Diabetic cardiomyopathy (DCM) is a chronic complication of diabetes mellitus, characterized by abnormalities of myocardial structure and function. Researches on the models of type 1 and type 2 diabetes mellitus as well as the application of genetic engineering technology help in understanding the molecular mechanism of DCM. DCM has multiple hallmarks, including hyperglycemia, insulin resistance, increased free radical production, lipid peroxidation, mitochondrial dysfunction, endothelial dysfunction, and cell death. Essentially, cell death is considered to be the terminal pathway of cardiomyocytes during DCM. Morphologically, cell death can be classified into four different forms: apoptosis, autophagy, necrosis, and entosis. Apoptosis, as type I cell death, is the fastest form of cell death and mainly occurs depending on the caspase proteolytic cascade. Autophagy, as type II cell death, is a degradation process to remove damaged proteins, dysfunctional organelles and commences by the formation of autophagosome. Necrosis is type III cell death, which contains a great diversity of cell death processes, such as necroptosis and pyroptosis. Entosis is type IV cell death, displaying "cell-in-cell" cytological features and requires the engulfing cells to execute. There are also some other types of cell death such as ferroptosis, parthanatos, netotic cell death, lysosomal dependent cell death, alkaliptosis or oxeiptosis, which are possibly involved in DCM. Drugs or compounds targeting the signals involved in cell death have been used in clinics or experiments to treat DCM. This review briefly summarizes the mechanisms and implications of cell death in DCM, which is beneficial to improve the understanding of cell death in DCM and may propose novel and ideal strategies in future.

Distinct Types of Cell Death and the Implication in Diabetic Cardiomyopathy.

Bone marrow mesenchymal stem cells (MSCs) are among the most common cell types to be used and studied for cardiac regeneration. Low survival rate and difficult retention of delivered MSCs in infarcted heart remain as major challenges in the field. Co-delivery of stem cell-derived exosomes (Exo) is expected to improve the recruitment and survival of transplanted MSCs. Exo was isolated from MSCs and delivered to an acute myocardial infarction (AMI) rat heart through intramyocardial injection with or without intravenous infusion of atrovastatin-pretreated MSCs on day 1, day 3, or day 7 after infarction. Echocardiography was performed to evaluate cardiac function. Histological analysis and ELISA test were performed to assess angiogenesis, SDF-1, and inflammatory factor expression in the infarct border zone. The anti-apoptosis effect of Exo on MSCs was evaluated using flow cytometry and Hoechst 33342 staining assay. We found that intramyocardial delivery of Exo followed by MSC transplantation (in brief, Exo+MSC treatment) into MI hearts further improved cardiac function, reduced infarct size, and increased neovascularization when compared to controls treated with Exo or MSCs alone. Of note, comparing the three co-transplanting groups, intramyocardially injecting Exo 30 min after AMI combined with MSCs transplantation at day 3 after AMI achieved the highest improvement in heart function. The observed enhanced heart function is likely due to an improved microenvironment via Exo injection, which is exemplified as reduced inflammatory responses and better MSC recruitment and retention. Furthermore, we demonstrated that pre-transplantation injection of Exo enhanced survival of MSCs and reduced their apoptosis both in vitro and in vivo. Combinatorial delivery of exosomes and stem cells in a sequential manner effectively reduces scar size and restores heart function after AMI. This approach may represent as an alternative promising strategy for stem cell-based heart repair and therapy.

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Combinatorial treatment of acute myocardial infarction using stem cells and their derived exosomes resulted in improved heart performance

Therapeutic potential of targeting oxidative stress in diabetic cardiomyopathy

Diabetic nephropathy (DN) as a global health concern is closely related to inflammation and oxidation. Isoliquiritigenin (ISL), a natural flavonoid compound, has been demonstrated to inhibit inflammation in macrophages. Herein, we investigated the effect of ISL in protecting against the injury in STZ-induced type 1 DN and in high glucose-induced NRK-52E cells. In this study, it was revealed that the administration of ISL not only ameliorated renal fibrosis and apoptosis, but also induced the deterioration of renal function in diabetic mice. Mediated by MAPKs and Nrf-2 signaling pathways, respectively, upstream inflammatory response and oxidative stress were neutralized by ISL in vitro and in vivo. Moreover, as further revealed by the results of molecular docking, sirtuin 1 (SIRT1) binds to ISL directly, and the involvement of SIRT1 in ISL-mediated renoprotective effects was confirmed by studies using in vitro models of SIRT1 overexpression and knockdown. In summary, by reducing inflammation and oxidative stress, ISL has a significant pharmacological effect on the deterioration of DN. The benefits of ISL are associated with the direct binding to SIRT1, the inhibition of MAPK activation, and the induction of Nrf-2 signaling, suggesting the potential of ISL for DN treatment.

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Isoliquiritigenin prevents hyperglycemia-induced renal injuries by inhibiting inflammation and oxidative stress via SIRT1-dependent mechanism.

Myocarditis is an important cause of heart failure in young patients. Autoreactive, most often, infection-triggered CD4+ T cells were confirmed to be critical for myocarditis induction. Due to a defect in clonal deletion of heart-reactive CD4+ T cells in the thymus of mice and humans, significant numbers of heart-specific autoreactive CD4+ T cells circulate in the blood. Normally, regulatory T cells maintain peripheral tolerance and prevent spontaneous myocarditis development. In the presence of tissue damage and innate immune activation, however, activated self-antigen-loaded dendritic cells promote CD4+ effector T cell expansion and myocarditis. So far, a direct pathogenic role has been described for both activated Th17 and Th1 effector CD4+ T cell subsets, though Th1 effector T cell-derived interferon-gamma was shown to limit myocarditis severity and prevent transition to inflammatory dilated cardiomyopathy. Interestingly, recent observations point out that various CD4+ T cell subsets demonstrate high plasticity in maintaining immune homeostasis and modulating disease phenotypes in myocarditis. These subsets include Th1 and Th17 effector cells and regulatory T cells, despite the fact that there are still sparse and controversial data on the specific role of FOXP3-expressing Treg in myocarditis. Understanding the specific roles of these T cell populations at different stages of the disease progression might provide a key for the development of successful therapeutic strategies.

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Regulatory Role of CD4+ T Cells in Myocarditis

Piceatannol alleviates inflammation and oxidative stress via modulation of the Nrf2/HO-1 and NF-κB pathways in diabetic cardiomyopathy.

Bone marrow-derived mesenchymal stem cells (BMSCs) have recently been introduced to treat cardiovascular diseases, such as myocardial infarction and dilated cardiomyopathy. Nevertheless, there are few researches focused on the application of BMSCs in treating viral myocarditis, not to mention its optimal intervention timer potential mechanisms. In our study, we concentrated on finding an optimal time window to perform BMSCs treatment in a murine model of myocarditis induced by coxsackievirus B3 (CVB3). On the 1st day, 3rd day, 7th day, and 14th day after BALB/c mice were infected by CVB3, we intravenously injected equivalent BMSCs into the treatment groups. With a 28-day follow-up after inoculation, we found that the ventricular function was significantly improved in the BMSCs treatment group and cardiac fibrosis markedly ameliorated, especially when BMSCs were injected between 1 and 2 weeks after CVB3 inoculation. Furthermore, we demonstrated that after BMSCs treatment, the expressions of TGF-β, col1α1, and col3α1 were significantly decreased. Therefore, we conclude that BMSCs may have a potential to improve CVB3-induced myocarditis by ameliorating cardiac fibrosis through the inhibition of TGF-β expression.

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The Optimal Intervention Time of Bone Marrow Mesenchymal Stem Cells in Ameliorating Cardiac Fibrosis Induced by Viral Myocarditis: A Randomized Controlled Trial in Mice

Xuliang Wang

Papers

Piceatannol alleviates inflammation and oxidative stress via modulation of the Nrf2/HO-1 and NF-κB pathways in diabetic cardiomyopathy.

The Optimal Intervention Time of Bone Marrow Mesenchymal Stem Cells in Ameliorating Cardiac Fibrosis Induced by Viral Myocarditis: A Randomized Controlled Trial in Mice