Heart disease is the leading cause of death worldwide. Cardiomyopathy is a disease characterized by the heart muscle damage, resulting heart in a structurally and functionally change, as well as heart failure and sudden cardiac death. The key pathogenic factor of cardiomyopathy is the loss of cardiomyocytes, but the related molecular mechanisms remain unclear. Ferroptosis is a newly discovered regulated form of cell death, characterized by iron accumulation and lipid peroxidation during cell death. Recent studies have shown that ferroptosis plays an important regulatory roles in the occurrence and development of many heart diseases such as myocardial ischemia/reperfusion injury, cardiomyopathy and heart failure. However, the systemic association of ferroptosis and cardiomyopathy remains largely unknown and needs to be elucidated. In this review, we provide an overview of the molecular mechanisms of ferroptosis and its role in individual cardiomyopathies, highlight that targeting ferroptosis maybe a potential therapeutic strategy for cardiomyopathy therapy in the future. 

Ferroptosis and its role in cardiomyopathy.

Atrial fibrosis and atrial inflammation are associated with the pathogenesis of atrial fibrillation (AF). Basic helix–loop–helix family member E40 (Bhlhe40) is an important transcription factor, which is involved in tumors, inflammation, apoptosis, viral infection, and hypoxia. However, its role and molecular mechanism in AF remain unclear. In this study, a mouse model of AF was induced by Ang II infusion. The atrial diameter was evaluated using echocardiography. Induction and duration of AF were measured by programmed electrical stimulation. Atrial structural remodeling was detected using routine histologic examinations. Our results showed that Bhlhe40 was significantly upregulated in angiotensin II (Ang II)-stimulated atrial cardiomyocytes and atrial tissues and in tissues from patients with AF. Cardiac-specific knockdown of Bhlhe40 in mice by a type 9 recombinant adeno-associated virus (rAAV9)-shBhlhe40 significantly ameliorated Ang II-induced atrial dilatation, atrial fibrosis, and atrial inflammation, as well as the inducibility and duration of AF. Mechanistically, cardiac-specific knockdown of Bhlhe40 attenuated Ang II-induced activation of NF-κB/NLRP3, TGF-1β/Smad2 signals, the increased expression of CX43, and the decreased expression of Kv4.3 in the atria. This is the first study to suggest that Bhlhe40 is a novel regulator of AF progression, and identifying Bhlhe40 may be a new therapeutic target for hypertrophic remodeling and heart failure.

/pdf/cardiac-specific-knockdown-of-bhlhe40-attenuates-angiotensin-24qcw990.pdf

Cardiac-specific knockdown of Bhlhe40 attenuates angiotensin II (Ang II)-Induced atrial fibrillation in mice

TREM2 Insufficiency Protects against Pulmonary Fibrosis by Inhibiting M2 Macrophage Polarization.

AIMS
The deacetylase Sirtuin 6 (SIRT6) is up-regulated during fibrogenesis in renal tubular cells and post-ischemia/reperfusion kidneys. Hence, our aim was to investigate the mechanism of SIRT6 up-regulation upon profibrotic stress.


MAIN METHODS
Immunohistochemical staining was used to detect the expression of UBC9 in the kidney section. The interaction of GSK-3β and SIRT6, and phosphorylation level of SIRT6 were detected by the immunoprecipitation assay. The wild-type and phosphorylated site mutant plasmids of SIRT6 were constructed and stably transfected to BUMPT cells to evaluate the phosphorylation function of SIRT6 by immunoblotting assay.


KEY FINDINGS
The phosphorylation of SIRT6 is significantly increased during TGF-β treatment in mouse renal tubular cells. GSK-3β can physically interact with SIRT6 in renal tubular cells, and this interaction is enhanced by TGF-β treatment. Moreover, GSK-3β is the phosphorylation kinase for SIRT6, and phosphorylates SIRT6 at Serine 326 residue to prevent its ubiquitination-mediated proteasomal degradation. Non-phosphorylatable mutant, S326A, of SIRT6, restores β-catenin activation and fibrotic changes in renal tubular cells.


SIGNIFICANCE
The present study demonstrates that a new mechanism for GSK-3β-mediated anti-fibrotic function in renal fibrosis through phosphorylation of SIRT6 to prevent its proteasomal degradation.

Phosphorylation by GSK-3β increases the stability of SIRT6 to alleviate TGF-β-induced fibrotic response in renal tubular cells.

Radiation-induced pulmonary fibrosis (RIPF) is a common consequence of radiation for thoracic tumors, and is accompanied by gradual and irreversible organ failure. This severely reduces the survival rate of cancer patients, due to the serious side effects and lack of clinically effective drugs and methods. Radiation-induced pulmonary fibrosis is a dynamic process involving many complicated and varied mechanisms, of which alveolar type II epithelial (AT2) cells are one of the primary target cells, and the epithelial–mesenchymal transition (EMT) of AT2 cells is very relevant in the clinical search for effective targets. Therefore, this review summarizes several important signaling pathways that can induce EMT in AT2 cells, and searches for molecular targets with potential effects on RIPF among them, in order to provide effective therapeutic tools for the clinical prevention and treatment of RIPF.

/pdf/the-promising-therapeutic-approaches-for-radiation-induced-1t7aal1h.pdf

The Promising Therapeutic Approaches for Radiation-Induced Pulmonary Fibrosis: Targeting Radiation-Induced Mesenchymal Transition of Alveolar Type II Epithelial Cells

Background Cardiomyopathies are a heterogeneous group of heart diseases that can gradually cause severe heart failure. In particular, dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are the two main types of cardiomyopathies, yet the independent and communal biological mechanisms of both remain far from elucidated. Meanwhile, ferroptosis is a non-apoptotic form of cell death that has been proven to be associated with cardiomyopathies, but the concrete nature of the interaction remains unclear. Hence, this study explored the pathogenesis and ferroptosis mechanism of HCM and DCM via a bioinformatics analysis. Methods Six datasets were downloaded from the Gene Expression Omnibus (GEO) database based on the study inclusion/exclusion criteria. After screening the differentially expressed genes (DEGs) and hub genes of HCM and DCM, subsequent analyses, including functional annotation, co-expression, validation, and transcription factors (TF)–mRNA–microRNA (miRNA) regulatory network construction, were performed. In addition, ferroptosis-related DEGs were also identified and verified in HCM and DCM. Results We found 171 independent DEGs of HCM mainly enriched in the regulation of ERK1 and ERK2 cascade, while 171 independent DEGs of DCM were significantly involved in cell adhesion. Meanwhile, 32 communal DEGs (26 upregulated genes and 6 downregulated genes) and 3 hub genes [periostin (POSTN), insulin-like growth factor-binding protein-5 (IGFBP5), and fibromodulin (FMOD)] were determined to be shared between HCM and DCM and the functional annotation of these genes highlighted the important position of growth hormone in HCM and DCM. Moreover, we identified activating transcription factor 3 (ATF3), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and solute carrier family 1 member 5 (SLC1A5) as ferroptosis-related genes in HCM and STAT3 as a ferroptosis-related gene in DCM. Conclusion The identified independent and communal DEGs contribute to uncover a potentially distinct and common mechanism of HCM and DCM and ferroptosis-related genes could provide us with a novel direction for exploration. In addition, 3 hub genes could be potential biomarkers or therapeutic targets in patients with cardiomyopathy.

/pdf/exploring-the-communal-pathogenesis-ferroptosis-mechanism-1f9qifg4.pdf

Exploring the Communal Pathogenesis, Ferroptosis Mechanism, and Potential Therapeutic Targets of Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy via a Microarray Data Analysis

Tissue remodeling/fibrosis is a main feature of idiopathic pulmonary fibrosis (IPF), which results in the replacement of normal lung parenchyma with a collagen-rich extracellular matrix produced by fibroblasts and myofibroblasts. Epithelial-mesenchymal transition (EMT) in type 2 lung epithelial cells is a key process in IPF, which leads to fibroblasts and myofibroblasts accumulation and excessive collagen deposition. DEC1, a structurally distinct class of basic helix-loop-helix proteins, is associated with EMT in cancer. However, the functional role of DEC1 in pulmonary fibrosis (PF) remains elusive. Herein, we aimed to explore DEC1 expression in IPF and bleomycin (BLM)-induced PF in mice and the mechanisms underlying the fibrogenic effect of DEC1 in PF in vivo and in vitro by Dec1-knockout (Dec1 −/−) mice, knockdown and overexpression of DEC1 in alveolar epithelial cells (A549 cells). We found that the expression of DEC1 was increased in IPF and BLM-injured mice. More importantly, Dec1 −/− mice had reduced PF after BLM challenge. Additionally, DEC1 deficiency relieved EMT development and repressed the PI3K/AKT/GSK-3β/β-catenin integrated signaling pathway in mice and in A549 cells, whereas DEC1 overexpression in vitro had converse effects. Moreover, the PI3K/AKT and Wnt/β-catenin signaling inhibitors, LY294002 and XAV-939, ameliorated BLM-meditated PF in vivo and relieved EMT in vivo and in vitro. These pathways are interconnected by the GSK-3β phosphorylation status. Our findings indicated that during PF progression, DEC1 played a key role in EMT via the PI3K/AKT/GSK-3β/β-catenin integrated signaling pathway. Consequently, targeting DEC1 may be a potential novel therapeutic approach for IPF.

/pdf/dec1-deficiency-ameliorates-pulmonary-fibrosis-through-the-2hqor2at.pdf

Dec1 Deficiency Ameliorates Pulmonary Fibrosis Through the PI3K/AKT/GSK-3β/β-Catenin Integrated Signaling Pathway

Background Although increasing evidence has reported an increased risk of atherosclerosis (AS) in rheumatoid arthritis (RA), the communal molecular mechanism of this phenomenon is still far from being fully elucidated. Hence, this article aimed to explore the pathogenesis of RA complicated with AS. Methods Based on the strict inclusion/exclusion criteria, four gene datasets were downloaded from the Gene Expression Omnibus (GEO) database. After identifying the communal differentially expressed genes (DEGs) and hub genes, comprehensive bioinformatics analysis, including functional annotation, co-expression analysis, expression validation, drug-gene prediction, and TF-mRNA-miRNA regulatory network construction, was conducted. Moreover, the immune infiltration of RA and AS was analyzed and compared based on the CIBERSORT algorithm, and the correlation between hub genes and infiltrating immune cells was evaluated in RA and AS respectively. Results A total of 54 upregulated and 12 downregulated communal DEGs were screened between GSE100927 and GSE55457, and functional analysis of these genes indicated that the potential pathogenesis lies in immune terms. After the protein-protein interaction (PPI) network construction, a total of six hub genes (CCR5, CCR7, IL7R, PTPRC, CD2, and CD3D) were determined as hub genes, and the subsequent comprehensive bioinformatics analysis of the hub genes re-emphasized the importance of the immune system in RA and AS. Additionally, three overlapping infiltrating immune cells were found between RA and AS based on the CIBERSORT algorithm, including upregulated memory B cells, follicular helper T cells and γδT cells. Conclusions Our study uncover the communal central genes and commonness in immune infiltration between RA and AS, and the analysis of six hub genes and three immune cells profile might provide new insights into potential pathogenesis therapeutic direction of RA complicated with AS.

/pdf/the-commonness-in-immune-infiltration-of-rheumatoid-1ebskih8.pdf

The commonness in immune infiltration of rheumatoid arthritis and atherosclerosis: Screening for central targets via microarray data analysis

Fatty acid synthase (FASN) promotes tumor progression in multiple cancers. In this study, we comprehensively examined the expression, prognostic significance, and promoter methylation of FASN, and its correlation with immune cell infiltration in pan-cancer. Our results demonstrated that elevated FASN expression was significantly associated with an unfavorable prognosis in many cancer types. Furthermore, FASN promoter DNA methylation can be used as a tumor prognosis marker. Importantly, high levels of FASN were significantly negatively correlated with tumor immune infiltration in 35 different cancers. Additionally, FASN was significantly associated with tumor mutational burden (TMB) and microsatellite instability (MSI) in multiple malignancies, suggesting that it may be essential for tumor immunity. We also investigated the effects of FASN expression on immunotherapy efficacy and prognosis. In up to 15 tumors, it was significantly negatively correlated with immunotherapy-related genes, such as PD-1, PD-L1, and CTLA-4. Moreover, we found that tumors with high FASN expression may be more sensitive to immunotherapy and have a good prognosis with PD-L1 treatment. Finally, we confirmed the tumor-suppressive effect of mir-195-5p through FASN. Altogether, our results suggested that FASN may serve as a novel prognostic indicator and immunotherapeutic target in various malignancies.

/pdf/comprehensive-analysis-of-fasn-in-tumor-immune-infiltration-20gq1owk.pdf

Comprehensive Analysis of FASN in Tumor Immune Infiltration and Prognostic Value for Immunotherapy and Promoter DNA Methylation

Corrigendum to "Identifying chronic alcoholism drug disulfiram as a potent DJ-1 inhibitor for cancer therapeutics" [Eur. J. Pharmacol. 926 (2022) 175035].

Mingyang Zhang

Papers

Exploring the Communal Pathogenesis, Ferroptosis Mechanism, and Potential Therapeutic Targets of Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy via a Microarray Data Analysis

Dec1 Deficiency Ameliorates Pulmonary Fibrosis Through the PI3K/AKT/GSK-3β/β-Catenin Integrated Signaling Pathway

The commonness in immune infiltration of rheumatoid arthritis and atherosclerosis: Screening for central targets via microarray data analysis

Comprehensive Analysis of FASN in Tumor Immune Infiltration and Prognostic Value for Immunotherapy and Promoter DNA Methylation

Corrigendum to "Identifying chronic alcoholism drug disulfiram as a potent DJ-1 inhibitor for cancer therapeutics" [Eur. J. Pharmacol. 926 (2022) 175035].