👤 Resat Unal

A dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP1) receptor agonist, tirzepatide (TZPD), is a novel cardioprotective agent, particularly in metabolic disturbances-related co-morbidities, however, there is no exact study to emphasize its possible unintended action in cardiac cells. Considering a relationship between the trafficking of incretin receptors in a manner not anticipated by the standard way of cAMP as a primary actor in TZPD action, together with the role of cAMP depression in cardiac dysfunction, here, we aimed to elucidate a pattern of unintended receptor interactions of TZPD and molecular processes underlying the pleiotropic effects of TZPD through modulation of the β-adrenoceptors (β-ARs) signaling in cardiomyocytes. To establish the multifaceted cardioprotective function and underlying mechanisms of TZPD against hyperglycemia (HG)-or senescence (SC)-induced cardiac dysfunction, H9c2 cells were treated with and without TZPD. We also used β The TZPD intervention ameliorated the HG or SC phenotypes in the cardiac cells via alleviation in protein levels of GLP-1R and GIP-R as well as production of cAMP or cGMP, even in the presence of these receptor antagonisms. TZPD also increased the levels of β Our findings indicate that TZPD, with its multifaceted role, has beneficial effects on cardiac cells by positively modulating β-ARs signaling and glucose metabolism rather than on-target receptor action. Furthermore, we demonstrated how TZPD can engage the different targets with distinct signaling motifs at the sarcolemma. Show less

Obesity and obesity-related breast cancer are major health problems that require alternative treatment strategies. Urtica dioica L. (U. dioica) stands out as a potential therapeutic candidate with its anti-oxidant, anti-cancer and lipid-lowering properties. In this study, the molecular effects of U. dioica were investigated by gene expression analysis and molecular docking methods. U. dioica significantly suppressed the expression of Brca1, Brca2, Fas, Lpl, Dgat1 and Mcp1 genes, resulting in significant changes in lipid metabolism, cancer susceptibility and inflammation. Molecular docking analyses showed that U. dioica components have strong binding affinities with target proteins. In particular, the interactions between Dgat1-Isorhamnetin rutinoside (-10.3 kcal/mol), Fas-Quercetin acetyl rutinoside (-10.3 kcal/mol), Lpl-Apigenin hexoside (-9.2 kcal/mol) and Mcp1-Quercetin acetyl rutinoside (-8.6 kcal/mol) were notable. In vitro and in silico analyses supported each other, revealing the effects of U. dioica in gene expression regulation and the potential for its constituents to interact with proteins. These findings indicate that U. dioica may be a promising alternative therapeutic agent in the treatment of obesity and obesity-related breast cancer and emphasize that its efficacy should be confirmed by clinical trials. Show less