Neuraminidase1 Inhibitor Protects Against Doxorubicin-Induced Cardiotoxicity via Suppressing Drp1-Dependent Mitophagy

Anthracyclines, such as doxorubicin (DOX), are among the effective chemotherapeutic drugs for various malignancies. However, their clinical use is limited by irreversible cardiotoxicity. This study sought to determine the role of neuraminidase 1 (NEU1) in DOX-induced cardiomyopathy and the potential cardio-protective effects of NEU1 inhibitor oseltamivir (OSE). Male Sprague–Dawley (SD) rats were randomized into three groups: control, DOX, and DOX + OSE. NEU1 was highly expressed in DOX-treated rat heart tissues compared with the control group, which was suppressed by OSE administration. Rats in the DOX + OSE group showed preserved cardiac function and were protected from DOX-induced cardiomyopathy. The beneficial effects of OSE were associated with the suppression of dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and mitophagy. In detail, the elevated NEU1 in cardiomyocytes triggered by DOX increased the expression of Drp1, which subsequently enhanced mitochondrial fission and PINK1/Parkin pathway-mediated mitophagy, leading to a maladaptive feedback circle towards myocardial apoptosis and cell death. OSE administration selectively inhibited the increased NEU1 in myocardial cells insulted by DOX, followed by reduction of Drp1 expression, inhibition of PINK1 stabilization on mitochondria, and Parkin translocation to mitochondria, thus alleviating excessive mitochondrial fission and mitophagy, alleviating subsequent development of cellular apoptotic process. This work identified NEU1 as a crucial inducer of DOX-induced cardiomyopathy by promoting Drp1-dependent mitochondrial fission and mitophagy, and NEU1 inhibitor showed new indications of cardio-protection against DOX cardiotoxicity.

Molecular Mechanisms and Epigenetic Regulation in Diabetic Cardiomyopathy

Diabetes mellitus (DM) is an important lifestyle disease. Type 2 diabetes is one of the prime contributors to cardiovascular diseases (CVD) and diabetic cardiomyopathy (DbCM) and leads to increased morbidity and mortality in patients with DM. DbCM is a typical cardiac disease, characterized by cardiac remodeling in the presence of DM and in the absence of other comorbidities such as hypertension, valvular diseases, and coronary artery disease. DbCM is associated with defective cardiac metabolism, altered mitochondrial structure and function, and other physiological and pathophysiological signaling mechanisms such as oxidative stress, inflammation, myocardial apoptosis, and autophagy. Epigenetic modifiers are crucial players in the pathogenesis of DbCM. Thus, it is important to explore the role of epigenetic modifiers or modifications in regulating molecular pathways associated with DbCM. In this review, we have discussed the role of various epigenetic mechanisms such as histone modifications (acetylation and methylation), DNA methylation and non-coding RNAs in modulating molecular pathways involved in the pathophysiology of the DbCM.

MicroRNA-383-5p Regulates Oxidative Stress in Mice with Acute Myocardial Infarction through the AMPK Signaling Pathway via PFKM

Objective. The purpose of this study is to explore the regulating role of microRNA-383-5p (miR-383-5p) in oxidative stress after acute myocardial infarction (AMI) through AMPK pathway via phosphofructokinase muscle-type (PFKM). Methods. We established the AMI model, and the model mice were injected with miR-383-5p agomir to study the effect of miR-383-5p in AMPK signaling pathways. The target gene for miR-383-5p was reported to be PFKM, so we hypothesized that overexpression of miR-383-5p inhibits activation of the AMPK signaling pathway. Results. In this research, we found that overexpression of miR-383-5p decreases myocardial oxidative stress, myocardial apoptosis, the expression level of PFKM malondialdehyde (MDA), and reactive oxygen species (ROS) in the myocardial tissues after AMI, and finally, AMI-induced cardiac systolic and diastolic function could be improved.Conclusion. This study demonstrated that miR-383-5p could reduce the oxidative stress after AMI through AMPK signaling pathway by targeting PFKM.

Yellow Wine Polyphenolic Compound Protects Against Doxorubicin-Induced Cardiotoxicity by Modulating the Composition and Metabolic Function of the Gut Microbiota

Background: Dietary polyphenols help to prevent cardiovascular diseases, and interactions between polyphenols and gut microbiota are known to exist. In this study, we speculated that gut microbiota-mediated metabolite regulation might contribute to the anticardiotoxic effects of yellow wine polyphenolic compound (YWPC) in doxorubicin (DOX)-treated rats. Methods: 16S-rDNA sequencing was performed to analyze the effects of YWPC on the gut microbiota in DOX-treated rats (n=6). Antibiotics were used to investigate the contribution of the altered microbiome to the role of YWPC (n=6). Plasma metabolomics were also analyzed by untargeted gas chromatography-mass spectrometry systems. Results: YWPC ameliorated DOX-mediated cardiotoxicity, as evidenced by increased cardiac and mitochondrial function and reduced levels of inflammation and myocardial apoptosis ( P <0.05 for all). The low abundance of Escherichia – Shigella , Dubosiella , and Allobaculum , along with enrichment of Muribaculaceae_unclassified , Ralstonia , and Rikenellaceae_RC9_gut_group in the gut, suggested that YWPC ameliorated DOX-induced microbial dysbiosis. YWPC also influenced the levels of metabolites altered by DOX, resulting in lower arachidonic acid and linoleic acid metabolism and higher tryptophan metabolite levels ( P <0.05 for all). Correlational studies indicated that YWPC alleviated DOX-induced inflammation and mitochondrial dysfunction by modulating the gut microbial community and its associated metabolites. Antibiotic treatment exacerbated cardiotoxicity in DOX-treated rats, and its effect on the gut microbiota partly abolished the anticardiotoxic effects of YWPC, suggesting that the microbiota is required for the cardioprotective role of YWPC. Conclusions: YWPC protected against DOX-induced cardiotoxicity in a gut microbiota–dependent manner. This supports the use of dietary polyphenols as a therapeutic approach for the treatment of cardiovascular diseases via microbiota regulation.