Fig 2: Proposed Mechanism of Naringin-Mediated Cardiac Protection. db/db cardiomyocytes displayed elevated diastolic [Ca2+]d, excessive production of ROS, increased lipid peroxidation, accumulation of AOPP, and elevated levels of NADPH, all indicative of heightened oxidative stress. Additionally, these mice exhibited reduced SOD activity and lower plasma APN levels, reflecting compromised antioxidant defenses and metabolic dysregulation. Furthermore, plasma biomarkers of cardiac injury were also significantly elevated, signaling myocardial damage. Administration of NRG markedly reduced [Ca2+]d, ROS production, lipid peroxidation, AOPP accumulation, and NADPH levels, indicating a substantial attenuation of oxidative stress. In parallel, NRG enhanced endogenous antioxidant defenses by upregulating SOD activity and restoring circulating APN concentrations. These molecular improvements were accompanied by a significant reduction in plasma cardiac injury markers, suggesting the preservation of myocardial structure and function. Mechanistically, the cardioprotective effects of NRG may be mediated, at least in part, through the upregulation of sarcolemmal KATP channels. Through the upregulation of the expression and/or activity of these channels, NRG facilitates the reduction of intracellular calcium overload and limits ROS generation, thereby disrupting a core pathophysiological mechanism that perpetuates oxidative stress and cardiac dysfunction in DCM.

Fig 3: Naringin elevates plasma APN levels in db/db mice. Plasma adiponectin (APN) concentrations were markedly lower in db/db mice (by 60%) compared to the control group. NRG treatment significantly increased APN levels in db/db mice (by 83%), with no notable effect observed in the control group. Data are presented as mean ± SD, with individual measurements shown as grey circles (n mice = 6 per group; n = 16–18). *Indicate p < 0.05.