Although there is accumulating evidence which suggests that the administration of ghrelin could be used to preserve cardiac function, delay the progression of heart failure post-myocardial infarction, and attenuate ventricular remodeling, there is still no definitive data that clearly highlights the mechanisms by which ghrelin exerts cardioprotective effects. The present study aimed to investigate whether ghrelin could affect nuclear factor erythroid 2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), and endothelial nitric oxide synthase (eNOS) expression and exert anti-inflammatory as well as antioxidant-like actions through this signaling pathway. Rats were assorted into four groups with 10 in each: Group I (Control), Group II (received ghrelin only), Group III (MI was induced by isoproterenol (ISO)), Group IV (MI was induced by isoproterenol and within 30 min of each ISO dose, rats received ghrelin; 100 mu g /kg subcutaneously two times per day). We assessed the effects of acylated ghrelin on the biochemical changes, ECG parameters, heart rate, histopathological scoring and the mRNA expression of eNOS, Nrf2 (confirmed immunohistochemically) as well as HO1 genes in the cardiac tissues. Nuclear factor-kappa B, tumor necrosis factor-alpha, interleukin-6, and inducible nitric oxide synthase were assessed as inflammatory markers. Ghrelin markedly improved the oxidative stress injury and inflammation, showed histological preservation of the cardiac muscle fibers morphology, ameliorated the ISO-induced ECG changes and caused a significant elevation in eNOS, HO-1, and Nrf2 expression. In conclusion, ghrelin exerts cardioprotective effect in ISO-induced myocardial infarction by promoting the eNOS/Nrf2/HO-1 pathway.

Doxorubicin (DOX)-induced nephrotoxicity remains a major limitation to its clinical use, yet the underlying epigenetic mechanisms are incompletely understood. This study investigated the role of epigenetic dysregulation and MyD88/STAT3 signaling in DOX-induced renal injury and evaluated the renoprotective efficacy of rutin-loaded nanostructured lipid carriers (RUT-NLCs) compared with free rutin (RUT). Thirty-six rats were allocated to six experimental groups, and renal function, oxidative stress, inflammation, DNA damage, epigenetic modifications, MyD88/STAT3 signaling, histopathology, and ultrastructural changes were assessed. DOX administration induced severe renal dysfunction, oxidative stress, DNA damage, tubular injury, global DNA hypermethylation, aberrant histone methylation, Klotho promoter hypermethylation, and activation of the MyD88/STAT3 inflammatory pathway. Treatment with RUT-NLCs significantly attenuated these alterations by restoring antioxidant defenses, normalizing epigenetic markers, reducing DNA damage, suppressing MyD88/STAT3 signaling, and improving renal histopathological and ultrastructural architecture. Overall, RUT-NLCs provided greater nephroprotection than free rutin, suggesting that modulation of epigenetic alterations and MyD88/STAT3 signaling represents a key mechanism underlying their therapeutic efficacy against DOX-induced nephrotoxicity.