50; p = 0.035; all-cause death: RR, 2.61; p = 0.003). Subgroup analysis and quadratic prediction fit analysis revealed the follow-up time was the potential determinant of freedom from AF for elderly patients after AF ablation. Conclusions: Our meta-analysis suggests that elderly patients may have inferior efficacy and safety outcomes to younger patients with AF ablation. Moreover, the follow-up time may be a potential determinant of outcome impact on freedom from AF for elderly patients after AF ablation.