Flavonoids are found in the roots, stems, leaves, and fruits of many plant taxa. They are related to plant growth and development, pigment formation, and protection against environmental stress. Flavonoids function as antioxidants and exert anti-inflammatory effects in the cardiovascular system by modulating classical inflammatory response pathways, such as the TLR4-NF-ĸB, PI3K-AKT, and Nrf2/HO-1 signalling pathways. There is increasing evidence for the therapeutic effects of flavonoids on hypertension, atherosclerosis, and other diseases. The potential clinical value of flavonoids for diseases of the cardiovascular system has been widely explored. For example, studies have evaluated the roles of flavonoids in the regulation of blood pressure via endothelium-dependent and non-endothelium-dependent pathways and in the regulation of myocardial systolic and diastolic functions by influencing calcium homeostasis and smooth muscle-related protein expression. Flavonoids also have hypoglycaemic, hypolipidemic, anti-platelet, autophagy, and antibacterial effects. In this paper, the role and mechanism of flavonoids in cardiovascular diseases were reviewed in order to provide reference for the clinical application of flavonoids in the future.

Inflammation and fibrosis induced by hyperglycemia are considered to play a critical role in the pathogenesis of diabetic nephropathy. As macrophage polarization may determine the severity and progression of inflammation, regulation of macrophage polarization may be an effective method to treat diabetic complications. Fasudil, a potent Rho-kinase inhibitor, reportedly exhibits anti-inflammatory activity. However, whether fasudil reduces hyperglycemia-induced diabetic nephropathy via regulation of macrophage polarization remains unclear. In this study, we investigate the effect of fasudil on diabetic nephropathy in streptozotocin-induced type 1 diabetic mice. Our data showed that fasudil significantly decreased urinary protein and serum creatinine in diabetic mice, whereas it had no effect on the body weight and blood glucose. We also found increased M1-type macrophages and related proinflammatory cytokines, adverse fibrosis in renal tissue of diabetic mice. Interestingly, treatment of diabetic mice with fasudil increased the number of M2-type macrophages and related anti-inflammatory cytokines, which attenuated renal injury in diabetic mice. Taken together, the results of this study suggest that fasudil could slow the progression of diabetic nephropathy. The possible mechanism might be associated with its induction of M2 macrophage polarization and the reduction of M1 macrophage polarization and inflammation.

In multicellular organisms, regulatory cell death is a crucial aspect of growth and development. Ferroptosis, which was postulated roughly ten years ago, is a mode of cell death that differs from apoptosis, autophagy, and pyrodeath. This distinct pattern of cell death is triggered by an imbalance between oxidants and antioxidants and strongly associated with the metabolism of iron, lipids, amino acids, and glutathione. A growing body of research has implicated ferroptosis in the incidence and progression of many organ traumas and degenerative diseases. Recently, ferroptosis has gained attention as a crucial regulatory mechanism underlying the initiation and development of a variety of cardiovascular diseases, including myocardial ischemia/reperfusion injury, cardiomyopathy, arrhythmia, chemotherapy, and Corona Virus-2-induced cardiac injury. Pharmacological therapies that inhibit ferroptosis have great potential for the management of cardiovascular disorders. This review discusses the prevalence and regulatory mechanisms of ferroptosis, effect of ferroptosis on the immune system, significance of ferroptosis in cardiovascular diseases, and potential therapeutic value of regulating ferroptosis in a variety of heart diseases.

High glucose- (HG-) induced cardiomyocyte injury is the leading cause of diabetic cardiomyopathy, which is associated with the induction of inflammatory responses and oxidative stress. TGR5 plays an important role in the regulation of glucose metabolism. However, whether TGR5 has cardioprotective effects against HG-induced cardiomyocyte injury is unknown. Neonatal mouse cardiomyocytes were isolated and incubated in a HG medium. Protein and mRNA expression was detected by western blotting and RT-PCR, respectively. Cell apoptosis was determined by Hoechst 33342 staining and flow cytometry. After treatment of cells with HG, TGR5-selective agonist INT-777 reduced the increase in expression of proinflammatory cytokines and NF-κB, whereas pretreatment of cells with TGR5 shRNA significantly reduced the inhibitory effects of INT-777. We also found that INT-777 increased the protein expression of Nrf2 and HO-1. In the presence of TGR5 shRNA, the expression of Nrf2 and HO-1 was reduced, indicating that TGR5 may exert an antioxidant effect partially through the Nrf2/HO-1 pathway. Furthermore, INT-777 treatment inhibited HG-induced ROS production and apoptosis that were attenuated in the presence of TGR5 shRNA or ZnPP (HO-1 inhibitor). Activation of TGR5 has cardioprotective effects against HG-induced cardiomyocyte injury and could be a pharmacological target for the treatment of diabetic cardiomyopathy.

Myocardial infarction (MI) elicits a tightly staged immune response in which macrophages coordinate early inflammation, subsequent tissue repair, and long-term ventricular remodeling. Growing evidence indicates that macrophage polarization is directed by immunometabolic reprogramming; however, the metabolic circuits that connect immune function to durable cardiac recovery remain incompletely defined. This review integrates current insights into the spatiotemporal, metabolic, and functional regulation of macrophages after MI. We summarize how glucose metabolism (glycolysis and the pentose phosphate pathway), TCA cycle rewiring and immunometabolic intermediates, lipid and amino-acid metabolism, iron handling and ferroptosis, purinergic and NAD⁺-dependent signaling, oxidative stress pathways, and vitamin-dependent regulation shape inflammatory versus reparative macrophage states. We highlight drug-targetable mediators-including lactate, succinate, α-KG, itaconate, kynurenine, and NAD⁺-linked pathways-and discuss how stage-specific targeting may suppress early injurious inflammation while promoting reparative remodeling. We also review advances in nanotechnology- and exosome-based delivery platforms that enable cardiac macrophage-directed interventions. Clinical translation will require deeper characterization of human macrophage heterogeneity, development of in vivo metabolic biomarkers, and validation in prospective multi-omics-anchored human studies. Temporally controlled combination therapies coupled with precision delivery systems may maximize cardiac repair while minimizing systemic metabolic toxicity. Macrophage immunometabolism is a central determinant of post-MI healing and remodeling. Therapeutic reprogramming of macrophage metabolism represents a promising precision-immunotherapy strategy to improve repair, limit heart failure progression, and expand future cardiovascular treatment options. Not applicable.