PLCE1 enhances mitochondrial dysfunction to promote GSDME-mediated pyroptosis in doxorubicin-induced cardiotoxicity.

BACKGROUND: The therapeutic value and long-term application of doxorubicin (DOX) were hampered by its severe irreversible cardiotoxicity. Phospholipase C epsilon 1 (PLCE 1) was reported as a new member of the phospholipase C (PLC) family which controls the level of phosphoinositides in cells. Pyroptosis is a newly discovered inflammatory type of regulated cell death. Recent studies have consolidated that chemotherapeutic drugs lead to pyroptosis. Additionally, the phosphoinositide signaling system has remarkable effects on the execution of cell death. We aim to investigate the role of PLCE1 and the mechanism of pyroptosis from the context of DOX-induced cardiotoxicity. METHODS: In the current study, in vitro and in vivo experiments were performed to dissect the underlying mechanism of cardiomyocyte pyroptosis during DOX-induced cardiac injury. The molecular mechanism of PLCE1 was identified by the human cardiomyocyte AC16 cell line and C57BL/6 mouse model. RESULTS: The results here indicated that PLCE1 high expressed and pyroptotic cell death presented in cardiomyocytes after DOX application, which was negatively correlated to heart function. DOX-induced cell model disclosed pyroptosis mediated by Gasdermin E (GSDME) protein and involved in mitochondrial damage. Conversely, the deletion of PLCE1 ameliorated mitochondrial dysfunction by suppressing ROS accumulation and reversing mitochondrial membrane potential, and then increased cell viability effectively. More importantly, the in vivo experiment demonstrated that inhibition of PLCE1 reduced pyroptotic cell death and improved heart effect. CONCLUSIONS: We discovered firstly that PLCE1 inhibition protected cardiomyocytes from DOX-induced pyroptotic injury and promoted cardiac function. This information offers a theoretical basis for promising therapy.

Long noncoding RNA RMRP ameliorates doxorubicin-induced apoptosis by interacting with PFN1 in a P53-Dependent manner.

Doxorubicin (DOX) often causes acute or chronic cardiotoxicity during its application. LncRNA RMRP has been reported to be associated with several biological processes, such as cartilage-hair hypoplasia, but the relationship between RMRP and DOX-induced cardiotoxicity and chronic heart failure remains obscure. To test this hypothesis, GSE124401 and GSE149870 were processed for bioinformatics, and differentially expressed RMRP was then verified in the peripheral blood of 21 patients with heart failure compared with 7 controls. For in vitro validation, we used AC16 and HEK-293T cells. qPCR was used to detect the mRNA expression levels. The degree of apoptosis was detected by Western blot and TUNEL staining. Furthermore, the interaction between RMRP and PFN1 mRNA was verified by dual-luciferase reporter assays. In bioinformatics, RMRP showed significant downregulation, which was verified in clinical samples (p < 0.001) and DOX-treated AC16 models (p < 0.0001). Next, overexpression of RMRP could significantly alleviate DOX-induced apoptosis, and a potential downstream molecule of RMRP, PFN1, was also negatively associated with this change. RESCUE experiments further confirmed that PFN1 could be regulated by RMRP at both the RNA and protein levels, serving as a downstream mediator of RMRP's cardioprotective effects. This interaction was then confirmed to be a direct combination (p < 0.0001). Finally, we found that overexpression of RMRP could inhibit the expression of p53 and its phosphorylation level by suppressing PFN1. In summary, RMRP could exert cardioprotective effects via the PFN1/p53 axis, holding great promise for serving as a therapeutic target and potential biomarker.

Exploring novel biomarkers in dilated cardiomyopathy­induced heart failure by integrated analysis and in vitro experiments.

Despite the availability of several effective and promising treatment methods, heart failure (HF) remains a significant public health concern that requires advanced therapeutic strategies and techniques. Dilated cardiomyopathy (DCM) is a crucial factor that contributes to the development and deterioration of HF. The aim of the present study was to identify novel biomarkers and biological pathways to enhance the diagnosis and treatment of patients with DCM-induced HF using weighted gene co-expression network analysis (WGCNA). A total of 24 co-expressed gene modules connected with DCM-induced HF were obtained by WGCNA. Among these, the blue module had the highest correlation with DCM-induced HF (r=0.91; P<0.001) and was enriched in the AGE-RAGE signaling pathway in diabetic complications, the p53 and MAPK signaling pathway, adrenergic signaling in cardiomyocytes, the Janus kinase-STAT signaling pathway and cGMP/PKG signaling. Eight key genes, including secreted protein acidic and rich in cysteine-related modular calcium-binding protein 2 (SMOC2), serpin family A member 3 (SERPINA3), myosin heavy chain 6 (MYH6), S100 calcium binding protein A9 (S100A9), tubulin α (TUBA)3E, TUBA3D, lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE1) and phospholipase C ε1 (PLCE1), were selected as the therapeutic targets of DCM-induced HF based on WGCNA and differentially expressed gene analysis. Immune cell infiltration analysis revealed that the proportion of naive B cells and CD4-activated memory T cells was markedly upregulated in DCM-induced HF tissues compared with tissues from healthy controls. Furthermore, reverse transcription-quantitative PCR in AC16 human cardiomyocyte cells treated with doxorubicin showed that among the eight key genes, only SERPINA3, MYH6, S100A9, LYVE1 and PLCE1 exhibited expression levels identical to those revealed by bioinformatics analysis, suggesting that these genes may be involved in the development of DCM-induced HF.

New insights and advances of sodium-glucose cotransporter 2 inhibitors in heart failure.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are newly emerging insulin-independent anti-hyperglycemic agents that work independently of ß-cells. Quite a few large-scale clinical trials have proven the cardiovascular protective function of SGLT2is in both diabetic and non-diabetic patients. By searching all relevant terms related to our topics over the previous 3 years, including all the names of agents and their brands in PubMed, here we review the mechanisms underlying the improvement of heart failure. We also discuss the interaction of various mechanisms proposed by diverse works of literature, including corresponding and opposing viewpoints to support each subtopic. The regulation of diuresis, sodium excretion, weight loss, better blood pressure control, stimulation of hematocrit and erythropoietin, metabolism remodeling, protection from structural dysregulation, and other potential mechanisms of SGLT2i contributing to heart failure improvement have all been discussed in this manuscript. Although some remain debatable or even contradictory, those newly emerging agents hold great promise for the future in cardiology-related therapies, and more research needs to be conducted to confirm their functionality, particularly in metabolism, Na+-H+ exchange protein, and myeloid angiogenic cells.

Detecting imperative genes and infiltrating immune cells in chronic Chagas cardiomyopathy by bioinformatics analysis.

Chronic Chagas cardiomyopathy (CCC) is an acquired inflammatory cardiomyopathy triggered by the protozoan Trypanosoma cruzi infection. Although microvascular and neurogenic dysfunction and inflammation with persistent parasite presence in the heart may play a major pathogenetic role, little is known about the overall picture of gene co-expression regulating CCC. In this study, we aimed to explore the key biological pathways, hub genes and the landscope of infiltrating immune cells associated with inflammation in chronic Chagas cardiomyopathy. A weighted gene co-expression network analysis (WGCNA) was conducted based on the gene expression profiles from patients with and without chronic Chagas cardiomyopathy (GSE84796). Twelve coexpression modules were identified from the top 25% variant genes. Among them, the turquoise and black module were significantly positively correlated with CCC, which were highly enriched in Th1 and Th2 cell differentiation, the Cytokine-cytokine receptor interaction,NF-kappa B signaling pathway and T cell receptor signaling pathway. In addition, four genes (TBX21, ZAP70,IL2RB and CD69) were selected as candidate hub genes. Gene expression for hub genes were higher in CCC tissues compared to tissues from healthy controls. Additionally, gene set enrichment analysis (GSEA) analysis showed that high expressions of these hub genes were significantly correlated with interferon α response and interferon γ response. The microarray dataset GSE41089 further confirmed that although CD69 was not detected, the expression of TBX21, IL2RB and ZAP70 was also significantly up-regulated in the CCC mice compared to controls. We further studied the immune cells infiltration in CCC patients with CIBERSORT. The fraction of Mast cells activated,T cells CD8 and T cells gamma delta were significantly increased in CCC patients compared with control. Our research provides a more effective understanding of the pathogenesis of CCC and could help in future strategies for new diagnostic and therapeutic approaches for CCC patients.

Identification of Crucial Genes and Infiltrating Immune Cells Underlying Sepsis-Induced Cardiomyopathy via Weighted Gene Co-Expression Network Analysis.

Sepsis-induced cardiomyopathy (SIC), with a possibly reversible cardiac dysfunction, is a potential complication of septic shock. Despite quite a few mechanisms including the inflammatory mediator, exosomes, and mitochondrial dysfunction, having been confirmed in the existing research studies we still find it obscure about the overall situation of gene co-expression that how they can affect the pathological process of SIC. Thus, we intended to find out the crucial hub genes, biological signaling pathways, and infiltration of immunocytes underlying SIC. It was weighted gene co-expression network analysis that worked as our major method on the ground of the gene expression profiles: hearts of those who died from sepsis were compared to hearts donated by non-failing humans which could not be transplanted for technical reasons (GSE79962). The top 25 percent of variant genes were abstracted to identify 10 co-expression modules. In these modules, brown and green modules showed the strongest negative and positive correlation with SIC, which were primarily enriched in the bioenergy metabolism, immunoreaction, and cell death. Next, nine genes (LRRC39, COQ10A, FSD2, PPP1R3A, TNFRSF11B, IL1RAP, DGKD, POR, and THBS1) including two downregulated and seven upregulated genes which were chosen as hub genes that meant the expressive level of which was higher than the counterparts in control groups. Then, the gene set enrichment analysis (GSEA) demonstrated a close relationship of hub genes to the cardiac metabolism and the necroptosis and apoptosis of cells in SIC. Concerning immune cells infiltration, a higher level of neutrophils and B cells native and a lower level of mast cells resting and plasma cells had been observed in patients with SIC. In general, nine candidate biomarkers were authenticated as a reliable signature for deeper exploration of basic and clinical research studies on SIC.

Employee-Organization Relationships and Team Performance: Role of Team Collective Efficacy.

Besides the previous social relationship perspective of employee-organization relationship (EOR) research, this study takes the social cognitive perspective to explore the role of team collective efficacy in mediating the relationship between EORs and team performance. This study further contends that team cohesion moderates the positive relationship between collective efficacy and team performance, thereby moderating the indirect relationship between EORs and team performance through collective efficacy. Data analyses of 231 teams in Study 1 and 63 teams in Study 2 support the hypotheses. Therefore, this study provides theoretical contributions to the EOR literature by introducing a new perspective at the team level and to the social cognitive literature by discussing a boundary condition of the effect of collective efficacy on team performance.